Effect of corticosteroids on cardiac function in growth-restricted fetuses.
To determine the acute effects of corticosteroids on the cardiovascular system in growth-restricted fetuses. This was a prospective cohort study conducted at a tertiary hospital between January 2011 and October 2013. Fetal cardiovascular function in fetuses with intrauterine growth restriction (IUGR) was assessed immediately before and 24 h after the first dose of betamethasone, administered in routine management of IUGR. Fetal arterial and venous Dopplers were assessed. Fetal cardiac function was evaluated by tissue Doppler echocardiography, with the assessment of both left and right ventricular function by calculating myocardial performance index (MPI') and E':A' ratios. Values were compared before and after exposure. Seventeen patients were included at a mean gestational age of 34 + 1 (range, 29 + 1 to 37 + 4) weeks. Fifteen fetuses were below the 5(th) percentile and two were below the 10(th) percentile for estimated fetal weight and abdominal circumference and all had no interval growth during a 2-week period. There was a decrease in right MPI' (from 0.56 to 0.47; P = 0.007) after corticosteroid exposure but no change in left MPI' (from 0.49 to 0.48). Right MPI' was higher than left MPI' before exposure (0.56 vs 0.49, respectively; P = 0.001), but not after exposure (P = 0.55). There was no change in left or right ventricular E':A' ratios and no difference was detected in umbilical artery, middle cerebral artery or ductus venosus pulsatility index following administration of corticosteroids. Corticosteroids altered right-sided, but not left-sided, tissue Doppler MPI' in IUGR fetuses, with no detectable change in arterial or venous Doppler pulsatility indices. Before exposure, the mean right MPI' was higher than the left. However, after exposure, there was no difference, suggesting that corticosteroids may reverse the negative effect of IUGR on fetal heart function. Large prospective studies with a larger sample size are needed to confirm this finding. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.


Intrapatient Comparison of 111In-PSMA I&T SPECT/CT and Hybrid 68Ga-HBED-CC PSMA PET in Patients With Early Recurrent Prostate Cancer.
The aim of this study was to evaluate the detection efficiency of In-PSMA-I&T SPECT/CT in comparison to hybrid Ga-PSMA HBED-CC PET in patients with early recurrent prostate cancer. Twenty-two patients (mean age, 68.2 ± 6.8 years; range, 52-76 years) with rising prostate-specific antigen (PSA; median, 1.03 ng/mL; range, 0.2-7.2ng/mL) and known positive lesions in hybrid Ga-PSMA HBED-CC PET scheduled for salvage surgery were included. Whole-body scintigraphy and SPECT/CT were performed 4 hours after application of 147.0 ± 24.8 MBq (range, 90-183 MBq) In-PSMA I&T. Images were evaluated for suspected lesions, and conspicuity of all lesions was rated using a 4-point-scale (0 = not seen, 1 = retrospectively seen in knowledge of Ga-PSMA HBED-CC PET, 2 = low signal, 3 = high signal). Tumor-to-background ratios were determined for SPECT and PET and compared. Tumor-to-background ratio of SPECT was correlated with lesion size as well as patients' Gleason score and PSA level. In-PSMA I&T SPECT/CT detected 14 of 29 PET-positive lesions (48.3%) with no additional lesions identified with In-PSMA I&T SPECT/CT. There was a significant weak to moderate correlation of PSA level with tumor-to-background ratio of In-PSMA I&T SPECT/CT (correlation coefficient r = 0.6406; 95% confidence interval, 0.1667-0.8741; P = 0.0136). There was no significant difference (P > 0.05), but a weak trend toward a higher detectability in In-PSMA I&T SPECT/CT regarding lesion size and initial PSA level. In a preselected collective of recurrent prostate cancer patients with low PSA values, In-PSMA I&T SPECT/CT showed lower detection rates than hybrid Ga-HBED-CC PSMA PET. However, In-PSMA I&T SPECT/CT showed a patient based detection rate of 59%, making it a potentially valuable imaging tool where PET is not available apart from its proven value as a PSMA-targeted probe for radioguided surgery.


Frontalis Suspension Using Autologous Fascia Lata in Children Under 3 Years Old.
To analyze functional results and complications of the use of autologous fascia lata in frontalis suspension in children under 3 years old and to confirm its technical viability. A retrospective review of 8 patients (12 eyes) who underwent frontalis suspension using autologous fascia lata sling. Twelve eyes of 8 patients were analyzed, with an average age of 1.8 ± 0.6 years. Preoperatively, the mean margin-to-reflex distance 1 was -0.17 ± 0.577 mm. Postoperatively the mean margin-to-reflex distance 1 was 2.66 ± 0.492 mm without any graft donor site or corneal complications. No recurrence was recorded in the follow-up period (mean follow-up period 28.5 ± 32.33 months). Autologous fascia lata is an eligible material in frontalis suspension in children under 3 years old, despite the traditional oculoplastic dogma that advises against.


Ingestion of genetically modified yeast symbiont reduces fitness of an insect pest via RNA interference.
RNA interference has had major advances as a developing tool for pest management. In laboratory experiments, double-stranded RNA (dsRNA) is often administered to the insect by genetic modification of the crop, or synthesized in vitro and topically applied to the crop. Here, we engineered genetically modified yeast that express dsRNA targeting y-Tubulin in Drosophila suzukii. Our design takes advantage of the symbiotic interactions between Drosophila, yeast, and fruit crops. Yeast is naturally found growing on the surface of fruit crops, constitutes a major component of the Drosophila microbiome, and is highly attractive to Drosophila. Thus, this naturally attractive yeast biopesticide can deliver dsRNA to an insect pest without the need for genetic crop modification. We demonstrate that this biopesticide decreases larval survivorship, and reduces locomotor activity and reproductive fitness in adults, which are indicative of general health decline. To our knowledge, this is the first study to show that yeast can be used to deliver dsRNA to an insect pest.


Whey protein hydrolysates improve high-fat-diet-induced obesity by modulating the brain-peripheral axis of GLP-1 through inhibition of DPP-4 function in mice.
Obesity is a growing global health concern. Recent literature indicates a prominent role of glucagon-like peptide-1 (GLP-1) in glucose metabolism and food intake. The synergistic action of GLP-1 in the gut and brain is responsible for its satiety-inducing effect, suggesting that upregulation of active GLP-1 levels could be an alternative strategy to combat obesity. Dipeptidyl peptidase-4 (DPP-4) is an exopeptidase known to inactivate GLP-1, suggesting that its inhibition could be a crucial strategy for effectively extending the half-life of endogenous GLP-1. Peptides derived from partial hydrolysis of dietary proteins are gaining traction due to their inhibitory activity on DPP-4. Whey protein hydrolysate from bovine milk (bmWPH) was produced using simulated in situ digestion, purified using RP-HPLC, and characterized for DPP-4 inhibition. The antiadipogenic and antiobesity activity of bmWPH was then studied in 3T3-L1 preadipocytes and high-fat diet-induced obesity (HFD) mice model, respectively. The dose-dependent inhibitory effect of bmWPH on the catalytic activity of DPP-4 was observed. Additionally, bmWPH suppressed adipogenic transcription factors and DPP-4 protein levels, leading to a negative effect on preadipocyte differentiation. In an HFD mice model, co-administration of WPH for 20 weeks downregulated adipogenic transcription factors, resulting in a concomitant reduction in whole body weight and adipose tissues. Mice fed with bmWPH also showed a marked reduction in DPP-4 levels in WAT, liver, and serum. Furthermore, HFD mice fed with bmWPH exhibited increased serum and brain GLP levels, which led to a significant decrease in food intake. In conclusion, bmWPH reduces body weight in HFD mice by suppressing appetite through GLP-1, a satiety-inducing hormone, in both the brain and peripheral circulation. This effect is achieved through modulation of both the catalytic and non-catalytic activity of DPP-4.


Understanding the Landscape of X-linked Variants Causing Intellectual Disability in Females Through Extreme X Chromosome Inactivation Skewing.
Intellectual disability (ID) affects 30% more males than females. This sex bias can be attributed to the enrichment of genes on the X chromosome playing essential roles in the central nervous system and their hemizygous state on males. Moreover, as a result of X chromosome inactivation (XCI), most genes on one of the X chromosomes in female somatic cells are epigenetically silenced, so that females carrying X-linked variants are not expected to be so severely affected as males. Consequently, the knowledge about X-linked ID (XLID) in females is still scarce. Herein, we used extreme XCI skewing (≥ 90%) to predict X-linked variants in females with idiopathic ID. XCI profiles from 53 probands were estimated from blood and buccal mucosa through a methylation-sensitive AR/RP2 assay. DNA samples with extreme XCI skewing were then submitted to array-comparative genomic hybridization and whole-exome sequencing. Seven females (13.2%) exhibited extreme XCI skewing, a percentage significantly higher than expected for healthy females in our population. XLID-potentially related variants were identified in five patients with extreme XCI skewing, including one pathogenic rstructural rearrangement [der(X) chromosome from a t(X;2)] and four single nucleotide variants in NLGN4X, HDAC8, TAF1, and USP9X genes, two of which affecting XCI escape genes. XCI skewing showed to be an outstanding approach for the characterization of molecular mechanisms underlying XLID in females. Beyond expanding the spectrum of variants/phenotypes associated with ID, our results pointed to compensatory biological pathways underlying XCI and uncover new insights into the involvement of escape genes on XLID, impacting genetic counseling.


