Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway.
Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to in vitro proliferation, migration and invasion, and in vivo on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT-PCR were used to identify proteins and signalling pathways involved. In vitro MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. In vivo xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.


Relationship between the release and uptake of noradrenaline by rat brain synaptosomes in the formation of defensive conditioned reflex.
The defensive conditioned reflex with two-way avoidance was developed in rats in a shuttle-box. Immediately and 30 min after learning the animals were decapitated and synaptosomes were isolated from the whole brain and brain cortex. Using [14C] and [3H]-noradrenaline (NA), the processes of uptake, spontaneous and potassium depolarization-induced (60 mM KCl) release of NA by brain synaptosomes of trained and control animals were studied in vitro. Immediately after learning the inhibition of NA uptake was observed, but 30 min following learning the ability of synaptosomes to take up NA was recovered to the initial level. Thirty minutes after learning the potassium depolarization-induced release of NA previously taken up by synaptosomes increased as compared to the control. NA spontaneous release did not change under these conditions. With the increase of Ca2+ concentration in the incubation medium from 1.2 mM to 2.4 mM, the induced NA release from brain synaptosomes of trained and control animals regularly increased. Changes in NA release and uptake are specific for the development of conditioned reflex


Defective excitation-contraction coupling in hearts of rats with congestive heart failure.
We examined the cellular basis for depressed cardiac contractility in rats with congestive heart failure (CHF) secondary to myocardial infarction. Six weeks after ligation of the left coronary artery, CHF was confirmed by haemodynamic measures and echocardiographic demonstration of reduced myocardial contractility in vivo. Papillary muscles from CHF animals developed less force than those from sham operated (SHAM) animals. Cell shortening was measured in isolated ventricular myocytes voltage-clamped with high resistance electrodes. Ca2+ transients were measured in fluo-4 loaded myocytes. Contractions triggered by depolarizing test steps from a post conditioning potential of -70 mV were significantly smaller and had significantly reduced velocity of shortening in CHF compared with SHAM myocytes. However, contractions initiated from -40 mV, were similar in amplitude and velocity of shortening in CHF and SHAM cells. L-type Ca2+ current was not significantly different between CHF and SHAM cells, whether activated from -70 or -40 mV. Therefore, in SHAM cells, excitation-contraction coupling exhibited higher gain when contractions were initiated from negative (-70 mV), as compared with depolarized potentials (-40 mV). However, in CHF myocytes, excitation-contraction coupling gain was selectively depressed with steps from -70 mV. This depression of gain in CHF was not accompanied by a significant reduction in sarcoplasmic reticulum Ca2+ content. Isoproterenol increased Ca2+ transients less in CHF than SHAM myocytes. In this post-infarction model of CHF, the contractile deficit was voltage dependent and the gain of excitation-contraction coupling was selectively depressed for contractions initiated negative to -40 mV.


Efficacy of levodopa/carbidopa/entacapone versus levodopa/carbidopa in patients with early Parkinson's disease experiencing mild wearing-off: a randomised, double-blind trial.
To compare the efficacy and safety of levodopa/carbidopa/entacapone (LCE) with levodopa/carbidopa (LC) on Parkinson's disease (PD) patients with mild, or only minimally disabling motor complications. A prospective 3-month, multicentre, parallel-group, double-blind, and randomised phase IV study was performed. The primary endpoint was to assess the efficacy of LCE compared to LC on ADLs using the UPDRS part II. Secondary endpoints were assessed by the UPDRS (I, III and IV) scores, QUICK and PDQ-39 questionnaires, and patient and investigator clinical global impression (CGI). Ninety-five patients were randomly assigned to treatment with LCE (100/25/200 or 150/37.5/200 mg tablets, n = 46) or LC (100/25 mg tablets, n = 49), at the same levodopa dose that were administered before randomization. Treatment with LCE resulted in significantly greater improvement in UPDRS part II (ADLs) scores compared to treatment with LC (adjusted mean difference between groups of -1.5 points) (p = 0.0288). Amelioration was also observed in UPDRS part III scores (p = 0.010), and CGI (patient and investigator) scores (p = 0.015, and p = 0.028, respectively). LCE and LC were generally well tolerated with 78 % of subjects completing the study. Most AEs (50 % in LCE and 71.4 % in LC) were classified as mild. No serious AEs were related to the treatment. Treatment with LCE results in improved efficacy compared to LC in PD patients with mild, or minimally disabling motor fluctuations, maintaining a good safety and tolerability profile.


Sulfhydryl oxidation using procedures and experimental conditions commonly used for Treponema pallidum.
Certain reducing agents containing sulfhydryl groups are important to the in-vitro survival of Treponema pallidum. Discrepancies occur, however, concerning the agents and the concentrations that are optimal. To clarify some of this confusion, sulfhydryl oxidation was determined using procedures and experimental conditions commonly used for T pallidum. Sulfhydryl oxidation varied according to the type of culture medium, the size of the culture vessels, the volume of the culture medium, and the gaseous environment within the culture vessels, as well as the method of extracting treponmes from infected testicular tissue. Dithiothreotol maintained highly reduced conditions by reducing disulfide groups to sulfhydryl groups. Lastly, the organisms influenced the sulfhydryl concentration by either direct oxidation or specific uptake. The sulfhydryl content was sharply decreased in the presence of viable preparations of T pallidum compared with heated preparations or membrane filtrates of viable preparations.


Chemokine biology on immune checkpoint-targeted therapies.
The use of antagonistic immune checkpoint-targeted monoclonal antibodies has profoundly modified the standard of care and significantly increased the survival for many cancers. However, many patients still do not respond to those treatments. Biomarkers predictive for efficacy or failure of such immunotherapies would allow developing treatment stratification strategies which could further increase the survival rates of patients with cancer. Chemokines are a subset of the immune cell messenger molecules known as cytokines. Chemokines are key chemoattractant molecules which are essential for the homing of immune cells, notably within tumours. Therefore, they are good candidates for providing predictive biomarkers of the clinical response to checkpoint blockade immunotherapies. In this review, we summarise the recent advances in our understanding of the role of chemokines and how chemokine concentrations may set the tone for the efficacy of immune checkpoint-targeted immunotherapies.


[Prognosis in limited disease (LD) small cell lung cancer (SCLC) patients according to status performance, local extension of lesions, type of treatment and the completeness of staging].
The aim of this study was to assess the prognosis in LD SCLC pts according to their performance status, local extension of lesions, type of treatment and the completeness of staging. In the period 01.01.1986-31.12.1996 in the Institute of Tuberculosis and Chest Diseases 579 consecutive SCLC pts were treated. LD was diagnosed in 345 pts. In 193 out of them the staging was complete that is in addition to chest x-ray, abdomen USG/CT, brain CT/MRI and bilateral bone marrow trepanobiopsy was done. 152 pts were also regarded as limited but the staging was not complete. LD pts proved by complete staging survived significantly longer (median survival 15.7 months) than others (median survival 10.2 months). The pts in whom complete staging was done were however in better performance status and had smaller local extension of lesions and had more often radiotherapy than others. Status performance, local extension of lesions and radiotherapy but also completeness of staging were independent prognostic factors in multivariate analysis.


Lycium barbarum polysaccharides attenuate oxidative stress and mitochondrial toxicity induced by mixed plasticizers in HepG2 cells through activation of Nrf2.
In daily life, it is common for humans to be exposed to multiple phthalate esters (PAEs). However, there is limited research on the mechanisms and intervention of combined PAEs toxicity. This study aims to explore the cytotoxicity of combined PAEs and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. LBP (62.5, 125 and 250 μg/mL) were applied to intervene HepG2 cells treated with DEHP and DBP mixtures (50, 100, 200, 400 and 800 μg/mL). Western Blot and different kits were mainly performed in our study. DEHP and DBP mixtures suppressed the expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and activated MAPK pathway by increasing ROS. Combined DEHP and DBP exposure reduced ATP content and inhibited the mitochondrial biogenesis pathway in HepG2 cells through oxidative stress, which in turn caused cytotoxicity. LBP reduced oxidative stress and cell death induced by mixed plasticizers, upregulated Nrf2 levels and mitochondrial biogenesis pathway levels and inhibited MAPK pathway activation. Notably, after treating HepG2 cells with Nrf2-specific inhibitor (ML385, 0.5 μM), we found that the activation of Nrf2 played a crucial role on LBP intervention of DEHP and DBP induced HepG2 cytotoxicity. This study not only enhances our understanding of the toxicological effects caused by combined PAEs exposure, but also has significant implications in devising strategies to mitigate the toxicological consequences of combined exposure to exogenous chemicals through the investigation of the role of LBP.


Cucurbitane triterpenoids from Momordica charantia and their cytoprotective activity in tert-butyl hydroperoxide-induced hepatotoxicity of HepG2 cells.
Two novel pentanorcucurbitane triterpenes, 22-hydroxy-23,24,25,26,27-pentanorcucurbit-5-en-3-one (1) and 3,7-dioxo-23,24,25,26,27-pentanorcucurbit-5-en-22-oic acid (2) together with a new trinorcucurbitane triterpene, 25,26,27-trinorcucurbit-5-ene-3,7,23-trione (3) were isolated from the methyl alcohol extract of the stems of Momordica charantia. The structures of the new compounds were elucidated by spectroscopic methods. Compounds 2 and 3 showed potent cytoprotective activity in tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity of HepG2 cells.


