Prognosis and Biological Function of miR-3195 in Non-Small Cell Lung Cancer.
Lung cancer has the highest mortality and morbidity rates worldwide. Among the subtypes of lung cancer, non-small cell lung cancer (NSCLC) accounts for approximately 85% of cases. The present study evaluated the potential prognostic value and biological function of miR-3195 in NSCLC. In total, 129 patients with NSCLC were enrolled in this study. The expression of miR-3195 expression in NSCLC tissues and cell lines was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival curve analysis and multivariate Cox regression analysis were used to elucidate the prognostic value of miR-3195. The Cell Counting Kit-8 (CCK-8) assay and Transwell cell migration experiments were carried out to explore the effective effect of miR-3195 on the biological behavior of NSCLC cells. The expression of miR-3195 was downregulated in NSCLC tissues and cell lines. Moreover, the decreased expression of miR-3195 was correlated with positive lymph node metastasis and high TNM stage. The overall survival of patients with low expression of miR-3195 was worse than those with high expression of miR-3195. Furthermore, miR-3195 was an independent prognostic indicator for overall survival in patients with NSCLC. Enhanced expression of miR-3195 restrained cell growth, migration, and invasion of NSCLC tumor cells, while attenuation of miR-3195 expression augmented cell proliferation activities, migration, and invasion potential. Our findings suggest that miR-3195 may be used as a prognostic biomarker for NSCLC and is likely to act as a tumor suppressor for NSCLC.


Contribution of low-cost sensor measurements to the prediction of PM2.5 levels: A case study in Imperial County, California, USA.
Regulatory monitoring networks are often too sparse to support community-scale PM2.5 exposure assessment while emerging low-cost sensors have the potential to fill in the gaps. To date, limited studies, if any, have been conducted to utilize low-cost sensor measurements to improve PM2.5 prediction with high spatiotemporal resolutions based on statistical models. Imperial County in California is an exemplary region with sparse Air Quality System (AQS) monitors and a community-operated low-cost network entitled Identifying Violations Affecting Neighborhoods (IVAN). This study aims to evaluate the contribution of IVAN measurements to the quality of PM2.5 prediction. We adopted the Random Forest algorithm to estimate daily PM2.5 concentrations at a 1-km spatial resolution using three different PM2.5 datasets (AQS-only, IVAN-only, and AQS/IVAN combined). The results show that the integration of low-cost sensor measurements is an effective way to significantly improve the quality of PM2.5 prediction with an increase of cross-validation (CV) R2 by ~0.2. The IVAN measurements also contributed to the increased importance of emission source-related covariates and more reasonable spatial patterns of PM2.5. The remaining uncertainty in the calibrated IVAN measurements could still cause apparent outliers in the prediction model, highlighting the need for more effective calibration or integration methods to relieve its negative impact.


[Place and role of caregivers of young people with autism spectrum disorders].
The question of the place and role of caregivers, most often parents, for children with autism spectrum disorders has undergone significant change in recent years. It is now proven that when a parent acquires knowledge about autism, he is able to interact in a functional way and thus to use more effective educational methods with his child.


The optimum pH for the derivative spectrophotometric determination of co-trimoxazole in binary mixtures.
Although the experimental assessment of co-trimoxazole by use of derivative spectrophotmetry underscores the usefulness of this method due to its relative simplicity with which it can be carried out over the official United States Pharmacopoeia (USP) high pressure liquid chromatography (hplc) methods for this drug, suitable optimum conditions ought to be refined for its universal acceptability. The objective of the present work was to obtain the optimum pH level for the UV assessment of co-trimoxazole. The aqueous solutions of the individual drugs and their binary mixtures were buffered with Sodium Acetate-Acetic Acid buffer in the pH ranges 2-7 and scanned on zero order and on first-order derivative at the wave length between 200- 300 nm. At the same drug solution concentrations, spectral shifts occurred with change in pH, especially between the wavelengths 200 and 240 nm, only seeming to converge from approximate wavelength 260 nm onwards. Absorbance fluctuations were also observed at the same drug concentrations in the pH range 2 to 3.5 and 5 to 7 when the solutions were scanned, even at the wavelength where the spectra seem to converge. However there were no absorbance differences between pH 4 and 5. The UV spectrophotometric method is dependent on the optimum pH and this has been found to range from 4 to 5.


CT radiomics-based machine learning classification of atypical cartilaginous tumours and appendicular chondrosarcomas.
Clinical management ranges from surveillance or curettage to wide resection for atypical to higher-grade cartilaginous tumours, respectively. Our aim was to investigate the performance of computed tomography (CT) radiomics-based machine learning for classification of atypical cartilaginous tumours and higher-grade chondrosarcomas of long bones. One-hundred-twenty patients with histology-proven lesions were retrospectively included. The training cohort consisted of 84 CT scans from centre 1 (n=55 G1 or atypical cartilaginous tumours; n=29 G2-G4 chondrosarcomas). The external test cohort consisted of the CT component of 36 positron emission tomography-CT scans from centre 2 (n=16 G1 or atypical cartilaginous tumours; n=20 G2-G4 chondrosarcomas). Bidimensional segmentation was performed on preoperative CT. Radiomic features were extracted. After dimensionality reduction and class balancing in centre 1, the performance of a machine-learning classifier (LogitBoost) was assessed on the training cohort using 10-fold cross-validation and on the external test cohort. In centre 2, its performance was compared with preoperative biopsy and an experienced radiologist using McNemar's test. The classifier had 81% (AUC=0.89) and 75% (AUC=0.78) accuracy in identifying the lesions in the training and external test cohorts, respectively. Specifically, its accuracy in classifying atypical cartilaginous tumours and higher-grade chondrosarcomas was 84% and 78% in the training cohort, and 81% and 70% in the external test cohort, respectively. Preoperative biopsy had 64% (AUC=0.66) accuracy (p=0.29). The radiologist had 81% accuracy (p=0.75). Machine learning showed good accuracy in classifying atypical and higher-grade cartilaginous tumours of long bones based on preoperative CT radiomic features. ESSR Young Researchers Grant.


Functional analysis of LDLR promoter and 5' UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia.
Familial hypercholesterolemia (FH) is a dominant disorder due to mutations in the LDLR gene. Several mutations in the LDLR promoter are associated with FH. Screening of 3,705 Spanish FH patients identified 10 variants in the promoter and 5' UTR. Here, we analyse the functionality of six newly identified LDLR variants. Mutations located in the LDLR promoter regulatory elements R2 and R3 (c.-155_-150delACCCCinsTTCTGCAAACTCCTCCC, c.-136C>G, c.-140C>G, and c.-140C>T) resulted in 6 to 15% residual activity in reporter expression experiments and changes in nuclear protein binding affinity compared to wild type. No reduction was observed when cells were transfected with c.-208T, c.-88A, and c.-36G mutant fragments. Our results indicate that mutations localized in R2 and R3 are associated with hypercholesterolemia, whereas mutations outside the LDLR response elements are not a cause of FH. This data emphasizes the importance of functional analysis of variants in the LDLR promoter to determine their association with the FH phenotype.


Grain yield and correlated traits of bread wheat lines: Implications for yield improvement.
Global wheat yields are suffering due to differences in regional climatic conditions and soil fertility. Plant breeders are continuously working to improve the yield per unit area of wheat crop through selecting superior lines as parents. The screening and field evaluation of available lines allow the selection of superior ones and subsequently improved varieties. Therefore, heritable distinctions among 33 bread wheat lines for yield and related attributes were assessed under field conditions. The experiment included thirty lines and three check varieties. Data relating to different plant characteristics was collected at maturity. Significant differences were recorded for yield and related traits of tested wheat lines and check varieties. Wheat lines V6, V12 and V20 proved better with reduced number of days to reach anthesis and other desirable traits compared to check varieties. Days to start heading had strong correlation with spike length and number of spikelets spike-1. Flag leaf area had positive relationship with peduncle length and yield related traits. The 1000-garin weight and grain yield were also correlated with each other. It is concluded that V6, V10 and V20 proved better for all studied traits than the rest of the lines. Therefore, these lines could be used in wheat breeding program as parents to improve yield.


Direct calibration ELISA: a rapid method for the simplified determination of association constants of unlabeled biological molecules.
We present a novel method for the rapid determination of association constants. The method is based on the direct calibration of an enzyme-linked immunosorbent assay (dcELISA) and does not require any external calibration. It combines kinetic and equilibrium binding experiments and can be performed on a single microtiter plate. The absorbance data are evaluated by several linearized plots without the need for sophisticated computations. The dcELISA has been used to analyze the binding of a monoclonal antibody, OKT9, to its cognate antigen, the human transferrin receptor, and yielded an association constant of Ka = 2.2 x 10(9) l/mol and a complex formation rate constant of kc = 2.7 x 10(-4) s-1. A 26% larger association constant was obtained with a radioimmunoassay (RIA)-based Scatchard analysis using 125I-labeled OKT9. By quantifying the binding of the same iodinated antibody with the dcELISA we were able to verify that the iodination modifies the binding properties of the antibody. The dcELISA thus appears to be superior to all methods requiring covalent modifications. In principle, the direct calibration method can also be combined with all other solid phase assays. It should thus expand their scope in quantifying the binding properties of biologically important molecules.


Symptoms, endoscopic findings and reflux monitoring results in candidates for bariatric surgery.
Gastroesophageal reflux disease (GERD) is common in patients with obesity. Diagnosing GERD is important as bariatric operations have different influence on GERD. We assessed reflux symptoms and objective findings prior to surgery. Work-up included esophageal symptoms quantification by VAS-scores, esophagogastroduodenoscopy (EGD) and 24-h impedance-pH (imp-pH) monitoring off PPI therapy. Imp-pH was classified as abnormal if either %time pH<4 was abnormal, total number of reflux episodes was elevated or symptom index (SI) was positive. Among 100 consecutive patients (68F, age 40±11years, BMI 44.9±6.9kg/m2) 54% reported heartburn and/or regurgitation, 71% had objective evidence of GERD (38% endoscopic lesions and 33% only abnormal imp-pH results). Imp-pH was superior to EGD in identifying GERD (sensitivity 85% vs. 54%, p<0.01). Symptomatic and asymptomatic patients had similar prevalence of esophageal lesions (37% vs. 39%) and abnormal imp-pH findings (68% vs. 50%). Sixty nine percent of patients with abnormal %time pH<4 had a normal number of reflux episodes. Half of patients with obesity reported typical GERD symptoms and >70% had evidence of GERD. Poor acid clearance was the main mechanisms. Since typical reflux symptoms don't predict objective findings, endoscopy and reflux monitoring should be part of the surgery work-up especially before restrictive procedures.


