Proteomics Analysis of Exosomes From Patients With Active Tuberculosis Reveals Infection Profiles and Potential Biomarkers.
Although mycobacterial proteins in exosomes from peripheral serum of patients with tuberculosis (TB) have been identified, other exact compositions of exosomes remain unknown. In the present study, a comprehensive proteomics analysis of serum exosomes derived from patients with active TB (ATB) was performed. Exosomes from patients with ATB were characterized using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and western blotting analysis. Then identified protein components were quantified by label-free proteomics and were determined via bioinformatics analysis. A total of 123 differential proteins were identified in ATB serum exosomes and analyzed with Gene Ontology (GO) analysis. Among these proteins heat shock protein70 (HSP70), CD81, major histocompatibility complex-I (MHC-I ) and tumor susceptibility gene101 (TSG101) were present in exosomes of ATB and normal individuals confirmed via western blotting. In addition, among identified exosomal proteins lipopolysaccharide binding protein (LBP) increased significantly, but CD36 and MHC-I decreased significantly in ATB exosomes. Meanwhile, MHC-I was down-expressed in serum and peripheral blood mononuclear cells (PBMCs) of ATB, but interestingly CD36 was down-regulated in serum and up-expressed in PBMCs of ATB patients validated with ELISA and flow cytometry. CD36 was up-regulated by M. tuberculosis H37Ra infection in macrophages and suppressed in exosomes from H37Ra infected macrophages detected by western blotting. This study provided a comprehensive description of the exosome proteome in the serum of patients with ATB and revealed certain potential biomarkers associated with TB infection.


Agonist and antagonist properties of serotonergic compounds in pigeons trained to discriminate either quipazine or L-5-hydroxytryptophan.
The serotonin (5-HT) receptor-related compounds metergoline, pirenperone, ketanserin, cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin were studied in pigeons trained to discriminate l-5-hydroxytryptophan (l-5-HTP) (18.0 mg/kg) from saline and in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline. Metergoline did not generalize to either quipazine or l-5-HTP but did antagonize drug-appropriate responding in both groups. Ketanserin potently blocked the quipazine discriminative stimulus and neither generalized to nor attenuated the l-5-HTP discriminative stimulus. Pirenperone, cinanserin, cyproheptadine, methylsergide, pizotyline and mianserin attenuated the quipazine discriminative stimulus at low doses and, at higher doses, generalized to the l-5-HTP discriminative stimulus. No antagonism of the l-5-HTP-discriminative stimulus or generalization to the quipazine-discriminative stimulus were observed with these compounds. A correlation coefficient of 0.93 was calculated between the potencies of 5-HT compounds to generalize to the l-5-HTP stimulus and the binding affinities of these compounds for a 5-HT1 receptor in rat brain. In addition, a correlation coefficient of 0.78 was calculated between the potencies of 5-HT compounds to attenuate the quipazine stimulus and the binding affinities of these compounds for the 5-HT2 receptor in rat brain. These observations suggest cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin are agonists at the 5-HT1 receptor in the l-5-HTP discrimination and antagonists at a 5-HT2 receptor in the quipazine discrimination in pigeons.


Root hypoxia reduces leaf growth : role of factors in the transpiration stream.
This study examined the potential role of restricted phloem export, or import of substances from the roots in the leaf growth response to root hypoxia. In addition, the effects of root hypoxia on abscisic acid (ABA) and zeatin riboside (ZR) levels were measured and their effects on in vitro growth determined. Imposition of root hypoxia in the dark when transpirational water flux was minimal delayed the reduction in leaf growth until the following light period. Restriction of phloem transport by stem girdling did not eliminate the hypoxia-induced reduction in leaf growth. In vitro growth of leaf discs was inhibited in the presence of xylem sap collected from hypoxic roots, and also by millimolar ABA. Disc growth was promoted by sap from aerated roots and by 0.1 micromolar ZR. The flux of both ABA and ZR was reduced in xylem sap from hypoxic roots. Leaf ABA transiently increased twofold after 24 hours of hypoxia exposure but there were no changes in leaf cytokinin levels.


An isotopic study of the effect of dietary carbohydrate on the metabolic fate of dietary leucine and phenylalanine.
The fate of dietary leucine and phenylalanine was studied in five healthy, young adult men, by using a dual, stable isotope-tracer infusion approach to estimate amino acid fluxes, splanchnic (Sp) uptake, and dietary of absorbed amino acid to the peripheral circulation. Subject received two, 4-h tracer infusions of [1-13C]leucine and [15N]phenylalanine infused through a feeding tube placed in the duodenum, and [5,5,5-2H3]leucine, [ring-2H5]phenylalanine, and [6,6-2H2]glucose infused simultaneously by vein. In one experiment subjects received an amino acid mixture (83 mg amino acid.kg-1.h-1) via the feeding tube and in the other experiment amino acids were supplied with carbohydrate (CHO) (167 mg.kg-1.h-1). Sp uptake of dietary leucine decreased with added dietary CHO (29% of ingested leucine for amino acids alone vs 20% with CHO; P < 0.05) but was not different for phenylalanine (P > 0.05). Addition of CHO decreased both release of leucine via protein breakdown and leucine oxidation and increased body leucine balance (P < 0.05).


Sarcomatoid renal cell carcinoma in a renal transplant recipient.
The incidence of transplanted kidneys derived from elderly donors is increasing because of the larger waiting lists and greater age of patients with end-stage renal failure. Compared with young donors, one of the problems is the heightened risk of neoplasm transmission. We report 2 cases of kidney recipients, both of whom developed a sarcomatoid renal cell carcinoma after receiving a kidney transplant from the same 68-year-old male donor, who did not show signs of a neoplasm on a previous abdominal ultrasound or a pretransplant biopsy. The first recipient was a 66-year-old woman who developed a kidney mass with several urologic obstructive complications, tumor dissemination, and death at 9 months after kidney transplantation. The second recipient was a 48-year-old asymptomatic man with normal renal function, who was studied after the results of the first recipient, revealing another renal tumor. Transplant nephrectomy was performed and a peritoneal implant was resected. The patient is alive without evidence of a neoplasm after 18 months. Herein we have discussed the mechanisms of neoplasm transmission in kidney transplantation and possible strategies for its prevention and treatment.


Depression as measured by the Beck Depression Inventory-II among injecting drug users.
This study conducts a confirmatory factor analysis of the Beck Depression Inventory-II (BDI-II) with a sample of 598 individuals who reported recent injecting drug use. Findings indicate that out of four models tested, the best model for this sample is a three-factor solution (somatic, affective, and cognitive) previously reported by Buckley, Parker, and Heggie. The findings that nearly 50% of participants provided BDI-II scores indicating significant depressive symptomatology reveals that these individuals are in need of treatment for their psychiatric symptoms as well as substance use. Somatic symptoms are endorsed more strongly than affective or cognitive symptoms of depression, suggesting a possible, but yet poorly defined, relationship between depressive symptomatology and drug use that centers on shared somatic symptomatology.


Copy-number variations associated with autism spectrum disorder.
Autism spectrum disorder (ASD) is a clinically heterogeneous developmental disorder with a strong genetic component. Rare genetic disorders and various chromosomal abnormalities are thought to account for approximately 10% of people with ASD. The etiology of the remaining cases remains unknown. Recent advances in array-based technology have increased the resolution in detecting submicroscopic deletions and duplications, referred to as copy-number variations. ASD-associated copy-number variations, which are considered to be present in individuals with ASD but not in unaffected individuals, have been extensively investigated. These data will provide us with an opportunity not only to search for genes causing or contributing to ASDs but also to understand the genetics of ASD.


The Association between Disproportionate Birth Weight to Placental Weight Ratio, Clinical Outcome, and Placental Histopathological Lesions.
High and low birth weight (BW) to placental weight (PW) ratios (BW/PW) have been proposed as markers of placental malfunction. We studied the association of clinical outcome and placental histopathology lesions with BW/PW ratios. During the period between 2008 and 2013, placentas from deliveries at gestational age (GA) ≥37 weeks, including both complicated and uncomplicated pregnancies, were sent for histopathology evaluation. Maternal and labor characteristics and pathological reports of the high BW/PW ratio group (>90th), normal BW/PW ratio group (10-90), and low BW/PW ratio group were compared (<10th). The BW/PW ratio increased as GA increased, with an average GA of 39.4 ± 1.2 weeks in the normal BW/PW ratio group (p < 0.001). Patients with diabetes mellitus and smokers were more common in the low BW/PW ratio group (p < 0.001). Placental maternal stromal vascular lesions and villitis of unknown etiology (VUE) were more common in the high BW/PW ratio group (p < 0.001 and p = 0.03, respectively). By logistic regression analysis, GA, placental maternal stromal vascular lesions, and VUE were found to be independently associated with a high BW/PW ratio, while diabetes mellitus and smoking were independently associated with a low BW/PW ratio. The BW/PW ratio increases significantly beyond 39th weeks, and is associated with an increased rate of placental maternal stromal vascular lesions and VUE.


Muscle emulation with DC motor and neural networks for biped robots.
This paper shows how to use a DC motor and its PID controller, to behave analogously to a muscle. A model of the muscle that has been learned by a NNARX (Neural Network Auto Regressive eXogenous) structure is used. The PID parameters are tuned by an MLP Network with a special indirect online learning algorithm. The calculation of the learning algorithm is performed based on a mathematical equation of the DC motor or with a Neural Network identification of the motor. For each of the two algorithms, the output of the muscle model is used as a reference for the DC motor control loop. The results show that we succeeded in forcing the physical system to behave in the same way as the muscle model with acceptable margin of error. An implementation in the knees of a simulated biped robot is realized. Simulation compares articular trajectories with and without the muscle emulator and shows that with muscle emulator, articular trajectories become closer to the human being ones and that total power consumption is reduced.