Reexpression of hSNF5 in malignant rhabdoid tumor cell lines causes cell cycle arrest through a p21(CIP1/WAF1)-dependent mechanism.
Loss of hSNF5 function is usually observed in malignant rhabdoid tumor (MRT), a highly aggressive pediatric neoplasm. Previous studies have shown that reexpression of hSNF5 in MRT cell lines causes G1 cell cycle arrest with p16(INK4A), p21(CIP1/WAF1), and cyclin D1 playing key roles in MRT cell growth control. However, we have shown that reexpression of hSNF5 induced cell cycle arrest in the absence of p16(INK4A) expression. These results indicate that the mechanism of hSNF5-induced cell cycle arrest is context dependent. Here, we investigated the relationship between p21(CIP1/WAF1) and hSNF5 in the regulation of growth using several MRT cell lines. We found that G1 cell cycle arrest occurred concomitant with an increase in p21(CIP1/WAF1) mRNA and protein levels and preceded p16(INK4A) mRNA and protein upregulation. Chromatin immunoprecipitation data confirmed that hSNF5 appeared at both p21(CIP1/WAF1) and p16(INK4A) promoters after reexpression. We further showed that p21(CIP1/WAF1) induction showed both p53-dependent and p53-independent mechanisms. We also showed that reduction of p21(CIP1/WAF1) expression by RNAi significantly inhibited hSNF5-induced G(1) arrest. Our results show that both p21(CIP1/WAF1) and p16(INK4A) are targets for hSNF5 and that p21(CIP1/WAF1) upregulation during hSNF5-induced G(1) arrest precedes p16(INK4A) upregulation. These findings indicate that SNF5 mediates a temporally controlled program of cyclin-dependent kinase inhibition to restrict aberrant proliferation in MRT cells.


Effect of heart rate correction on pre- and post-exercise heart rate variability to predict risk of mortality-an experimental study on the FINCAVAS cohort.
The non-linear inverse relationship between RR-intervals and heart rate (HR) contributes significantly to the heart rate variability (HRV) parameters and their performance in mortality prediction. To determine the level of influence HR exerts over HRV parameters' prognostic power, we studied the predictive performance for different HR levels by applying eight correction procedures, multiplying or dividing HRV parameters by the mean RR-interval (RRavg) to the power 0.5-16. Data collected from 1288 patients in The Finnish Cardiovascular Study (FINCAVAS), who satisfied the inclusion criteria, was used for the analyses. HRV parameters (RMSSD, VLF Power and LF Power) were calculated from 2-min segment in the rest phase before exercise and 2-min recovery period immediately after peak exercise. Area under the receiver operating characteristic curve (AUC) was used to determine the predictive performance for each parameter with and without HR corrections in rest and recovery phases. The division of HRV parameters by segment's RRavg to the power 2 (HRVDIV-2) showed the highest predictive performance under the rest phase (RMSSD: 0.67/0.66; VLF Power: 0.70/0.62; LF Power: 0.79/0.65; cardiac mortality/non-cardiac mortality) with minimum correlation to HR (r = -0.15 to 0.15). In the recovery phase, Kaplan-Meier (KM) survival analysis revealed good risk stratification capacity at HRVDIV-2 in both groups (cardiac and non-cardiac mortality). Although higher powers of correction (HRVDIV-4and HRVDIV-8) improved predictive performance during recovery, they induced an increased positive correlation to HR. Thus, we inferred that predictive capacity of HRV during rest and recovery is augmented when its dependence on HR is weakened by applying appropriate correction procedures.


Accumulation of the antimalarial microtubule inhibitors trifluralin and vinblastine by Plasmodium falciparum.
Malaria is a disease in desperate need of new chemotherapeutic approaches. Certain microtubule inhibitors, including vinblastine and taxol, have highly potent activity against malarial parasites and disrupt the normal microtubular structures of intra-erythrocytic parasites at relevant concentrations. While these inhibitors are useful tools, their potential as anti-malarial drugs is limited by their high toxicity to mammalian cells. In contrast, two classes of antimitotic herbicide, namely dinitroanilines (e.g. trifluralin and oryzalin) and phosphorothioamidates (e.g. amiprophosmethyl), exhibit moderate activity against the major human malarial parasite Plasmodium falciparum in culture but very low mammalian cytotoxicity. We examined the dynamics and kinetics of uptake and subcellular compartmentation of [14C]trifluralin in comparison with [3H]vinblastine. We wished to determine whether the relatively modest activity of trifluralin was the consequence of poor uptake into parasite cells. Trifluralin accumulated in parasite-infected erythrocytes to approximately 300 times the external concentration and vinblastine at up to approximately 110 times. Accumulation into uninfected erythrocytes was much lower. Uptake of trifluralin was rapid, non-saturable and readily reversed. It appears that the hydrophobic nature of trifluralin leads to accumulation largely in the membranes of the parasite, reducing the levels in the soluble fraction and limiting access to its microtubular target. By contrast, vinblastine accumulated predominantly in the soluble fraction and uptake was saturable and mostly irreversible, consistent with binding predominantly to tubulin. The results indicate that synthesis of more polar trifluralin derivatives may be a promising approach to designing microtubule inhibitors with more potent antimalarial activity.


Feather vs. non-feather bedding for asthma.
Two recent epidemiological studies have reported that children using non-feather pillows suffered from more frequent episodes of wheeze than those using feather pillows To evaluate the efficacy of using feather bedding in the control of asthma symptoms. The Cochrane Airways Group asthma clinical trials register, derived from MEDLINE, EMBASE and hand searching of major journals, was searched using the terms: feather OR bed* OR linen* OR pillow Only randomised or controlled clinical trials were to be included. No trials met the inclusion criteria for the review. 126 abstracts were identified. Ten of these were identified as possibly meeting the entry criteria, but on review of the full paper not were suitable. The reasons for exclusion were: not a randomised trial (n=6); allocation of bedding type combined with another intervention (n=4). Whilst recent epidemiological studies suggest that feather bedding is associated with less frequent wheeze than man-made fibre fillings, the evidence currently available is insufficient to assess the clinical benefits of feather bedding in the management of asthma.


Characteristics of photonic band gaps in woodpile three-dimensional terahertz photonic crystals.
Based on plane wave expansion method, complete photonic band gaps (PBGs) of a woodpile three-dimensional (3-D) terahertz (THz) photonic crystal (PC) with face-centered-tetragonal (fct) symmetry are optimized by varying structural parameters and the highest band gap ratio can reach 26.71%. In order to further optimize the complete PBGs, we propose a novel woodpile lattice with comparatively decreased symmetry and the highest band gap ratio can be increased to 27.61%. The woodpile THz PCs with two different symmetries both have a wide range of filling ratios to gain high quality complete PBGs, making the manufacturing process convenient. Woodpile 3-D PCs will be very promising materials for THz functional components.


Power-dependent photoluminescence decay kinetics of silicon nanocrystals under continuous and pulsed excitation.
Power-dependent photoluminescence (PL) decay kinetics of silicon nanocrystals (Si NCs) in solid and liquid samples were studied under cw and pulsed excitation. The lifetime distribution and, consequently the measured PL kinetics are shown to depend on the excitation pulse duration until it is not sufficiently short (pulsed limit) or long (cw limit). These two excitation limits, however, are proven to excite different distributions of lifetime components and cannot be directly compared. We derive and experimentally confirm the equality of lifetimes averaged over amplitude and intensity for cw and pulsed excitation, accordingly. The absorption cross section (ACS) of Si NCs in solid and liquid samples is assessed and compared by two approaches under cw-excitation based on the treatment of power-modulated PL kinetics or PL amplitude saturation curves under low and moderate excitation powers, respectively. The discrepancy in extracted ACS values as well as the long-debated phenomena of incomplete PL saturation of matrix-embedded Si NCs is explained by a proposed model that is based on saturation of various components in an ensemble distribution at different excitation powers. The model finally allows us to explain the mystery of average decay lifetime dependence on excitation power in the non-linear power regime. By varying the excitation from cw to pulsed, we showed the reduction of average decay lifetime in the later case and attribute this to the increased relative PL contribution of fast lifetime components that results in at least one order of magnitude lower ACS values. Finally, exciting the solid sample with very high excitation powers, we detected a PL intensity decrease region that allowed us to extract the Auger lifetime which is about 170 ns.


Effect of beta-naphthoflavone on calf liver metabolism of aflatoxin B1.
Eight male Holstein calves were raised to 6 wk of age on whole milk at 8% of body weight and calf starter ration (15% crude protein) free choice. For each of 2 days prior to sacrifice, four of the calves were selected at random and administered the mixed function oxidase inducer beta-napthoflavone by bolus in starch carrier at .005% of metabolic body weight. After sacrifice, 10,000 X g postmitochondrial supernatant preparations were made from the excised livers and incubated with a 50-micrograms challenge of aflatoxin B1. Although there was no significant difference in total percent of the challenge metabolized, there was a large increase in aflatoxin M1 production by liver preparations from calves administered the flavone inducer. If the flavone family of inducers could alter the metabolic profile for aflatoxin in the adult lactating bovine, aflatoxin M1 excretion rates could be increased and pathways for production of mutagenic metabolites could be enhanced.


Primary resection and anastomosis for perforated left colon lesions.
The records of 33 patients with perforated left colon lesions over a 6-year period from 1992 to 1998 were examined retrospectively for clinical course and complications. All patients had a free perforation, feculent or purulent peritonitis, and/or a large inflammatory mass. All patients had primary resection and anastomosis without a protective colostomy or ileostomy. Indications included diverticulitis in 28 patients, obstructing colorectal carcinoma in 3, and iatrogenic perforations in 2. Complications occurred in 10 patients, including atelectasis in 1, urinary retention in 2, urinary tract infections in 2, wound infections in 3, line catheter sepsis in 1, and acute tubular necrosis in 1. There was one anastomotic dehiscence, which was successfully converted to a Hartmann procedure. Patients were discharged an average of 7 days after surgery. Two patients required surgery after discharge: one had a fascial dehiscence and the other an incisional ventral hernia. There was no mortality. Primary resection and anastomosis of selected perforated left colon lesions can be performed with a morbidity and mortality rate lower than that usually reported for the Hartmann procedure.


Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1.
The C-terminal domain of BRCA1(BRCT) is involved in the DNA repair pathway by recognizing the pSXXF motif in interacting proteins. It has been reported that short peptides containing this motif bind to BRCA1(BRCT) in the micromolar range with high specificity. In this work, the binding of pSXXF peptides has been studied computationally and experimentally in order to characterize their interaction with BRCA1(BRCT). Elucidation of the contacts that drive the protein-ligand interaction is critical for the development of high affinity small-molecule BRCA1 inhibitors. Molecular dynamics (MD) simulations revealed the key role of threonine at the peptide P+2 position in providing structural rigidity to the ligand in the bound state. The mutation at P+1 had minor effects. Peptide extension at the N-terminal position with the naphthyl amino acid exhibited a modest increase in binding affinity, what could be explained by the dispersion interaction of the naphthyl side-chain with a hydrophobic patch. Three in silico end-point methods were considered for the calculation of binding free energy. The Molecular Mechanics Poisson-Boltzmann Surface Area and the Solvated Interaction Energy methods gave reasonable agreement with experimental data, exhibiting a Pearlman predictive index of 0.71 and 0.78, respectively. The MM-quantum mechanics-surface area method yielded improved results, which was characterized by a Pearlman index of 0.78. The correlation coefficients were 0.59, 0.61 and 0.69, respectively. The ability to apply a QM level of theory within an end-point binding free energy protocol may provide a way for a consistent improvement of accuracy in computer-aided drug design.


Use of phenotypic and molecular serotype identification methods to characterize previously nonserotypeable group B streptococci.
Among 1,762 isolates of Streptococcus agalactiae (group B streptococcus [GBS]), 207 (12%) initially nonserotypeable isolates were tested by improved conventional serotyping methods (Lancefield antigen extraction with 0.1 and 0.2 N HCl, latex agglutination assays, and use of antisera against all known serotypes [Ia, Ib, and II to IX]) and a molecular serotype identification system (multiplex PCR-based reverse line blot [mPCR/RLB] assays targeting serotype-specific sites in the region spanning cpsH to cpsM). Serotypes were assigned to 71 (34%) of the 207 isolates by using antisera and to 204 (98.5%) of them by mPCR/RLB. Sequencing of a portion of the cpsE-cpsF-cpsG region of 141 persistently nonserotypeable isolates and 1 with discrepant conventional and molecular serotyping results was attempted. Major mutations were identified in 34 isolates (24%), including 11 (8%) from which no amplicons were obtained and 23 (16%) with sequence variation compared with published sequences; of the latter, 21 (15%) were associated with amino acid changes. By contrast, mutations were identified in only 12 (2.3%) of 516 serotypeable isolates for which this region has been sequenced previously. In summary, an improved serotyping scheme allowed serotype identification of more than one-third of the previously nonserotypeable GBS isolates. Molecular serotypes were assigned to almost all of the isolates by mPCR/RLB. Significant mutations (with no amplicons or with associated amino acid changes) were found in the cpsE-cpsF-cspG region of a higher proportion of nonserotypeable than of serotypeable isolates (32/141 versus 8/516; P < 0.001), but further investigation is needed to determine the genetic basis for most nonserotypeable GBS isolates.


Stability of caffeic acid phenethyl ester and its fluorinated derivative in rat plasma.
The stability of caffeic acid phenethyl ester (CAPE) and its fluorinated derivative (FCAPE) in rat plasma and conditions preventing their degradation are reported. Reverse-phase high-pressure liquid chromatography (HPLC) using taxifolin as an internal standard was applied for the quantitative determination of CAPE and FCAPE in rat plasma extracted with ethyl acetate. The assay was validated over a linear range of 0.25-10 microg/mL plasma (r(2) > 0.9990, n = 3). No endogenous interferences were observed in the chromatographic region of interest. The limits of quantification and detection were set at 0.25 and 0.1 microg/mL, respectively. The precision ranged from 0.7 to 13.7% for CAPE, and from 0.4 to 10.4% for FCAPE. Accuracy ranged from -2.8 to 12.4% for CAPE and from -0.6 to 6.8% for FCAPE. The stability was conducted at 4, 25 and 37 degrees C. First-order kinetics was observed for the degradation of CAPE and FCAPE. The energies of activation of CAPE and FCAPE were found to be 17.9 and 20.1 kcal/mol, respectively. Addition of 0.4% of sodium chloride and pH adjustment to 6 prevented their degradation in rat plasma for 24 h and at least one month at -20 degrees C. This study provides useful information for the future pharmacokinetic study of CAPE and FCAPE in rat.


Transcriptional Profiles of Non-neuronal and Immune Cells in Mouse Trigeminal Ganglia.
Non-neuronal cells constitute 90-95% of sensory ganglia. These cells play critical roles in modulation of nociceptive signal transmissions by sensory neurons. Accordingly, the aim of this review-study was to identify, profile and summarize TG non-neuronal cell types in naïve male mice using published and our own data generated by single-cell RNA sequencing (scRNA-seq), flow cytometry (FC) and immunohistochemistry (IHC). TG contains 5 types of non-neuronal cells: glial, fibroblasts, smooth muscle, endothelial and immune cells. There is agreement among publications for glial, fibroblasts, smooth muscle and endothelial cells. Based on gene profiles, glial cells were classified as Schwann cells and satellite glial cells (SGC). Mpz had dominant expression in Schwann cells, and Fabp7 is specific for SCG. Two types of Col1a2 + fibroblasts located throughout TG were distinguished using gene profiles. TG smooth muscle and endothelial cells representing blood vessels were detected with well recognized markers. Our study split reported single TG immune cell group into 3 types of macrophages and 4 types of neutrophils. Macrophages were located among neuronal bodies and nerve fibers, and were sub-grouped by unique transcriptomic profiles and using Ccr2 , Cx3cr1 and Iba1 as markers. S100a8 + neutrophils were located in dura surrounding TG and were sub-grouped by clustering and expressions of Csf3r , Ly6G, Ngp, Elane and Mpo . Overall, generated and summarized here dataset on non-neuronal TG cells could provide essential and fundamental information for studies on cell plasticity, interactomic network between neurons and non-neuronal cells and function during variety of pain conditions in the head and neck region.


Cardiac issues in adults with the mucopolysaccharidoses: current knowledge and emerging needs.
The growing availability of innovative treatments for rare genetic diseases with a cardiac component-such as the mucopolysaccharidoses (MPSs)-has changed these syndromes from 'back of the textbook' curiosities of childhood to chronic, but rare, adult cardiac conditions that require both centres of expertise and knowledgeable subspecialists. The MPSs are inherited progressive lysosomal storage diseases, occurring in about 1:25 000 births and resulting from absence of functional hydrolases responsible for the degradation of glycosaminoglycans, naturally occurring complex sugars ubiquitous throughout the body. In the heart, accumulation of glycosaminoglycans occurs within the cardiac valves, the epicardial coronary arteries, the myocytes and cardiac interstitium and the walls of the great vessels. As a consequence, cardiac valve regurgitation and stenosis, diffuse coronary artery stenosis, myocardial dysfunction and aortic root dilation often occur. Haematopoietic cell transplantation and enzyme replacement therapy have changed the previously lethal natural history of the MPSs to one of survival well into adulthood. Despite this improved lifespan, the left-sided cardiac valves continue to show progressive functional involvement and cardiac valve replacement is not uncommon, especially in adults. The risk of any intervention is increased in these patients because of the systemic effects of the disease on the respiratory system and cervical cord. Our current understanding of other cardiac issues in adults with the MPSs, especially with the coronary circulation and myocardium, is meagre and more needs to be known to effectively care for this emerging population of adults. Incorporation of the MPSs, as well as other now-treatable rare diseases, into the educational curriculum of current and future adult subspecialists is an important next step.


Use of estrogens among middle-aged Massachusetts women.
This study describes estrogen use among 45- to 55-year-old white women in Massachusetts from 1981 to 1987. In a 1981 cross-sectional survey, 7705 white women (77 percent response rate) returned a questionnaire or were interviewed by phone. Premenopausal women were invited into a 4.5-year follow-up study including telephone interviews every nine months, and 2236 (approximately 91 percent of the eligible women) had a complete follow-up. In the cross-sectional survey, 7.9 percent had used oral estrogens in the last two weeks, but most (77 percent) had had a hysterectomy; use varied notably from one area to another. Vaginal estrogens were used by 2.9 percent. Users and nonusers of oral estrogens were quite similar in regard to sociodemographic background. Data from the follow-up surveys showed that estrogen use increased throughout the study period and by the final follow-up women with higher education status reported more estrogen use than those with lower education status. Most women used estrogens only for a short time.


Sodium depletion increases sympathetic neurite outgrowth and expression of a novel TMEM35 gene-derived protein (TUF1) in the rat adrenal zona glomerulosa.
The adrenal zona glomerulosa (ZG) secretes aldosterone to regulate sodium balance. Chronic sodium restriction increases aldosterone accompanied by ZG expansion. The ZG is innervated by sympathetic, vasoactive intestinal polypeptide (VIP) and neuropeptide tyrosine (NPY), and sensory, calcitonin gene-related peptide, nerves. It is unclear whether innervation is affected by ZG growth. Therefore, we measured neurite outgrowth in the ZG of adult male rats after dietary sodium manipulation. In response to 1 wk sodium restriction, VIP and NPY fibers elongated in parallel with expansion of the ZG, shown by aldosterone synthase (AS) expression, but calcitonin gene-related peptide fibers were not affected. Sodium repletion resulted in parallel regression in VIP and NPY fiber length and AS expression. These results show that sympathetic, but not sensory, innervation is coordinated with ZG growth. Mediators underlying changes in innervation are unknown; therefore, we characterized a novel gene TMEM35 [termed the unknown factor-1 (TUF1) due to its unknown function] that shows extensive overlap with AS in ZG. After sodium restriction, TUF1 expanded in parallel with the ZG. TUF1 bound the low-affinity neurotrophin receptor, p75NTR, which was expressed in NPY fibers and showed a response similar to TUF1 after sodium manipulation. TUF1- p75NTR binding was competitively displaced by nerve growth factor but not by TUF1 lacking the p75NTR binding motif. Moreover, TUF1 mRNA in rat ZG cells increased after angiotensin II exposure in vitro. Collectively, these findings suggest that TMEM35/TUF1 is a candidate for modulating neurite outgrowth in the ZG after sodium depletion.