Typologies of recanting of lifetime cigarette, alcohol and marijuana use during a six-year longitudinal panel study.
To identify if there are different typologies for adolescent self-reporters and recanters for alcohol, cigarette and marijuana use. This study is a secondary data analysis and utilized four waves of the National Longitudinal Survey of Youth child panel data. The study included adolescents aged ten and older who self-reported ever use of cigarettes (n=872), marijuana (n=854) or alcohol (n=837). Consistent responders were those who reported lifetime use of a specific substance and continued to report such use at each latter wave of data collection. Latent class analyses were utilized to investigate if there are different types of self-reporters for each substance class. Three unique groups for each substance was identified. The first group of users, who had a late age of onset, tended to be consistent self-reporters across waves. Those who were early onset users of cigarettes and marijuana tended to recant their use while early onset alcohol users were consistent reporters. Those with moderate ages of onset had no consistent recanting patterns. The highest degree of recanting was found among the early onset marijuana users. The results suggest that youth who begin their use at an earlier age may not be as reliable reporters as youth who initiate use at later ages. Our results suggest that the veracity of prevalence estimates for licit and illicit substances could be different depending on the age of the respondent.


Pars plana vitrectomy for diabetic traction retinal detachment.
One hundred twenty-five consecutive cases of traction macular detachment secondary to diabetic retinopathy are analyzed. Visual results show 72% to have improvement. Long-term follow-up (average 39 months) of the initial 75 cases revealed that 62% of the initially improved cases remained improved. Neovascular glaucoma rate continues to be higher in aphakic eyes as compared to phakic eyes.


Preoperative use of pirfenidone and reduced risk of postoperative severe respiratory complications in patients with idiopathic pulmonary fibrosis: Propensity score-matched analysis using a nationwide database in Japan.
Patients with idiopathic pulmonary fibrosis (IPF) often develop postoperative severe respiratory complications such as acute exacerbation. Pirfenidone, an oral anti-fibrotic drug, may reduce the incidence of such complications. However, the preventive effect of pirfenidone on postoperative severe respiratory complications remains unclear. We identified patients with IPF who underwent surgery with general anaesthesia from July 2010 to March 2018 using the Diagnosis Procedure Combination database. We compared the occurrence of postoperative severe respiratory complications (receiving mechanical ventilation under endotracheal intubation and/or intravenous infusion of a high-dose corticosteroid and in-hospital death within 30 days after surgery) between patients who did and did not receive preoperative treatment with pirfenidone. Pearson's chi-square test and logistic regression analysis fitted with a generalized estimating equation were conducted in 1:4 propensity score-matched patients. Among 631 patients identified, 19% were treated with pirfenidone before surgery. The 30-day mortality rate was 3.1% and 1.7% in the control patients (n = 510) and pirfenidone-treated patients (n = 121), respectively. In the propensity score-matched population, preoperative treatment with pirfenidone was significantly associated with a lower proportion of postoperative severe respiratory complications (OR: 0.24; 95% CI: 0.07-0.76; p = 0.015). In this Japanese nationwide cohort, preoperative treatment with pirfenidone was significantly associated with a lower risk of postoperative severe respiratory complications in patients with IPF. Preoperative pirfenidone may thus be useful in preventing postoperative severe respiratory complications in patients with IPF who are planning to undergo surgery with general anaesthesia.


Residues of dioxins (PCDD/Fs) and PCBs in eggs, fat and livers of laying hens following consumption of contaminated feed.
Laying hens were fed with feed from the Belgian dioxin incident diluted ten-fold with non-contaminated feed, resulting in concentrations of 61 ngTEQkg(-1) PCDD/Fs, 23 ngTEQkg(-1) non-ortho PCBs, 116 ngTEQkg(-1) mono-ortho PCBs and 3.2 mgkg(-1) of the seven indicator PCBs. Following exposure for seven days, feed was replaced by non-contaminated feed for a period up to six weeks. Concentrations of PCDD/Fs in eggs showed a maximum of 214 pgTEQg(-1) fat after nine days and decreased to 44 pgTEQg(-1) after seven weeks. Dioxin concentrations in abdominal fat of chickens killed just after the last treatment, or after 1, 3 or 6 weeks on clean feed were 69, 84, 54 and 41 pgTEQg(-1) fat, respectively. Concentrations in livers decreased more rapidly, being 35, 7, 4 and 3 pgTEQg(-1) tissue, respectively. In both eggs and tissues, total TEQ concentrations were 3-4 times higher. Concentrations of the seven indicator PCBs in egg fat showed a stronger decrease with concentrations of 16.5 microgg(-1) at the peak (day 9) and 2.2 microgg(-1) after seven weeks. Corresponding concentrations in abdominal fat were, respectively, 4.6 and 2.6 microgg(-1) fat, and in livers 0.77 and 0.14 microgg(-1) tissue. The ratio of indicator PCBs to PCDD/Fs in feed was 52200. In eggs this ratio was initially higher (85000), but decreased towards 50000 after six weeks on clean feed. In abdominal fat the ratio varied between 49000 and 67000. In livers, the ratio was initially low (22000) but increased to 45000 towards the end of the study. It is concluded that the behaviour of PCDD/Fs and PCBs in laying hens is comparable and that the use of indicator PCBs appears to be a good alternative for PCDD/Fs but only in the case of co-exposure to both PCBs and PCDD/Fs, such as in incidents with PCB oil.


Cardiomyocyte-specific disruption of the circadian BMAL1-REV-ERBα/β regulatory network impacts distinct miRNA species in the murine heart.
Circadian disruption increases cardiovascular disease (CVD) risk, through poorly understood mechanisms. Given that small RNA species are critical modulators of cardiac physiology/pathology, we sought to determine the extent to which cardiomyocyte circadian clock (CCC) disruption impacts cardiac small RNA species. Accordingly, we collected hearts from cardiomyocyte-specific Bmal1 knockout (CBK; a model of CCC disruption) and littermate control (CON) mice at multiple times of the day, followed by small RNA-seq. The data reveal 47 differentially expressed miRNAs species in CBK hearts. Subsequent bioinformatic analyses predict that differentially expressed miRNA species in CBK hearts influence processes such as circadian rhythmicity, cellular signaling, and metabolism. Of the induced miRNAs in CBK hearts, 7 are predicted to be targeted by the transcriptional repressors REV-ERBα/β (integral circadian clock components that are directly regulated by BMAL1). Similar to CBK hearts, cardiomyocyte-specific Rev-erbα/β double knockout (CM-RevDKO) mouse hearts exhibit increased let-7c-1-3p, miR-23b-5p, miR-139-3p, miR-5123, and miR-7068-3p levels. Importantly, 19 putative targets of these 5 miRNAs are commonly repressed in CBK and CM-RevDKO heart (of which 16 are targeted by let-7c-1-3p). These observations suggest that disruption of the circadian BMAL1-REV-ERBα/β regulatory network in the heart induces distinct miRNAs, whose mRNA targets impact critical cellular functions.


Neuronal oscillations and synchronicity associated with gamma-hydroxybutyrate during resting-state in healthy male volunteers.
Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, an anesthetic agent, and a treatment for neuropsychiatric disorders. In previous electroencephalography (EEG) studies, GHB was shown to induce an electrophysiological pattern of "paradoxical EEG-behavioral dissociation" characterized by increased delta and theta oscillations usually associated with sleep during awake states. However, no detailed source localization of these alterations and no connectivity analyses have been performed yet. We tested the effects of GHB (20 and 35 mg/kg, p.o.) on current source density (CSD), lagged phase synchronization (LPS), and global omega complexity (GOC) of neuronal oscillations in a randomized, double-blind, placebo-controlled, balanced cross-over study in 19 healthy, male participants using exact low-resolution electromagnetic tomography (eLORETA) of resting-state high-density EEG recordings. Compared to placebo, GHB increased CSD of theta oscillations (5-7 Hz) in the posterior cingulate cortex (PCC) and alpha1 (8-10 Hz) oscillations in the anterior cingulate cortex. Higher blood plasma values were associated with higher LPS values of delta (2-4 Hz) oscillations between the PCC and the right inferior parietal lobulus. Additionally, GHB decreased GOC of alpha1 oscillations. These findings indicate that alterations in neuronal oscillations in the PCC mediate the psychotropic effects of GHB. Theta oscillations emerging from the PCC in combination with stability of functional connectivity within the default mode network might explain the GHB-related "paradoxical EEG-behavioral dissociation." Our findings related to GOC suggest a reduced number of relatively independent neuronal processes, an effect that has also been demonstrated for other anesthetic agents.


A frequency reconfigurable dipole antenna with solid-state plasma in silicon.
A frequency reconfigurable dipole antenna based on a silicon radiator is presented. The silicon radiator is activated with the aid of highly dense solid-state plasma by injecting carriers into the intrinsic region of p-i-n diodes. The fabrication and design guideline of the reconfigurable dipole antenna with this plasma radiator are described. When the plasma radiator is activated or deactivated, the length of the dipole arm changes, which means that the operating frequency of the dipole antenna is reconfigurable. When all the channels in the plasma radiator are activated, the operating frequency is tuned from 6.3 GHz to 4.9 GHz. The measured tunable bandwidth of our fabricated dipole antenna is approximately 31%, which is a practical value in comparison to conventional frequency reconfigurable antennas whose tunable bandwidth is in a range from 20% to 50%. To further support the validity of our results, we provide the well-matched simulation results from an antenna simulation. These results demonstrate that silicon with its commercial technology, which has not attracted attention in comparison to a metal antennas, is a promising tunable material for a frequency reconfigurable antenna. This plasma-based reconfigurable antenna has great potential for use in the dynamic communication environment.


Age and prior caffeine use alter the cardiovascular and adrenomedullary responses to oral caffeine.
The effects of age and chronic caffeine use (approximately 300 mg/day) on the cardiovascular and humoral responses to 250 mg of oral caffeine (the equivalent of 2 to 3 cups of coffee) were examined. Older subjects had greater increases in blood pressure than younger subjects (p less than 0.03), and caffeine nonusers had greater blood pressure increases than caffeine users, regardless of age (p less than 0.05). Caffeine increased the product of systolic blood pressure and heart rate (an estimate of myocardial oxygen demand) in older caffeine nonusers, but this effect was absent in older caffeine users (p less than 0.01). Cardiovascular effects of caffeine could not be related temporally to changes in plasma epinephrine, which were greater in caffeine nonusers and younger subjects, or to plasma norepinephrine, renin activity or vasopressin, which did not change. Thus, age accentuates and moderate prior caffeine use attenuates the cardiovascular effects of oral caffeine; these effects are not mediated solely through the sympathoadrenal system.