Reduced anxiety in the mice expressing mutant (N141I) presenilin 2.
Alzheimer's disease (AD) is characterized by progressive cognitive impairment. The effect of presenilin 1 (PS1) and PS2 mutation on cognition has been well characterized in a variety of transgenic mice. However, noncognitive behaviors have not been considered in these mice. In the present study, we found that transgenic mice expressing mutant PS2 (N141I) displayed decreased anxiety behavior determined by the elevated plus maze test and the light dark box test. However, these mice showed biphasic ambulatory activity (hyperactivity followed by hypoactivity) in an open field test. Correlated well with the reduced anxiety, expression of GABA(A)alpha(1) receptor was higher whereas c-Fos was lower in the cortex, hippocampus, and amygdala of the mice expressing PS2 mutation than those of the wild-type PS2 or nontransgenic control mice. These data indicate that PS2 mutation causes reduction of anxiety, and this effect may be related to the change of the expression of GABA(A)alpha(1) receptor and c-Fos. These findings could be useful in the understanding and the treatment of AD patients.


[Effects of combination of midazolam and propofol on anterograde amnesia in critical patients].
To observe the effects of sedation with midazolam and propofol on anterograde amnesia in critical patients. Sixty selected patients on mechanical ventilation in intensive care unit (ICU) were randomly divided into three subgroups (propofol, midazolam, and midazolam and propofol combination group), with 20 cases in each group. Patients who were awakened from sedation were showed with a card depicted with different colors, figures and numbers. When patients were totally conscious after weaning from mechanical ventilation,the influence of the different methods of sedation on anterograde amnesia of these critically ill patients was assessed. (1) 70%, 95% and 90% of patients manifested amnesia in propofol, midazolam and the combination group, respectively. All the patients recovered their memory immediately in 30 minutes after withdrawal of the sedatives. (2) When midazolam was compared with propofol and combination group, time of onset was obviously prolonged after an intravenous injection of a load dose in midazolam group [(2.7+/-1.1) minutes and (3.1+/-1.3) minutes vs. (5.1+/-2.8) minutes], also was time of extubation after regaining of consciousness [(0.7+/-0.2) hour and (1.2+/-0.6) hours vs. (2.7+/-0.3) hours, all P<0.01]. There was no significant difference between propofol group and the combination group in time of onset and extubation (both P>0.05). (3) Cost of propofol [(2,100+/-125) yuan] was 75% higher than that of midazolam [(1,200+/-112) yuan, P<0.01], but cost of sedatives in the combination group [(1,300+/-132) yuan] was similar to that in midazolam group (P>0.05). Combination of midazolam and propofol can not only ensure anterograde amnesia in critical patients, reduce drug dosage and adverse reactions, but also can help reduce the hospital expenses. This method may be a better sedation program in ICU.


Epidemiologic data on vulvar cancer: comparison of hospital with population-based data.
Data on vulvar cancer are subject to a possible selection bias because older patients with vulvar cancer are sometimes not referred to specialized centers. The aim of this study was to compare the variables obtained from the population as a whole with variables obtained from referral and nonreferral hospitals. Population-based data on age, stage, histological type, and treatment modality were registered for 138 patients with vulvar cancer. The characteristics of the patients who were referred to a gynecologic oncology center were compared with those of the patients treated in nonreferral hospitals. The age-adjusted incidence was 2.3 per 100,000 women. Basal cell cancer was less common in the referral center than in the nonreferral centers (3% versus 28%). No difference was found in FIGO stage distribution in the different subgroups. Groin node dissection was omitted in 80% of the patients not referred to a center. Omission of groin node dissection was more common in patients older than 74 years (P = 0.002). Population-based data on vulvar cancer differ significantly from hospital-based data and give better insight into the real characteristics of patients with vulvar cancer.


Cosmetic Procedure Screening Questionnaire (COPS): creation and validation of the Polish language version.
Body dysmorphic disorder (BDD) is a disabling mental disorder characterized by excessive preoccupation with appearance. Trying to fix imagined defects many individuals with BDD search for aesthetic dermatology treatments. Due to omitting preliminary evaluation for BDD in subjects undergoing cosmetic procedures and lack of proper diagnostic tools among this group of individuals, the results of such interventions may face their disapproval and disappointment. To translate and validate the Polish version of a Cosmetic Procedure Screening Questionnaire (COPS), which can be used in a cosmetic procedure setting to screen patients suspected to be suffering from BDD. Both forward and backward translations of the original English version of the questionnaire to Polish were performed in accordance with international standards. The validation was conducted on 33 individuals undergoing aesthetic procedures, who completed the questionnaire twice with 3-6 days' interval. Moreover, the subjects were also asked to fill the Polish versions of BIQLI (Body Image Quality of Life Inventory) and HADS (Hospital Anxiety and Depression Scale) for convergent validity procedure. The Polish version of COPS demonstrated good internal consistency (Cronbach α coefficient value of 0.76) and reproducibility (Intraclass Correlation Coefficient, ICC, of 0.79). COPS correlated strongly with BIQLI (r = -0.66, p < 0.01) as well as with HADS, in both depression and anxiety subscales (r = 0.68, p < 0.01 and r = 0.66, p < 0.01, respectively). The Polish version of the COPS questionnaire showed sufficient internal consistency and reliability. It can be used for BDD screening among the Polish speaking subjects undergoing aesthetic dermatology procedures.


[Terrorists' target World Cup 2006: disaster medicine on the sidelines?! Aspects of hospital disaster planning].
Focussing on possible mass casualty situations during events such as the soccer world championship in 2006, the Professional Board of Surgeons in Germany and the German Society for Surgery canvassed surgeons-in-chief in the last quarter of 2003 concerning disaster plans for hospitals. The rate of returned questionnaires amounted to 26% covering the following areas of interest: plans-ready to use, known by the employees as well as by the rescue coordination center, performance of exercises, and concepts on decontamination and detoxification. Based on past numbers of casualties during soccer disasters, an excursus into details also includes a description of an approach to reduce the danger of bottleneck effects at doors. A preliminary concept based on the upcoming system for funding hospitals in Germany and including new partnerships is outlined, succeeded by some hopefully helpful hints for a web-based hospital disaster plan.


Single-locus latitudinal clines and their relationship to temperate adaptation in metabolic genes and derived alleles in Drosophila melanogaster.
We report a study in Drosophila melanogaster of latitudinal clines for 23 SNPs embedded in 13 genes (Pgi, Gapdh1, UGPase, Pglym78, Pglym87, Eno, Men, Gdh, Sod, Pgk, Mdh1, TreS, Treh) representing various metabolic enzymes. Our samples are from 10 populations spanning latitude from southern Florida to northern Vermont. Three new clines with latitude were detected. These are the amino acid polymorphisms in the NAD-dependent glutamate dehydrogenase (Gdh) and trehalase (Treh) genes, and a silent site polymorphism in the UDP-glucose pyrophosphorylase gene (UGPase). The result, when combined with the overall incidence and pattern of reports for six other genes (Adh, Gpdh, Pgm, G6pd, 6Pgd, Hex-C), presents a picture of latitudinal clines in metabolic genes prevalent around the branch point of competing pathways. For six of the seven amino acid polymorphisms showing significant latitudinal clines in North America, the derived allele is the one increasing with latitude, suggesting temperate adaptation. This is consistent with a model of an Afrotropical ancestral species adapting to temperate climates through selection favoring new mutations.


Biomarkers to Distinguish Bacterial From Viral Pediatric Clinical Pneumonia in a Malaria-Endemic Setting.
Differential etiologies of pediatric acute febrile respiratory illness pose challenges for all populations globally, but especially in malaria-endemic settings because the pathogens responsible overlap in clinical presentation and frequently occur together. Rapid identification of bacterial pneumonia with high-quality diagnostic tools would enable appropriate, point-of-care antibiotic treatment. Current diagnostics are insufficient, and the discovery and development of new tools is needed. We report a unique biomarker signature identified in blood samples to accomplish this. Blood samples from 195 pediatric Mozambican patients with clinical pneumonia were analyzed with an aptamer-based, high-dynamic-range, quantitative assay (~1200 proteins). We identified new biomarkers using a training set of samples from patients with established bacterial, viral, or malarial pneumonia. Proteins with significantly variable abundance across etiologies (false discovery rate <0.01) formed the basis for predictive diagnostic models derived from machine learning techniques (Random Forest, Elastic Net). Validation on a dedicated test set of samples was performed. Significantly different abundances between bacterial and viral infections (219 proteins) and bacterial infections and mixed (viral and malaria) infections (151 proteins) were found. Predictive models achieved >90% sensitivity and >80% specificity, regardless of number of pathogen classes. Bacterial pneumonia was strongly associated with neutrophil markers-in particular, degranulation including HP, LCN2, LTF, MPO, MMP8, PGLYRP1, RETN, SERPINA1, S100A9, and SLPI. Blood protein signatures highly associated with neutrophil biology reliably differentiated bacterial pneumonia from other causes. With appropriate technology, these markers could provide the basis for a rapid diagnostic for field-based triage for antibiotic treatment of pediatric pneumonia.