Perseveration by NK1R-/- ('knockout') mice is blunted by doses of methylphenidate that affect neither other aspects of their cognitive performance nor the behaviour of wild-type mice in the 5-Choice Continuous Performance Test.
The underlying cause(s) of abnormalities expressed by patients with attention deficit hyperactivity disorder (ADHD) have yet to be delineated. One factor that has been associated with increased vulnerability to ADHD is polymorphism(s) of TACR1, which is the human equivalent of the rodent NK1 (substance P-preferring) receptor gene (Nk1r). We have reported previously that genetically altered mice, lacking functional NK1R (NK1R-/-), express locomotor hyperactivity, which was blunted by the first-line treatment for ADHD, methylphenidate. Here, we compared the effects of this psychostimulant (3, 10 and 30 mg/kg, intraperitoneally) on the behaviour of NK1R-/- mice and their wild types in the 5-Choice Continuous Performance Test, which emulates procedures used to study attention and response control in ADHD patients. Methylphenidate increased total trials (a measure of 'productivity') completed by wild types, but not by NK1R-/- mice. Conversely, this drug reduced perseveration by NK1R-/- mice, but not by wild types. Other drug-induced changes in key behaviours were not genotype dependent, especially at the highest dose: for example, % omissions (an index of inattentiveness) was increased, whereas % false alarms and % premature responses (measures of impulsivity) declined in both genotypes, indicating reduced overall response. These findings are discussed in the context of the efficacy of methylphenidate in the treatment of ADHD. Moreover, they lead to several testable proposals. First, methylphenidate does not improve attention in a subgroup of ADHD patients with a functional deficit of TACR1. Second, these patients do not express excessive false alarms when compared with other groups of subjects, but they do express excessive perseveration, which would be ameliorated by methylphenidate.


GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling.
The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.


Expression of epithelial cadherin in the human male reproductive tract and gametes and evidence of its participation in fertilization.
Epithelial cadherin (E-cadherin) has been involved in several calcium-dependent cell-cell adhesion events; however, its participation in gamete interaction has not been fully investigated. Our results have demonstrated expression of E-cadherin mRNA in the human male reproductive tract showing higher levels in the caput, corpus and cauda epididymis than in the testis. The mature 122 kDa E-cadherin was detected in epididymal protein extracts and was localized in the epithelial cells from the three epididymal regions. Moreover, the 86 kDa E-cadherin ectodomain was found in cauda epididymal and seminal plasma. Western immunoblotting of human sperm protein extracts allowed the identification of four E-cadherin forms (122, 105, 97 and 86 kDa). The protein was localized in the acrosomal region of intact spermatozoa, remained associated with the head of acrosome-reacted cells and was also detected on the oocyte surface. A similar localization was determined for other proteins of the adhesion complex (beta-catenin and actin). Spermatozoa incubated with anti-E-cadherin antibodies showed impaired binding to homologous zona pellucida (ZP); in addition, presence of these antibodies inhibited the penetration of human spermatozoa to ZP-free hamster oocytes. The results presented here describe the expression of E-cadherin in the male reproductive tract and gametes and strongly suggest its involvement in adhesion events during human fertilization. The identification of proteins involved in gamete interaction will contribute to the understanding of the molecular basis of fertilization and help in the diagnosis and treatment of infertility.


Forensic psychiatry in Europe: The perspective of the Ghent Group.
The Ghent Group was established in 2004 as a forum for forensic psychiatrists from different countries in Europe in order to bridge the gaps in knowledge, experience, practice and care which exist between them due to their different legal traditions and constitutions in dealing with people having mental disorders who come into conflict with the law. The Ghent Group considers itself as a loosely organised think tank to which all interested and invited professionals can contribute without statutory restraints. Its aim is to facilitate communication with mentally disordered offenders appearing in court, to understand the procedures of our neighbouring countries and to find common ground between clinicians. The major focus of the Ghent Group is on teaching and training both at a national level, where one can learn about the methods of training from each other, and at a European level. The group of trainees from different countries experiment in seminars in solving medico-legal cases considering European Human Rights issues and their respective national procedures and institutions. This helps not only to understand the differences between the national medico-legal procedures but also to deepen the understanding of the principles and practice in one's own country.


Time-Dependent Impact of Irreversible Electroporation on Pathology and Ablation Size in the Porcine Liver: A 24-Hour Experimental Study.
Irreversible electroporation causes cell death through low frequency, high voltage electrical pulses and is increasingly used to treat non-resectable cancers. A recent systematic review revealed that tissue damage through irreversible electroporation is time-dependent, but the impact of time on the ablation zone size remains unknown. Irreversible electroporation ablations were performed hourly during 24 consecutive hours in the peripheral liver of 2 anaesthetized domestic pigs using clinical treatment settings. Immediately after the 24th ablation, the livers were harvested and examined for tissue response in time based on macroscopic and microscopic pathology. The impact of time on these outcomes was assessed with Spearman rank correlation test. Ablation zones were sharply demarcated as early as 1 hour after treatment. During 24 hours, the ablation zones showed a significant increase in diameter (rs = 0.493, P = .014) and total surface (rs = 0.499, P = .013), whereas the impact of time on the homogeneous ablated area was not significant (rs = 0.172, P = .421). Therefore, the increase in size could mainly be attributed to an increase in the transition zone. Microscopically, the ablation zones showed progression in cell death and inflammation. This study assessed the dynamics of irreversible electroporation on the porcine liver during 24 consecutive hours and found that the pathological response (ie, cell death/inflammation), and ablation size continue to develop for at least 24 hours. Consequently, future studies on irreversible electroporation should prolong their observation period.


Two-stream Graph Convolutional Networks with Task-specific Loss for Dual-task Gait Analysis.
Dual-task gait systems can be utilized to assess elderly patients for cognitive decline. Although numerous research studies have been conducted to estimate cognitive scores, this field still faces two significant challenges. Firstly, it is crucial to fully utilize dual-task cost representations for diagnosis. Secondly, the design of optimal strategies for effectively extracting dual-task cost representations remains a challenge. To address these issues, in this paper, we propose a deep learning-based framework that implements a spatio-temporal graph convolutional neural network (ST-GCN) with single-task and dual-task pathways for cognitive impairment detection in gait. We also introduce a novel loss, termed task-specific loss, to ensure that single-task and dual-task representations are distinguishable from each other. Furthermore, dual-task cost representations are calculated as the difference between dual-task and single-task representations, which are resilient to individual differences and contribute to the robustness of the framework. These representations provide a comprehensive view of single-task and dual-task gait information to generate task predictions. The proposed framework outperforms existing approaches with a sensitivity of 0.969 and a specificity of 0.940 for cognitive impairment detection.


Changing to U100 insulins.
The change of insulin strength to 100 units/mL is underway, and patients should be changed now. Make sure the syringe is changed at the same time. Only in those patients having a dose greater than 100 units will the syringe (ordinary medical 2.0 mL syringe) be the same, but the volume is different. Further information and help may be obtained from the insulin manufacturers, hospital diabetic clinics, State offices of the Diabetes Federation of Australia, or the Hot Line Service.


Induction of vascular smooth muscle cell tenascin-C gene expression by denatured type I collagen is dependent upon a beta3 integrin-mediated mitogen-activated protein kinase pathway and a 122-base pair promoter element.
Tenascin-C is an extracellular matrix glycoprotein, the expression of which is upregulated in remodeling arteries. In previous studies we showed that the presence of tenascin-C alters vascular smooth muscle cell shape and amplifies their proliferative response by promoting growth factor receptor clustering and phosphorylation. Moreover, we demonstrated that denatured type I collagen induces smooth muscle cell tenascin-C protein production via beta3 integrins. In the present study, we examine the pathway by which beta3 integrins stimulate expression of tenascin-C, and define a promoter sequence that is critical for its induction. On native collagen, A10 smooth muscle cells adopt a stellate morphology and produce low levels of tenascin-C mRNA and protein, whereas on denatured collagen they spread extensively and produce high levels of tenascin-C mRNA and protein, which is incorporated into an elaborate extracellular matrix. Increased tenascin-C synthesis on denatured collagen is associated with elevated protein tyrosine phosphorylation, including activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). beta3 integrin function-blocking antibodies attenuate ERK1/2 activation and tenascin-C protein synthesis. Consistent with these findings, treatment with the specific MEK inhibitor, PD 98059, results in suppression of tenascin-C protein synthesis. To investigate whether beta3 integrin-dependent activation of ERK1/2 regulates the tenascin-C promoter, we transfected A10 cells with a full-length (approx. 4 kb) mouse tenascin-C gene promoter-chloramphenicol acetyltransferse reporter construct and showed that, relative to native collagen, its activity is increased on denatured collagen. Next, to identify regions of the promoter involved, we examined a series of tenascin-C promoter constructs with 5' deletions and showed that denatured collagen-dependent promoter activity was retained by a 122-base pair element, located -43 to -165 bp upstream of the RNA start site. Activation of this element was suppressed either by blocking beta3 integrins, or by preventing ERK1/2 activation. These observations demonstrate that smooth muscle cell binding to beta3 integrins activates the mitogen activated protein kinase pathway, which is required for the induction of tenascin-C gene expression via a potential extracellular matrix response element in the tenascin-C gene promoter. Our data suggest a mechanism by which remodeling of type I collagen modulates tenascin-C gene expression via a beta3 integrin-mediated signaling pathway, and as such represents a paradigm for vascular development and disease whereby smooth muscle cells respond to perturbations in extracellular matrix composition by altering their phenotype and patterns of gene expression.