Chemical aversion therapy in the treatment of cocaine dependence as part of a multimodal treatment program: treatment outcome.
A pilot feasibility study of chemical aversion therapy in the treatment of cocaine dependence as part of a multimodal treatment program was conducted at the Schick Shadel Hospital of Santa Barbara. Twenty (20) patients (9 treating for cocaine only and 11 treating for cocaine/alcohol), who primarily snorted cocaine, completed a program which included chemical aversion therapy to develop a conditioned aversion to the sight, smell, and taste of a cocaine substitute (tetracaine, mannitol, and quinine with Psychem. Ninety-five (95) percent of patients were followed up in six months with a total abstinence rate from cocaine of 56% (78% current abstinence of at least 30 days prior to follow-up) in the cocaine only group and total abstinence from cocaine of 70% (also 70% current abstinence) for the cocaine/alcohol group. Ninety (90) percent were followed up at 18 months. Thirty eight (38) percent of the cocaine only group had been totally abstinent (75% were currently abstinent). Fifty (50) percent of the cocaine/alcohol group had been totally abstinent (80% were currently abstinent). Validation of results was obtained from "significant others" for 90% of patients.


Effect of combined low dose praziquantel and oxamniquine on different stages of schistosome maturity.
Combined low doses of praziquantel and oxamniquine were tested against different stages of Schistosoma mansoni in infected Swiss albino mice. The effect of combination therapy (1/3 the curative dose of praziquantel plus 1/3 the curative dose of oxamniquine) was compared with the effect of each drug alone, in reduced or full dose. Comparison with infected untreated controls was also made. Drug effects were evaluated on different growth stages of schistosomes by administering the drugs 24 h before infection and 4 h, 1, 2, 3, 4 and 5 weeks after infection. Animals were killed 8 weeks after infection. Worm burden, distribution, tissue egg load and oogram pattern were used in assessing drug efficacy. A potentiating effect was observed in animals receiving combination therapy. The combination regimen was most effective 4 h after infection, producing 96% worm reduction; eggs were not detected in the liver or intestine. Five weeks after infection the same regimen resulted in 98% reduction in the tissue egg load.


Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer's Disease and Other Dementias.
With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer's disease (AD), and 2) MCI from other non-AD dementias (OD). 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.


Pancreatic exocrine enzyme-producing cell differentiation via embryoid bodies from human embryonic stem cells.
Mouse embryonic stem cells (ESCs) can be induced to form pancreatic exocrine enzyme-producing cells in vitro in a stepwise fashion that recapitulates the development in vivo. However, there is no protocol for the differentiation of pancreatic-like cells from human ESCs (hESCs). Based upon the mouse ESC model, we have induced the in vitro formation of pancreatic exocrine enzyme-producing cells from hESCs. The protocol took place in four stages. In Stage 1, embryoid bodies (EBs) were formed from dissociated hESCs and then treated with the growth factor activin A, which promoted the expression of Foxa2 and Sox17 mRNAs, markers of definitive endoderm. In Stage 2, the cells were treated with all-trans retinoic acid which promoted the transition to cells that expressed gut tube endoderm mRNA marker HNF1b. In Stage 3, the cells were treated with fibroblast growth factor 7 (FGF7), which induced expression of Pdx1 typical of pancreatic progenitor cells. In Stage 4, treatment with FGF7, glucagon-like peptide 1, and nicotinamide induced the expression amylase (AMY) mRNA, a marker for mature pancreatic exocrine cells. Immunohistochemical staining showed the expression of AMY protein at the edges of cell clusters. These cells also expressed other exocrine secretory proteins including elastase, carboxypeptidase A, chymotrypsin, and pancreatic lipase in culture. Production of these hESC-derived pancreatic enzyme-producing cells represents a critical step in the study of pancreatic organogenesis and in the development of a renewable source of human pancreatic-like exocrine cells.


Mechanochemical Synthesis of Primary Amides.
Ball milling of aromatic, heteroaromatic, vinylic, and aliphatic esters with ethanol and calcium nitride afforded the corresponding primary amides in a transformation that was compatible with a variety of functional groups and maintained the integrity of a stereocenter α to carbonyl. This methodology was applied to α-amino esters and N-BOC dipeptide esters and also to the synthesis of rufinamide, an antiepileptic drug.


The transcription factor SlNAP1 increases salt tolerance by modulating ion homeostasis and ROS metabolism in Solanum lycopersicum.
NAC transcription factors (TFs) play an important role in the plant resistant response to biotic and abiotic stresses. However, the functions of the most NAC TFs are still unknown, especially in tomato. Here, we identified and functionally characterized an NAC TFs, SlNAP1, in tomato, and found that SlNAP1 was significantly induced by salt stress. Under 150 mM NaCl treatments, morphological indexes of SlNAP1 over-expressed (SlNAP1-OE) transgenic tomato lines were significantly better than the wild-type (WT) plants. The content of Na+ in leaves and roots of SlNAP1-OE transgenic plants decreased, while the K+ content in leaves, roots, and stems increased compared with WT plants. The expression of the salt stress-related genes (NHX1, HKT1;2 and SOS1) in SlNAP1-OE plants were also significantly up-regulated under salt stress. The SOD, POD and CAT activities and the expression level of antioxidant oxidase synthesis genes of SlNAP1-OE lines were significantly increased. In addition, the SlNAP1-OE lines accumulated less MDA, H2O2 and O2•-, improved antioxidant defense systems which contributed to increase salt tolerance. In summary, our data suggest that SlNAP1 positively regulates salt tolerance in tomato by regulating ion homeostasis and ROS metabolism.


Protein phi and psi dihedral restraints determined from multidimensional hypersurface correlations of backbone chemical shifts and their use in the determination of protein tertiary structures.
The chemical shifts of the backbone atoms of proteins can be used to obtain restraints that can be incorporated into structure determination methods. Each chemical shift can be used to define a restraint and these restraints can be simultaneously used to define the local, secondary structure features. The global fold can be determined by a combined use of the chemical shift based restraints along with the long-range information present in the NOEs of partially deuterated proteins or the amide-amide NOEs but not from such limited NOE data sets alone. This approach has been demonstrated to be capable of determining the overall folding pattern of four proteins. This suggests that solution-state NMR methods can be extended to the structure determination of larger proteins by using the information present in the chemical shifts of the backbone atoms along with the data that can be obtained on a small number of labeled forms.


Comparison of beliefs and practices of ethnic Viet and Lao Hmong concerning illness, healing, death and mourning: implications for hospice care with refugees in Canada.
This research paper examines the background, cosmology, and health, illness, healing, death, and mourning-related beliefs and practices of two groups of refugees in Canada, the ethnic Viet and the Lao Hmong. Emphasis is placed on the syndrome of uprootedness among refugees which exacerbates the patient's sense of loss in the palliative care setting. Practical recommendations to improve care of these patients and their families are made.


High-normal albuminuria and risk of heart failure in the community.
Albuminuria has been associated with cardiovascular risk, but the relationship of high-normal albuminuria to subsequent heart failure has not been well established. Prospective observational study, the Atherosclerosis Risk in Communities (ARIC) Study. 10,975 individuals free from heart failure were followed up from the fourth ARIC Study visit (1996-1998) through January 2006. Urinary albumin-creatinine ratio (UACR), analyzed continuously and categorically as optimal (<5 mg/g), intermediate-normal (5-9 mg/g), high-normal (10-29 mg/g), microalbuminuria (30-299 mg/g), and macroalbuminuria (≥300 mg/g). Incident heart failure was defined as a heart failure-related hospitalization or death. Cox proportional hazard models were used to calculate the HR of heart failure after adjustment for age, race, sex, estimated glomerular filtration rate (eGFR), and other cardiovascular risk factors. Individuals were followed up for a median of 8.3 years and experienced 344 heart failure events. Compared with normal UACR, albuminuria was associated with a progressively increased risk of heart failure from intermediate-normal (adjusted HR, 1.54; 95% CI, 1.12-2.11) and high-normal UACR (adjusted HR, 1.91; 95% CI, 1.38-2.66) to microalbuminuria (adjusted HR, 2.49; 95% CI, 1.77-3.50) and macroalbuminuria (adjusted HR, 3.47; 95% CI, 2.10-5.72). Results were similar in secondary analyses of participants censored at the time of coronary heart disease event and along a range of eGFRs. UACR was measured as a single random sample. Albuminuria is associated with subsequent heart failure, even in individuals with few cardiovascular risk factors and UACR within the normal range. Our results suggest that the association between albuminuria and heart failure may not be mediated fully by ischemic heart disease or kidney disease, measured using eGFR.


A new chemoinformatics approach with improved strategies for effective predictions of potential drugs.
Fast and accurate identification of potential drug candidates against therapeutic targets (i.e., drug-target interactions, DTIs) is a fundamental step in the early drug discovery process. However, experimental determination of DTIs is time-consuming and costly, especially for testing the associations between the entire chemical and genomic spaces. Therefore, computationally efficient algorithms with accurate predictions are required to achieve such a challenging task. In this work, we design a new chemoinformatics approach derived from neighbor-based collaborative filtering (NBCF) to infer potential drug candidates for targets of interest. One of the fundamental steps of NBCF in the application of DTI predictions is to accurately measure the similarity between drugs solely based on the DTI profiles of known knowledge. However, commonly used similarity calculation methods such as COSINE may be noise-prone due to the extremely sparse property of the DTI bipartite network, which decreases the model performance of NBCF. We herein propose three strategies to remedy such a dilemma, which include: (1) adopting a positive pointwise mutual information (PPMI)-based similarity metric, which is noise-immune to some extent; (2) performing low-rank approximation of the original prediction scores; (3) incorporating auxiliary (complementary) information to produce the final predictions. We test the proposed methods in three benchmark datasets and the results indicate that our strategies are helpful to improve the NBCF performance for DTI predictions. Comparing to the prior algorithm, our methods exhibit better results assessed by a recall-based evaluation metric. A new chemoinformatics approach with improved strategies was successfully developed to predict potential DTIs. Among them, the model based on the sparsity resistant PPMI similarity metric exhibits the best performance, which may be helpful to researchers for identifying potential drugs against therapeutic targets of interest, and can also be applied to related research such as identifying candidate disease genes.