Chemotherapy as Adjuvant Treatment for Intermediate-High Risk Early-Stage Endometrial Cancer: A Pilot Study.
This study aimed to assess primarily the role of chemotherapy as adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA G3, IB G2-G3, and II endometrial cancer (EC) in terms of disease-free interval and overall survival, and secondarily, the rate of local and distant recurrence. The present prospective pilot study includes 68 patients with surgical staged EC who referred between 2007 and 2011 to the Division of Gynecologic Oncology at the University Campus Bio-Medico of Rome. All enrolled patients received adjuvant chemotherapy every 3 weeks according to the scheme carboplatin, dosed at an area under the curve of 6, and paclitaxel 175 mg/mq given every 3 weeks for at least 3 cycles. The median number of chemotherapy cycles was 6 (range, 3-6 cycles). Chemotherapy was well tolerated. The 3-year overall survival was 92.8% and 91.6% for stages I and II, respectively. The 3-year disease-free interval was 91.8% and 83.3% for stages I and II, respectively. Of 68 patients, 7 (10.3%) relapsed: 5 patients with a FIGO stage I and 2 patients with FIGO stage II EC. Platinum-based chemotherapy is feasible and safe and it could be used in adjuvant setting for early-stage ECs. Although its effectiveness is comparable to radiotherapy, chemotherapy represents an excellent treatment option due to its systemic action. Further randomized studies will be needed to confirm our promising data.


Mycobacteria-induced granuloma necrosis depends on IRF-1.
In a mouse model of mycobacteria-induced immunopathology, wild-type C57BL/6 (WT), IL-18-knockout (KO) and IFN-alphabeta receptor-KO mice developed circumscript, centrally necrotizing granulomatous lesions in response to aerosol infection with M. avium, whereas mice deficient in the IFN-gamma receptor, STAT-1 or IRF-1 did not exhibit granuloma necrosis. Comparative, microarray-based gene expression analysis in the lungs of infected WT and IRF-1-KO mice identified a set of genes whose differential regulation was closely associated with granuloma necrosis, among them cathepsin K, cystatin F and matrix metalloprotease 10. Further microarray-based comparison of gene expression in the lungs of infected WT, IFN-gamma-KO and IRF-1-KO mice revealed four distinct clusters of genes with variable dependence on the presence of IFN-gamma, IRF-1 or both. In particular, IRF-1 appeared to be directly involved in the differentiation of a type I immune response to mycobacterial infection. In summary, IRF-1, rather than being a mere transcription factor downstream of IFN-gamma, may be a master regulator of mycobacteria-induced immunopathology.


Characteristics of 3,5,3'-triiodothyronine sulfate metabolism in euthyroid man.
The sulfated conjugate of T3 (T3S) has long been recognized as a normal product of peripheral thyroid hormone metabolism. In order to better understand the role that T3S may play in this process, the metabolic handling of T3S was studied in euthyroid man. After the iv administration of [125I]T3S in man, T3S was found to be rapidly metabolized with estimated mean MCR of 135 +/- 15 liters/day (L/D) after a bolus injection and 127 +/- 8 L/D employing a constant infusion. The primary route of T3S disposal was by deiodination with an efficiency of 92%. The administration of propylthiouracil (PTU, 300 mg every 6 h x 5 days) and iopanoic acid (IA, 500 mg every day x 5 days), both inhibitors of deiodination, decreased clearance compared to control (87 +/- 9 L/D, P less than 0.01 and 46 +/- 10 L/D, P less than 0.002, respectively). A 3-day fast also reduced the clearance of T3S (56 +/- 10 L/D, P less than 0.002). All three maneuvers decreased the total urinary deiodination fraction of tracer T3S (control 91 +/- 2%, PTU 70 +/- 9%, P less than 0.04, IA 26 +/- 3%, P less than 0.0001, and fasting 58 +/- 6%, P less than 0.01). A strong correlation between T3S clearance and deiodination was noted for fasting and IA only (r = 0.78, P less than 0.003). However, no relationship between clearance and deiodination was noted with PTU administration presumably as a result of a compensatory increase in biliary losses of T3S. The urinary thyronine excretion pattern demonstrated the presence of small amounts of labeled T3,3,3'-T2, and 3,3'-T2S with the major metabolite being T3S itself. TSH levels were not influenced by the infusion of stable T3S designed to achieve a serum value greater than 50 ng/dL. No absorption of intact T3S was detected after its oral ingestion. In conclusion, T3S is rapidly cleared from the serum, primarily by deiodination, may undergo nondeiodinative disposal when hepatic deiodination is inhibited by PTU but not with IA or fasting, and has no intrinsic biological activity. Thus, T3S may serve as a metabolite of T3 for its rapid deiodinative disposal. Although the precise role T3S plays in human thyroid hormone metabolism has not been defined, the metabolic characteristics of T3S appear similar to that of an unidentified alternate T4 metabolite formed in low T3 states of fasting and nonthyroidal illness.


Antiseptic Povidone-Iodine Heals the Grain Boundary of Perovskite Solar Cells.
Povidone, also know as polyvinylpyrrolidone (PVP), is used as a reservoir for iodine, and the povidone-iodine (PVP-I) complex has antiseptic properties for wound healing by releasing iodine. In this report, we utilized this unique characteristic of PVP-I to heal the photovoltaic parameters of perovskite solar cells (PSCs). PVP-I was added in the perovskite precursor solution, where the effect of the PVP-I concentration on the photovoltaic performance was investigated. The power conversion efficiency (PCE) of PSC was enhanced from 20.73% to 22.59% by addition of 0.1 mg/mL PVP-I, mainly due to an improved fill factor from 0.76 to 0.80 together with a slight increase in current density. Scanning electron microscopy revealed that the grain boundaries were passivated by PVP-I. Conductive atomic force microscopy combined with time-resolved photoluminesence and space charge-limited current studies showed that the addition of PVP-I decreased the defect density of the perovskite film together and enhanced the film conductivity. Furthermore, better stability was observed from the PVP-I-treated PSCs than the control device without the additive, which is probably owing to the grain boundary healing effect.


A novel chemiluminescence system for the determination of daidzein and its hydroxyl radical-scavenging capacity.
A novel chemiluminescence (CL) system was established for the determinations of daidzein in pharmaceutical preparations and to assess its ability to scavenge hydroxyl radicals. It was shown that a strong CL signal generated when eosin Y was mixed with Fenton reagent was decreased significantly when daidzein was added to the reaction system due to partial scavenging of the hydroxyl radicals in the solution. The extent of decrease in the CL intensity had a good stoichiometric relationship with the daidzein concentration. Based on this, we developed a new method for the determination of daidzein, using a flow-injection chemiluminescence (FI-CL) technique. Under the optimal conditions, the linear range of daidzein concentration was 8.0 × 10(-8) -3.0 × 10(-6) mol/L (R = 0.9982), with a detection limit of 9.0 × 10(-9) mol/L (S:N = 3), and the RSD was 5.8% for 1.0 × 10(-6) mol/L daidzein (n = 11). This method was successfully used in the determination of daidzein in tablets and for evaluation of the hydroxyl radical-scavenging capacity of daidzein. The possible reaction mechanism of the CL system is discussed.


Secretory profile of immunoreactive growth hormone-releasing hormone (IR-GHRH) during sleep in man and its clinical value.
To clarify the role of growth hormone-releasing hormone (GHRH) in the regulation of the episodic growth hormone (GH) secretion which is known to occur constantly in the initial slow wave stage of nocturnal sleep in man, we studied the relation between the secretions of plasma immunoreactive(IR)-GHRH and GH while recording electroencephalograms. In subjects who showed a normal sleep pattern, the plasma IR-GHRH level increased 3- to 4-fold just before the surge of plasma GH, suggesting that GH release in the initial slow wave stage of sleep is mainly mediated by GHRH. However, when there was an apparent GH surge just before the onset of sleep, the magnitude of the GH response associated with the initial slow wave stage tended to be blunted, even when sufficient IR-GHRH was released. We also observed no appreciable fluctuations of plasma IR-GHRH during nocturnal sleep in a patient diagnosed as having GH-deficient dwarfism, suggesting the primary lesion was on the hypothalamus level, not the pituitary, in such a patient. In a case of multiple endocrine neoplasia (MEN) type I with an ectopic (GHRH-producing pancreatic tumor, no remarkable elevation of plasma IR-GHRH was detected in the initial slow wave stage of nocturnal sleep. We conclude that the present study is significant not only in demonstrating the physiology of GHRH release, but also in establishing a safe, reliable and practical test for routine clinical use to investigate intrinsic ability to release GHRH and the primary lesions in patients with disorders of GH secretion.


Perspectives in sequential pneumatic compression of the lower extremities (SCD) for laparoscopic surgery.
During most cases of laparoscopic surgery, a pneumoperitoneum of 12-14 mm Hg CO2 is established. Although not always detected in healthy patients, a pneumoperitoneum will cause clinically relevant pathophysiological changes. Among other side effects, a pneumoperitoneum will alter the venous blood return from the lower extremities and depress cardiac function. Results from experimental and clinical studies concerning the influence of a pneumoperitoneum on venous blood return and cardiac function are reviewed and a simple model of cardiac function impairment during laparoscopic surgery with a pneumoperitoneum is presented. Sequential pneumatic compression of the lower extremities is effective in reducing venous stasis during and after conventional surgery. Several clinical trials determined the hemodynamic effect of intraoperative SCD (sequential compression device) during laparoscopic surgery. In the following text the results of these studies are summarized and possible implications for the clinical use of SCD in laparoscopic surgery are discussed. Although potential benefits of SCD-therapy have been shown only in studies of low methodological quality, intraoperative SCD-therapy is recommended during prolonged laparoscopic surgery.


Impact of thoracic computed tomography on radiation therapy planning in Hodgkin disease.
Over 5 years, CT of the thorax was performed on 53 patients with Hodgkin disease and mediastinal lymphadenopathy prior to the institution of therapeutic irradiation. Information obtained from CT prompted major alterations in the plan of therapy in 11 of 53 (21%) of the patients. These included changes of treatment portal size, the addition of localized boost therapy, and a revision of diagnosis.