Pharmacokinetic analysis and antiepileptic activity of N-valproyl derivatives of GABA and glycine.
To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four conjugation products of valproic acid (VPA), glycine and GABA were investigated: valproyl glycine, valproyl glycinamide, valproyl GABA and valproyl gabamide. Only valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic profile. Valproyl glycinamide was more potent than one of the major antiepileptic agents--VPA and showed a better margin between activity and neurotoxicity. Valproyl glycine and valproyl GABA were partially excreted unchanged in the urine (fe = 50% and 34%, respectively), while the urinary metabolites of the amide derivatives were valproyl glycine and valproyl GABA. The four investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDS) of glycine or GABA, but acted rather as drugs on their own. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.


Tissue-specific expression of ALA synthase-1 and heme oxygenase-1 and their expression in livers of rats chronically exposed to ethanol.
5-Aminolevulinic acid synthase-1 (ALAS1) and heme oxygenase-1 (HO-1) are the rate-controlling enzymes for heme biosynthesis and degradation, respectively. Expression of these two genes showed tissue-specific expression pattern at both mRNA and protein levels in selected non-treated rat tissues. In the livers of rats receiving oral ethanol for 10 weeks, ALAS1 mRNA levels were increased by 65%, and the precursor and mature ALAS1 protein levels were increased by 1.8- and 2.3-fold, respectively, while no changes were observed in HO-1 mRNA and protein levels, compared with pair-fed controls. These results provide novel insights into the effects of chronic ethanol consumption on hepatic heme biosynthesis and porphyrias.


CpG islands in vertebrate genomes.
Although vertebrate DNA is generally depleted in the dinucleotide CpG, it has recently been shown that some vertebrate genes contain CpG islands, regions of DNA with a high G+C content and a high frequency of CpG dinucleotides relative to the bulk genome. In this study, a large number of sequences of vertebrate genes were screened for the presence of CpG islands. Each CpG island was then analysed in terms of length, nucleotide composition, frequency of CpG dinucleotides, and location relative to the transcription unit of the associated gene. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes. A few genes contained both 5' and 3' CpG islands, separated by several thousand base-pairs of CpG-depleted DNA. The 5' CpG islands extended through 5'-flanking DNA, exons and introns, whereas most of the 3' CpG islands appeared to be associated with exons. CpG islands were generally found in the same position relative to the transcription unit of equivalent genes in different species, with some notable exceptions. The locations of G/C boxes, composed of the sequence GGGCGG or its reverse complement CCGCCC, were investigated relative to the location of CpG islands. G/C boxes were found to be rare in CpG-depleted DNA and plentiful in CpG islands, where they occurred in 3' CpG islands, as well as in 5' CpG islands associated with tissue-specific and housekeeping genes. G/C boxes were located both upstream and downstream from the transcription start site of genes with 5' CpG islands. Thus, G/C boxes appeared to be a feature of CpG islands in general, rather than a feature of the promoter region of housekeeping genes. Two theories for the maintenance of a high frequency of CpG dinucleotides in CpG islands were tested: that CpG islands in methylated genomes are maintained, despite a tendency for 5mCpG to mutate by deamination to TpG+CpA, by the structural stability of a high G+C content alone, and that CpG islands associated with exons result from some selective importance of the arginine codon CGX. Neither of these theories could account for the distribution of CpG dinucleotides in the sequences analysed. Possible functions of CpG islands in transcriptional and post-transcriptional regulation of gene expression were discussed, and were related to theories for the maintenance of CpG islands as "methylation-free zones" in germline DNA.


Evaluation of the filter paper blood collection method for detecting Og4C3 circulating antigen in bancroftian filariasis.
Serological diagnosis of filariasis is generally known to be more reliable than detection of microfilariae. The recently developed Og4C3 enzyme-linked immunosorbent assay (ELISA) for detecting Wuchereria bancrofti circulating antigen has been shown to be very sensitive in diagnosing filiariasis using serum samples. The commercially available form of this ELISA, using whole blood collected on filter paper, has not been validated independently. We evaluated the sensitivity of this new method against standard 20 microL night blood films in 1808 paired samples from 18 communities in different endemic areas of Ghana. The diagnostic performance of the method was consistently low in all but 2 communities (sensitivity = 50.3%). This method of diagnosing filariasis is not suitable for field use in its present form.


Dysphagia and disability in minor strokes - An institutional study.
Minor strokes, defined as NIHSS ≤5 are considered non-disabling, associated with a favourable outcome. Our aim was to study prevalence and predictors of dysphagia in patients with minor stroke and its impact on functional outcome. Single centre retrospective study of all minor strokes admitted to Comprehensive Stroke care centre with 1 year completed follow-up were recruited. Clinical and imaging details and follow-up data were extracted from medical records. We had 147 patients with minor stroke, 72.1% men with median age 61 years. 71% presented within 24 h of symptom onset. Most common etiology was lacunar .Median NIHSS at admission was 3(IQR 2). 85 patients had anterior circulation strokes and 34 had chronic infarcts in imaging.19 had significant dysphagia and 10 were discharged with nasogastric feeding tube. Admission NIHSS and white mater changes in imaging were predictive of post stroke dysphagia. Excellent recovery of dysphagia was found within 1 month post stroke in all, except one who required percutaneous gastrostomy. At 3 months 76% had excellent outcome. Presence of dysphagia and diabetes were found to be predictive of short term outcome, independent of admission stroke severity. At 12 months, post stroke dysphagia, female gender and white mater changes in imaging were predictive of unfavourable outcome. Minor strokes are disabling in a small fraction of patients. Over 10% of them can have significant post stroke dysphagia necessitating nasogastric feeding short term. This patient subgroup tend to have less favourable outcome on short and long term follow-up.


A comparison of protocols for simulating hemorrhage in humans: step versus ramp lower body negative pressure.
Lower body negative pressure (LBNP) elicits central hypovolemia, and it has been used to simulate the cardiovascular and cerebrovascular responses to hemorrhage in humans. LBNP protocols commonly use progressive stepwise reductions in chamber pressure for specific time periods. However, continuous ramp LBNP protocols have also been utilized to simulate the continuous nature of most bleeding injuries. The aim of this study was to compare tolerance and hemodynamic responses between these two LBNP profiles. Healthy human subjects (N = 19; age, 27 ± 4 y; 7 female/12 male) completed a 1) step LBNP protocol (5-min steps) and 2) continuous ramp LBNP protocol (3 mmHg/min), both to presyncope. Heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), middle and posterior cerebral artery velocity (MCAv and PCAv), cerebral oxygen saturation (ScO2), and end-tidal CO2 (etCO2) were measured. LBNP tolerance, via the cumulative stress index (CSI, summation of chamber pressure × time at each pressure), and hemodynamic responses were compared between the two protocols. The CSI (step: 911 ± 97 mmHg/min vs. ramp: 823 ± 83 mmHg/min; P = 0.12) and the magnitude of central hypovolemia (%Δ SV, step: -54.6% ± 2.6% vs. ramp: -52.1% ± 2.8%; P = 0.32) were similar between protocols. Although there were no differences between protocols for the maximal %Δ HR (P = 0.88), the %Δ MAP during the step protocol was attenuated (P = 0.05), and the reductions in MCAv, PCAv, ScO2, and etCO2 were greater (P ≤ 0.08) when compared with the ramp protocol at presyncope. These results indicate that when comparing cardiovascular responses to LBNP across different laboratories, the specific pressure profile must be considered as a potential confounding factor.NEW & NOTEWORTHY Ramp lower body negative pressure (LBNP) protocols have been utilized to simulate the continuous nature of bleeding injuries. However, it unknown if tolerance or the physiological responses to ramp LBNP are similar to the more common stepwise LBNP protocol. We report similar tolerance between the two protocols, but the step protocol elicited a greater increase in cerebral oxygen extraction in the presence of reduced blood flow, presumably facilitating the matching of metabolic supply and demand.


Frontiers and Challenges in Electrochemical Corrosion Monitoring; Surface and Downhole Applications.
Corrosion sensing is essential to monitor and safeguard the materials' health and control the maintenance cost of corrosion-prone materials used in various industries. The petroleum industry is a major sufferer of corrosion costs among various industries due to pipelines and downhole applications. This review article encompasses an overview of various technologies used in early detection stages for more reliable corrosion sensing and warnings. This review provides a summary of corrosion types, corrosion causing chemical species, different destructive and non-destructive technologies used in monitoring corrosion and a comprehensive overview of the state-of-the-art of various electrochemical techniques used for surface and downhole corrosion monitoring. Finally, the existing challenges for corrosion monitoring in surface and downhole conditions and prospects are discussed.


3p partial trisomy and 13q partial monosomy with congenital malformations and psychomotor developmental delay.
We examined a girl presenting neuropsychomotor developmental delay and multiple malformations including antenatal and postnatal growth retardation, congenital heart defect, and facial dysmorphisms. Cytogenetic analysis was performed on peripheral blood lymphocytes with the GTG-banding technique, which revealed an unbalanced translocation: 46,XX,der(13)(13pter→13q34::3p24→3pter)pat. Karyotype analysis of the father demonstrated a balanced translocation, 46,XY,t(3;13)(p24;q34), indicating the inheritance of the derivative chromosome 13. The mother karyotype was normal. We suggest that most of the structural malformations seen in this patient are due to the 3p trisomy, while the neuropsychomotor alterations are a consequence of both chromosome aberrations.