Thiourea-Derived Single-Source Molecular Precursor For Spin-Coated PbS Thin Films.
In search of a suitable single-source precursor for the deposition of nanostructured PbS thin films at moderate temperatures under ambient conditions, we have synthesized the ligand N-(thiomorpholine-4-carbothioyl)benzamide and its corresponding lead(II) complex. The structures of both compounds were determined by single-crystal X-ray diffraction. In the complex, two ligands coordinate to a lead(II) atom in hemi-directed geometry through S and O atoms. Secondary intermolecular Pb⋅⋅⋅S interactions group the complexes into pairs. As bulk powders, both the ligand and complex show nominal composition and purity as evidenced by elemental analysis, 1 H NMR and IR spectroscopy. Thermal analysis of the lead(II) complex was carried out to understand its thermal decomposition behaviour for establishing a thin film fabrication protocol. Thin films of phase-pure PbS were fabricated using this new molecular precursor at the comparatively low annealing temperature of 250 °C. The film showed nanoparticles with cuboidal morphology and a blue-shifted optical absorption.


The molecular weight of aspermatogenic antigen as determined by equilibrium ultracentrifugation.
The extraction of antigen from testis and sperm is described. This antigen, when administered in microgram amounts in a single injection, induces aspermatogenesis in 100% of guinea pigs so treated. The deletion of the seminiferous cell line is specific (no cross-reactions) and provides a tool for investigating inhibition of cell replication as well as reproductive control. The antigen is a polypeptide-polysaccharide complex and has been determined to have a molecular weight of 10,520, using the equilibrium ultracentrifugation method.


A N6-methyladenosine-related long noncoding RNAs model for predicting prognosis in oral squamous cell carcinoma: Association with immune cell infiltration and tumor metastasis.
We aim to investigate the prognostic value of potential prognostic m6A-related lncRNAs in oral squamous cell carcinoma (OSCC) samples and construct a m6A-related lncRNAs prognostic model of OSCC survival outcomes, find new clues for OSCC prognosis improvement. Data of m6A-related lncRNAs were obtained from OSCC samples in TCGA database. Prognostic m6A-related lncRNAs were selected by univariate Cox regression analysis. M6A-related lncRNAs prognostic signature was analyzed by least absolute shrinkage and selection operator (LASSO) regression. 271 m6A-related lncRNAs were identified in OSCC lncRNAs, 16 of which were highly correlated with OSCC survival outcomes. Two clusters were created based on 16 prognostic valuable m6A-related lncRNAs. Characteristics of tumor immune and metastasis were identified in cluster 2 and the overall survival (OS) was worse of cluster 2 than that of cluster 1. Eleven m6A-related lncRNAs were selected from prognostic lncRNAs to establish a risk prediction signature via LASSO regression. Results showed that the OS of 1 year was lower in the high-risk group than low-risk group. The area under the curve in the training cohort was 0.704 at 1 year and 0.880 at 5 years. Multivariate Cox regression results suggested that the risk score calculated based on the m6A-related lncRNAs differential expressions was an independent predictor of OS in both two cohorts. We identified prognostic valuable m6A-related lncRNAs and demonstrated a reliable m6A-related lncRNA prognostic model for OSCC patients.


Lead accumulation and soil microbial activity in the rhizosphere of the mining and non-mining ecotypes of Athyrium wardii (Hook.) Makino in adaptation to lead-contaminated soils.
Better understanding of microbial activity in the rhizosphere soils associated with lead (Pb) uptake by plants may help with the phytoremediation of Pb-contaminated soils. In this work, the effects of Pb exposure (0, 200, 400, 600, 800 mg kg-1) on Pb accumulation and soil microbial activity in the rhizosphere of the mining ecotype (ME) and corresponding non-mining ecotype (NME) of Athyrium wardii (Hook.) Makino were investigated through a pot experiment. Although the plant growth of the two ecotypes was inhibited under Pb stress, the ME showed a less biomass decrease (12.6-44.0%) for aboveground than the NME, showing a greater tolerance to Pb stress. Pb concentrations as well as Pb accumulation in the two ecotypes showed an increasing trend with increasing soil Pb concentrations. The ME presented greater Pb accumulation ability than the NME, especially in underground parts. Pb availability in the rhizosphere soils of the two ecotypes after harvest decreased compared with those before transplantation. Available Pb in the rhizosphere of the ME was 1.4-4.8 times higher than that of the NME under exposure to 200-800 mg kg-1 Pb. The ME shows a greater ability to mobilize Pb in the rhizosphere soils. Pb exposure resulted in an inhibition of microbial activity in the rhizosphere of the two ecotypes. The ME demonstrated greater soil respiration and microbial biomass carbon (MBC) in the rhizosphere than the NME when treated with 200-800 mg kg-1 Pb. The ME showed a less decrease for MBC and a less increase for metabolic quotient in the rhizosphere soils than the NME when exposed to Pb generally. Microorganisms in the rhizosphere soils of the ME seem to be much more adapted to Pb stress, thus showing a great benefit for Pb accumulation and the phytostabilization of Pb-contaminated soils by the ME.


Urethroplasty after radiation therapy for prostate cancer.
To report urethroplasty outcomes in men who developed urethral stricture after undergoing radiation therapy for prostate cancer. Our urethroplasty database was reviewed for cases of urethral stricture after radiation therapy for prostate cancer between June 2004 and May 2010. Patient demographics, prostate cancer therapy type, stricture length and location, and type of urethroplasty were obtained. All patients received clinical evaluation, including imaging studies post procedure. Treatment success was defined as no need for repeat surgical intervention. Twenty-nine patients underwent urethroplasty for radiation-induced stricture. Previous radiation therapy included external beam radiotherapy (EBRT), radical prostatectomy (RP)/EBRT, EBRT/brachytherapy (BT) and BT alone in 11 (38%), 7 (24%), 7 (24%), and 4 (14%) patients, respectively. Mean age was 69 (±6.9) years. Mean stricture length was 2.6 (±1.6) cm. Anastomotic urethroplasty was performed in 76% patients, buccal mucosal graft in 17%, and perineal flap repair in 7%. Stricture was localized to bulbar urethra in 12 (41%), membranous in 12 (41%), vesicourethra in 3 (10%), and pan-urethral in 2 (7%) patients. Overall success rate was 90%. Median follow-up was 40 months (range 12-83). Time to recurrence ranged from 6-16 months. Multiple forms of urethroplasty appear to be viable options in treating radiation-induced urethral stricture. Future studies are needed to examine the durability of repairs.


Self-assembled monolayers: solidification of carbamazepine in Form II at an interface.
A self-assembled monolayer incorporating well-spaced biphenyl moieties initiates solidification of carbamazepine at its interface. A detailed analysis of the resulting crystals using X-ray powder diffraction, FTIR-ATR as well as thermomicroscopy, indicates a preference for its crystallization in trigonal (Form II) polymorph.


Individual quality of life and the environment - towards a concept of livable areas for persons with disabilities in Poland.
The United Nations Convention on the Rights of Persons with Disabilities [1] highlights the need to create proper socioeconomic and political conditions for persons with disabilities, with a special focus on their immediate living conditions. According to the Convention, these conditions should be built to ensure that persons with disabilities have the potential to enjoy a high quality of life (QoL), and this principle is reflected in the notion of livable areas. The crucial aspect of this framework is the relationship between the individual QoL and the environment, broadly understood as the socioeconomic as well as the technical conditions in which persons with disabilities function. The basic research problem was to assess the relationship between individual QoL for the population with disabilities as a dependent variable and livability indicators as independent variables, controlling for individual characteristics. The study used a dataset from the EU-SILC (European Union Statistics on Income and Living Conditions) survey carried out in 2015 in Poland. The research concept involved several steps. First, we created a variable measuring the QoL for the entire population with disabilities. To measure the multidimensional QoL, we used Sen's capability approach as a general concept, which was operationalized by the MIMIC (multiple indicators multiple causes) model. In the second step, we identified the livability indicators available in the official statistics, and merged them with survey data. Finally, in the last step, we ran the regression analysis. We also checked the data for the nested structure. We confirmed that the general environmental conditions, focused on creating livable areas, played a significant role in shaping the QoL of persons with disabilities; i.e., we found that the higher the level of the local Human Development Index, the higher the quality of life of the individuals living in this area. This relationship held even after controlling for the demographic characteristics of the respondents. Moreover, we found that in addition to the general environmental conditions, the conditions created especially for persons with disabilities (i.e., services for this group and support for their living conditions) affected the QoL of these individuals. The results illustrate the need to strengthen policies aimed at promoting the QoL of persons with disabilities by creating access to community assets and services that can contribute to improving the life chances of this population.


Stereoselective palladium-catalyzed functionalization of homoallylic alcohols: a convenient synthesis of di- and trisubstituted isoxazolidines and β-amino-δ-hydroxy esters.
Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring-closing carbonylative amidation to produce isoxazolidines 16/17 (≤50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N-Boc-protected esters of β-amino-δ-hydroxy acids and their γ-substituted homologues 37. The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C=C bond (19→21), as revealed by the reaction of 15, which afforded isoxazolidine 18 with high diastereoselectivity.


Cell proliferation in the descending colon of dimethylhydrazine treated rats and in dimethylhydrazine induced adenocarcinomata.
A stathmokinetic technique which has estimable precision has been used to estimate mitotic rates in the crypts of Lieberkühn in the descending colon of normal, and of dimethylhydrazine (DMH)-treated rats, as well as in DMH-induced adenocarcinomata. Estimates of the mean number of proliferating and of non-proliferating cells per crypt of Lieberkühn were also made in normal and in DMH-treated rats. In normal rats, epithelial cell proliferation was found to be relatively slow in the basal one-fifth of the crypts of Lieberkühn and to be most rapid in the second one-fifth of the crypt. In DMH-treated rats the number of cells around the circumference of transversely sectioned crypts was significantly increased, as was the number of proliferating cells present in longitudinally sectioned crypts. The region of relatively slow cell proliferation in the base of the crypts was expanded to occupy the lower two-fifths of the crypt in DMH-treated rats whilst the region of most rapid cell proliferation was displaced upwards to occupy the third one-fifth of the crypt. In DMH-induced adenocarcinomata cell proliferation occurred at a rate similar to that in the relatively quiescent zone at the bases of the colinic crypts in normal animals. However, tumour cell proliferation was substantially slower than that in the second one-fifth of the crypt in normal animals.