Intra-articular Injections of Hyaluronic Acid on Osteochondral Lesions of the Talus After Failed Arthroscopic Bone Marrow Stimulation.
The purpose of the study was to compare clinical and functional outcomes before and after hyaluronic acid (HA) injections in patients with osteochondral lesions of the talus who experienced a failure of their primary treatment with arthroscopic microfracture surgery. A total of 40 patients were included in the final study. These patients had received microfracture surgery but continued to experience postoperative pain over an average of 13.0 months (range, 0-81 months) and were available for investigation with a mean follow-up for 29.1 months (SD 14.7; range 2.6-79.6 months). All patients received intra-articular injections of HA once per week for 3 weeks. We assessed clinical and functional outcomes before and after injection using the American Orthopaedic Foot & Ankle Society (AOFAS) score, Foot and Ankle Outcome Score (FAOS), Short Form Health Survey (SF-36), the visual analog scale (VAS) for pain, and the Alexander subjective scale. The AOFAS score significantly increased from 50.7 ± 13.8 to 79.9 ± 13.8 and the FAOS scores for symptom, pain, daily living, and sports were significantly higher postinjection compared to preinjection (all P < .001). Similarly, the mean VAS for pain was significantly decreased after 6 weeks following injection and continued to decrease over the follow-up period; the mean VAS was significantly lower postinjection compared to preinjection at 12 months (P < .001). Intra-articular HA injections on average significantly improved clinical and functional scores after failed primary operative treatment. HA injections may provide an alternative to secondary operative treatment and provide better clinical outcomes than other conservative treatments. Level II, prospective observational cohort study.


Fasciola hepatica: comparison of immature and mature immunoreactive glycoproteins.
A comparison of the 35S-methionine metabolically labelled immunoreactive glycoproteins of immature and mature F. hepatica was carried out by one-and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Sera of rabbits infected for 3 weeks reacted much more strongly with glycoproteins of immature flukes than with glycoproteins of mature flukes as compared to sera of rabbits infected for 9 weeks. Several of the immunoreactive glycoproteins were also released by immature F. hepatica into the culture medium. At least one was a component of the T1 type granules. Analysis of the in vitro translation products of mature F. hepatica indicated that the initial humoral immune response of rabbit hosts may be directed against carbohydrate moieties.


Necrotizing fasciitis of the chest wall.
Necrotizing fasciitis (NF) is an uncommon infection caused by microorganisms called 'flesh eating bacteria'. It remains a life-threatening condition associated with high mortality rate. Its location to the chest wall is exceptional. Herein, we report the case of a 39-year-old female, without comorbidity, presenting a NF of the chest wall complicating an empyema. We describe the surgical management with a three-step procedure: antibiotherapy-debridement, vacuum-assisted closure and delayed surgical reconstruction.


[Imported dengue fever following a stay in the tropics].
We report on a tourist returning from Thailand, who presented with classical dengue fever. While in Thailand a 36-year-old Swiss female laboratory assistant suddenly developed fever, devastating headache, retro-ocular pain, myalgia and arthralgia, photophobia, nausea and diarrhea. In addition she suffered from epistaxis, urogenital and skin bleeding, and a morbilliform exanthema. After her return to Switzerland we noted lymphadenopathy and splenomegaly, enanthema and laboratory findings of mild hepatitis, thrombocytopenia and leukopenia. The diagnosis of dengue virus infection was verified serologically. Apart from a long lasting convalescent asthenia we observed restitutio ad integrum within days under symptomatic therapy. Epidemiological clinical and diagnostic aspects of dengue virus infection are discussed.


Granulomatous and eccrinotropic lymphomatoid papulosis.
Lymphomatoid papulosis has been classically described as a chronic, recurrent and self-healing papulonecrotic or papulonodular skin eruption, which is clinically benign and histopathologically malignant. The histologic characteristics of lymphomatoid papulosis are suggestive of a cluster of differentiation 30+ (CD30+) malignant lymphoma, and it is best regarded as a low grade cutaneous T cell lymphoma (CTCL). We hereby report a case of granulomatous and eccrinotropic lymphomatoid papulosis in a 40- year-old male. There was no systemic involvement. The patient was treated with low dose oral methotrexate with good response.


Management of vascular access for hemodialysis after successful kidney transplantation.
There is a lack of data concerning the fate of arterio-venous fistulas (AVF) after successful kidney transplantation. The objective of this study was to assess the evolution of AVF in transplanted patients and to discuss the management of such vascular access once dialysis has been stopped. We reviewed 160 renal transplant patients who had undergone an AVF 0 to 312 months (mean 29) before transplantation. 136 (85%) of AVF were created in the forearm/wrist region and 21 (13%) at the elbow. The mean follow-up was 69 months from renal transplantation and 95 months from constitution of the AVF. Vascular access had to be closed in 7.5% of cases. Thrombosis occurred in 31% of cases, mainly in distal fistulas (85%). AVF was still functional in 61% of patients at the end of follow-up. AVF remains functional in the majority of patients after renal transplantation and is not usually associated with any significant morbidity. Systematic closure of AVF does not seem warranted as it would deprive patients of a useful vascular access should dialysis become again necessary in the long term.


Clearance of autophagy-associated dying retinal pigment epithelial cells - a possible source for inflammation in age-related macular degeneration.
Retinal pigment epithelial (RPE) cells can undergo different forms of cell death, including autophagy-associated cell death during age-related macular degeneration (AMD). Failure of macrophages or dendritic cells (DCs) to engulf the different dying cells in the retina may result in the accumulation of debris and progression of AMD. ARPE-19 and primary human RPE cells undergo autophagy-associated cell death upon serum depletion and oxidative stress induced by hydrogen peroxide (H2O2). Autophagy was revealed by elevated light-chain-3 II (LC3-II) expression and electron microscopy, while autophagic flux was confirmed by blocking the autophago-lysosomal fusion using chloroquine (CQ) in these cells. The autophagy-associated dying RPE cells were engulfed by human macrophages, DCs and living RPE cells in an increasing and time-dependent manner. Inhibition of autophagy by 3-methyladenine (3-MA) decreased the engulfment of the autophagy-associated dying cells by macrophages, whereas sorting out the GFP-LC3-positive/autophagic cell population or treatment by the glucocorticoid triamcinolone (TC) enhanced it. Increased amounts of IL-6 and IL-8 were released when autophagy-associated dying RPEs were engulfed by macrophages. Our data suggest that cells undergoing autophagy-associated cell death engage in clearance mechanisms guided by professional and non-professional phagocytes, which is accompanied by inflammation as part of an in vitro modeling of AMD pathogenesis.


A multicenter assessment of the use of single-photon emission computed tomography myocardial perfusion imaging with appropriateness criteria.
The aim of this study was to assess the feasibility of evaluation for appropriate use of radionuclide myocardial perfusion imaging (MPI) in multiple clinical sites and to determine use patterns as well as identify areas of apparent inappropriate use. Although cardiac imaging is highly valued for decision-making, the growth and expense related to these procedures has raised questions regarding overuse. The publication of appropriate use criteria (AUC), including those for MPI, were designed to provide guidance in the rational use of testing. However, limited data regarding the implementation and evaluation of AUC are available. Six diverse clinical sites enrolled consecutive patients undergoing MPI, collecting point-of-service data entered into an online form. An automated algorithm assigned a specific indication from the AUC that was classified as appropriate, uncertain, or inappropriate. Site-specific feedback was later provided to each practice on ordering patterns. Of the 6,351 patients enrolled, 93% were successfully assigned an appropriateness level. Inappropriate use of MPI was found in 14.4% of patients, with a range of 4% to 22% among practices. Women and younger patients were more likely to undergo inappropriate MPI. Asymptomatic, low-risk patients accounted for 44.5% of inappropriate testing. Elimination of the 5 most common inappropriate use indications would reduce overall imaging volume by 13.2%. Inappropriate use by physicians from within the practice performing imaging was not greater than physicians outside of the practice. Educational feedback might have resulted in reduced inappropriate test ordering in 1 site. The tracking of appropriate use is feasible in clinical practice, with an automated system that can readily identify practice patterns and targets for educational and quality improvement initiatives. This approach might provide an alternative to utilization management.


Activation of a truncated PR-1 promoter by endogenous enhancers in transgenic plants.
PR-1 genes are induced by various environmental stimuli such as pathogen attack or exposure of the plants to certain chemicals. To examine the regulation of these genes, the 5' flanking regions of the PR-la gene and of two PR-1 pseudogenes were joined by a transcriptional fusion to the Escherichia coli beta-glucuronidase (GUS) gene. These constructs were stably integrated into the tobacco genome and independent primary transformants were monitored for the expression of the reporter gene. Unexpectedly, out of 55 transformants analysed, four plants exhibited considerable GUS activities without any inductive treatment of the plants. Expression of the endogenous PR-1 genes, however, could not be detected in these plants. Primer extension analyses revealed correct initiation of the PR1/GUS hybrid transcripts from the PR-1a TATA box. When the plants were analysed at the cellular level, clear differences regarding the tissue specificity of expression of the reporter gene were observed. These results strongly suggest that the PR1/GUS hybrid promoter expression cassettes may be activated when integrated in the vicinity of heterologous enhancer elements dispersed in the tobacco genome. In order to support this hypothesis, domain B of the enhancer of the 35S RNA promoter from cauliflower mosaic virus (CaMV) was fused to various PR1/GUS hybrid genes upstream as well as downstream from the RNA start site. These constructs were stably introduced into the tobacco genome. In any primary transformant analysed, strong GUS activities were observed with the PR1/GUS hybrid RNAs originating from the normal transcription start site of the PR-1a gene. The tissue specificity of gene expression was identical to that described previously for the CaMV 35S domain B enhancer element. Thus, modulations of the transcriptional activity of the PR-1 promoter can be achieved by heterologous enhancers in transgenic plants and may be encountered upon random integration of PR-1 promoter constructs into the tobacco genome.