Inverse relationship between markers of nitric oxide formation and plasma matrix metalloproteinase-9 levels in healthy volunteers.
Nitric oxide (NO) is a major regulator of cardiovascular homeostasis and has anti-atherogenic properties. Reduced NO formation is associated with endothelial dysfunction and with cardiovascular risk factors. Although NO downregulates the expression and activity of the pro-atherogenic enzyme matrix metalloproteinase-9 (MMP-9), no previous clinical study has examined whether endogenous NO formation is inversely associated with the circulating levels of pro-MMP-9, which are associated with cardiovascular events. We examined this hypothesis in 175 healthy male subjects who were non-smokers. To assess NO bioavailability, the plasma concentrations of nitrite, nitrate, and cGMP were determined using an ozone-based chemiluminescence assay and an enzyme immunoassay. Pro-MMP-9 and pro-MMP-2 levels were measured in plasma samples by gelatin zymography. We found significant negative correlations between pro-MMP-9 levels and plasma nitrite (P=0.035, rs= -0.159), nitrate (P=0.040, rs= -0.158), and cGMP (P=0.011, rs= -0.189) concentrations. However, no significant correlations were found between pro-MMP-2 levels and the plasma concentrations of markers of NO bioavailability (all P>0.05). There is an inverse relationship between markers of NO formation and plasma MMP-9 levels. This finding may shed some light on the possible mechanisms involved in the increased cardiovascular risk of apparently healthy subjects with low NO bioavailability or high circulating levels of pro-MMP-9.


Functional and morphological relationships between the feline main pancreatic and bile duct sphincters.
To analyze the relationships between the bile duct and main pancreatic duct sphincters, the resistance to flow through these sphincters was studied simultaneously with perfusion techniques in anesthetized cats. Basal flow resistance was higher in the pancreatic sphincter than in the bile duct sphincter. The pressure in one duct system was not affected by the flow in the other. The muscular activities in the sphincters were usually well coordinated. Distention of the upper biliary tract or the pancreatic duct system reduced the flow resistance in both sphincters. Cholecystokinin-8 (0.01 micrograms), duodenal distention, and sublingual glyceryl trinitrate (0.4 mg) also relaxed both sphincters, whereas secretin in a dose that induced pancreatic secretion had no consistent effect. Morphine increased flow resistance in both systems. These functional studies indicate that the 2 sphincters share smooth muscle fibers at the level where the flow resistances arise, and there are thus no grounds for separate control of the sphincters. There was no evidence of a functionally common sphincter ampulla. The conclusions drawn from the manometric results were supported by morphological findings in this study.


Differential urinary gonadotrophin profiles in early pregnancy and early pregnancy loss.
Early pregnancy loss (EPL), detected by patterns of human chorionic gonadotrophin (hCG) in urine, is the biomarker employed in investigations of the impact of personal, workplace or environmental reproductive toxins on human fertility. An issue central to these studies is what, in terms of urinary hCG expression, constitutes an EPL. This report describes the urinary molecular forms of hCG expressed in menstrual cycles in which a normal pregnancy was conceived, or an EPL occurred, or no apparent conception occurred. Qualitative and significant quantitative differences in the expression of hCG-associated analytes were found between normal pregnancy cycles and EPL cycles. Discriminant analysis calculation based on mole fractions of the different hCG-associated molecules afforded 91 per cent and 80 per cent correct classification of clinical pregnancy cycles and EPL cycles, respectively. Although hCG-associated molecules unique to either EPL or normal pregnancy were not found, what is thought to be an early form of hCG is expressed both at a high frequency and at a significantly higher concentration in early normal pregnancy when compared with EPL. The relative absence of this molecule very early in pregnancy may signal a pregnancy loss.


Isochromosome 17q in two cases of acute blast transformation in myeloproliferative disorders.
Two cases of acute blast cell transformation in myeloproliferative disorders associated with a dicentric 17q isochromosome are reported. In both cases, the karyotypes also included a Philadelphia 9q;22q translocation, and in one case, an additional chromosome 8 (trisomy 8).


Leachate delineation and aquifer vulnerability assessment using geo-electric imaging in a major dumpsite around Calabar Flank, Southern Nigeria.
A near-surface resistivity investigation was undertaken to investigate soil contamination and aquifer vulnerability due to leachate percolation in a major dumpsite in Calabar. The study was undertaken using 2-D electrical resistivity tomography (ERT) and vertical electrical sounding. Ten traverse lines were created within and outside the dumpsite and geo-electric measurement was conducted using dipole-dipole and Schlumberger electrode configurations. Interpretation of the measured data was carried out using DIPROWIN and WinResist program. 2-D resistivity structures were produced, showing four resistivity layers. Conductive layers with a resistivity of less than 14Ωm were delineated as leachate infiltrated and soil-contaminated zones. The study has shown that leachate has spread across all the survey lines except the two control stations outside the dumpsite. The investigation has further revealed that leachate has percolated the subsurface up to 25 m in the area. Subsequently, twenty vertical electrical soundings were carried out to evaluate aquifer protective capacity/vulnerability in the area. The interpretation shows the area is underlain by four to five geo-electric layers. Total longitudinal conductance values were calculated. Two VES points (14 and 19), representing 10% of the sounding points, showed a weak protective capacity rating; eight VES points (1, 7, 9, 11, 12, 13, and 18), representing 35% of the soundings, showed a moderate protective capacity rating; ten VES points (2, 3, 4, 5, 6, 8, 10, 15, 16, 17, and 20), representing 55% of the total soundings, showed a good protective capacity rating. Three (3) hand-dug wells were sampled with the view to obtaining the groundwater and leachate flow direction within the dump vicinity. An electric water level recorder was used to determine the static water level (SWL) of the three wells, and the leachate flow direction was determined to be north-easterly.


[Clinico-morphological characteristics of extrahepatic pathology caused by the hepatitis B virus].
The current literature and the authors data on the clinics and morphology of the extrahepatic (visceral) pathology provoked by the hepatitis virus are analysed.


Traumatic compaction of the axonal cytoskeleton induces argyrophilia: histological and theoretical importance.
It was earlier established that one of the primary morphopathological consequences of experimental traumatic brain injury is a dramatic reduction in the distances between the neurofilaments (cytoskeletal compaction) inside a number of axon segments that appear to be randomly distributed among normal axons in an otherwise undamaged parenchymal environment. The present results demonstrate that the cytoskeletal compaction instantly induces argyrophilia, thereby rendering possible selective visualisation of the affected axon segments for light microscopy through use of a special silver staining method. On combination of this method with electron microscopy, it was revealed that the cytoskeletal compaction is completed in much shorter times and extends to much longer axon segments than previously assumed.


Computerized Assessment of Wheezing in Children With Respiratory Syncytial Virus Bronchiolitis Before and After Hypertonic Saline Nebulization.
Studies suggest an effect of nebulized hypertonic saline solution on air-flow limitation in subjects with respiratory syncytial virus (RSV) bronchiolitis, but results are based on subjective scores of clinical severity and are not clear. In this observational study, we used a noninvasive computerized tool to quantify wheezing before and after nebulization with hypertonic saline in children admitted for RSV infection. Twenty-seven children (≤ 24 months old) admitted to the pediatric ward of the Medical Center Leeuwarden with polymerase chain reaction-confirmed RSV bronchiolitis were included. Subjects were simultaneously assessed both clinically and by computerized acoustic monitoring before and 15 min after treatment with nebulized hypertonic saline solution. Clinical assessment, defined by the Respiratory Distress Assessment Instrument score, did not change after nebulization (n = 27, 5.0 vs 4.7, P = .17). Computerized acoustic monitoring showed no improvement in wheezing (n = 27, 3.4% vs 2.0%, P = .05) or inspiration/expiration ratio (0.85 vs 0.85, P = .93) after nebulization. Hypertonic saline nebulization does not improve air flow, as assessed by both clinical and computerized acoustic scores, in children admitted for RSV.


Feasibility Study of Pulsatile Left Ventricular Assist Device for Prolonged Ex Vivo Lung Perfusion.
Ex vivo lung perfusion (EVLP) has the potential to increase the donor pool for lung transplantation by facilitating resuscitation and extended evaluation of marginal organs. Current EVLP methodology employs continuous flow (CF) pumps that produce non-pulsatile EVLP hemodynamics. In this feasibility study, we tested the hypothesis that a pulsatile flow (PF) pump will provide better EVLP support than a CF pump through delivery of physiologic hemodynamics. Porcine lungs were supported in an EVLP model by centrifugal CF (n = 3) or PF (n = 4) left ventricular assist devices. Lungs were ventilated at 4 to 5 mL/kg, 0.21 fraction of inspired oxygen (FiO2), and perfused with an acellular, albumin-based solution corrected for osmolarity, acid-base balance, and carbon dioxide pressure (≤20 hours at 30°C) for a minimum of 12 hours support. Prostaglandin E1 and 30% albumin were infused continuously. Hemodynamic, respiratory, and blood gas parameters were continuously monitored and digitally recorded hourly. Parenchymal biopsies were used for quantification of wet to dry weight ratio. All lungs maintained function in the EVLP circuit for a minimum of 12 hours (mean 14.7 ± 1 hours) and demonstrated minimal edema formation. The PF EVLP produced higher pulsatility as demonstrated by greater energy equivalent pressure and surplus hemodynamic energy compared with CF EVLP (p < 0.05). There were no statistically significant differences in pulmonary impedance, arterial partial pressure of oxygen/fraction of inspired oxygen, wet to dry weight ratio, and peak airway pressure between CF and PF EVLP. The CF and PF EVLP systems successfully maintained lungs 12+ hours using a modified Steen perfusate (XVIVO Perfusion, Inc, Goteborg, Sweden); however, there were no statistically significant differences between CF and PF groups despite higher pulsatility, suggesting that PF may not offer immediate benefits over CF for prolonged ex vivo lung preservation.