Quality of life and mental health in hemodialysis and peritoneal dialysis patients: the role of health beliefs.
Patients' beliefs regarding their health are important to understand responses to chronic disease. The present study aimed to determine (i) whether beliefs about health differ between different renal replacement therapies in end-stage renal disease (ESRD) patients and (ii) whether these beliefs are associated with health-related quality of life (HQoL), as well as with mental health. A sample of 89 ESRD patients, 41 on hemodialysis (HD) treatment and 48 on peritoneal dialysis (PD) treatment, completed the World Health Organization Quality of Life instrument, the General Health Questionnaire, the State-Trait Anxiety Inventory, the Center for Epidemiologic Studies Depression Scale, and the Multidimensional Health Locus of Control. Regarding differences in health beliefs between the two groups, HD patients focused more on the dimension of internal health locus of control than PD patients. This dimension was associated with better QoL (P = <0.01) and general health (P = 0.03) in the total sample. On the contrary, the dimension of important others in health locus of control was associated with higher depression (P = 0.02). The beliefs that dialysis patients hold about their illness appear to be related to the type of renal replacement therapy. These cognitions are associated with HQoL and with mental health.


Solitary fibrous tumor in the thigh: review of the literature.
Solitary fibrous tumors (SFT) of extremities, especially the thighs are very rare. Despite SFTs are generally benign, well-circumscribed soft tissue tumors new cases should be presented and followed up carefully to monitor their biological behavior. In general for tumor classification a biopsy is state of the art. Histological including immunohistochemical patterns for SFTs are defined. MRI and ultrasound are not sufficient for differential diagnosis. Once property identified and defined by size and location, resection with intact tumor capsule may result in full recovery of the patient. Reviewing the literature there are no validated reasons for a wider resection. The current patient was a 41-year-old male. Four years after an arthroscopy of the left knee the patient has been suffering an ongoing swelling of the lateral thigh. Because MRI scan data suggested a synovial sarcoma a biopsy was performed. The tumor was classified as a benign SFT. The diagnosis based on histological findings and the presence of the positive immunohistochemical markers Vimentin, CD34, and CD99. The complete tumor resection with intact capsule was achieved in a final operation. Clinical and in MRI after 54-month outcome period there were no local recurrences.


Food insecurity, state fragility and youth mental health: A global perspective.
Youth in fragile settings face disproportionate risks of experiencing food insecurity and poor mental health. Cross-national evidence is lacking on the association between food insecurity and mental health in youth populations, and on state fragility as a social determinant of these experiences. We analysed data from six cycles of the Gallup World Poll (2014-2019), an annual survey that contains multi-item scales of food insecurity, mental health problems and positive wellbeing. The analytic sample included 164,118 youth aged 15-24 years in 160 states. We linked individual responses to state-level data from the Fragile States Index-an aggregate measure of state vulnerability to collapse or conflict (coded: sustainable, stable, warning, or alert) and estimated adjusted relative risk (RR) of food insecurity as a function of state fragility. We then used linear regression to examine associations of state fragility and food insecurity with mental health and wellbeing. The prevalence of moderate or severe food insecurity rose from 22.93% in 2014 to 37.34% in 2019. State fragility (alert vs. sustainable) was related to an increased risk of food insecurity (RR = 2.28 [95% CI 1.30 to 4.01]), more mental health symptoms (b = 6.36 [95% CI 1.79 to 10.93]), and lower wellbeing (b = -4.49 [95% CI -8.28 to -0.70]) after controlling for state wealth and household income. Increased food insecurity (severe vs. none or mild) was uniquely related to more mental health symptoms (b = 18.44 [95% CI 17.24 to 19.64]) and reduced wellbeing (b = -9.85 [95% CI -10.88 to -8.83]) after state fragility was also controlled. Globally, youth experience better mental health where states are more robust and food access is more secure. The findings underscore the importance of strong governance and coordinated policy actions that may improve youth mental health.


Dumping syndrome as a complication of laparoscopic Nissen fundoplication in an adult.
Dumping syndrome is a recognized complication of various gastric surgical procedures, such as vagotomy, pyloroplasty, and gastrojejunostomy. However, it has not to date been reported following laparoscopic Nissen fundoplication in adults. We describe the case of a 34-year-old woman who developed late dumping syndrome following an uneventful laparoscopic Nissen fundoplication for gastroesophageal reflux disease. This condition should be considered in patients who develop hypoglycemic symptoms following laparoscopic fundoplication.


Corticotropin releasing factor induction of leukocyte-derived immunoreactive ACTH and endorphins.
Human peripheral leukocytes infected by virus or treated with endotoxin will, like unstimulated mouse spleen macrophages, synthesize immunoreactive corticotrophin (ir-ACTH) and endorphins. The ir-ACTH produced appears to be identical with authentic ACTH, while enough of the material has been produced in hypophysectomized mice infected with virus to demonstrate a steroidogenic response. Because the production of ACTH by in vivo pituitary cells and by leukocytes is suppressed by dexamethasone both in vitro and in vitro, suggesting that the production of ACTH and endorphins by leukocytes is indeed controlled, we have investigated the effects of corticotropin releasing-factor (CRF), which is known to regulate the pituitary production of both ACTH and beta-endorphin. We now report that the production of ACTH and endorphins by leukocytes is indeed induced by synthetic CRF and, in turn, suppressed by dexamethasone, suggesting that, as in pituitary cells, the proopiomelanocortin (POMC) gene may be expressed and similarly controlled in leukocytes.


Paramagnetic relaxation-based 19f MRI probe to detect protease activity.
A novel design principle for 19F MRI probes detecting protease activity was developed. This principle is based on 19F MRI signal quenching by the intramolecular paramagnetic effect from Gd3+. The intramolecular Gd3+ dramatically attenuated the 19F probe signal, and the paramagnetic effect was cancelled by the probe hydrolyzation by caspase-3. Using this probe, it was shown that the probe could detect caspase-3 activity spatially from a phantom image using 19F MRI.


Analysis of cellular composition of co-culture spheroids.
3D spheroids and in particular co-culture spheroids reflect the natural organization of cells in tissues much better than 2D cell cultures as indicated by differences in cellular phyisology. However, most methods to analyze cells were established for 2D cultures and cannot easily be applied to spheroids. This study has aimed to demonstrate the possibility of quantification of the cellular composition of co-culture spheroids without previous dissociation into single cells. Prior to the generation of the spheroids, human endothelial cells, osteoblasts and fibroblasts were stained with fluoresent dyes for living cells. Co-culture spheroids of defined stoichiometric compositions were generated by the liquid overlay technique, cultivated for one, three or six days, respectively, and afterwards snap-frozen in liquid nitrogen. Cryo-sections of co-culture spheroids were analyzed by fluorescence microscopy and a newly established semi-automatic measuring routine. In order to compare the results, spheroids of one group were dissociated and the cellular composition was quantified by FACS-analysis. Staining efficiencies were higher than 95% as quantified in preliminary experiments with 2D cultures. Depending on the staining procedure, variations from uniform to punctate signals were detected. The size of all co-culture spheroids decreased over time and snap-freezing did not lead to shrinkage of the spheroids. We were able to detect organizational patterns of different cell types within the spheroids. It was possible to determine the cellular composition by quantitative microscopic analyses of cryo-sections as it could be confirmed by flow cytometric analyses. Depending on the experimental requirements, a combination of both methods might lead to valuable synergy.


Functional mechanism of EGR3 in cerebral ischemia/reperfusion injury in rats by modulating transcription of pri-miR-146a/146b to miR-146 and suppressing SORT1 expression.
EGR3 is implicated in angiogenesis in rats with cerebral ischemia/reperfusion injury (CIRI). This research aimed to explore the effect and in vivo and ex vivo mechanisms of EGR3 in CIRI. CIRI rat models were established via middle cerebral artery occlusion. Cell models were established via oxygen-glucose deprivation/reoxygenation (OGD/R). Brain injury was assessed by neurological scoring, HE, and TTC staining. Inflammatory factors and oxidative stress markers were measured using corresponding kits. Mitochondrial membrane potential and mitochondrial respiration were examined by flow cytometry and respirometry. EGR3-miR-146 network was predicted on TransmiR v2.0 database. Target genes of miR-146 were screened on Starbase, Targetscan, and miRDB databases. miR-146 expression was determined by RT-qPCR. Levels of EGR3 and SORT1 were determined by Western blot. Binding relationships among EGR3, miR-146, and SORT1 were validated by dual-luciferase assay. EGR3, miR-146, and SORT1 levels were altered by injection or cell transfection to observe their functions. EGR3 was poorly-expressed in CIRI rats and OGD/R-induced neurons. EGR3 overexpression reduced inflammatory factor levels and attenuated oxidative stress and mitochondrial injury in CIRI rats and OGD/R-induced neurons. EGR3 bound to miR-146b promoter region. EGR3 promoted pri-miR-146a/146b processing and stimulated miR-146 transcription. miR-146 overexpression ameliorated oxidative stress and mitochondrial injury and miR-146 downregulation abolished the effect of EGR3 overexpression in vitro. miR-146 targeted SORT1. SORT1 overexpression invalidated the protective function of miR-146 overexpression on oxidative stress and mitochondrial injury in vitro. EGR3 protected against CIRI by mitigating oxidative stress and mitochondrial injury via the miR-146/SORT1 axis.


Converting synthetic azo dye and real textile wastewater into clean energy by using synthesized CuO/C as photocathode in dual-photoelectrode photocatalytic fuel cell.
Cathode in photocatalytic fuel cell (PFC) plays a crucial role in degradation of organic contaminants. In this study, synthesized copper oxide (CuO) was loaded on carbon plate and used as photocathode in PFC for degradation of synthetic azo dye Reactive Black 5 (RB5) and real textile wastewater. Morphology and structural phase of the synthesized CuO were analyzed using scanning electron microscopy (SEM) and X-ray diffraction (XRD), respectively. Several operating parameters had been investigated such as light irradiation, initial dye concentration, and pH of azo dye solution within 6 h of irradiation time. The lowest initial concentration of RB5 (10 mg L-1) achieved 100% color removal compared to the highest initial concentration (40 mg L-1) which only achieved 77.1% color removal within 6 h of irradiation time. The influence of external resistance was significant in electricity generation but trivial in dye degradation efficiency. The external resistance of 6000 Ω yielded highest maximum power density, with Pmax of 0.2631 μW cm-2, followed by 1000 Ω (0.2196 μW cm-2) and 8000 Ω (0.1587 μW cm-2), respectively. The real textile wastewater with dilution ratio (DR) 1:6 yielded the highest energy conversion efficiency, η (3.62%), followed by DR 1:4 (3.19%) and DR 1:2 (1.96%), respectively.