Chymase participates in chronic dermatitis by inducing eosinophil infiltration.
An epicutaneous application of 2,4-dinitrofluorobenzene (DNFB) to a mouse ear caused a transient skin swelling, and the repetition of the challenge enlarged the contact dermatitis. The repeated challenge with DNFB also induced eosinophil infiltration on the application site. Administration of a chymase inhibitor significantly inhibited the ear swelling as well as eosinophil accumulation. An intradermal injection of human chymase to the mouse ear also elicited transient skin swelling and eosinophil infiltration, both of which were augmented in proportion to the number of injections. Human serum albumin and heat-inactivated chymase failed to induce such skin reactions, suggesting the participation of proteolytic activity of the enzyme. In addition, chymase stimulated eosinophil migration in vitro in a concentration-dependent manner. Taken together, these observations suggest that mast cell chymase may contribute to development of the DNFB-induced dermatitis, probably by promoting eosinophil infiltration. It is therefore possible that chymase plays a role in pathogenesis of chronic dermatitis such as atopic dermatitis.


Posttransplantation cyclophosphamide vs. antithymocyte globulin as GVHD prophylaxis for mismatched unrelated hematopoietic stem cell transplantation.
Posttransplant cyclophosphamide (PT-Cy) is an efficient GVHD prophylaxis but has not been extensively evaluated in mismatched unrelated donor (MMUD) allo-HSCT, for which antithymocyte globulin (ATG) is still considered as a standard. Thus, we evaluated the outcome of MMUD allo-HSCT with PT-Cy (n = 22) and performed a historical comparison with a control group receiving ATG (n = 40) in a single center experience. Compared with the ATG group, the risk of grade 2-4 acute GVHD was significantly lower in the PT-Cy group (HR = 0.12, 95% CI = [0.03-0.48], p = 0.002). No difference was observed in the cumulative incidence of chronic GVHD. The risk of both NRM and relapse was significantly lower in the PT-Cy group (NRM: HR = 0.05, 95% CI = [0.00-0.63], p = 0.021; relapse: HR = 0.31; 95% CI = [0.09-1.10], p = 0.07). Thus, we observed significantly better PFS (HR = 0.22, 95% CI = (0.07-0.65); p = 0.006), OS (HR = 0.24, 95% CI = (0.07-0.84); p = 0.026), and GRFS (HR = 0.37, 95% CI = (0.17-0.80); p = 0.011) in the PT-Cy group. We conclude that PT-Cy is an effective GVHD prophylaxis in the setting of MMUD allo-HSCT, resulting in a better outcome compared with standard prophylaxis using ATG. This suggests that as it was shown in the setting of haploidentical allo-HSCT, the use of PT-Cy can overcome the impact of HLA disparity, leading to promising survivals that approach those observed after HLA matched allo-HSCT.


Chronic Antiplatelet Use Associated With Increased Blood Loss in Lumbar Spinal Surgery Despite Adherence to Protocols.
There are conflicting reports regarding postoperative bleeding risks associated with discontinuation of antiplatelet therapy at least 7 days preoperatively. Most of the studies in the spine literature are based on surveys or anecdotal evidence. The majority of surgeons discontinue therapy 7 days preoperatively, but this varies widely from 5 to 21 days. The purpose of this retrospective study was to assess whether chronic antiplatelet use is associated with increased intraoperative blood loss, need for transfusion, and perioperative complications. Of 454 patients who underwent elective lumbar spinal surgery, 85 were on antiplatelet therapy and 369 were not. All patients stopped antiplatelet therapy at least 7 days preoperatively with approval from their cardiologist or primary care provider. Multiple regression analysis was performed and corrected for age, sex, antiplatelet therapy, number of levels decompressed/fused/instrumented, preoperative hematocrit, and postoperative hematocrit. Results showed that preoperative antiplatelet therapy, despite at least 7 days of discontinuation, is a statistically significant predictor (P=.04) of increased intraoperative blood loss. Blood transfusion was not associated with antiplatelet use but was associated with the number of levels fused, age, and low preoperative hematocrit (all P<.01). There were no recorded complications in either group. The authors conclude that antiplatelet therapy is associated with an increased risk of intraoperative blood loss in spine patients despite discontinuation at least 7 days preoperatively, but the clinical significance of this is unclear given the lack of association with blood transfusions and perioperative complications. [Orthopedics. 2016; 39(4):e695-e700.].


Silanediol-catalyzed carbon dioxide fixation.
Carbon dioxide is an abundant and renewable C1 source. However, mild transformations with carbon dioxide at atmospheric pressure are difficult to accomplish. Silanediols have been discovered to operate as effective hydrogen-bond donor organocatalysts for the atom-efficient conversion of epoxides to cyclic carbonates under environmentally friendly conditions. The reaction system is tolerant of a variety of epoxides and the desired cyclic carbonates are isolated in excellent yields.


Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults.
Sensory hair cells receive near constant stimulation by omnipresent auditory and vestibular stimuli. To detect and encode these stimuli, hair cells require steady ATP production, which can be accompanied by a buildup of mitochondrial byproducts called reactive oxygen species (ROS). ROS buildup is thought to sensitize hair cells to ototoxic insults, including the antibiotic neomycin. Work in neurons has shown that neurotransmission is a major driver of ATP production and ROS buildup. Therefore, we tested whether neurotransmission is a significant contributor to ROS buildup in hair cells. Using genetics and pharmacology, we disrupted two key aspects of neurotransmission in zebrafish hair cells: presynaptic calcium influx and the fusion of synaptic vesicles. We find that chronic block of neurotransmission enhances hair-cell survival when challenged with the ototoxin neomycin. This reduction in ototoxin susceptibility is accompanied by reduced mitochondrial activity, likely due to a reduced ATP demand. In addition, we show that mitochondrial oxidation and ROS buildup are reduced when neurotransmission is blocked. Mechanistically, we find that it is the synaptic vesicle cycle rather than presynaptic- or mitochondrial-calcium influx that contributes most significantly to this metabolic stress. Our results comprehensively indicate that, over time, neurotransmission causes ROS buildup that increases the susceptibility of hair cells to ototoxins.


Activation of T Cells by Autoantigen Immobilized by Specific Antibodies
A convenient microtiter-plate assay that uses immobilized antibody to capture specific antigens for presentation to T cells has been developed. Initial experiments used KLH as the antigen, immune antisera and draining lymph node cells from immunized NOD mice as the source of antibody and T cells, and spleen cells from naive NOD mice as the source of antigen-presenting cells (APCs). The resulting proliferation of the T cells was shown to be antibody- and antigen-specific, suggesting that the APCs had internalized and processed the captured antigen, presenting it to the T cells in the form of peptide/MHC complexes. The approach was also tested for an autoimmune disease as part of an effort to identify autoantigens responsible for the proliferation of T cells in the synovial fluid of rheumatoid arthritis patients. When immunoglobulin from autologous synovial fluid was captured on plates coated with anti-human immunoglobulin antibodies, the addition of HLA-DR4 peripheral blood mononuclear cells as APCs and synovial fluid-reactive HLA-DR4-restricted T-cell clones resulted in significant proliferation, indicating that the specific antigen in the crude synovial fluid was human immunoglobulin. This response was also shown to be antigen-specific and HLA-DR4-restricted. This assay format should permit the definition of autoantigens by capturing with antibodies to crude autoantigen extracts, followed by the addition of the appropriate APC and T-cell populations.


Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses.
Variable treatment responses to glucocorticoids occur in patients with rheumatoid arthritis (RA). In renal transplantation and asthma treatment responses correlate with in vitro tests of glucocorticoid immunosuppression. We compared in vitro methylprednisolone suppression of concanavalin A stimulated cellular proliferation with clinical responses to methylprednisolone in patients with RA. Patients found to be glucocorticoid sensitive by in vitro testing had significantly greater improvements in joint score and soluble interleukin 2 receptor (sIL-2R) levels compared to control patients, indicating that individual responsiveness to glucocorticoid exists in RA. Similar in vitro and in vivo changes of sIL-2R levels suggests that they reflect cell mediated immune events in vivo.


Differences in game statistics between winning and losing rugby teams in the six nations tournament.
The objective of the present study was to analyze the differences in rugby game statistics between winning and losing teams. The data from 58 games of round robin play from the Six Nations tournament from the 2003-2006 seasons were analyzed. The groups of variables studied were: number of points scored, way in which the points were scored; way teams obtained the ball and how the team used it; and technical and tactical aspects of the game. A univariate (t-test) and multivariate (discriminant) analysis of data was done. Winning teams had average values that were significantly higher in points scored, conversions, successful drops, mauls won, line breaks, possessions kicked, tackles completed, and turnovers won. Losing teams had significantly higher averages for the variables scrums lost and line-outs lost. The results showed that: a) in the phases of obtaining the ball and more specifically in scrummage and line-out, winning teams lose fewer balls than losing teams (winning teams have an efficacy of 90% in both actions); b) the winning team tends to play more with their feet when they obtain the ball, to utilize the maul as a way of attacking, and to break the defensive line more often than the losing team does; and c) On defence, winning teams recovered more balls and completed more tackles than losing teams, and the percentage of tackles completed by winning teams was 94%. The value presented could be used as a reference for practice and competition in peak performance teams. Key pointsThis paper increases the knowledge about rugby match analysis.Give normative values to establish practice and match goals.Give applications ideas to connect research with coaches practice.