History of the Biodiversity of Ladybirds (Coccinellidae) at the Black Sea Coast of the Russian Caucasus in the Last 120 Years-Does the Landscape Transformation and Establishment of Harmonia axyridis Have an Impact?
Studies of the history of regional insect fauna are important for understanding the changes in ecosystems. We analyzed the dynamics of ladybird fauna at the main sea resort of Russia over a period of 120 years to determine the following: (1) what species disappeared and what species appeared during landscape transformation; (2) what alien species introduced for pest control have been observed to date; and (3) whether the establishment of the global invader Harmonia axyridis (Coccinellidae) caused the extinction of some ladybird species in the Caucasus. We examined specimens collected by us and 54 other collectors including specimens from old museum collections and detected 62 species, 50 of which were collected in recent years (2011-2020). Landscape transformation and recreational use have caused not a decrease but an increase in ladybird biodiversity. Twenty-nine of 34 species recorded before 1930 have been observed in the region to date. Twenty-three other species have spontaneously spread to the region between 1930 and 2020 because of the creation of suitable anthropogenic habitats or because of unintentional introduction. Rodolia cardinalis, Cryptolaemus montrouzieri, Lindorus lophanthae, and Serangium montazerii were released for pest control, and they occur in gardens and streets but not in natural habitats. Harmonia axyridis, which appeared approximately 10 years ago, is abundant in urban and natural habitats, but there is no evidence that it caused the elimination of any ladybird species.


The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Uses its C-Terminus to Regulate the A2B Adenosine Receptor.
CFTR is an apical membrane anion channel that regulates fluid homeostasis in many organs including the airways, colon, pancreas and sweat glands. In cystic fibrosis, CFTR dysfunction causes significant morbidity/mortality. Whilst CFTR's function as an ion channel has been well described, its ability to regulate other proteins is less understood. We have previously shown that plasma membrane CFTR increases the surface density of the adenosine 2B receptor (A2BR), but not of the β2 adrenergic receptor (β2AR), leading to an enhanced, adenosine-induced cAMP response in the presence of CFTR. In this study, we have found that the C-terminal PDZ-domain of both A2BR and CFTR were crucial for this interaction, and that replacing the C-terminus of A2BR with that of β2AR removed this CFTR-dependency. This observation extended to intact epithelia and disruption of the actin cytoskeleton prevented A2BR-induced but not β2AR-induced airway surface liquid (ASL) secretion. We also found that CFTR expression altered the organization of the actin cytoskeleton and PDZ-binding proteins in both HEK293T cells and in well-differentiated human bronchial epithelia. Furthermore, removal of CFTR's PDZ binding motif (ΔTRL) prevented actin rearrangement, suggesting that CFTR insertion in the plasma membrane results in local reorganization of actin, PDZ binding proteins and certain GPCRs.


Microsatellite instability status is determined by targeted sequencing with MSIcall in 25 cancer types.
Microsatellite instability (MSI) occurs in solid tumors and is a predictive biomarker for remarkable response to immune checkpoint inhibitors. Detection of MSI status has been conventionally conducted by PCR-electrophoresis-based assay (MSI-PCR) and immunohistochemistry (IHC) of mismatch repair proteins. However, these approaches require visual confirmation and involve some difficulties in determining MSI statuses from equivocal results. We performed amplicon-based targeted sequencing of 76 microsatellite loci (MSI-NGS) in 184 formalin-fixed paraffin-embedded (FFPE) tumor tissues and baseline control samples. A bioinformatics tool, MSIcall, was used to calculate the quantitative values based on the aligned sequence reads and evaluated MSI status. Furthermore, we examined the concordance between the results from MSI-NGS and MSI-PCR/IHC. Diagnostic accuracy, sensitivity, and specificity were estimated by receiver operating characteristic (ROC) curve analysis. For validation cohort, we studied additional 50 tumor samples to determine the MSI status. Of 184 tumor samples, MSI-PCR and IHC analysis classified 161 tumors as MSS/pMMR and 23 as MSI-H/dMMR. Using MSI-NGS combined with MSIcall, we predicted MSI status with high accuracy (98.9%), specificity (91.3%), and sensitivity (100%) in 25 types of cancers. This method achieved an area under the ROC curve (AUC) value of 0.9986. Furthermore, we achieved the 100% concordant results using additional 50 samples for validation. We demonstrated newly developed MSI-NGS with MSIcall accurately determines the MSI status of FFPE tumor tissues thorough sequencing of tumor samples alone without patient-matched normal controls. This approach can be applied to all types of solid tumors to determine responders to immune-oncology therapy.


Quality of life in stable and progressive 'early-stage' keratoconus patients.
To analyse the vision-related quality of life (vr-QoL) in stable and progressive keratoconus (KC) patients with a still good visual acuity. Combined prospective/cross-sectional study design. The Refractive Status and Vision Profile (RSVP) and the National Eye Institute Visual Functioning - 25 (NEI-25) questionnaire were used in 16 emmetropic, 32 myopic and 56 KC patients, whereby KC patients with a stable (n = 26) and patients with a progressive stage (n = 30) and some of them before and after corneal cross-linking (CXL; n = 10) were included. All patients had a DCVA in at least one eye of ≥0.7 (decimal chart). The analyses revealed a minor decline of the vr-QoL from emmetropes to myopes to early KC patients with a stable disease. Nonetheless, sociological subscales (i.e. 'social functioning', 'role difficulties' and 'dependency') did not display statistically significant differences comparing these groups. In progressive KC, we could demonstrate a statistically significant decline also of these sociological subscales, which did not improve after CXL. Due to a still high and almost unaffected vr-QoL in early KC patients and the distinct decline after progression without rehabilitation after CXL, a reconsideration of current strategies to perform CXL only after a progression is diagnosed should be re-evaluated.


Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model.
The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients.


Cytochemical study of the fluorescence reaction of chromatin by the porphyrin derivative meso-tetra (4-N-methylpyridyl) porphine.
Application of meso-tetra (4-N-methylpyridyl) porphine (TMPP) on smears of chicken blood revealed an intense red fluorescence on the nuclei under blue-violet exciting light, which seemed to be dependent on the DNA component of chromatin. The possibility that an intercalative binding mechanism based on hydrophobic interaction occurs between TMPP molecules and paired bases of DNA is briefly discussed.


[Favourable erythrocyte rheology in patients with glucose-6-phosphate dehydrogenase deficiency (author's transl)].
The rheological properties of erythrocytes of 6 patients with glucose-6-phosphate dehydrogenase deficiency were studied. A method of filtration and measurements of viscosity of erythrocyte suspensions with a hematocrit of 80% were used. The erythrocytes of all patients were more flexible than the erythrocytes of healthy controls. The erythrocytes of the patients passed the polycarbonate filters with a pore diameter of 5 micron more rapidly and showed a lower viscosity of erythrocyte suspensions. The increased flexibility of erythrocytes was due to a lower hemoglobin content which was measured in isolated ghosts. After incubation of the cells with acetylphenylhydrazine, Heinz bodies formed in the erythrocytes of controls. The flexibility of these cells decreased markedly. Though more Heinz bodies were found in the erythrocytes of the patients when the cells were incubated under identical conditions, even these erythrocytes became less rigid than the erythrocytes of controls. From these results we condlude that the more flexible erythrocytes of the patients could pass the splenic sinus even when they contain Heinz bodies. The rheological properties of the erythrocytes explain why splenectomy is not efficient in glucose-6-phosphate dehydrogenase deficiency.


Value of computerized tomography in evaluation of kidney.
The use of intravenous iodinated contrast material after a preliminary computerized axial tomographic scan of the kidney has been an extremely valuable adjunct in differentiating benign, malignant, and some inflammatory processes. The diagnosis of type of lesion present has been facilitated and allows direction for further diagnosis and therapy.


Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine.
Growing evidence suggests that the activation of the inflammatory/immune system contributes to depression pathogenesis, a hypothesis that might hold strong clinical implication. Indeed more than 30% of depressed patients fail to achieve remission, which poses the necessity to identify systems that may represent novel targets for medications. Accordingly, goal of this study was to evaluate the ability of the antidepressant agomelatine to modulate specific components of the immune response in the rat brain following an inflammatory challenge with lipopolysaccharide (LPS). To this aim, adult male rats were chronically treated with agomelatine before being acutely challenged with LPS 16 h after the last drug administration. Rats were sacrificed 2, 6, or 24h after the challenge and several components of the inflammatory response have been investigated by using real-time PCR or ELISA. We found that agomelatine significantly reduced the LPS-induced up-regulation of the pro-inflammatory cytokines interleukin-1β and interleukin-6 in the rat brain as well as at peripheral level. At central level, these effects are associated to the inhibition of NF-κB translocation as well as to alterations of mechanisms responsible for microglia activation. In addition, we found that agomelatine was also able to alter the expression of enzymes related to the kynurenine pathway that are thought to represent important mediators to inflammation-related depression. These data disclose novel properties that may contribute to the therapeutic effect of agomelatine providing evidence for a crucial role of specific components of the immune/inflammatory system in the antidepressant response and thereby in depression etiopathology.


Harnessing epigenetics to study human evolution.
Recent advances in ancient DNA extraction and high-throughput sequencing technologies enabled the high-quality sequencing of archaic genomes, including the Neanderthal and the Denisovan. While comparisons with modern humans revealed both archaic-specific and human-specific sequence changes, in the absence of gene expression information, understanding the functional implications of such genetic variations remains a major challenge. To study gene regulation in archaic humans, epigenetic research comes to our aid. DNA methylation, which is highly correlated with transcription, can be directly measured in modern samples, as well as reconstructed in ancient samples. This puts DNA methylation as a natural basis for comparative epigenetics between modern humans, archaic humans and nonhuman primates.