High hemoglobin is associated with increased in-hospital death in patients with chronic obstructive pulmonary disease and chronic kidney disease: a retrospective multicenter population-based study.
Chronic kidney disease (CKD) is a common comorbidity of chronic obstructive pulmonary disease (COPD). Although high hemoglobin (Hb) is detrimental to CKD patients, its relationship with poor outcomes in the COPD population has not been reported. This study aimed to investigate the relationship between high Hb and in-hospital mortality and to explore reference Hb intervals in patients with COPD and CKD. This retrospective study was multicenter population-based. A total of 47,209 patients who presented with COPD between January 2012 and December 2016 were included. The average Hb level during hospitalization was used as the Hb level. CKD and advanced CKD were defined as estimated glomerular filtration rates < 60 and < 30 ml/min/1.73 m2, respectively. The association between Hb level (measured in 1 g/dL intervals) and in-hospital mortality was analyzed in different multivariable logistic regression models by CKD stratification. The Hb level was decreased in the CKD subgroup. In the non-CKD group, a higher Hb level was not associated with an increased risk of in-hospital death. However, the Hb level and mortality showed a U-shaped relationship in the CKD group. After adjusting for age and Charlson Comorbidity Index, multivariable regression analysis showed that an Hb level > 17 g/dL was associated with an increased risk of death in the CKD group with an odds ratio (OR) of 2.085 (95% CI, 1.019-4.264). Hb > 14 g/dL was related to an increased risk of death in advanced CKD patients (OR, 4.579 (95% CI, 1.243-16.866)). High Hb is associated with an increased risk of in-hospital death in COPD patients with CKD, especially among those with advanced CKD. In this group of patients, attention should be paid to those with high Hb levels.


Structural regions of the cardiac Ca channel alpha subunit involved in Ca-dependent inactivation.
We investigated the molecular basis for Ca-dependent inactivation of the cardiac L-type Ca channel. Transfection of HEK293 cells with the wild-type alpha or its 3' deletion mutant (alpha) produced channels that exhibited prominent Ca-dependent inactivation. To identify structural regions of alpha involved in this process, we analyzed chimeric alpha subunits in which one of the major intracellular domains of alpha was replaced by the corresponding region from the skeletal muscle alpha subunit (which lacks Ca-dependent inactivation). Replacing the NH terminus or the III-IV loop of alpha with its counterpart from alpha had no appreciable effect on Ca channel inactivation. In contrast, replacing the I-II loop of alpha with the corresponding region from alpha dramatically slowed the inactivation of Ba currents while preserving Ca-dependent inactivation. A similar but less pronounced result was obtained with a II-III loop chimera. These results suggest that the I-II and II-III loops of alpha may participate in the mechanism of Ca-dependent inactivation. Replacing the final 80% of the COOH terminus of alpha with the corresponding region from alpha completely eliminated Ca-dependent inactivation without affecting inactivation of Ba currents. Significantly, Ca-dependent inactivation was restored to this chimera by deleting a nonconserved, 211-amino acid segment from the end of the COOH terminus. These results suggest that the distal COOH terminus of alpha can block Ca-dependent inactivation, possibly by interacting with other proteins or other regions of the Ca channel. Our findings suggest that structural determinants of Ca-dependent inactivation are distributed among several major cytoplasmic domains of alpha.


Thermal tolerance following artificially induced polycythaemia.
Polycythaemia has been shown to improve physical performance, possibly due to increased arterial oxygen transport. Enhanced thermoregulatory function may also accompany this manipulation, since a greater proportion of the cardiac output becomes available for heat dissipation. We further examined this possibility in five trained men, who participated in three-phase heat stress trials (20 min rest, 20 min cycling at 30% peak power (Wpeak) and 20 min at 45% Wpeak at 38.3 (SEM 0.7) degrees C [relative humidity 41.4 (SEM 2.9)%]. Trials were performed during normocythaemia (control) and polycythaemia, obtained by reinfusion of autologous red blood cells and resulting in significant elevation of arterial oxygen transport. During the polycythaemic trials, the subjects demonstrated diminished thermal strain, as evidenced by a significant reduction in cardiac frequency (fc: 12 beats.min-1 lower throughout the test; P < 0.05), and reduced auditory canal temperatures (Tac) during the latter 20-min phase (P < 0.05). Forearm sweat onset was more rapid (363.0 compared to 1083.0 s; P < 0.05), and forearm sweat rate (msw) sensitivity was elevated from 1.80 to 2.91.mg.cm-2.min-1.degrees C-1 (P < 0.05). Forehead msw was depressed during the final 20 min, while forearm msw was greater during all test phases, averaging 0.94 and 1.20 mg.cm-2.min-1, respectively, over the 60 min. Skin blood flows for the upper back, upper arm and forearm were reduced (P < 0.05). Polycythaemia enhanced thermoregulation, through an elevation in forearm sweat sensitivity and msw, but not via increased cutaneous blood flow. These modifications occurred simultaneously with decreases in fc and Tac, resulting in greater thermal tolerance.


Patterns of Upper Extremity Reconstruction for Patients With Tetraplegia Across the United States: A Retrospective Study.
The rates of upper extremity reconstruction for patients with tetraplegia remain low. We performed a retrospective study to assess recent reconstruction rates and delineate factors associated with the occurrence of reconstruction. We examined the National Inpatient Sample database (2012-2017) for the rate of reconstruction for patients with tetraplegia. The details of provider distribution characteristics and neighborhood attributes were obtained from the American Medical Association Physician Masterfile and based on the area deprivation index, respectively. We calculated the mean reconstruction rate per year and generated multivariable logistic regression models to examine the influence of patient factors, hospital characteristics, and provider distribution on the odds of undergoing functional reconstruction for tetraplegia patients. Among 404,660 encounters with patients with tetraplegia, only 1,430 (0.4%) patients underwent upper extremity reconstruction from 2012 to 2017, with a mean rate of 238 procedures per year. We identified 5,450 hand surgeons, 12,751 physiatrists, and 444 spinal cord injury specialists, with variation in their national distribution. A greater number of surgeons near SCIS was associated with increased probability of reconstruction (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.03-1.12). The odds of surgery were greater for patients receiving care at urban teaching (OR 5.00, 95% CI 3.35-7.47) or urban nonteaching (OR 1.71, 95% CI 1.11-2.63) hospitals, whereas those at private nonprofit (OR 0.67, 95% CI 0.58-0.78) or investor-owned (OR 0.65, 95% CI 0.52-0.82) hospitals had lower odds. Although most patients had insurance coverage, patients with a higher income or those who received subsidized care had greater odds of undergoing reconstruction. Reconstruction rates remain low and are correlated with the environment of care, financial factors, and provider availability. Policies that focus on reducing these factors in addition to increasing interspecialty collaboration could improve access to surgery for patients with tetraplegia. Prognostic I.


Losing my loss aversion: The effects of current and past environment on the relative sensitivity to losses and gains.
It is often assumed that most people are loss averse, placing more weight on losses than commensurate gains; however, some research identifies variability in loss sensitivity that reflects features of the environment. We examined this plasticity in loss sensitivity by manipulating the size and distribution of possible outcomes in a set of mixed gambles, and assessing individual stability in loss sensitivity. In each of two sessions, participants made accept-reject decisions for 64 mixed-outcome gambles. Participants were randomly assigned to conditions defined by the relative range of losses and gains (wider range of losses vs. wider range of gains), and the currency-units at stake ('pennies' vs. 'pounds'). Participants showed modest but non-trivial consistency in their sensitivity to losses; though loss sensitivity also varied substantially with our manipulations. When possible gains had greater range than possible losses, most participants were loss averse; however, when possible losses had the greater range, reverse loss aversion was the norm (i.e., more weight on gains than losses). This is consistent with decision-by-sampling theory, whereby an outcome's rank within a consideration-set determines its value, but can also be explained by the gamble's expected-value rank within the decision-set, or by adapting aspirations to the decision-environment. Loss aversion was also reduced in the second session of decisions when the stakes had been higher in the previous session. This illustrates the influence of prior context on current sensitivity to losses, and suggests a role for idiosyncratic experiences in the development of individual differences in loss sensitivity.


Trace metal content in annually banded scleractinian coral 'Porites lobata' across the northern Persian Gulf.
Concentrations of trace metals in skeleton growth bands of dominant scleractinian coral 'Porites lobata' in different years were investigated in Kharg and Hebourabi islands in the northern coast of the Persian Gulf. The highest average concentrations of metals respectively were Sr> Mg> Zn> Ba> Cu> U> Ni> Mn> Cr> Co> Pb> V> Cd in Kharg and Sr> Mg> Ba> Cu> U> Ni> Zn> Mn> Cr> Co> V> Pb> Cd in Hendourabi. The coefficient of variation percentages (CV%) of Cr, Mn, Zn, Ba, and Pb in Kharg and Cu and Ba in Hendourabi were more than 50%. Results of PCA analyses revealed that the levels of trace metals in Kharg were defined by three principle components: the first component (Mn, V, Pb, Zn, Ni and half of Mg, Cr and Co) corresponding to the past regional military conflicts and oil pollution, the second component (Sr, U, and Mg) corresponding to sea surface temperature (SST) changes, and the third component (Cr and Co) corresponding to other factors. The results of PCA analyses revealed that trace metals in Hendourabi were defined by two principle components including the first component (Co, Ni, Cr, Mn, and half of Ba) corresponding to annual precipitation changes and the second component (U, Zn, and Ba) corresponding to coastal constructions. The results showed that trace metal contamination in Kharg is higher than those of Hendourabi as a result of the oil exploration-related activities and war.