Cytokeratin positivity in paraffin-embedded malignant melanomas: comparative study of KL1, A4 and Lu5 antibodies.
The unclear role of cytokeratin (CK) in the progression and diagnostics of malignant melanomas stimulated us to compare the reactivity of three antibodies directed to CK in 109 paraffin-embedded melanomas. By far the majority of melanomas did not express cytokeratin even at the<1% level, only vimentin. In about 6% of melanomas it was possible to find CK expression ranging between 3 and 40% of melanoma cells. There was a correlation between CK expression and pT-stage. Cytokeratin-expressing tumours were found in the more advanced pT-stages. The independent prognostic values of none of the three CK antibodies investigated could be shown.


Response surface optimization, kinetic and thermodynamic studies for effective removal of rhodamine B by magnetic AC/CeO2 nanocomposite.
The activated carbon (AC) was obtained from waste scrap tires and modified by bimetallic Fe and Ce nanoparticles in order to combine both the high surface area and the active sites for enhanced adsorption of the dye. The produced nanocomposite was used as a novel cost-effective magnetic in rhodamine B (RhB) removal from aqueous solutions. The FT-IR, SEM, EDX, TEM, and surface area analysis methods were implemented to characterize the morphological, chemical, thermal and surface properties of the developed adsorbent. The optimum batch experimental conditions were found under the response surface methodology. The adsorption equilibrium data were well fitted by the Langmuir isotherm model. The adsorption capacity was 324.6 mg g-1. The kinetic and thermodynamics studies were also carried out to understand the adsorption mechanism. The study indicated that RhB adsorption by the AC/Fe/Ce magnetic adsorbent has an endothermic character and followed the pseudo-second-order kinetics model. By using ethanol solution, RhB was desorbed at high efficiency and the prepared material could be recycled for up to ten cycles. Thus, the magnetic nanocomposite is an effective and promising adsorbent for the cleaning treatment of RhB ions from wastewater by a large scale designed adsorption system.


Evaluation of jawbone calcification in osteopetrotic (op/op) mice using computed tomography.
The study was conducted to evaluate the degree of calcification in the jawbones of 3 pairs of 4-week-old male op/op mice and littermates using computed tomography (CT) numbers. The mean CT numbers for op/op mice (n = 3) were 251.3 HU (range, 226 to 278) in the maxillary bone and 353.7 HU (range, 320 to 398) in the mandibular bone. The mean CT numbers for littermates were 336.7 HU (range, 324 to 350) and 596.6 HU (range, 580 to 604), respectively. The CT numbers of littermates were higher than in op/op mice for both maxillary and mandibular bones. These results indicated that the degree of bony calcification in littermates was higher than that in 4-week-old op/op mice in both the maxillary and mandibular bones. CT is able to demonstrate the degree of bony calcification in the jawbones of op/op mice using CT numbers, and it is suggested that CT is an extremely effective tool for examining the conditions of bone in vivo. This study also shows that op/op mice are useful for investigation of bone calcification or maturation.


Short and Atom-Economic Enantioselective Synthesis of the σ1-Receptor Ligands (S)- and (R)-Fluspidine-Important Tools for Positron Emission Tomography Studies.
Aryl bromides 2a and 2b bearing an alkynyl substituent in the o-position reacted with n-butyllithium and 1-benzylpiperidin-4-one in a one-pot Domino reaction to form ester 3 and aldehyde 5, respectively. Enantiomeric alcohols (R)-8 and (S)-8 were obtained by conjugate NaBH4 reduction of α,β-unsaturated ester 3 in the presence of chiral cocomplexes (R,R)-10 and (S,S)-10. Starting from orthoester 2a, the precursors (R)-8 and (S)-8 for the synthesis of fluspidine enantiomers (R)-1/[18F](R)-1 and (S)-1/[18F](S)-1 were obtained in only two reaction steps without additional steps for N-protection in an atom-economic manner in 95.6% ee and 97.2% ee, respectively.


Healthcare utilization patterns among persons who use drugs during the COVID-19 pandemic.
Persons with drug use disorders are an underserved and stigmatized population, and the COVID-19 pandemic could exacerbate these issues. The discussion around those with drug use disorders in the midst of the pandemic has focused on the need to ensure uninterrupted treatment access; however, very few in this population actually receive treatment, and retention is a substantial issue among those who do. Evidence from other chronic conditions suggests persons at high risk for severe COVID-19 complications are foregoing care due to fear of contracting the virus. Persons with drug use disorders tend to fall into this high-risk category, and thus may be avoiding healthcare facilities. Our data suggest this is true. If so, adverse outcomes, and increased severity of use disorders and associated health complications, could become prevalent. Clinicians should identify persons with drug use disorders who may be foregoing treatment, and engage them using methods that minimize the risk of COVID-19 transmission.


Opportunistic pathogen Candida albicans elicits a temporal response in primary human mast cells.
Immunosuppressed patients are frequently afflicted with severe mycoses caused by opportunistic fungal pathogens. Besides being a commensal, colonizing predominantly skin and mucosal surfaces, Candida albicans is the most common human fungal pathogen. Mast cells are present in tissues prone to fungal colonization being expectedly among the first immune cells to get into contact with C. albicans. However, mast cell-fungus interaction remains a neglected area of study. Here we show that human mast cells mounted specific responses towards C. albicans. Collectively, mast cell responses included the launch of initial, intermediate and late phase components determined by the secretion of granular proteins and cytokines. Initially mast cells reduced fungal viability and occasionally internalized yeasts. C. albicans could evade ingestion by intracellular growth leading to cellular death. Furthermore, secreted factors in the supernatants of infected cells recruited neutrophils, but not monocytes. Late stages were marked by the release of cytokines that are known to be anti-inflammatory suggesting a modulation of initial responses. C. albicans-infected mast cells formed extracellular DNA traps, which ensnared but did not kill the fungus. Our results suggest that mast cells serve as tissue sentinels modulating antifungal immune responses during C. albicans infection. Consequently, these findings open new doors for understanding fungal pathogenicity.


Cardiopulmonary Resuscitation May Not Stop Glutamate Release in the Cerebral Cortex.
Cardiopulmonary resuscitation (CPR) may not be sufficient to halt the progression of brain damage. Using extracellular glutamate concentration as a marker for neuronal damage, we quantitatively evaluated the degree of brain damage during resuscitation without return of spontaneous circulation. Extracellular cerebral glutamate concentration was measured with a microdialysis probe every 2 minutes for 40 minutes after electrical stimulation-induced cardiac arrest without return of spontaneous circulation in Sprague-Dawley rats. The rats were divided into 3 groups (7 per group) according to the treatment received during the 40 minutes observation period: mechanical ventilation without chest compression (group V); mechanical ventilation and chest compression (group VC) and; ventilation, chest compression and brain hypothermia (group VCH). Chest compression (20 min) and hypothermia (40 min) were initiated 6 minutes after the onset of cardiac arrest. Glutamate concentration increased in all groups after cardiac arrest. Although after the onset of chest compression, glutamate concentration showed a significant difference at 2 min and reached the maximum at 6 min (VC group; 284±48 μmol/L vs. V group 398±126 μmol/L, P =0.003), there was no difference toward the end of chest compression (513±61 μmol/L vs. 588±103 μmol/L, P =0.051). In the VCH group, the initial increase in glutamate concentration was suddenly suppressed 2 minutes after the onset of brain hypothermia. CPR alone reduced the progression of brain damage for a limited period but CPR in combination with brain cooling strongly suppressed increases in glutamate levels.


Hernia incidence following single-site vs standard laparoscopic colorectal surgery.
Compared with standard laparoscopic (SDL) approaches, less is known about the incidence of hernias after single-site laparoscopic (SSL) colorectal surgery. This study hypothesized that SSL colorectal surgery was associated with an increased risk of hernia development. Institutional retrospective chart review (September 2008-June 2013) identified 276 evaluable patients who underwent laparoscopic colorectal procedures. The following data were collected: demographic data, risk factors for the development of a hernia, operative details and postoperative course including the development of a hernia. Patients were stratified by laparoscopic technique to compare the characteristics of those undergoing SDL and SSL. Patients were subsequently stratified by the presence or absence of a hernia to identify associated factors. One hundred and nineteen patients (43.1%) underwent SDL and 157 patients (56.9%) underwent SSL surgery. The development of an incisional hernia was observed in 7.6% (9/119) of SDL patients compared with 17.0% (18/106) of SSL patients (P = 0.03) over a median 18-month follow-up. Similar proportions of patients developed parastomal hernias in both groups [SDL 16.7% (10/60) vs SSL 15.9% (13/80)]. Hernias were diagnosed at a median of 8.1 (SDL) and 6.5 (SSL) months following the index operation and were less likely to be incarcerated in the SSL group [SDL 38.9% (7/18) vs SSL 6.5% (2/31), P = 0.01]. SSL colorectal surgery is associated with an increase in the incidence of incisional hernias but not parastomal hernias. Site of specimen extraction in SSL may contribute to the development of an incisional hernia.


Emerging enteropathogenic Escherichia coli strains?
Escherichia coli strains of nonenteropathogenic serogroups carrying eae but lacking the enteropathogenic E. coli adherence factor plasmid and Shiga toxin DNA probe sequences were isolated from patients (children, adults, and AIDS patients) with and without diarrhea in Brazil. Although diverse in phenotype and genotype, some strains are potentially diarrheagenic.