Hepatic siderosis in alcoholics.
In a population of 157 (120 males, 37 females) predominantly British alcoholics with liver disease, the incidence of some degree of hepatic siderosis, as estimated by stainable parenchymal iron, was 57.3%. The incidence of significant siderosis (grades III and IV) was 7%, and was similar for both sexes. In the female alcoholics there was a significant correlation between age and the degree of siderosis (P less than 0.05)--four of the five females with significant siderosis being premenopausal. In the male alcoholics there was a significant inverse relationship between the grams of ethanol consumed per day and the degree of siderosis (P less than 0.05) and a significant correlation between the percentage saturation of iron-binding protein and the degree of siderosis (P less than 0.05). The mean daily iron intake from alcoholic beverages was 1.5 mg; there was no relationship between the amount of iron ingested in the alcohol and the degree of siderosis. In this population of alcoholics the incidence of significant siderosis in both sexes was low.


Fluoxetine versus amitriptyline in the treatment of major depression: a multicenter trial.
Fluoxetine, a serotonin uptake inhibitor, and amitriptyline, a tricyclic antidepressant, were compared in a 5-week, multicenter, double-blind, randomized trial in 136 out-patient men and women, aged 21-70 years, with major depressive disorder. Overall efficacy was comparable with fluoxetine and amitriptyline [Hamilton 21-Item Rating Scale for Depression (HAM-D21), Raskin, Covi, Clinical Global Impressions-Severity and -Improvement, Patient's Global Impressions]. Mean +/- standard deviation decreases in HAM-D21 total score were 12.9 +/- 9.9 and 11.6 +/- 10.3 (p = 0.423), respectively. Response rates (> or = 50% decrease in HAM-D21 total score) for patients treated > or = 4 weeks were 46.7% and 66.0% (p = 0.039) and remission rates (HAM-D21 total score < or = 7) were 18.3% and 28.3% (p = 0.209), respectively. Response and remission rates for all patients were comparable with fluoxetine and amitriptyline. Study completions were higher with fluoxetine than amitriptyline (87.7% vs 66.2%; p = 0.003). Discontinuations for adverse events were higher with amitriptyline than fluoxetine (22.5% vs 6.2%; p = 0.007). More treatment-emergent nausea and insomnia were reported with fluoxetine (p < or = 0.05); more anticholinergic and orthostatic events and weight gain were reported with amitriptyline (p < or = 0.05). Statistically, but not clinically, significant changes were observed in vital signs. Both fluoxetine and amitriptyline were effective treatments for out-patients with major depressive disorder. Fluoxetine had a more favorable safety profile than amitriptyline.


Influence of humectants on the thermotropic behaviour and nanostructure of fully hydrated lecithin bilayers.
Humectants are used widely in topical formulations as they provide cosmetic and health benefits to skin. Of particular interest to our laboratories is the interaction of humectants in phospholipid based topical skin care formulations. This study probed the effects of three exemplary humectants on a fully hydrated lecithin system (DPPC) by use of X-ray scattering and differential scanning calorimetry. While the three humectants affected the nanostructure of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC, bilayers in a similar manner, leading to an increased membrane order, differences in the effect on the thermal behaviour of DPPC suggest that betaine and sarcosine interacted via a different mechanism compared to acetic monoethanolamide, AMEA. At concentrations above 0.4 M, betaine and sarcosine stabilised the gel phase by depletion of the interfacial water via the preferential exclusion mechanism. At the same time, a slight increase in the rigidity of the membrane was observed with an increase in the membrane thickness. Overall, the addition of betaine or sarcosine resulted in an increase in the pre- and main transition temperatures of DPPC. AMEA, on the other hand, decreases both transition temperatures, and although the interlamellar water layer was also decreased, there was evidence from the altered lipid chain packing, that AMEA molecules are present also at the bilayer interface, at least at high concentrations. Above the melting point in the fluid lamellar phase, none of the humectants induced significant structural changes, neither concerning the bilayer stacking order nor its overall membrane fluidity. An humectant-induced increase in the Hamaker constant is the most plausible explanation for the observed reduction of the inter-bilayer distances, both in the gel and fluid phase.


Nuclear replacement strategies.
Although still a technology in its infancy, nuclear replacement promises a potential alternative to arthrodesis for patients with discogenic back pain. It is ideally suited to those patients presenting early in the degenerative cascade with minimal to no arthritic changes or disc collapse. The physical nature of the implants seeks to restore the visco-elastic, biomechanical, and fluid characteristics of the natural disc, thus reducing pain while maintaining motion and function.


The emerging roles of the interaction between m6A modification and c-Myc in driving tumorigenesis and development.
N6-methyladenosine (m6A) is an extremely common and conservative posttranscriptional modification, that can specifically target and regulate the expression or stability of a series of tumor-related genes, thus playing critical roles in the occurrence and development of tumors. c-Myc is an important tumorigenic transcription factor that promotes tumorigenesis and development by mainly regulating the expression of downstream target genes. Increasing evidence shows that m6A modification, as well as abnormal expression and regulation of c-Myc, is critical molecular mechanisms driving tumorigenesis and development. Although more evidence has been uncovered about the individual roles of m6A modification or c-Myc in tumors, the interaction between m6A modification and c-Myc in tumorigenesis and development has not been systematically summarized. Therefore, this review is focused on the mutual regulation between m6A modification and c-Myc expression and stability as well as its roles in tumorigenesis and development. We also summarized the potential value of the interaction between m6A modification and m6A expression and stability in tumor diagnosis and treatment, which provides a specific reference for revealing the mechanism of tumor occurrence and development as well as clinical diagnosis and treatment.


Traumatic closed index extensor tendon rupture at the musclotendinous junction: a report of two cases.
This report describes two cases of traumatic closed index extensor tendon rupture at the musclotendinous junction. Both patients were injured when their work gloves were caught in the revolving parts of machines, and both were treated surgically. One of the patients completely ruptured the index extensor digitorum communis (EDC) and the extensor indicis proprius (EIP) tendons at the musclotendinous junction of dorsal forearm. In this patient, the distal stump of the index EDC tendon was sutured to the middle EDC tendon in an end-to-side juncture. The other patient completely ruptured the EIP tendon and partially ruptured the index EDC tendon at the musclotendinous junction. In this patient, tendon transfer of the extensor digiti minimi (EDM) to the EIP tendon and plication of the index EDC tendon were performed. In both cases, surgical intervention enabled the patients to extend their index fingers almost normally; however, the former complained of inability to extend his index finger independently. Tendon transfer of the EDM in cases of index extensor tendon rupture at the musclotendinous junction is a good method to restore ability to independently extend the index finger. However, consideration should be given to anatomical variation in the little finger. The EDC tendon is sometimes absent leaving the EDM tendon as the only extensor tendon to the little finger.


Is supplemental regional anesthesia associated with more complications and readmissions after ankle fracture surgery in the inpatient and outpatient setting?
There is concern that regional anesthesia is associated with increased risk of complications, including return to the hospital for uncontrolled pain once the regional anesthetic wears off. Retrospective database review of patients who underwent open reduction and internal fixation of a closed ankle fracture from 2014-16 who received general anesthesia alone (GA) or general anesthesia plus regional anesthesia (RA). 9459 patients met inclusion criteria. Patients in the RA group had significantly longer operative duration in both inpatient (GAI=71min vs RAI=79min, p=0.002) and outpatient setting (GAO=66min vs RAI=72min, p<0.001), lower overall LOS (GA=1.7 days vs RA=1.1 days, p<0.001), and higher readmission rate for pain (RAO=4 [0.3%] vs GAO=1 [0.0%], p=0.007). Patients who received supplemental regional anesthesia had shorter hospital LOS, increased operative time, and increased readmission rates for rebound pain. However, the small number of patients needing readmission are not clinically significant demonstrating that regional anesthesia is safe, effective and readmission for rebound pain should not be a concern. III.


Adverse effect of beta-tricalcium phosphate with zeta potential control in repairing critical defects in rats' calvaria.
To evaluate whether a new biphasic cement composed of calcium sulfate and beta tricalcium phosphate with zeta potential control could induce or lead to bone neoformation in critical defects. A critical defect of diameter 8 mm was made in the calvaria of forty male Wistar rats. In the Test Group (n = 20), the defects were filled with cement. In the Control Group (n = 20), the defect was not filled and only coagulum was present. The animals were sacrificed 7, 14, 21 and 42 days after the operation. Calvaria specimens were subjected to microtomography and were then prepared for histological analysis. The analyses included morphological assessment on the histopathology of the repair; comparative morphometric evaluation of the area of formation of bone trabeculae between the groups; and histochemical staining by means of tartrate-resistant phosphatase (TRAP) in order to identify osteoclasts. Microtomographic images of the defects filled by the cement did not show any decrease in area over the course of postoperative evolution. In the Test Group, the material continued to present a foreign-body response until the last observational periods. Histomorphological analysis showed that there were more significant groupings of giant cells in the Test Group and greater maturity of neoformed bone in the Control Group. Exogenous material was also present. Histomorphometric analysis showed that in the Control Group, the total area of bone neoformation was significantly greater (p = 0.009) and grew progressively. The giant cells presented a positive reaction to TRAP but no osteoclasts were observed. The ceramic cement did not induce or lead to bone neoformation from the microtomographic or histological point of view.