Biomonitoring of polycyclic aromatic hydrocarbons in urban and industrial environments of the Western Black Sea Region, Turkey.
This research was carried out in the cities of Zonguldak and Eregli, which have been characterized as urban and industrial environments of the Western Black Sea Region, Turkey, in order to assess the contamination of polycyclic aromatic hydrocarbons (PAHs) using mosses as biomonitors. The methodology involved the collection of moss samples (Hypnum cupressiforme), ultrasonic extraction with dichloromethane, cleanup using silica gel and analysis by liquid chromatography with ultraviolet detection. The total PAH concentrations ranged from 78.1 to 1693.5 ng g(-1) in Zonguldak and from 15.2 to 275.1 ng g(-1) in Eregli. The total PAH concentration in Eregli was about six times lower than that in Zonguldak, revealing the importance of switching from coal to natural gas in residential heating. The diagnostic ratios and the correlation analysis have indicated that coal combustion and traffic emissions were the major PAH sources at both sites. The contour maps were constructed for the determination of spatial distributions of total PAHs, and it was shown for Zonguldak as well as for Eregli that the PAH pollution was much more predominant in highly populated regions. Moving away from the city centres, a gradual decrease in PAH pollution rates was observed.


A Review on the Immunomodulatory Mechanism of Acupuncture in the Treatment of Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is a chronic inflammatory disease with a high prevalence and canceration rate. The immune disorder is one of the recognized mechanisms. Acupuncture is widely used to treat patients with IBD. In recent years, an increasing number of studies have proven the effectiveness of acupuncture in the treatment of IBD, and some progress has been made in the mechanism. In this paper, we reviewed the studies related to acupuncture for IBD and focused on the immunomodulatory mechanism. We found that acupuncture could regulate the innate and adaptive immunity of IBD patients in many ways. Acupuncture exerts innate immunomodulatory effects by regulating intestinal epithelial barrier, toll-like receptors, NLRP3 inflammasomes, oxidative stress, and endoplasmic reticulum stress and exerts adaptive immunomodulation by regulating the balance of Th17/Treg and Th1/Th2 cells. In addition, acupuncture can also regulate intestinal flora.


Lower-extremity electromyography measures during walking with ankle-destabilization devices.
Ankle-destabilization devices are rehabilitation tools that may improve neuromuscular control by increasing lower-extremity muscle activation. Their effects should be tested in healthy individuals before being implemented in rehabilitation programs. To compare EMG activation of lower-extremity muscles during walking while wearing 2 different ankle-destabilization devices. Crossover. Laboratory. 15 healthy young adults (5 men, 10 women). Surface EMG activity was recorded from the anterior tibialis, peroneus longus, lateral gastrocnemius, rectus femoris, biceps femoris, and gluteus medius as subjects walked on a treadmill shod, with an ankle-destabilization boot (ADB), and an ankle-destabilization sandal (ADS). Normalized amplitudes 100 ms before and 200 ms after initial heel contact, time of onset activation relative to initial contact, and percent of activation time across the stride cycle were calculated for each muscle in each condition. The precontact amplitudes of the peroneus longus and lateral gastrocnemius and the postcontact amplitudes of the lateral gastrocnemius were significantly greater in the ADB and ADS conditions. In the ADB condition, the rectus femoris and biceps femoris postcontact amplitudes were significantly greater than shod. The peroneus longus and lateral gastrocnemius were activated significantly earlier, and the anterior tibialis, lateral gastrocnemius, and rectus femoris were activated significantly longer across the stride cycle in the ADB and the ADS conditions. In addition, the peroneus longus was activated significantly longer in the ADB condition when compared with shod. Both ankle-destabilization devices caused an alteration in muscle activity during walking, which may be favorable to an injured patient. Therefore, implementing these devices in rehabilitation programs may be beneficial to improving neuromuscular control.


A Comprehensive Study on Colorectal Polyp Segmentation With ResUNet++, Conditional Random Field and Test-Time Augmentation.
Colonoscopy is considered the gold standard for detection of colorectal cancer and its precursors. Existing examination methods are, however, hampered by high overall miss-rate, and many abnormalities are left undetected. Computer-Aided Diagnosis systems based on advanced machine learning algorithms are touted as a game-changer that can identify regions in the colon overlooked by the physicians during endoscopic examinations, and help detect and characterize lesions. In previous work, we have proposed the ResUNet++ architecture and demonstrated that it produces more efficient results compared with its counterparts U-Net and ResUNet. In this paper, we demonstrate that further improvements to the overall prediction performance of the ResUNet++ architecture can be achieved by using Conditional Random Field (CRF) and Test-Time Augmentation (TTA). We have performed extensive evaluations and validated the improvements using six publicly available datasets: Kvasir-SEG, CVC-ClinicDB, CVC-ColonDB, ETIS-Larib Polyp DB, ASU-Mayo Clinic Colonoscopy Video Database, and CVC-VideoClinicDB. Moreover, we compare our proposed architecture and resulting model with other state-of-the-art methods. To explore the generalization capability of ResUNet++ on different publicly available polyp datasets, so that it could be used in a real-world setting, we performed an extensive cross-dataset evaluation. The experimental results show that applying CRF and TTA improves the performance on various polyp segmentation datasets both on the same dataset and cross-dataset. To check the model's performance on difficult to detect polyps, we selected, with the help of an expert gastroenterologist, 196 sessile or flat polyps that are less than ten millimeters in size. This additional data has been made available as a subset of Kvasir-SEG. Our approaches showed good results for flat or sessile and smaller polyps, which are known to be one of the major reasons for high polyp miss-rates. This is one of the significant strengths of our work and indicates that our methods should be investigated further for use in clinical practice.


Discovery of a large-magnitude, late pleistocene volcanic eruption in alaska.
An extensive blanket of dacitic tephra was deposited across Alaska and the western Yukon Territory by a plinian eruption about 80,000 years ago. The volume of tephra erupted probably exceeded 50 cubic kilometers and the source was probably in the Wrangell Mountains. This widespread layer of tephra serves as an excellent late Pleistocene stratigraphic marker.


Recent Updates on Development of Drug Molecules for Human African Trypanosomiasis.
Human African trypanosomiasis (HAT, better called as sleeping sickness), caused by two morphologically identicalprotozoan parasite Trypanosoma bruceiis transmitted by the bite of tsetse flies of Glossinagenus, mainly in the rural areas of the sub-Saharan Africa. HAT is one of the neglected tropical diseases and is characterized by sleep disturbance as the main symptom, hence is called as sleeping sickness. As it is epidemic in the poorest population of Africa, there is limited availability of safe and cost-effective tools for controlling the disease. Trypanosoma bruceigambiense causes sleeping sickness in Western and Central Africa, whereas Trypanosoma bruceirhodesiense is the reason for prevalence of sleeping sickness in Eastern and Southern Africa. For the treatment of sleeping sickness, only five drugs have been approved suramin, pentamidine, melarsoprol, eflornithine and nifurtimox. Various small molecules of diverse chemical nature have been synthesized for targeting HAT and many of them are in the clinical trialsincluding fexinidazole (phase I completed) and SCYX-7158 (advanced in phase I). The present work has been planned to review various types of small molecules developed in the last 10 years having potent antitrypanosoma activity likely to be beneficial in sleeping sickness along with different natural anti-HAT agents.


Quality control in management of pain.
Since 1987 several pain clinics in The Netherlands have started with some kind of computer-assisted recording of data, mainly for purposes of quality control. However, this has not yet led to routinely generated reports about the quality of these clinics because a consensus on how to assess quality in pain-treatment is missing. Using classical system-development methods a global specification for an information system for quality assessment was defined on which a prototype application was based. Various changes were adopted into this prototype, which ultimately resulted in explicit requirements stating: 1. Which data to record, 2. What organisational prerequisites to fulfil for such a system, 3. The user-interface, and 4. Interactions with other information systems. The final application was implemented in a number of pain clinics where its usefulness in quality control is currently assessed.


Pedunculated malignant melanoma.
A woman had a primary pedunculated malignant melanoma. This is a rare form of presentation and may result in clinical confusion with seborrheic keratosis, fibroepithelial papilloma, or granuloma pyogenicum. The aggressive nature of the lesion was indicated by the presence of erosion and bleeding. Though the tumor cells were present only in the pedunculated mass, it had metastasized to regional lymph nodes at the time of surgery.


Effect of Platinum-Based Chemoradiotherapy on Cellular Proliferation in Bone Marrow and Spleen, Estimated by (18)F-FLT PET/CT in Patients with Locally Advanced Non-Small Cell Lung Cancer.
Historically, it has been difficult to monitor the acute impact of anticancer therapies on hematopoietic organs on a whole-body scale. Deeper understanding of the effect of treatments on bone marrow would be of great potential value in the rational design of intensive treatment regimens. 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a functional radiotracer used to study cellular proliferation. It is trapped in cells in proportion to thymidine-kinase 1 enzyme expression, which is upregulated during DNA synthesis. This study investigates the potential of (18)F-FLT to monitor acute effects of chemotherapy on cellular proliferation and its recovery in bone marrow, spleen, and liver during treatment with 2 different chemotherapy regimens. Sixty patients with non-small cell lung cancer underwent concurrent radical chemoradiotherapy to 60 Gy in 6 wk with either cisplatin/etoposide (C/E, n = 28) weeks 1 and 5 or weekly carboplatin/paclitaxel (C/P, n = 32) regimens. (18)F-FLT and (18)F-FDG PET with CT were performed at baseline, week 2 (day 9 for (18)F-FLT and day 10 for (18)F-FDG PET), and week 4 (day 23 for (18)F-FLT and day 24 for (18)F-FDG PET). Visual and semiquantitative standardized uptake value (SUV) measurements were performed in bone marrow outside the radiotherapy field, liver, spleen, and small bowel. These were correlated to blood counts and smears in a subset of patients. The C/E group exhibited a drop in bone marrow (18)F-FLT uptake at week 2 (median SUVmax [maximum SUV] decrease to 31%, 8.7-6.0, P < 0.001), with recovery at week 4, reflecting the absence of chemotherapy between these times. By contrast, the weekly C/P group showed gradually declining bone marrow uptake (P > 0.05). Spleen uptake in both cohorts decreased at week 2, with intense rebound activity at week 4 (SUVmax week 4 at 58% above baseline: 2.4-3.8, for C/E, respectively, 30% for C/P: 2.7-3.5, P < 0.001). Liver uptake changed little. (18)F-FLT changes preceded neutrophil count reductions. (18)F-FDG uptake in marrow liver and spleen changed much less than (18)F-FLT. (18)F-FLT imaging may be used to quantify impairment and recovery of bone marrow by specific chemotherapy regimens and may also enable imaging of organ-specific processes such as spleen activation. (18)F-FLT is superior to (18)F-FDG for this purpose. This technology may support novel treatment planning and monitoring approaches in oncology patients.