[Results of reconstructive surgery with formation of low colorectal anastomoses after previous Hartmann's procedure].
To evaluate the efficacy and safety of original access to short rectal stump compared to traditional direct one. A retrospective-prospective cohort comparative study was conducted between 2012 and 2018. Inclusion criterion was previous Hartmann's procedure with formation of a short rectal stump. Short stump was determined by its length from anal-skin line to the cupola <7 cm. There were 93 patients who were divided into 2 groups: the main group - new approach (n=38), the control group - traditional direct approach (n=55). We analyzed surgery time, blood loss, intraoperative, early and late postoperative morbidity. Surgery time and blood loss were similar in both groups (299.9 vs. 288.3 min, p=0.82; 204.5 vs. 112.4 ml, p=0.94, respectively). Intraoperative complications occurred in 7 patients of the control group (0 vs. 12.7% (7/55), p=0.02). Incidence of early postoperative complications was similar (28.9% (11/38) vs. 25.5% (14/55), p=0.71). Adverse events Clavien-Dindo grade I and IIIa were more common in the main group, grade IIIb and IVa - in the control group. Incidence of delayed postoperative complications were similar (10.5% (4/38) vs. 7.3% (4/55), p=0.58). Colorectal anastomosis stricture prevailed in the control group, ureteral stricture - in the main group. Neurophysiological and complex urodynamic examinations revealed no between-group differences. The new method ensures access to the rectal stump and formation of colorectal anastomosis under direct visual control. Postoperative outcomes demonstrated safety and effectiveness of this technique.


[Food-induced anaphylaxis. A new French multicenter survey].
The frequency of food-induced anaphylactic shocks (FIAS) has been investigated beside 46 emergency departments, 29 departments of Dermatology, and 19 departments of Intern Medicine or Pneumology. 794 A.S. have been reported. FIAS represent 10.2% of the etiologies. More than a third of them are relapsing anaphylaxis. Food allergy had been previously identified in 23.4% of cases. The allergen was present as a hidden allergen or inadvertently consumed in 30.8% of FIAS. 9.9% of the patients were asthmatic. An enhancing factor was heightened in 25.9% of cases: alcohol, exercise, simultaneous intake of aspirin, beta-blockers, conversion enzyme inhibitors. Other factors predisposing to food anaphylaxis were a cross-reactivity shared by pollens and fruit, latex and exotic fruit, house dust mites and snails, or mastocytosis. More than 15 allergens were detected: egg (11.6%), fish (10.4%), crustaceans (10.4%), milk (6.5%), fruit-latex group (6.5%), peanut and other leguminosae (soy, peas, lentils, guar gum...), celery, garlic, etc... The food allergen still remained unknown in 25% of cases. However, the rate of efficiency of the diagnosis reached 94% in the Allergy Units. In addition 10.2% of A.S. were considered idiopathic, raising the hypothesis of allergy to masked food allergens. Compared to a previous study from the 1982's, this survey shows a striking increased prevalence of FIAS.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of chronic metabolic acidosis on renal growth and renal sodium handling in uninephrectomized rats.
Paucity studies have indicated that a systemic metabolic acidosis cause a decrease in salt and water reabsorption in the kidney. The following study was undertaken on male Wistar-Hannover rats (200-250 g) to investigate the effects of a chronic, NH4Cl-induced metabolic acidosis on the renal handling of Na+ in sham-operated and uninephrectomized rats, by lithium clearance. The present study shows that chronic acidosis (blood pH, 7.16 +/- 0.13) caused a sustained increase in renal fractional Na+ excretion (267.9 +/- 36.4%), accompanied by a rise in the fractional proximal (113.3 +/- 3.6%) and post-proximal (179.7 +/- 20.2%) Na+ and fractional K+ (163.4 +/- 5.6%) excretions when compared to pair-fed rats. These differences occurred in spite of an unchanged creatinine clearance and Na+ filtered load. On the other hand, a body growth impairment was observed in the acidotic (control, 258 +/- 3.7 g versus acidotic, 232 +/- 4.6 g) and pair-fed rats (225 +/- 3.6 g), whereas there was significant enhance in the kidney weights in acidotic rats (1.73 +/- 0.05 g) compared to other experimental groups (control, 1.46 +/- 0.05 g; pair-fed, 1.4 +/- 0.05 g). The renal growth indexes after metabolic acidosis NH4Cl-induced did not shown statistical difference at 1.5, 3.0 and 12 hours after uninephrectomy when were compared with pair-fed groups. However, from the fifth to tenth day after unilateral nephrectomy the renal growth index of acidotic group was significantly greater than pair-fed groups. Unilateral nephrectomy in acidotic animals caused a striking additional but transient increase in fractional renal sodium (FENa+) and potassium (FEK+) excretion from 1.5 to 3 hours post-surgery meanly associated with an enhanced post-proximal sodium excretion when compared to pair-fed uninephrectomized rats. By the fifth postoperative day the all functional values returned to baseline levels. This altered renal Na+ handling and K+ excretion may result from a reciprocal relationship between tubular metabolic pathway stimuli and ion transport. Further studies are required to investigate the acidosis involvement on functional kidney response.


The metabolism of triglyceride-rich lipoproteins revisited: new players, new insight.
Peripheral lipoprotein lipase (LPL)-mediated lipolysis of triglycerides is the first step in chylomicron/VLDL clearance involving heparan sulfate proteoglycans (HSPGs) displayed at the cell surface of the capillaries in adipose tissue, heart and skeletal muscle. The newly generated chylomicron remnant particles are then cleared by the liver, whereas VLDL remnant particles are either further modified, through the action of hepatic lipase (HL) and cholesteryl ester transfer protein (CETP), into LDL particles or alternatively directly cleared by the liver. Two proteins, lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), have been recently identified and have revised our current understanding of LPL maturation and LPL-mediated lipolysis. Moreover, new insights have been gained with respect to hepatic remnant clearance using genetically modified mice targeting the sulfation of HSPGs and even deletion of the most abundant heparan sulfate proteoglycan: syndecan1. In this review, we will provide an overview of novel data on both peripheral TG hydrolysis and hepatic remnant clearance that will improve our knowledge of plasma triglyceride metabolism.


Initial coin offerings (ICOs): Why do they succeed?
Recent literature has addressed initial coin offering (ICO) projects, which are an innovative form of venture financing through cryptocurrencies using blockchain technology. Many features of ICOs remain unexplored, leaving much room for additional research, including the success factors of ICO projects. We investigate the success of ICO projects, with our main purpose being to identify factors that influence a project's outcome. Following a literature review, from which several potential variables were collected, we used a database comprising 428 ICO projects in the banking/financial sector to regress several econometric models. We confirmed the impacts of several variables and obtained particularly valuable results concerning project and campaign variables. We confirmed the importance of a well-structured and informative whitepaper. The proximity to certain markets with high availability of financial and human capital is also an important determinant of the success of an ICO. We also confirm the strong dependency on cryptocurrency and the impact of cryptocurrency valuations on the success of a project. Furthermore, we confirm the importance of social media in ICO projects, as well as the importance of human capital characteristics. Our research contributes to the ICO literature by capturing most of the success factors previously identified and testing their impacts based on a large database. The current research contributes to the building of systems theory and signaling theory by adapting their frameworks to the ICO environment. Our results are also important for regulators, as ICOs are mainly unregulated and have vast future potential, and for investors, who can benefit from our analysis and use it in their due diligence.


Effect of brief intrusive force on human pulpal blood flow.
The purpose of this study was to evaluate the effect of a 4-minute application of intrusive orthodontic force on human pulpal blood flow (PBF) with laser-Doppler flowmetry. Eight subjects had an intrusive force applied to a maxillary central incisor through a lever system. A cast chrome-cobalt coping was fabricated to fit over the incisor of each subject, and thus provided a reproducible point of force application as well as stabilization for the laser-Doppler flowmetry probe. Each subject participated in five testing sessions. During each session, PBF was measured during a 4-minute baseline period, then during the 4-minute force application, and then for a 12-minute period after removal of the force. Weights of 0, 5, 50, or 500 gm were attached to the end of the lever to produce intrusive forces ranging from 75 to 4498 gm. During the fifth testing session, local anesthetic with vasoconstrictor (epinephrine 1:100,000) was administered in place of the force application to determine the ability of this experimental paradigm to detect reductions in PBF. Baseline PBF values did not differ among sessions. Force levels had no statistically significant effect on PBF. However, PBF did drop significantly after administration of the vasoconstrictor. These results suggest that PBF is not altered during the application of a brief intrusive orthodontic force.


Using a laparoscope manipulator (LAPMAN) in laparoscopic gynecological surgery.
The LAPMAN (Medsys, Gembloux, BELGIUM) is a dynamic laparoscope holder guided by a joystick clipped onto the laparoscopic instruments under the index finger of the operator. It confers optimal control of the visual field while operating, ensures stable and smooth displacement of the laparoscope, and allows the operator to work in conditions of restricted surgical assistance, due to either unavailability of staff or economic constraints. It has been tested successfully in pilot studies in laparoscopic gynecologic surgery.


MEDAS: an open-source platform as a service to help break the walls between medicine and informatics.
In the past decade, deep learning (DL) has achieved unprecedented success in numerous fields, such as computer vision and healthcare. Particularly, DL is experiencing an increasing development in advanced medical image analysis applications in terms of segmentation, classification, detection, and other tasks. On the one hand, tremendous needs that leverage DL's power for medical image analysis arise from the research community of a medical, clinical, and informatics background to share their knowledge, skills, and experience jointly. On the other hand, barriers between disciplines are on the road for them, often hampering a full and efficient collaboration. To this end, we propose our novel open-source platform, i.e., MEDAS-the MEDical open-source platform As Service. To the best of our knowledge, MEDAS is the first open-source platform providing collaborative and interactive services for researchers from a medical background using DL-related toolkits easily and for scientists or engineers from informatics modeling faster. Based on tools and utilities from the idea of RINV (Rapid Implementation aNd Verification), our proposed platform implements tools in pre-processing, post-processing, augmentation, visualization, and other phases needed in medical image analysis. Five tasks, concerning lung, liver, brain, chest, and pathology, are validated and demonstrated to be efficiently realizable by using MEDAS. MEDAS is available at http://medas.bnc.org.cn/.