Association Between Systolic Blood Pressure Variability and Major Adverse Cardiovascular Events in Korean Patients With Chronic Kidney Disease: Findings From KNOW-CKD.
Background Whether visit-to-visit systolic blood pressure (SBP) variability can predict major adverse cardiovascular events (MACE) in patients with chronic kidney disease is unclear. Methods and Results We investigated the relationship between SDs of visit-to-visit SBP variability during the first year of enrollment and MACE among 1575 participants from KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease). Participants were categorized into 3 groups according to tertiles of visit-to-visit SBP variability (SD). The study end point was MACE, defined as a composite of nonfatal myocardial infarction, unstable angina, revascularization, nonfatal stroke, hospitalization for heart failure, or cardiac death. During 6748 patient-years of follow-up (median, 4.2 years), MACE occurred in 64 participants (4.1%). Compared with the lowest tertile of visit-to-visit SBP variability (SD), the hazard ratios (HRs) for the middle and the highest tertile were 1.64 (95% CI, 0.80-3.36) and 2.23 (95% CI, 1.12-4.44), respectively, in a multivariable cause-specific hazard model. In addition, the HR associated with each 5-mm Hg increase in visit-to-visit SBP variability (SD) was 1.21 (95% CI, 1.01-1.45). This association was consistent in sensitivity analyses with 2 additional definitions of SBP variability determined by the coefficient of variation and variation independent of the mean. The corresponding HRs for the middle and highest tertiles were 2.11 (95% CI, 1.03-4.35) and 2.28 (95% CI, 1.12-4.63), respectively, in the analysis with the coefficient of variation and 1.76 (95% CI, 0.87-3.57) and 2.04 (95% CI, 1.03-4.03), respectively, with the variation independent of the mean. Conclusions Higher visit-to-visit SBP variability is associated with an increased risk of MACE in patients with chronic kidney disease. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.


Coping with stress, control of emotions and biochemical markers as a common protective element in the inflammatory response to stress.
Based on a comprehensive approach to the problem of stress, we have decided to evaluate all components of a stress response - immunological (IL-1, IL-2, IL-6, IL-10, CRP, TNF-alpha) and hormonal one (CRH, ACTH), as well as to evaluate the psychological indicators of stress, coping with stress, and controlling emotional reactions as psychological markers that predispose to the most beneficial adaption in relation to stressors affecting flight personnel taking part in peace missions abroad. The research studies being the subject matter of the project were conducted among 113 antiterrorists and 123 representatives of aircrew (236 respondents in total) who participated in peace missions outside Poland. The study was conducted both before departure and during the missions. The study included a biochemical evaluation (IL-1, IL-2, IL-6, IL-10, CRP, TNF-alpha, CRH, ACTH) as well as a psychological assessment based on the Perceived Stress Scale by S. Cohen (PSS-10) and the Courtauld Emotional Control Scale (CECS) by M. Watson and S. Greer, and the COPE Inventory by J. Corver. Based on a statistical analysis of the variables, a relationship between the level of perceived stress and the methods of coping with it as well as between the selected methods of emotion control and inflammatory response indicators, was found. In difficult situations, accompanied by an increase in the variables responsible for the biochemical inflammatory response of an organism, the effective model of coping with difficult situations and emotioncontrol increases, while the subjective level of perceived stress drops.


Abortion Patients' Experience and Perceptions of Waiting Periods: Survey Evidence before Arizona's Two-visit 24-hour Mandatory Waiting Period Law.
More than one-half of U.S. states now have laws requiring women to wait at least 24 hours between receiving information about abortion and the actual abortion procedure, with a few requiring longer waits, and one-fourth requiring that women receive this information in person. Although public discussions of waiting periods focus on how they affect women, we know little about abortion patients' perceptions of these requirements. We collected data from 379 women seeking abortion care at an abortion facility in Arizona before Arizona's 24-hour waiting period two-visit requirement went into effect. Surveys focused on patients' experiences receiving abortion care before the waiting period and perceptions about how the additional clinic visit would affect them. Most women reported one or more financial or logistical challenges in obtaining abortion care. More than two-thirds reported difficulty paying abortion appointment-related expenses. These expenses prevented or delayed almost one-half from paying other expenses, such as rent, bills, and food, with lower income women more affected. The majority expected that the additional visit would result in additional financial and logistical hardships and delay them in having an abortion, with 90% reporting that the waiting period would lead to at least one hardship. Eight percent reported that the waiting period would have a positive effect on emotional well-being, and more than one-half reported that it would have a negative effect on emotional well-being. Only a small minority of women seeking abortion care view a two-visit waiting period law as benefiting them; the overwhelming majority expect a waiting period to have adverse consequences.


Childhood stuttering and dissociations across linguistic domains.
The purpose of this investigation was to evaluate the possible presence of dissociations in the speech and language skills of young children who do (CWS) and do not stutter (CWNS) using a correlation-based statistical procedure [Bates, E., Appelbaum, M., Salcedo, J., Saygin, A. P., & Pizzamiglio, L. (2003). Quantifying dissociations in neuropsychological research. Journal of Clinical and Experimental Neuropsychology, 25, 1128-1153]. Participants were 45 preschool CWS and 45 CWNS between the ages of 3;0 and 5;11 (years;months), with the two groups matched by age, gender, race, and parental socioeconomic status. Children participated in a parent-child interaction for the purpose of disfluency analysis and responded to four standardized speech-language tests for subsequent analyses as main dependent variables. Findings indicated that CWS were over three times more likely than CWNS to exhibit dissociations across speech-language domains, with 44 cases of dissociation for CWS and 14 for CWNS across 10 possible comparisons. Results suggest that there may be a subgroup of CWS who exhibit dissociations across speech-language domains, which may result in a greater susceptibility to breakdowns in speech fluency. The reader will be able to: (1) summarize findings from previous studies examining differences in speech and language performance between children who do and do not stutter; (2) describe what is meant by "dissociations" in the speech and language skills of young children who do and do not stutter; and (3) discuss three hypotheses that could account for the present findings that suggest CWS, more often than CWNS, exhibit dissociations in their speech-language system.


Neighborhood effects examined through the lens of residential mobility programs.
Although researchers have consistently found that neighborhoods matter, relatively little is known about the processes through which neighborhood-level characteristics influence individual outcomes, and whether interventions targeting improving neighborhood characteristics will be beneficial for children. I examine whether relocating from high- to low-poverty neighborhoods affected low-income Black children's exposure to promotive developmental experiences. Participating families voluntarily relocated from high-poverty, minority segregated, inner-city Chicago neighborhoods to mostly White, low-poverty, suburban and Chicago neighborhoods. Data come from retrospective qualitative interviews with 22 Gautreaux One families an average of 15 years after initial relocation, and from interviews with 43 Gautreaux Two families as they relocated into their new communities. I find that children primarily benefited from the institutional versus the social interaction resources in their new neighborhoods. Furthermore, suburban placement was key in facilitating children's access to higher quality resources.


Interspecies cross-reactivity of monoclonal antibodies to various epitopes of human plasminogen.
The immunological cross-reactivities of three conformationally specific monoclonal antibodies to distinct epitopes on human plasminogen toward plasminogens purified from 14 additional species have been examined. Antibody 10-F-1, which is produced against an epitope on the kringle 4 region of human plasminogen, shows a high degree (greater than 80%) of cross-reactivity against baboon, goat, monkey, ovine, and rabbit plasminogens; more limited (20-50%) cross-reactivity against bovine, equine, goose, guinea pig, mouse, rat, and porcine plasminogens; and little comparable cross-reactivity against canine and chicken plasminogens. Antibody 10-H-2, generated to an epitope of the kringles 1-3 region of human plasminogen, shows extensive cross-reactivity (72%) only toward monkey plasminogen, more limited (22-35%) cross-reactivity toward equine and rabbit plasminogens, and much less cross-reactivity toward any other of the above plasminogens. Antibody 10-V-1, also produced against an epitope on the kringle 1-3 region of human plasminogen, which is distinct from the 10-H-2 epitope, shows extensive cross-reactivity (72-100%) with baboon, monkey, and rabbit plasminogens; more limited cross-reactivity with equine (48%) and mouse (28%) plasminogens; and a low level of such reactivity with the remaining plasminogens. These studies show that the extent of interspecies cross-reactivity of various plasminogens greatly depends upon the epitope in question. The K4 region of these molecules appears more extensively conserved than the K1-3 region, at least in regard to the particular epitopes examined in this study.


Association of Apolipoprotein A1 Gene Polymorphisms with Serum Lipid Spectrum in Adolescents in East Siberia.
We studied the incidence of genotypes of polymorphic alleles (-75)G>A and (+83)C>T of apolipoprotein A1 gene in healthy Russian adolescents, residents of East Siberia. Genotyping was carried out by PCR with subsequent restriction fragment length polymorphism analysis. The incidence of allele (-75)A was 22.5%, of allele (+83)T - 7.3%. Association of allele (-75) A with high blood cholesterol level was revealed.


Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale.
In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013). Our findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.


Saphenous vein graft failure and clinical outcomes: toward a surrogate end point in patients following coronary artery bypass surgery?
Saphenous vein graft (SVG) failure is a common finding in patients following coronary artery bypass graft (CABG) surgery. In the literature SVG failure rates have been reported from 25 to over 50% within 10 years. Although common, it remains unclear to what extent SVG failure affects clinical outcome, due to differences in definition, patient selection and follow-up. Particularly the lack of agreement on a universal definition makes comparisons between studies, and therefore generalizability of associations with outcomes, challenging. We suggest using a definition of SVG failure that is based on imaging as well as clinical parameters, that includes reporting SVG failure on both graft and patient level. The use of non-invasive imaging may help improve follow-up rates, and provide a more accurate picture of the real incidence and clinical impact of SVG failure. Given the lack of supportive evidence showing a consistent association between SVG failure and major adverse cardiovascular events, SVG failure should not be considered a valid surrogate endpoint at this time.