Early prediction of in-hospital mortality utilizing multivariate predictive modelling of electronic medical records and socio-determinants of health of the first day of hospitalization.
In France an average of 4% of hospitalized patients die during their hospital stay. To aid medical decision making and the attribution of resources, within a few days of admission the identification of patients at high risk of dying in hospital is essential. We used de-identified routine patient data available in the first 2 days of hospitalization in a French University Hospital (between 2016 and 2018) to build models predicting in-hospital mortality (at ≥ 2 and ≤ 30 days after admission). We tested nine different machine learning algorithms with repeated 10-fold cross-validation. Models were trained with 283 variables including age, sex, socio-determinants of health, laboratory test results, procedures (Classification of Medical Acts), medications (Anatomical Therapeutic Chemical code), hospital department/unit and home address (urban, rural etc.). The models were evaluated using various performance metrics. The dataset contained 123,729 admissions, of which the outcome for 3542 was all-cause in-hospital mortality and 120,187 admissions (no death reported within 30 days) were controls. The support vector machine, logistic regression and Xgboost algorithms demonstrated high discrimination with a balanced accuracy of 0.81 (95%CI 0.80-0.82), 0.82 (95%CI 0.80-0.83) and 0.83 (95%CI 0.80-0.83) and AUC of 0.90 (95%CI 0.88-0.91), 0.90 (95%CI 0.89-0.91) and 0.90 (95%CI 0.89-0.91) respectively. The most predictive variables for in-hospital mortality in all three models were older age (greater risk), and admission with a confirmed appointment (reduced risk). We propose three highly discriminating machine-learning models that could improve clinical and organizational decision making for adult patients at hospital admission.


The amygdaloid complex, corticotropin releasing factor and stress-induced gastric ulcerogenesis in rats.
The amygdaloid complex and corticotropin releasing factor (CRF) are both important in stress reactions and we thus evaluated the effects of intra-amygdalar CRF on stress ulceration in rats. Bilateral micro-applications of CRF (0.05, 0.5 or 5.0 micrograms) into the central amygdala (CEA) attenuated cold restraint-induced gastric mucosal lesions in a dose-related manner. Similar gastric cytoprotective effects were seen with intra-CEA noradrenaline (NA; 3.0 micrograms), whereas the NA neurotoxin, DSP-4 (25 micrograms), or the beta-adrenoceptor antagonist, propranolol (1 microgram), aggravated stress ulcer pathology. Intra-CEA pretreatment with DSP-4 or propranolol clearly reversed the ulceroprotective effects of CRF during stress. These results indicate that the CEA is a neural substrate for CRF effects, and CRF-NA interactions in this limbic area are crucial for the regulation of stress ulcerogenesis.


Prevalence of atypical antipsychotic use in psychiatric outpatients: comparison of women of childbearing age with men.
To characterize current treatment practices, we compared the use of atypical antipsychotic drugs among women of childbearing age to men based on electronic medical records of 1073 hospital-based psychiatric outpatients given at least one second-generation antipsychotic drug. One quarter of psychiatric outpatients sampled were prescribed at least one atypical antipsychotic, in more than half of cases for off-label indications. Women were significantly more likely than men to be diagnosed with mood or anxiety disorders than psychotic disorders and to be prescribed quetiapine (60.7 vs. 48.0 %) or aripiprazole (31.2 vs. 23.9 %), but less likely risperidone (15.8 vs. 26.1 %) or ziprasidone (10 vs. 14 %).


Immune response and susceptibility of Nile tilapia fish to Aeromonas hydrophila infection following the exposure to Bifenthrin and/or supplementation with Petroselinum crispum essential oil.
Bifenthrin (BF) is a widely used 3rd generation type I pyrethroid with a potential toxic effect in fish. Nevertheless, its effect on the immune system remains unclear. In the present study, Oreochromis niloticus was exposed to BF at 0.68 μg/L for 60 days, followed by evaluating the hematological, biochemical, and immunological responses. Additionally, the potential of parsley (Petroselinum crispum) essential oil (PEO) to ameliorate the BF-induced toxic insults was explored. Our data have shown reductions in the growth performance with alterations observed in the hematological variables, protein profile and serum biomarkers of stress. DNA oxidative damage was evidenced by elevation of serum 8-hydroxy-2-deoxyguanosine (8-OHdG) content. BF-exposed fish presented also decline in serum lysozyme activity and levels of immunoglobulins (IgG and IgM) and nitric oxide (NO), with diminished resistance to Aeromonas hydrophila challenge. Furthermore, the RT-PCR analysis showed an upregulated expression pattern of immune -related genes including interleukin 1β (IL-1β), interferon - γ (IFN-γ) and tumor necrosis factor - α (TNF-α) genes in the liver tissue. Dietary co-supplementation of PEO at 1 or 2 mL/kg diet with concomitant BF exposure, alleviated the adverse effects of the insecticide in a dose-dependent manner. The observations from this study demonstrate the immunomodulation by BF and provide further insight into the protective properties of PEO and strengthen its applicability as a promising feed supplement to fish.


Mycobacterium avium intracellularae complex associated extrapulmonary axillary lymphadenitis in a HIV-seropositive infant--a rare case report.
Opportunistic infections by Mycobacterium avium intracellulare complex in HIV infected patients, though common in adults, are rarely seen in infants. We herewith report an interesting case of an eight month old infant presenting with isolated axillary lymphadenitis, later on diagnosed to be tubercular lymphadenitis by Mycobacterium avium intracellulare and finally proved to be seropositive for HIV infection born to previously undetected HIV seropositive parents.


Need for caspases in apoptosis of trophic factor-deprived PC12 cells.
PC12 cells are a useful model system for studying neuronal apoptosis. Like neurons, they undergo apoptosis when deprived of trophic support. Involvement of caspases [interleukin 1beta-converting enzyme (ICE)-related proteases] has been implicated in apoptosis induced by various stimuli in many cell types, including neurons. In the present study we investigated the need for caspases participation in apoptosis induced by growth factor deprivation in naive and neuronal PC12 cells. For this purpose we generated PC12 cell lines that consistently express the viral caspases inhibitor genes p35 or crmA, and analyzed their susceptibility to trophic factor deprivation. We also examined the effects of cell-permeable peptide inhibitors of caspases. Our results showed that broad-spectrum inhibitors of the caspases, namely the baculovirus p35 gene and the peptide benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, effectively inhibit the death of both naive and neuronal PC12 cells. However, caspase-1 (ICE)-specific inhibitors, namely the peptides Ac-Try-Val-Ala-Asp-chloromethylketone and Ac-Try-Val-Ala-Asp-aldehyde, as well as crmA, were much less effective. These findings demonstrate that caspases, but not caspase-1, are needed for apoptosis induced by trophic factor deprivation in both naive and neuronal PC12 cells. Northern and Western blot analyses showed that PC12 cells express caspase-3. We therefore examined the involvement of caspase-3 in the death process of trophic factor-deprived PC12 cells. Our results showed that the pro-caspase-3 and its substrate poly-(ADP-ribose) polymerase are cleaved at similar rates in serum-deprived PC12 cells. Moreover, cell lysates prepared from these cells possess caspase-3-like activity, as determined by their ability to cleave the fluorogenic peptide substrate Ac-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin. These findings strongly suggest that caspase-3 or caspase-3-like proteases are activated in trophic factor-deprived PC12 cells.


Evolution of biliary complications after liver transplantation: a single European series.
The aim of this study was to analyze the evolution of biliary complications over 20 years among adult patients undergoing liver transplantation (OLT) at our institution. Between 1985 and 2007, we performed 1000 OLT in 789 adults and 211 children. To ascertain the evolution of biliary complications among adult OLT from October 1988 to September 2007, we compared the first 100 to with the last 200 adult OLT. Duct-to-duct was the most common biliary anastomosis performed in both periods (1st; 89% and 2nd; 94%; P = NS). However, a T-tube was used more frequently in the first period (1st; 46% vs 2nd; 6.6%; P < .001). The remaining cases underwent a hepaticojejunostomy (1st; 11% vs 2nd; 7.6%). Biliary complications were more frequent in the first period (1st; 20% vs 2nd; 9%; P < .01). In the first period, the use of a T-tube caused 32% of complications, all of them being bile leaks; but there were none in the second period. Arterial thrombosis or strictures were related to biliary complications in 10% and 33.3% among the first and second periods, respectively. The severity of complications according to the Clavien classification was similar in both periods: IIIa, 15% versus 33.3%; IIIb, 55% versus 55.5%; and IV, 15% versus 11.1%, respectively (P = NS). The biliary complication rate among adult patients post-OLT decreased over 20 years at our institution, probably owing to the abandonment of the routine use of a T-tube as well as to advances in immunosuppressive protocols, organ preservation, and preoperative patient management.


Decreased endopelvic fascia elastin content in uterine prolapse.
Genital prolapse is a debilitating manifestation of pelvic floor dysfunction. The cause of this condition has not been elucidated. The purpose of this study was to determine elastin content and RNA expression of related enzymes of elastin synthesis in uterosacral ligament biopsies from women with severe prolapse, and controls with normal pelvic support. Biopsies were taken from the uterosacral ligament tissue of 31 women with Grade III or greater prolapse and 29 women with normal pelvic support. Elastin content was assessed by measuring desmosine using radioimmunoassay, and quantitative real time PCR was performed to quantify mRNA levels of lysyl oxidase (LOX), lysyl oxidase like-1 (LOXL1), LOXL2 and fibulin-5 (FIB-5). The mean desmosine concentration found in uterosacral ligaments of women with prolapse (n =26) was 103.3+/-59.3 pmolD/mgP compared to controls (n =29) 120.5+/-47.4 pmolD/mgP (p =0.1943). In the subgroup of subjects with complete procidentia (n =8), mean desmosine concentration was 50.6+/-25.8 and 127.1+/-42.2 pmolD/mgP in age-matched controls (n =12) (p <0.05). In tissue from subjects with more than 2 vaginal deliveries (n =18), the mean desmosine concentration was 99.9+/-60.7 and 133.0+/-44.0 pmolD/mgP in controls (n =17) (p <0.05). Expression of LOX, LOXL1 and LOXL2 decreased 8.2-fold+/-3.4, 5.0-fold+/-1.7 and 15.2-fold+/-5.2, respectively (mean+/-SD) in cases versus controls (p<0.05). Expression of FIB-5 was increased 3.1-fold+/-0.7 compared to controls (p<0.05). Significantly decreased desmosine content was measured in the uterosacral ligament tissue from women with prolapse versus controls in women with parity >2 and in women with complete procidentia. Suppression of mRNA for LOX and two LOX isoenzymes was correspondingly present. These results suggest that altered elastin metabolism is present in women with uterine prolapse.