Stimulus-induced myoclonus treated effectively with clonazepam in genetically confirmed Coffin-Lowry syndrome.
Coffin-Lowry syndrome (CLS) is a rare X-linked semidominant syndromic genetic disorder that is characterized by typical facial and radiologic findings, psychomotor and growth retardation, and various skeletal anomalies. A distinctive paroxysmal disorder called stimulus-bound myoclonus is clinically heterogeneous and is generally characterized by a sudden loss of muscle tone that is regained within a few seconds and is induced by sudden auditory or tactile stimulus. As the pathophysiology of stimulus-induced drop episodes (SIDEs) is not well understood, there is no definite therapy for those episodes. We report a 15-year-old female with stimulus-induced drop episodes occurring many times a day that resulted in failure to perform her daily activities. Because her SIDEs were misdiagnosed as atonic seizures, she was treated with several antiepileptic drugs, including valproic acid, levetiracetam, lamotrigine, primidone, carbamazepine, and clobazam. We realized that her clinical and radiological findings, together with SIDEs, are compatible with Coffin-Lowry syndrome. All of her medications were discontinued following the diagnosis of SIDE, and she was started on clonazepam. After treatment, she became more independent and was able to perform her daily activities. Subsequently, her episodes decreased from 3 times a day to 1-2 times a month. Sodium oxybate and fluoxetine were added to the treatment protocol without remarkable improvement. Her genetic analysis revealed a heterozygous variation of CLS. We conclude that SIDE should be included in a differential diagnosis of epileptic seizures in patients with CLS and that clonazepam is an effective choice in the treatment of SIDEs.


23-hydroxybetulinic acid-induced HL-60 cell autophagic apoptosis and its molecular mechanism.
This study investigates the effects of 23-hydroxybetulinic acid (23-HBA) in inducing HL-60 autophagic apoptosis and explores its potential molecular mechanism. The generation depression effects of HL-60 cells cultured in vitro were detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method (p < 0.05), and dosage time-dependent relationships were found. Numerous autophagic vacuoles and empty vacuoles were observed in HL-60 cells treated with 12.5 µM 23-HBA for 24 h by electron microscopy; it was also observed that the process of cell division diminished. Using flow cytometry, the number of apoptotic cells was seen to obviously increase, and the G1/S phase was retarded. It was observed that 23-HBA tended to arrest cells at the G1 phase of the cell cycle. The percentage of the apoptotic cells increased as treatment duration and concentration increased. Beclin-1 expression enhanced with an increase in 23-HBA concentration. We can conclude that 23-HBA can induce autophagic apoptosis in HL-60; the autophagic apoptosis induced by 23-HBA is related to the upregulation of expression of the apoptotic gene beclin-1.


Smart toe® implant versus buried Kirschner wire for proximal interphalangeal joint arthrodesis: a comparative study.
The surgical correction of hammer digits offers a variety of surgical treatments ranging from arthroplasty to arthrodesis, with many options for fixation. In the present study, we compared 2 buried implants for arthrodesis of lesser digit deformities: a Smart Toe® implant and a buried Kirschner wire. Both implants were placed in a prepared interphalangeal joint, did not violate other digital or metatarsal joints, and were not exposed percutaneously. A retrospective comparative study was performed of 117 digits with either a Smart Toe® implant or a buried Kirschner wire, performed from January 1, 2007 to December 31, 2010. Of the 117 digits, 31 were excluded because of a lack of 90-day radiographic follow-up. The average follow-up was 94 to 1130 days. The average patient age was 61.47 (range 43 to 84) years. Of the 86 included digits, 48 were left digits and 38 were right. Of the digits corrected, 54 were second digits, 24 were third digits and 8 were fourth digits. Fifty-eight Smart Toe® implants were found (15 with 19-mm straight; 2 with 19-mm angulated; 34 with 16-mm straight; and 7 with 16-mm angulated). Twenty-eight buried Kirschner wires were evaluated. No statistically significant difference was found between the Smart Toe® implants and the buried Kirschner wires, including the rate of malunion, nonunion, fracture of internal fixation, and the need for revision surgery. Of the 86 implants, 87.9% of the Smart Toe® implants and 85.7% of the buried Kirschner wires were in good position (0° to 10° of transverse angulation on radiographs). Osseous union was achieved in 68.9% of Smart Toe® implants and 82.1% of buried Kirschner wires. Fracture of internal fixation occurred in 12 of the Smart Toe® implants (20.7%) and 2 of the buried Kirschner wires (7.1%). Most of the fractured internal fixation and malunions or nonunions were asymptomatic, leading to revision surgery in only 8.6% of the Smart Toe® implants and 10.7% of the buried Kirschner wires. Both the Smart Toe® implant and the buried Kirschner wire offer a viable choice for internal fixation of an arthrodesis of the digit compared with other studies using other techniques.


Learning a Nonnegative Sparse Graph for Linear Regression.
Previous graph-based semisupervised learning (G-SSL) methods have the following drawbacks: 1) they usually predefine the graph structure and then use it to perform label prediction, which cannot guarantee an overall optimum and 2) they only focus on the label prediction or the graph structure construction but are not competent in handling new samples. To this end, a novel nonnegative sparse graph (NNSG) learning method was first proposed. Then, both the label prediction and projection learning were integrated into linear regression. Finally, the linear regression and graph structure learning were unified within the same framework to overcome these two drawbacks. Therefore, a novel method, named learning a NNSG for linear regression was presented, in which the linear regression and graph learning were simultaneously performed to guarantee an overall optimum. In the learning process, the label information can be accurately propagated via the graph structure so that the linear regression can learn a discriminative projection to better fit sample labels and accurately classify new samples. An effective algorithm was designed to solve the corresponding optimization problem with fast convergence. Furthermore, NNSG provides a unified perceptiveness for a number of graph-based learning methods and linear regression methods. The experimental results showed that NNSG can obtain very high classification accuracy and greatly outperforms conventional G-SSL methods, especially some conventional graph construction methods.


The role of computed tomography scan in the diagnosis of COVID-19 pneumonia.
To summarize current literature evidence on the role of computed tomography (CT) scan in the diagnosis and assessment of coronavirus disease 2019 (COVID-19) pneumonia. Recent guidelines on the use of CT scans in COVID-19 vary between countries. However, the consensus is that it should not be used as the first line; a notion supported by the WHO. Currently, several investigations are being used including reverse transcription PCR testing, chest radiographs, and ultrasound scans, and CT scans. They are ideally performed later during the disease process as the sensitivity and specificity are highest by that time. Typical COVID-19 features on CT scans vary but include vascular enlargement, ground-glass opacities, and ground glass opacification together with consolidation. Since COVID-19 was declared as a global pandemic, there was a push towards identifying appropriate diagnostic tests that are both reliable and effective. There is a general agreement that CT scans have a high sensitivity but low specificity in diagnosing COVID-19. However, the quality of available studies is not optimal, so this must always be interpreted with the clinical context in mind. Clinicians must aim to weigh up the practicalities and drawbacks of CT scans when considering their use for a patient. The ease and speed of use of CT scans must be balanced with their high radiation doses, and infection control considerations.


Differential cell counts using center-point networks achieves human-level accuracy and efficiency over segmentation.
Differential cell counts is a challenging task when applying computer vision algorithms to pathology. Existing approaches to train cell recognition require high availability of multi-class segmentation and/or bounding box annotations and suffer in performance when objects are tightly clustered. We present differential count network ("DCNet"), an annotation efficient modality that utilises keypoint detection to locate in brightfield images the centre points of cells (not nuclei) and their cell class. The single centre point annotation for DCNet lowered burden for experts to generate ground truth data by 77.1% compared to bounding box labeling. Yet centre point annotation still enabled high accuracy when training DCNet on a multi-class algorithm on whole cell features, matching human experts in all 5 object classes in average precision and outperforming humans in consistency. The efficacy and efficiency of the DCNet end-to-end system represents a significant progress toward an open source, fully computationally approach to differential cell count based diagnosis that can be adapted to any pathology need.


Macrophage scavenger receptor 1 (Msr1, SR-A) influences B cell autoimmunity by regulating soluble autoantigen concentration.
The class A macrophage scavenger receptor Msr1 (SR-A, CD204) has been reported to participate in the maintenance of immunological tolerance. We investigated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in K/BxN TCR transgenic mice decreased the incidence and severity of arthritis because of decreased autoantibody production. Despite normal initial activation of autoreactive CD4(+) T cells, potentially autoreactive B cells in Msr1(-/-) K/BxN mice retained a naive phenotype and did not expand. This was not due to an intrinsic B cell defect. Rather, we found that macrophages lacking Msr1 were inefficient at taking up the key autoantigen glucose-6-phosphate isomerase and that Msr1-deficient mice had elevated serum concentrations of glucose-6-phosphate isomerase. Arthritis developed normally when bone marrow from Msr1(-/-) K/BxN mice was transplanted into hosts whose macrophages did express Msr1. Thus, Msr1 can regulate the concentration of a soluble autoantigen. In this model, the absence of Msr1 led to higher levels of soluble autoantigen and protected mice from developing pathogenic autoantibodies, likely because of altered cognate interactions of autoreactive T and B cells with impaired differentiation of follicular Th cells.