Bacterial infections in pediatric patients during early post liver transplant period: A prospective study in Iran.
Bacterial infection in early period after liver transplant (LT) is the main cause of morbidity and mortality; however, data on children is limited. To investigate the frequency, characteristics, and the associated factors of bacterial infection during hospitalization after LT, we prospectively enrolled all consecutive children with LT for a one-year, case-control study at the unique referral center of pediatric LT in Iran. Eighty-five events of bacterial infection were detected among 51 out of 94 LT recipients (54.3%) (infection group). Forty-three patients without bacterial infection constituted the control group. The frequency of bacterial infection based on the 51 microbiologically documented events was 31.9% (30 out of 94 patients). Major site of bacterial isolation were abdomen (43.6%). The following variables were associated with bacterial infection in univariate analysis: younger age (5.6 vs 8.9 years old), longer duration of JP Drain (13.4 vs 6.3 days), central venous catheter (14.6 vs 7.6 days), and Foley catheter insertion (7.3 vs 4.5 days), reoperation (57% vs 12% of patients), mean frequency of reoperation (1.1 vs 0.1 times), and intensive care unit stay (12.1 vs 6.5 days). In multivariate analysis, only longer hospital stay after transplant (23.6 vs 10.9 days) was independently associated with bacterial infection. All ten deaths occurred within the infection group and half of which directly caused by infection. These infections were associated with longer hospital stay and higher mortality rate. Conducting further studies with larger sample size and investigating more effective prophylactic measures should be considered in future studies.


Chicken spermatogenesis is accompanied by a genomic-wide loss of DNA methylation.
Renaturation kinetics of DNA obtained from chicken testis cell nuclei separated by sedimentation at unit gravity showed that the undermethylation, previously observed in meiotic and postmeiotic cells, is not a peculiarity of repetitive sequences, but is also a feature of unique sequences. The large proportion of slowly renaturing, intermediately renaturing and rapidly renaturing DNAs contain 27, 32 and 31% less methylcytosines in meiotic and postmeiotic cells than the corresponding fractions of premeiotic cells. DNA methyltransferase activity is lower in meiotic cells containing undermethylated DNA than in immature testis, enriched in spermatogonia, with higher levels of DNA methylation.


Manganese induces p21 expression in PC12 cells at the transcriptional level.
Manganese is a common environmental and occupational pollutant. Excessive intake of manganese can cause toxicity known as manganism. Recently it has been demonstrated that unusual expression of cell cycle proteins and aberrant cell cycle progression in the central nervous system are involved in the pathogenesis of neurodegenerative diseases. The present studies were initiated to investigate whether p21 are induced after manganese exposure and its potential effects in vitro, with particular attention being given to understand the underlying regulatory mechanism of p21 induction by manganese in this process. We found that manganese induced DAergic cells injury and upregulation of p21 levels in nigrostriatal regions. Treatment of the PC12 cells with manganese resulted in a time- and concentration-dependent loss of cell viability. Analysis of cell cycle profile indicated that manganese blocked cell cycle progression by arresting the cell cycle at G2/M phase. Moreover, manganese treatment resulted in an increase in the mRNA and protein levels of p21, but did not have the same effect on other related factors. Silencing p21 by RNA interference showed a marked reversal of both G2/M arrest and the decrease in cell viability induced by manganese. Manganese did not stabilize the p21 protein and mRNA, and caused a marked increase in p21 mRNA levels together with an increase in its promoter activity, indicating a transcriptional mechanism. Overall, the in vivo and in vitro data suggest that exposure to manganese can increase p21 levels. An altered cell cycle status of PC12 cells can be induced by manganese through p21 up-regulation, and the induction of p21 occurs at the transcriptional level via promoter activation and mRNA induction.


High-efficient adsorption for versatile adsorbates by elastic reduced graphene oxide/Fe3O4 magnetic aerogels mediated by carbon nanotubes.
Fabrication of highly elastic three-dimensional aerogel adsorbents with outstanding adsorption capacities is a long pursuit for the treatment of industrial contaminated water. In this work, a magnetic reduced graphene oxide (rGO)/Fe3O4/carbon nanotubes (CNTs) aerogel material was constructed by the electrostatic attraction between the negatively charged GO and positively charged CNTs following a one-pot water bath treatment. The as-synthesized aerogel demonstrated high compressive stress (28.4 kPa) and lower density (24.11 mg/cm3) with exceptional adsorption capacities for versatile adsorbates which are attributed to CNTs and magnetic Fe3O4 nanoparticles. The effect of pH, initial concentration of adsorbates (dyes, Cd (ІІ) ions, organic solvents, and pump oil), content of CNTs and cyclic times on the adsorption capacities of the aerogel were investigated in detail. Furthermore, from simulation, the adsorption kinetics, and thermodynamics of the aerogel for adsorbates were more satisfied by endothermic quasi-second-order kinetic model with characteristic physical adsorption. Thus, the optimized rGO/Fe3O4/CNTs-10 aerogel adsorbent can be used as a powerful and versatile tool to deal with contaminated industrial or domestic wastewater.


Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma.
The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.


The diagnosis of alcohol, cocaine, and other drug dependence in an inpatient treatment population.
The diagnosis of alcohol, cocaine, and other drug dependence in inpatient treatment populations is important to identify for clinical prognosis, treatment, and genetic research. The use of alcohol by cocaine addicts is a common cause for relapse to cocaine. The treatment of cocaine addiction is simplified if alcohol dependence is also present because the same methods can be used for both. In this study, 94% of those patients who qualified for the diagnosis of cocaine dependence were also diagnosed as having alcohol and other drug dependence. The demographic characteristics of these cocaine addicts (n = 413) compared to those patients with the diagnosis of alcohol dependence only (n = 677) and alcohol dependence and drug dependence other than cocaine (n = 453).


Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system.
Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G, resulting in successful prediction of CLr and the plasma concentration-time profiles in both healthy subjects and CKD patients. A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects.


Capillary blood glucose monitor. Evaluation in a newborn nursery.
The performance of a rapid capillary blood glucose monitor, the Glucoscan 2000, was evaluated in a neonatal patient population by comparison with a reference method on 283 paired patient samples. The median glucose was 56 mg/dL (3.1 mmol/L). The slope of the regression line was .93 with a correlation coefficient r of .82. The average error in Glucoscan values at low, intermediate and high glucose ranges was 43%, 20% and 12% respectively. Precision analysis by replicate determinations also showed an increased coefficient of variation, 7.4%, at low glucose values.


Prevalence of dental caries based on personality types of 35-44 years old residents in Davangere city.
To assess dental caries experience of different personality types of 35-44 years old residents in Davangere city. A cross-sectional survey was conducted in field setting. Based on Jenkins Activity Survey Questionnaire11 used to assess the personality types, a personality questionnaire was designed consisting of 20 items. Questionnaire was used to assess and categorize personality types as Type A, Type B and Type AB. Data were analyzed using SPSS software version 17. Standard descriptive statistics were generated. Evaluation of data was done using chi square test. Prevalence of dental caries was 96.6% in Type A personality and 95.9% in Type B personality and this difference was not statistically significant (person chi square p value = 0.53). In a cross-sectional survey it is difficult to inspect personality types which is a qualitative variable with some people giving different responses at different occasions. There are chances of social desirability bias. Hence, longitudinal studies should be conducted to ascertain the association between personality types and dental carries.


Malignant Mesothelioma and Delivery of Polyphenols.
Malignant Mesothelioma (MM) is a rare form of cancer that affects the thin cell wall lining of the body's internal organs and structures.[...].


Trophoblast invasion: Lessons from abnormally invasive placenta (placenta accreta).
The invasion of the uterine wall by extravillous trophoblast is acknowledged as a crucial component of the establishment of pregnancy however, the only part of this process that has been clearly identified is the differentiation of cytotrophoblast (CTB) into the invasive extravillous trophoblast (EVT). The control of invasion, both initiation and termination, have yet to be elucidated and even the mechanism of differentiation is unclear. This review describes our studies which are designed to characterize the intracellular mechanisms that drive differentiation. We have used the over-invasion observed in abnormally invasive placenta (AIP; placenta accreta) to further interrogate this mechanism. Our results show that first trimester CTB to EVT differentiation is accomplished via an epithelial-mesenchymal transition (EMT), with EVT displaying a metastable, mesenchymal phenotype. In the third trimester, while the invasiveness of the EVT is lost, these cells still demonstrate signs of the EMT, albeit diminished. EVT isolated from AIP pregnancies do not however, show the same degree of reduction in EMT shown by normal third trimester cells. They exhibit a more mesenchymal phenotype, consistent with a legacy of greater invasiveness. The master regulatory transcription factor controlling the EMT appears, from the observational data, to be ZEB2 (zinc finger E-box binding protein 2). We verified this by overexpressing ZEB2 in the BeWo and JEG3 trophoblast cell lines and showing that they became more stellate in shape, up-regulated the expression of EMT-associated genes and demonstrated a substantially increased degree of invasiveness. The identification of the differentiation mechanism will enable us to identify the factors controlling invasion and those aberrant processes which generate the abnormal invasion seen in pathologies such as AIP and preeclampsia.