Efficacy and Safety of Sonic Hedgehog Inhibitors in Basal Cell Carcinomas: An Updated Systematic Review and Meta-analysis (2009-2022).
Basal cell carcinoma (BCC) of the skin is the most common form of skin cancer in the United States. In life-threatening, advanced BCC, sonic hedgehog inhibitors (SSHis) remain a pre-eminent treatment option for locally advanced BCC and metastatic BCC. In this updated systematic review and meta-analysis, we aimed to better characterize the efficacy and safety of SSHis by including final updates from pivotal clinical trials and additional new recent studies. An electronic database search was performed for articles including clinical trials, prospective case series, and retrospective medical record reviews on human subjects. Overall response rates (ORRs) and complete response rates (CRRs) were the primary outcomes. For safety assessment, the prevalence of the following adverse effects was analyzed: muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, myalgias, vomiting, skin squamous cell carcinoma, increased creatine kinase, diarrhea, decreased appetite, and amenorrhea. Analyses were performed using R statistical software. Data were pooled using linear models with fixed effects meta-analysis for primary analyses, along with 95% confidence intervals (CIs) and p-values. Intermolecular differences were calculated using Fisher's exact test. A total of 22 studies (N = 2384 patients) were included in the meta-analysis: 19 studies assessing both efficacy and safety, 2 studies assessing safety only, and 1 study assessing efficacy only. Overall, the pooled ORR for all patients was 64.9% (95% CI 48.2-81.6%), implicating there is at least a partial response (z = 7.60, p < 0.0001) in most patients receiving SSHis. The ORR for vismodegib was 68.5% and 50.1% for sonidegib. The most common adverse effects for vismodegib and sonidegib were muscle spasms (70.5% and 61.0%, respectively), dysgeusia (58.4% and 48.6%, respectively), and alopecia (59.9% and 51.1%, respectively). Patients were likely to experience weight loss (35.1%, p < 0.0001) from vismodegib. Alternatively, patients taking sonidegib experienced more nausea, diarrhea, increased creatine kinase levels, and decreased appetite compared with those receiving vismodegib. SSHis are an effective treatment for advanced BCC disease. Given the high discontinuation rates, management of patient expectations is warranted for compliance and achieving long-term efficacy. It is essential to stay updated with the latest discoveries on the efficacy and safety of SSHis.


Biosynthetic capacity of hepatocytes after storage at 4 degrees C.
Capacity to synthesize glucose, urea, and ketone bodies is well maintained in hepatocytes after storage for at least 24 h at 4 degrees C. Substrates and albumin are the only requirements.


Comparison of colloidal bismuth subcitrate tablets and liquid in duodenal ulcer healing.
A double-blind trial using 51 outpatients was aimed at comparing the effectiveness of colloidal bismuth subcitrate (C.B.S.) in tablet and liquid form in the healing of duodenal ulcer. Criteria of entry included endoscopically proven duodenal ulcer, duration of symptoms greater than 4 weeks, and the absence of other major systemic disease. Patients were given either C.B.S. tablets (1 four times daily) or C.B.S. liquid (5 ml four times daily) for 4 weeks. Ulcer symptoms and their relief were recorded by patients, along with data on cigarette, alcohol, and drug intake. Endoscopy was performed after 4 weeks to assess healing. By 4 weeks, 18 of 26 patients taking tablets (69%) and 19 out of 25 patients taking liquid (76%), had healed (p = 0.82). Symptomatic improvement was similar with both tablets and liquid. Smoking and analgesic ingestion did not influence healing rate. We conclude that C.B.S. tablets and liquid are equally effective in healing duodenal ulcer.


Core-Shell Imidazoline-Functionalized Mesoporous Silica Superparamagnetic Hybrid Nanoparticles as a Potential Theranostic Agent for Controlled Delivery of Platinum(II) Compound.
As widely used chemotherapeutic agents, platinum compounds have several therapeutic challenges, such as drug resistance and adverse effects. Theranostic systems, macromolecular or colloidal therapeutics with companion diagnostics, not only address controlled drug delivery but also enable real-time monitoring of tumor sites. Synthesis of magnetic mesoporous silica nanoparticles (MMSNs) was performed for dual magnetic resonance imaging and drug delivery. MMSN surfaces were modified by imidazoline groups (MMSN-Imi) for cisplatin (Cis-Pt) conjugation via free N-termini to achieve well-controlled drug-release kinetics. Cis-Pt adsorption isotherms and drug-release profile at pH 5 and 7.4 were investigated using inductively coupled plasma atomic emission spectroscopy. MMSN-Imi showed a specific surface area of 517.6 m2 g-1, mean pore diameter of 3.26 nm, and saturated magnetization of 53.63 emu/g. A relatively high r2/r1 relaxivity value was obtained for MMSN-Imi. The nanoparticles provided high Cis-Pt loading with acceptable loading capacity (~30% w:w). Sustained release of Cis-Pt under acidic conditions led to specific inhibitory effects on the growth of human epithelial ovarian carcinoma cells, determined using MTT assays. Dual acridine orange-propidium iodide staining was investigated, confirming induction of apoptosis and necrotic cell death. MMSN-Imi exhibited potential for applications in cancer chemotherapy and combined imaging.


An automated liver segmentation in liver iron concentration map using fuzzy c-means clustering combined with anatomical landmark data.
To estimate median liver iron concentration (LIC) calculated from magnetic resonance imaging, excluded vessels of the liver parenchyma region were defined manually. Previous works proposed the automated method for excluding vessels from the liver region. However, only user-defined liver region remained a manual process. Therefore, this work aimed to develop an automated liver region segmentation technique to automate the whole process of median LIC calculation. 553 MR examinations from 471 thalassemia major patients were used in this study. LIC maps (in mg/g dry weight) were calculated and used as the input of segmentation procedures. Anatomical landmark data were detected and used to restrict ROI. After that, the liver region was segmented using fuzzy c-means clustering and reduced segmentation errors by morphological processes. According to the clinical application, erosion with a suitable size of the structuring element was applied to reduce the segmented liver region to avoid uncertainty around the edge of the liver. The segmentation results were evaluated by comparing with manual segmentation performed by a board-certified radiologist. The proposed method was able to produce a good grade output in approximately 81% of all data. Approximately 11% of all data required an easy modification step. The rest of the output, approximately 8%, was an unsuccessful grade and required manual intervention by a user. For the evaluation matrices, percent dice similarity coefficient (%DSC) was in the range 86-92, percent Jaccard index (%JC) was 78-86, and Hausdorff distance (H) was 14-28 mm, respectively. In this study, percent false positive (%FP) and percent false negative (%FN) were applied to evaluate under- and over-segmentation that other evaluation matrices could not handle. The average of operation times could be reduced from 10 s per case using traditional method, to 1.5 s per case using our proposed method. The experimental results showed that the proposed method provided an effective automated liver segmentation technique, which can be applied clinically for automated median LIC calculation in thalassemia major patients.


A two-hybrid system reveals previously uncharacterized protein-protein interactions within the Helicobacter pylori NIF iron-sulfur maturation system.
Iron-sulfur (Fe-S) proteins play essential roles in all living organisms. The gastric pathogen Helicobacter pylori relies exclusively on the NIF system for biosynthesis and delivery of Fe-S clusters. Previously characterized components include two essential proteins, NifS (cysteine desulfurase) and NifU (scaffold protein), and a dispensable Fe-S carrier, Nfu. Among 38 proteins previously predicted to coordinate Fe-S clusters, two proteins, HP0207 (a member of the Nbp35/ApbC ATPase family) and HP0277 (previously annotated as FdxA, a member of the YfhL ferredoxin-like family) were further studied, using a bacterial two-hybrid system approach to identify protein-protein interactions. ApbC was found to interact with 30 proteins, including itself, NifS, NifU, Nfu and FdxA, and alteration of the conserved ATPase motif in ApbC resulted in a significant (50%) decrease in the number of protein interactions, suggesting the ATpase activity is needed for some ApbC-target protein interactions. FdxA was shown to interact with 21 proteins, including itself, NifS, ApbC and Nfu, however no interactions between NifU and FdxA were detected. By use of cross-linking studies, a 51-kDa ApbC-Nfu heterodimer complex was identified. Attempts to generate apbC chromosomal deletion mutants in H. pylori were unsuccessful, therefore indirectly suggesting the hp0207 gene is essential. In contrast, mutants in the fdxA gene were obtained, albeit only in one parental strain (26695). Taken together, these results suggest both ApbC and FdxA are important players in the H. pylori NIF maturation system.


Knockdown of ribosomal protein S7 causes developmental abnormalities via p53 dependent and independent pathways in zebrafish.
Ribosomal proteins (RPs), structural components of the ribosome involved in protein synthesis, are of significant importance in all organisms. Previous studies have suggested that some RPs may have other functions in addition to assembly of the ribosome. The small ribosomal subunits RPS7, has been reported to modulate the mdm2-p53 interaction. To further investigate the biological functions of RPS7, we used morpholino antisense oligonucleotides (MO) to specifically knockdown RPS7 in zebrafish. In RPS7-deficient embryos, p53 was activated, and its downstream target genes and biological events were induced, including apoptosis and cell cycle arrest. Hematopoiesis was also impaired seriously in RPS7-deficient embryos, which was confirmed by the hemoglobin O-dianisidine staining of blood cells, and the expression of scl, gata1 and α-E1 globin were abnormal. The matrix metalloproteinase (mmp) family genes were also activated in RPS7 morphants, indicating that improper cell migration might also cause development defects. Furthermore, simultaneously knockdown of the p53 protein by co-injecting a p53 MO could partially reverse the abnormal phenotype in the morphants. These results strengthen the hypothesis that specific ribosomal proteins regulate p53 and that their deficiency affects hematopoiesis. Moreover, our data implicate that RPS7 is a regulator of matrix metalloproteinase (mmp) family in zebrafish system. These specific functions of RPS7 may provide helpful clues to study the roles of RPs in human disease.


Analysis of P-glycoprotein expression in osteosarcoma.
Current treatment of high-grade osteosarcoma combines surgical removal of the lesion with chemotherapy. In this study we evaluated whether the expression of P-glycoprotein, a protein closely associated with multidrug resistance, may be helpful in identifying the patients whose tumours will be further resistant to specific agents. By using multidrug-resistant osteosarcoma cell lines as standards, the expression of P-glycoprotein was evaluated in 105 cases of primary and metastatic osteosarcoma by semiquantitative immunofluorescence. Overexpression of the protein was shown in 23% of primary and in 50% of metastatic lesions. In 38 cases, homogeneously treated and followed-up for at least 24 months, overexpression of P-glycoprotein appeared to be associated with a higher relapse rate and with a trend toward a worse outcome. These data support the role of P-glycoprotein in the response to chemotherapy and its involvement in the determination of the outcome of osteosarcoma patients.