Electronic textile-based electrocardiogram monitoring in cardiac patients: a scoping review.
The objectives of this scoping review were to explore, organize and present the existing research literature on the use of electronic textile (e-textile)-based resting, signal-averaged, ambulatory or exercise electrocardiogram (ECG) monitoring to evaluate the application of e-textile technologies for ECG cardiac monitoring. E-textile-based ECG monitoring of cardiac patients offers a possible new alternative for in-hospital monitoring and post-discharge monitoring during cardiac rehabilitation. Studies that included patients (inpatients or outpatients) who qualified for cardiac rehabilitation programs or continuous ambulatory ECG monitoring were considered. The key concepts that were addressed included resting, signal-averaged, ambulatory or exercise ECG monitoring based on e-textile technologies or e-textile-based cardiac rehabilitation. Studies were excluded if they focused only on specific aspects of the e-textile ECG system rather than a complete ECG system. Research reports, dissertations or books that evaluated e-textile-based ECG monitoring of cardiac patients in a hospital or at home, written in English, and published between January 2000 and March 2018 were considered for inclusion. Published and unpublished literature was located through databases including Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed Central (PMC), Institute of Electrical and Electronics Engineers (IEEE Xplore), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Database of Systematic Reviews, Web of Science, Scopus, Expanded Academic ASAP, ProQuest Dissertations and Theses Global, SPORTDiscus, and ENGINE-Australian Engineering Database (Informit). Two independent reviewers screened citations for inclusion while the third reviewer resolved any discrepancies. Meta-data from each study were extracted, and a narrative summary was used to present the results. Furthermore, 38 study authors were contacted to request missing or additional data as required, with 16 responding within eight weeks. Of the 207 studies that were eligible for full-text review, only 8% (n = 17) were included in the final study. Eighty-eight percent (n = 15) of included studies were conducted with an adult population, and 11 studies reported an in-hospital application. Only three groups of researchers reported e-textile integration beyond the textile electrodes, mostly in the form of wiring and custom-made printed circuit boards. Eight studies utilized two ECG sensors, while single-lead ECG was the most common configuration, used in 10 studies. ECG result was the primary parameter reported across the included studies. Resting ECG was the most common form of ECG acquired (n = 10), followed by exercise ECG (n = 6) and ambulatory ECG (n = 5). Eight studies addressed the issue of power requirements, and seven studies used Bluetooth for wireless communication. The primary problem reported across all studies was noise from motion artifact. The recent advances in signal quality and noise reduction for e-textile-based ECG applications are promising. However, the use of a 12-lead, personalized, home-based cardiac rehabilitation monitor system containing fully textile-integrated electronics with diagnostic capability is yet to be reported. Therefore, there is potential for future research in this area. Additionally, motion artifact continues to be a challenge.


[Parametric visualization of cerebral perfusion by intravenous digital angiography].
Intravenous digital subtraction angiography is often used for evaluation of the extracranial and major intracranial vessels. The information obtained by this examination concerning cerebral perfusion is usually judged visually. In 50 patients a time-density curve at a specific point was analysed using 128 X 128 matrix. The level of grey scale at the moment of arrival of the bolus permits estimation of the haemodynamics of the intracranial vessels and provides a simple demonstration of differences of perfusion.


Study of the protective effects of Katha (Heartwood Extract of Acacia catechu) in liver damage induced by iron overload.
This study evaluated the ameliorating effect of 70% methanol extract of Acacia catechu heartwood, or Katha (ACME) on liver injury induced by iron overload. Iron overload in mice was caused by intraperitoneal administration of 100 mg/kg iron-dextran. ACME was administered orally for 21 days, starting from the day after the first iron-dextran injection. The biochemical markers of hepatic damage and liver iron, protein carbonyl, and hydroxyproline contents were measured in response to the oral administration of ACME. Apart from those, the release of iron from ferritin by ACME was further assessed to determine the efficiency of ACME as an iron-chelating drug. Treatment with different doses of ACME (50, 100, and 200 mg/kg body weight) showed dose-dependent reductions in liver iron, lipid peroxidation, protein oxidation, liver fibrosis, serum enzymes, and ferritin. The antioxidant enzymes levels were enhanced and the reductive release of ferritin iron increased significantly with gradually increasing concentrations of ACME. These results indicate that ACME has a potent hepatoprotective action against hepatic damage induced by iron overload in mice, probably by ameliorating the antioxidant defense activities and reductively releasing ferritin iron.


[Human colostrum: a natural source of probiotics?]
OBJECTIVE: The aim of the present study was to obtain data on the microbiota of human colostrum, and to correlate it with a possible source of probiotics transferred from mother to infant during breastfeeding. METHODS: 70 samples of milked human colostrum were analyzed as to the presence of mesophylic, thermoduric, psychrotrophic, proteolytic, proteolytic-psychrotrophic, lipolytic microorganisms, molds and yeasts, Staphylococcus aureus, total coliforms, fecal coliforms, Group D Streptococcus species and lactic acid bacteria. RESULTS: the microbiological analyses revealed several classical groups of microorganisms: mesophylic (68.6%); thermoduric (38.6%); psychrotrophic (8.6%); proteolytic (15.7%); proteolytic-psychrotrophic (1,4%); lipolytic (4.3%); molds and yeasts (11.4%); Staphylococcus aureus (44.3%); total coliforms (7.2%); and lactic acid bacteria (37.2%), thus characterizing a diversified microbiota. Thermoduric-psychrotrophic microorganisms, fecal coliforms and Group D Streptococcus species were not identified in any of the samples. CONCLUSIONS: The results show a microbiota rich in lactic acid bacteria, which may work as probiotics if delivered to infants within the first days of life.


Factors influencing caregiver burden in chronic pain patients: A retrospective study.
Chronic pain coexists with disability, anxiety, depression, and sleep disturbances, which are factors of pain chronicity in the fear-avoidance model. Self-efficacy for managing pain plays a protective role against pain chronicity. For chronic pain sufferers, social support from caregivers is important. However, such caregivers face enormous physical and mental burdens. This study aimed to assess how self-efficacy and factors related to the fear-avoidance model affect caregiver burden. Participants were 135 chronic pain patients and their caregivers who visited our outpatient pain special clinic. In clinical assessments, numeric rating scale (NRS), pain catastrophizing scale (PCS), hospital anxiety and depression scale (HADS), Athens insomnia scale (AIS), pain disability assessment scale (PDAS), pain self-efficacy questionnaire (PSEQ) for the patients and Zarit Burden Interview (ZBI) for their caregivers were evaluated. Participants were divided into 2 groups (L group ZBI < 24 points and H group ZBI ≥ 24 points) and compared. Regression analyses were conducted to identify factors correlated with the ZBI scores. Compared to L group, H group showed significantly higher NRS and HADs depression scores, and lower PSEQ scores. In univariate regression analysis, ZBI scores were significantly correlated with NRS, PCS, HADS anxiety, HADS depression, PDAS and PSEQ. Multiple linear regression analysis revealed that ZBI scores were significantly correlated with PSEQ. The caregivers who perceived high caregiver burden had significantly higher patients' pain intensity, depression, and lower self-efficacy than those who perceived low caregiver burden. Caregiver burden correlated with the pain intensity, pain catastrophizing, anxiety, depression, disability, and self-efficacy of chronic pain patients. Among these factors, self-efficacy was the most negatively correlated with caregiver burden. Treatments focused on increasing self-efficacy for managing pain have the potential to reduce caregiver burden.


Effectiveness of Noninvasive Fibrosis Markers for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B and Chronic Hepatitis B+D Induced Cirrhosis.
Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, the incidence and mortality of hepatocellular carcinoma (HCC) continue to rise. To obtain the best treatment result for HCC, early diagnosis is the key. In this study, we investigated the accuracy of noninvasive fibrosis markers, which have been typically used to predict liver fibrosis in recent years, in the prediction of HCC development in patients with chronic hepatitis B and chronic hepatitis B + D-induced cirrhosis. Between 2004 and 2018, 1216 patients with chronic liver disease were retrospectively reviewed, and 331 patients (27%) with hepatitis B and hepatitis B+D virus-related cirrhosis were enrolled in our study. Patients were divided into 2 groups based on HCC diagnosis (HCC and non-HCC group). Eleven noninvasive fibrosis markers were evaluated in the groups. These markers included 3 alpha-fetoprotein (AFP)-based models (PAPAS index, Fibro-alpha, and BRC score) and 8 non-AFP based models (Lok index, FIB-4, Fibro-O index, APRI, King's score, Forns index, Bonacini score, and HUI model) for each Child-Pugh score in the prediction of HCC. AFP-based models were higher in HCC group patients, and statistically significant outcomes were detected with these methods in each Child-Pugh score group for HCC prediction (P < .05). Non-AFP based-methods showed different and inconsistent results in each Child-Pugh score group. These easily applied fibrosis markers, particularly AFP-based models, may provide an effective, simple, and low-cost way to predict HCC development in patients with hepatitis B and hepatitis B + D cirrhosis.


Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils.
Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. In the present study, we demonstrate a pivotal role of Stat3 expressed in innate immune cells during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis induced by CLP. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. Despite enhanced inflammatory responses, the mice failed to facilitate bacterial clearance as compared with the control mice. In addition, the mice exhibited an increased lethality after i.p. inoculation of live bacteria recovered from CLP-mice. In vitro, resident peritoneal macrophages from mice with Stat3 deficiency impaired bactericidal activity relative to the control whereas productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2 and LPS. Elicited macrophages and neutrophils with Stat3 deficiency also impaired bactericidal activity as compared with those with Stat3. Lysosomal enzyme release, an effector molecule for bacterial clearance, was significantly decreased in elicited leukocytes with Stat3 deficiency while increasing the production of inflammatory cytokines. Altogether, these results suggest that macrophage/neutrophil-specific STAT3 is crucial in not only modulating multiple organ failure associated with systemic inflammation but also intensifying the bactericidal activity, which highlight the significance of cell-specific Stat3 in the protective immunity during sepsis.