Switching tenofovir/emtricitabine plus lopinavir/r to raltegravir plus Darunavir/r in patients with suppressed viral load did not result in improvement of renal function but could sustain viral suppression: a randomized multicenter trial.
Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load. This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation. 58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD). Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load. ClinicalTrials.gov NCT01294761 http://clinicaltrials.gov/ct2/show/NCT01294761?term=SPARE&rank=2, Umin Clinical Trials Registry UMIN000005116 http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J).


Central statistical monitoring of investigator-led clinical trials in oncology.
Investigator-led clinical trials are pragmatic trials that aim to investigate the benefits and harms of treatments in routine clinical practice. These much-needed trials represent the majority of all trials currently conducted. They are however threatened by the rising costs of clinical research, which are in part due to extensive trial monitoring processes that focus on unimportant details. Risk-based quality management focuses, instead, on "things that really matter". We discuss the role of central statistical monitoring as part of risk-based quality management. We describe the principles of central statistical monitoring, provide examples of its use, and argue that it could help drive down the cost of randomized clinical trials, especially investigator-led trials, whilst improving their quality.


Fluorescence turn-on chemodosimetric sensing of cyanide by cyanovinylterpyridine modified phthalonitrile and subphthalocyanine.
Terpyridine-attached phthalonitrile (Pn-TP) linked by cyanovinyl bond has been synthesized and employed for the preparation of subphthalocyanine (SubPc-TP) bearing conjugated terpyridine moieties. Both Pn-TP and SubPc-TP exhibited highly selective fluorescence turn-on in the presence of cyanide anions (CN-) based on chemodosimetric sensing mechanism. The conjugation of the Pn-TP molecule was interrupted by the addition of CN- at the cyanovinyl bond, showing the ratiometric fluorescence turn-on behavior. This sensing mechanism was further supported by density functional theory calculation and nuclear magnetic resonance titration studies. Optical and photophysical responses of SubPc-TP towards CN- were also investigated, in which similar fluorescence enhancement was observed due to the addition of CN- at the reactive boron trimer. The detection limit was estimated to be 94 nM, much below the World Health Organization-allowed level (1.9 μM) of CN- in water.


Associative structure of integrated temporal relationships.
According to the temporal-coding hypothesis (TCH; Savastano & Miller, Behavioural Processes 44:147-162, 1998), acquired associations include temporal information concerning the interval between the associated elements. Moreover, the TCH posits that subjects can integrate two independently acquired associations that share a common element (e.g., S2-S1 and S1-US), which results in the creation of a third association with its own temporal relationship (S2-US). Some evidence has suggested that such temporal integration occurs at the time of testing (Molet, Miguez, Cham, & Miller, Journal of Experimental Psychology: Animal Behavior Processes 38:369-380, 2012). Here we report two fear-conditioning experiments with rats conducted to identify the associative structure of the integrated temporal relationship. The goal was to distinguish between two possible associative structures that could exist following an initial test on which temporal integration occurs: (1) Conditioned responding to S2 on subsequent tests could be the result of recurring successive activation of two independently learned temporal maps that remain independently stored in memory (i.e., S2-S1 plus S1-US). (2) Temporal integration at the moment of initial testing could result in the formation of a direct S2-US (or S2-response) temporal map. Integration was found to occur at test and to produce a new association that was independent of associations with the common element (S1). However, the associative status of S1 appeared to modulate whether or not the new association with S2 was US-specific (S2-US) or directly activated a fear response (S2-response).


Avoidance of blood transfusion in coronary artery surgery: a trial of hydroxyethyl starch.
Banked blood transfusion, with its attendant hazards, may be avoided in certain instances. A search for an acceptable plasma substitute was made. A randomized prospective trial of hydroxyethyl starch (HES) versus plasma for postoperative volume replacement is described. Ninety patients undergoing operations for coronary artery disease were studied over a six-month period. Ten received banked blood in the immediate postoperative period and were excluded from the study. The remaining 80 were randomized into two groups. Group 1 received plasma, and Group 2 received HES. All patients initially had autologous blood transfusion, and in 7 patients this sufficed; these patients were excluded from the study except for regression analysis. Postoperative blood loss and urine output did not differ between groups, but Group 2 patients required significantly more volume replacement (p less than 0.02). In a total of 27 patients drawn from both groups, coagulation factors and colloid osmotic pressure were investigated. There were no significant differences in fibrinogen titer and prothrombin time between groups, but return to normal values was significantly delayed in the HES group (p less than 0.01). Activated clotting time and partial thromboplastin time were unaffected. Colloid osmotic pressure was significantly higher at one week in the HES group (p less than 0.001) and was correlated with the volume of HES given (r = 0.525; p less than 0.01). There were no untoward effects attributable to HES. It is concluded that HES is a safe, cheap, and effective plasma substitute for volume replacement following cardiac surgical procedures.


Characteristics of Migration Among HIV-Positive MSM - Guangxi Zhuang Autonomous Region, China, 2005-2021.
Migration has a significant impact on the transmission of human immunodeficiency virus (HIV). To date, there have been few studies examining the characteristics of migration among HIV-positive men who have sex with men (MSM). The prevalence of migrants among newly reported HIV-positive MSM in Guangxi Zhuang Autonomous Region increased from 2005 to 2021. Yulin Prefecture had the highest proportion of out-migrant MSM (12.6%), while Nanning Prefecture had the highest proportion of in-migrant MSM (55.9%). Risk factors associated with migration among MSM included being in the 18-24 age range, having a college education or higher, and being a student. A complex prefecture-level network of HIV-positive MSM exists in Guangxi. To ensure effective follow-up management and antiretroviral therapy for migrant MSM, effective measures must be taken.


Improved differentiation of pancreatic tumors using contrast-enhanced endoscopic ultrasound.
Endoscopic ultrasound is a widely accepted imaging method for staging of ductal adenocarcinoma and the localization of neuroendocrine tumors of the pancreas. We prospectively evaluated conventional color Doppler imaging and contrast-enhanced endoscopic Doppler ultrasound (CE-EDUS) as a new imaging technique for further characterization and differentiation of solid pancreatic tumors. From 300 patients with pancreatic lesions investigated using contrast-enhanced endoscopic ultrasound we could finally include 93 patients with an undetermined, solitary, predominantly solid, lesion 40 mm or less, and a definite histologically proven diagnosis. After bolus injection of the contrast agent SHU 508A 4 g (400 mg/dL) the vascular pattern of the lesion during the arterial phase was compared with the vascularity of the residual pancreatic parenchyma. Color Doppler imaging did not reveal vascularity of the pancreatic parenchyma in any of the patients, and therefore tumor hypovascularity could not be determined in contrast to all CE-EDUS-examined patients revealing at least some degree of parenchymal vascularity. Fifty-seven of 62 patients with ductal adenocarcinoma of the pancreas showed a hypovascularity of the tumor using CE-EDUS. All other pancreatic lesions revealed an isovascular or hypervascular pattern using contrast-enhanced endoscopic ultrasound (20 neuroendocrine tumors, 10 serous microcystic adenomas, and 1 teratoma). Hypovascularity as a sign of malignancy in contrast-enhanced endoscopic ultrasound obtained 92% (82%-97%) sensitivity and 100% specificity (89%-100%). Contrast-enhanced endoscopic ultrasound is effective in differentiating small solid pancreatic tumors of different origin in most cases. Hypovascularity indicates malignancy of pancreatic tumors.


Factors related to satisfaction with life in veterans with mild traumatic brain injury.
Satisfaction with life (SWL) is an important measure of outcome in rehabilitation. Previous research suggests that those with a history of traumatic brain injury (TBI), even mild TBI, report lower levels of life satisfaction when compared with the noninjured population. Although is it possible that TBI has a direct effect on SWL, various medical and psychosocial factors commonly affecting those recovering from TBI likely contribute to SWL. The present study aimed to identify factors related to SWL in 95 veterans of Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) with a history of mild TBI. Regression analyses indicated that headache impact, pain interference, sleep quality, posttraumatic stress symptom severity, and social support were all significantly related to SWL. However, when secondary analyses were conducted including posttraumatic stress symptom severity as a covariate before the entry of other predictors, only sleep quality and social support remained significantly associated with SWL. These results indicate the importance of properly identifying and treating symptoms of posttraumatic stress in veterans with a history of mTBI, as posttraumatic stress symptoms appear to be strongly related to SWL in those with a history of mild TBI. Optimizing sleep quality and social support may also be important in improving SWL.


Marketing technology in macroeconomics.
In this paper, we incorporate a marketing technology into a dynamic stochastic general equilibrium model by assuming a matching friction for consumption. An improvement in matching can be interpreted as an increase in matching technology, which we call marketing technology because of similar properties. Using a simulation analysis, we confirm that a positive matching technology shock can increase output and consumption.


Cortical organization in adulthood is modified by neonatal infarct: a case study.
To assess anomalous cortical organization of somatosensory function in a 23-year-old man who had had a neonatal infarct involving the left middle cerebral artery. The infarct destroyed the primary and secondary somatosensory areas of the subject's left hemisphere but caused only mild perturbation of somatosensation on the right side of his body. With magnetic source imaging, the authors integrated magnetoencephalographic data with magnetic resonance imaging data to create magnetic source localization images that showed the mapping between brain function and structure. Electrical stimulation of the right median nerve evoked activity in two nontraditional areas: (a) an intact region of the left inferior temporal gyrus and (b) the ipsilateral right medial parietal cortex. These data suggest that bilateral neural reorganization can be induced by unilateral neonatal damage.