Determination of left ventricular filling pressure by Doppler echocardiography in patients with coronary artery disease: critical role of left ventricular systolic function.
This study was designed to determine the usefulness of transthoracic Doppler measurements in detecting increased left ventricular (LV) end-diastolic pressure in patients with coronary artery disease, specifically examining the influence of systolic function on the accuracy of these methods. Studies that have correlated Doppler indexes with LV filling pressures primarily involved patients with LV systolic dysfunction. The reliability of Doppler indexes in estimating filling pressures in patients with coronary artery disease and preserved systolic function is unclear. Pulsed wave Doppler transmitral and pulmonary venous flow velocity curves and LV pressure were recorded in 83 patients with coronary artery disease. Conventional Doppler indexes (deceleration time of mitral E wave velocity, ratio of peak mitral E to A wave velocities and pulmonary venous systolic fraction) correlated with LV filling pressure in patients with an ejection fraction (EF) < or = 50% but not in those with an EF > 50%. Previously published regression analysis for prediction of LV filling pressure was accurate in patients with an EF < or = 50% but not in those with an EF > 50%. The difference between flow duration with atrial contraction in the pulmonary veins and transmitral flow duration with atrial contraction correlated with LV filling pressure in both groups. Analysis of the early diastolic portion of the transmitral or pulmonary venous flow velocity curves can be used to predict LV filling pressures in patients with systolic dysfunction, but are inaccurate in patients with preserved systolic function. The combined analysis of both flow velocity curves at atrial contraction is a reliable, feasible predictor of increased LV filling pressure, irrespective of systolic function.


Transcription Factors in Deriving β Cell Regeneration: A Potential Novel Therapeutic Target.
Recently, remarkable advances have been achieved in the molecular biopathology field and researchers turned to evaluate the role, molecular mechanisms, and clinical value of transcription factors in curing a variety of parenchymal degenerative pathologies. Special agents have the capability to cell lineage reprogramming termed transcription factors with a capacity for gene expression modification. Therefore, whatever niche factor may modify gene expression is termed as a transcription factor. A variety of transcription factors have been identified to participate in the regulation of pancreatic stem cell maturation, differentiation, and proliferation; primarily, not only Pdx1, NeuroG3, and MafA, but transcription factors can also transdifferentiate somatic cells in between, liver and gallbladder cells into insulin-producing cells. These heterogenic capabilities of the transcription factors are of clinical significance since they can control cells' regeneration capacity. Physiologically, the pancreatic cells are subdivided into exocrine and endocrine cells. Pancreatic endocrine dysfunction is clinically more common and of more clinical relevance. The paper will illustrate the role and possible mechanisms of transcription factors in the transdifferentiation of endodermderived somatic cells into pancreatic beta-like cells. Clinically, understanding the potential mechanisms in generating physiologic beta cells is extremely crucial to optimize current therapies and evaluate new therapeutic targets via recruiting specific transcription factors. The transcription factors can be applied to both types of diabetes and chronic pancreatitis.


Promoter methylation downregulates CDX2 expression in colorectal carcinomas.
CDX2 (caudal type homeobox transcription factor 2) is a homeobox protein, which is expressed in intestinal epithelium. CDX2 has been considered to play a role as a tumor suppressor gene in colorectal cancer because its expression is lacking in colorectal carcinomas, but preserved in adenomas. The point mutations have been found to account for loss of CDX2 expression, but the main mechanism responsible for CDX2 gene inactivation is less understood. We analyzed methylation and expression status of CDX2 in colorectal cancer cell lines and primary tumors. There are two CpG-rich sites in promoter region of CDX2 gene, -1570 to -1200 and -220 to +880. By COBRA (combined bisulfite restriction analysis) assay, the upper CpG-rich site was heavily methylated in all cell lines, but the lower CpG-rich site was methylated in limited cell lines. Bisulfite sequencing analysis and RT-PCR revealed that methylation of the lower CpG site was associated with down-regulation of CDX2. In addition, gene expression was restored in COLO201, a methylated cell line with 5-aza-2'-deoxycytidine, confirming that methylation caused gene down-regulation. We also examined CDX2 promoter methylation of primary tumors by MSP (methylated-allele specific PCR) assay and found that nearly 40% of cases have a methylated CDX2 gene. Our results demonstrate that CDX2 methylation is frequently present in colorectal cancers and may play a key role in inactivating CDX2 expression.


Modeling the glucose regulatory system in extreme preterm infants.
Premature infants represent a significant proportion of the neonatal intensive care population. Blood glucose homeostasis in this group is often disturbed by immaturity of endogenous regulatory systems and the stress of their condition. Hypo- and hyperglycemia are frequently reported in very low birth weight infants, and more mature infants often experience low levels of glycemia. A model capturing the unique fundamental dynamics of the neonatal glucose regulatory system could be used to develop better blood glucose control methods. A metabolic system model is adapted from adult critical care to the unique physiological case of the neonate. Integral-based fitting methods were used to identify time-varying insulin sensitivity and non-insulin mediated glucose uptake profiles. The clinically important predictive ability of the model was assessed by assuming insulin sensitivity was constant over prediction intervals of 1, 2 and 4h forward and comparing model-simulated versus actual clinical glucose values for all recorded interventions. The clinical data included 1091 glucose measurements over 3567 total patient hours, along with all associated insulin and nutritional infusion data, for N=25 total cases. Ethics approval was obtained from the Upper South A Regional Ethics Committee for this study. The identified model had a median absolute percentage error of 2.4% [IQR: 0.9-4.8%] between model-fitted and clinical glucose values. Median absolute prediction errors at 1-, 2- and 4-h intervals were 5.2% [IQR: 2.5-10.3%], 9.4% [IQR: 4.5-18.4%] and 13.6% [IQR: 6.3-27.6%] respectively. The model accurately captures and predicts the fundamental dynamic behaviors of the neonatal metabolism well enough for effective clinical decision support in glycemic control. The adaptation from adult to a neonatal case is based on the data from the literature. Low prediction errors and very low fitting errors indicate that the fundamental dynamics of glucose metabolism in both premature neonates and critical care adults can be described by similar mathematical models.


Generalized hydrodynamics of the Lennard-Jones liquid in view of hidden scale invariance.
In recent years lines along which structure and dynamics are invariant to a good approximation, so-called isomorphs, have been identified in the thermodynamic phase diagrams of several model liquids and solids. This paper reports computer simulation data of the transverse and longitudinal collective dynamics at different length scales along an isomorph of the Lennard-Jones system. Our findings are compared to corresponding results along an isotherm and an isochore. Confirming the theoretical prediction, the reduced-unit dynamics of the transverse momentum density is invariant to a good approximation along the isomorph on all time and length scales. Likewise, the wave-vector dependent shear-stress autocorrelation function is found to be isomorph invariant (with minor deviations at very short times). A similar invariance is not seen along the isotherm or the isochore. Using a spatially nonlocal hydrodynamic model for the transverse momentum-density time-autocorrelation function, the macroscopic shear viscosity and its wave dependence are determined, demonstrating that the shear viscosity is isomorphic invariant on all length scales studied. This analysis implies the existence of a length scale that is isomorph invariant in reduced units, i.e., which characterizes each isomorph. The transverse sound-wave velocity, the Maxwell relaxation time, and the rigidity shear modulus are also isomorph invariant. In contrast to the isomorph invariance of all aspects of the transverse dynamics, the reduced-unit dynamics of the mass density is not invariant on length scales longer than the interparticle distance. By fitting to a generalized hydrodynamic model, we extract values for the wave-vector-dependent thermal diffusion coefficient, sound attenuation coefficient, and adiabatic sound velocity. The isomorph variation of these quantities in reduced units on long length scales can be eliminated by scaling with the density-scaling exponent, a fundamental quantity in the isomorph theory framework; this is an empirical observation that remains to be explained theoretically.


Shame Mediates the Relationship Between Pain Invalidation and Depression.
The experience of pain is subjective, yet many people have their pain invalidated or not believed. Pain invalidation is associated with poor mental health, including depression and lower well-being. Qualitative investigations of invalidating experiences identify themes of depression, but also social withdrawal, self-criticism, and lower self-worth, all of which are core components of shame. Despite this, no studies have quantitatively assessed the interrelationship between pain invalidation, shame, and depression. To explore this relationship, participants recounted the frequency of experienced pain invalidation from family, friends, and medical professionals, as well as their feelings of internalized shame and depressive symptoms. As shame has been shown to be a precursor for depression, we further explored the role of shame as a mediator between pain invalidation and depressive symptoms. All sources of pain invalidation were positively associated with shame and depressive symptoms, and shame fully mediated the relationship between each source of pain invalidation and depression. Relative to other sources, pain invalidation from family was most closely tied to shame and depression. Overall, findings indicate that one mechanism by which pain invalidation may facilitate depression is via the experience of shame. Future research may explore shame as a potential upstream precursor to depression in the context of pain. Findings provide more insight into the harmful influence of pain invalidation on mental health and highlight the impact of interpersonal treatment on the experiences of people in pain.


Second cancer following cutaneous melanoma and cancers of the brain, thyroid, connective tissue, bone, and eye in Connecticut, 1935-82.
The risk of second primary cancers developing was evaluated in individuals with 6 rare tumors in Connecticut between 1935 and 1982. Small but significant excesses of all second cancers occurred in patients with cutaneous melanoma (42%), and cancers of the brain (59%), thyroid (49%), connective tissue (23%), bone (66%), and eye (40%). In individuals with cutaneous melanoma, the highest risks were for subsequent cutaneous melanomas [relative risk (RR) = 8.5] that persisted throughout all intervals of observation. The risk for second melanomas was higher in persons under age 40, consistent with a heritable component. Connective tissue tumors and breast cancers also occurred in excess. Among patients with brain cancer, an increase of melanoma was observed that may represent an underlying neural crest abnormality, although no excess of brain cancer was seen after melanoma. Reciprocal increases of bone cancer after connective tissue cancer and connective tissue cancer after bone cancer point to shared risk factors, such as high dose radiotherapy or genetic susceptibility states. An anticipated high risk of osteogenic sarcoma following Ewing's sarcoma was not seen. An excess of breast cancer (RR = 1.9) after thyroid cancer indicates common etiologic factors. Expected excesses of bilateral retinoblastoma and bone cancer after retinoblastoma were seen. Tumors commonly treated with alkylating agents or nitrosoureas (melanoma, brain, connective tissue) showed slightly elevated risks of acute nonlymphocytic leukemia. Prostate cancer was frequently found to be in excess, but this is likely an artifact due to ascertainment bias.