Wnt inhibitory factor 1 ameliorated diabetic retinopathy through the AMPK/mTOR pathway-mediated mitochondrial function.
Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and will lead to visual impairment. We aim to explore the effects and mechanisms of wnt inhibitory factor 1 (WIF1) in the progression of DR. To establish DR in vitro and in vivo, human retinal pigment epithelium (RPE) cell line ARPE-19 was treated with high-glucose (HG) and diabetic mice models were induced by streptozotocin (STZ), respectively. Different dose of recombinant WIF1 protein was used to treat DR. qRT-PCR and western blotting results demonstrated that WIF1 was downregulated, while VEGFA was upregulated in HG-induced ARPE-19 cells. WIF1 overexpression promoted cell migration. The ARPE-19 cells culture medium treated with WIF1 inhibited retinal endothelial cell tube formation and downregulated VEGFA expression. Moreover, WIF1 decreased the levels of ROS and MDA, while increasing the activity of SOD and GPX. WIF1 increased the ΔΨm in the mitochondria and downregulated the expression of mitochondrial autophagy-related proteins including Parkin, Pink1, LC3-II/LC3-I ratio, cleaved caspase 3, and cyt-c, which ameliorated mitochondrial dysfunction. The in vivo studies further demonstrated the consistent effects of WIF1 in STZ-induced mice. Taken together, WIF1 ameliorated mitochondrial dysfunction in DR by downregulating the AMPK/mTOR pathway.


Retinal Degeneration Associated With the G1606A Mitochondrial Mutation.
The guanine-to-adenine substitution at nucleotide 1606 (G1606A) mutation in the mitochondrial DNA transfer RNA-valine gene has been reported to cause sensorineural deafness, ataxia, myoclonus, seizures, and mental retardation. This study hereby presents a single case report of a new retinal phenotype associated with this mutation: a middle-aged woman with retinal pigment epithelium stippling, atrophy, and peripapillary (retinal pigment epithelium) dropout on fundus examination. The patient was administered an empiric trial of a mitochondrial cocktail with close monitoring of her systemic symptoms. This study identified a novel G1606A mutation to cause early-onset macular pathology resembling that previously described in the A3243G mutation. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:116-119.].


Technical Considerations for Dynamic Myocardial Computed Tomography Perfusion as Part of a Comprehensive Evaluation of Coronary Artery Disease Using Computed Tomography.
Dynamic myocardial computed tomography perfusion (DM-CTP) has good diagnostic accuracy for identifying myocardial ischemia as compared with both invasive and noninvasive reference standards. However, DM-CTP has not yet been implemented in the routine clinical examination of patients with suspected or known coronary artery disease. An important hurdle in the clinical dissemination of the method is the development of the DM-CTP acquisition protocol and image analysis. Therefore, the aim of this article is to provide a review of critical parameters in the design and execution of DM-CTP to optimize each step of the examination and avoid common mistakes. We aim to support potential users in the successful implementation and performance of DM-CTP in daily practice. When performed appropriately, DM-CTP may support clinical decision making. In addition, when combined with coronary computed tomography angiography, it has the potential to shorten the time to diagnosis by providing immediate visualization of both coronary atherosclerosis and its functional relevance using one single modality.


Interferon therapy in the chronic aggressive viral hepatitis.
The effects of interferon (INT) therapy in the chronic aggressive hepatitis of viral origin (CAVH) are critically reviewed. The main factor which favours the progress of acute viral hepatitis to chronic forms is the persistence of viral replication in conditions of immune deficit of the host. INT has antiviral, immunomodulating and antitumoral action. The INT alpha class proved to be the most adequate for the CAVH treatment. Many recent clinical trials have demonstrated the INT alpha effectiveness in CAVH. The results of such studies are separately analysed for each hepatitis virus. The importance of various factors, i.e., dose, treatment duration, race, sex, age, histologic lesions, ALAT level, viral DNA titer, associations with adenine-arabinoside, acyclovir, corticosteroids, a.o., is discussed in relation with the rate of therapeutic response and the risk of viral infection recurrences.


Three new compounds from Aspergillus terreus PT06-2 grown in a high salt medium.
To investigate the structurally novel and bioactive natural compounds from marine-derived microorganisms under high salinity, the fungus Aspergillus terreus PT06-2 was isolated from the sediment of the Putian Sea Saltern, Fujian, China. Three new compounds, terremides A (1) and B (2) and terrelactone A (3), along with twelve known compounds (4-15) were isolated and identified from the fermentation broth of A. terreus PT06-2 at 10% salinity. Among these metabolites, compounds 4 and 15 only produced in the 10% salinity culture, were identified as methyl 3,4,5-trimethoxy-2-(2-(nicotinamido) benzamido) benzoate, and (+)-terrein, respectively. The new compounds 1 and 2 exhibited antibacterial activity against Pseudomonas aeruginosa and Enterobacter aerogenes with MIC values of 63.9 and 33.5 μM, respectively. Compounds 5 showed moderate anti-H1N1 activity and lower cytotoxicity with IC₅₀ and CC₅₀ values of and 143.1 and 976.4 μM, respectively.


Indoor/outdoor concentrations and elemental composition of PM10/PM2.5 in urban/industrial areas of Kocaeli City, Turkey.
This study presents indoor/outdoor PM2.5 and PM10 concentrations measured during winter and summer in 15 homes in Kocaeli, which is one of the most industrialized areas in Turkey. Indoor and outdoor PM2.5 and PM10 mass concentrations and elemental composition were determined using an X-ray fluorescence spectrometer. Quantitative information was obtained on mass concentrations and other characteristics such as seasonal variation, indoor/outdoor (I/O) ratio, PM2.5/PM10 ratio, correlations and sources. Average indoor and outdoor PM2.5 concentrations were 29.8 and 23.5 microg/m(3) for the summer period, and 24.4 and 21.8 microg/m(3) for the winter period, respectively. Average indoor and outdoor PM10 concentrations were 45.5 and 59.9 microg/m(3) for the summer period, and 56.9 and 102.3 microg/m(3) for the winter period, respectively. A varimax rotated factor analysis (FA) was performed separately on indoor and outdoor datasets in an effort to identify possible heavy metal sources of PM2.5 and PM10 particle fractions. FA of outdoor data produced source categories comprising polluted soil, industry, motor vehicles, and fossil fuel combustion for both PM fractions, while source categories determined for indoor data for both PM2.5 and PM10 comprised industry, polluted soil, motor vehicles, and smoking, with an additional source category of cooking activities detected for the PM2.5 fraction. Practical Implications In buildings close to industrial areas or traffic arteries, outdoor sources may have an important effect on indoor air pollution. Therefore, indoor and outdoor investigations should be conducted simultaneously to assess the relationship between indoor and outdoor pollution. This study presents the simultaneous measurement of PM fractions (PM2.5 and PM10) and their elemental compositions to determine the sources of respirable PM and the heavy metals bound to these particles in indoor air. Factor analysis of indoor data indicated that the contribution of outdoor pollutant sources to indoor pollution was about 70%, making these sources the most significant for indoor heavy metal pollution, wheras other sources of indoor pollution included smoking and cooking activities.


Identification of PTC725, an orally bioavailable small molecule that selectively targets the hepatitis C Virus NS4B protein.
While new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug-resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC50) of 1.7 nM and an EC90 of 9.6 nM and demonstrated a >1,000-fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection.


[Immunoserological area--with special reference to the current topics on antinuclear antibodies].
In 1948, Hargraves described the phenomenon of the LE cells and equated it with systemic lupus erythematosus (SLE). Kunkel and his colleagues elucidated the immunochemical basis of this phenomenon, showing that it was related to the circulating autoantibodies to deoxyribonucleoprotein (DNP). Their pioneering studies led to the continuing discoveries of antinuclear antibodies (ANA) and today's considerable knowledge concerning the molecular identity of antigens and further consolidation of ANA. In addition to the role of diagnostic markers, spontaneously occurring autoantibodies, including anti-PCNA (proliferating cell nuclear antigen) antibody and anticentromere antibody (ACA), turned out to be useful as powerful probes for cell biology. In this study, the sera of patients with primary biliary cirrhosis (PBC) along with collagen diseases were examined for the presence of antinuclear antibodies. In using HEp-2 cells and chromosomes derived from K 562 as the substrates for the immunofluorescence method, the frequency of ANA and ACA in PBC sera were 84% and 44% respectively. Anti-DNA, antiSS-A and antiSS-B antibodies were found in one, 4 and one sera respectively. On the other hand, antibodies to nRNP, Sm and Scl-70 were not found in PBC sera. In some PBC patients with ACA, various complications related to collagen diseases were found to coexist. Our results indicated that there might be common serological abnormalities among patients with PBC, CREST syndrome and Sjögren's syndrome.


Can google trends search inform us about the population response and public health impact of abrupt change in alcohol policy? A case study from India during the covid-19 pandemic.
Sudden alcohol prohibition in India during the COVID-19 pandemic presented an opportunity to test whether Google Trends data could indicate population responses and the public health impact of alcohol policy. We hypothesized, following prohibition: there would be a significant change in the relative search volumes (RSV) of alcohol-related queries; that temporal analysis of the trends would reflect a public response to policy changes; and that geospatial analysis of RSV would correlate with the prevalence of alcohol use. Three different search periods were used to test the hypotheses. The search inputs were based on potential public response to alcohol prohibition, as evidenced by the literature, newspaper articles, and consensus. We used RSV as the unit of analysis. Mean RSV of search queries, pre-post implementation of prohibition, were compared. Smoothing of scatter plots examined the temporal association of trends with policy measures. Multiple linear regression tested the relationship of state-wise RSV and alcohol use prevalence. Post-implementation of prohibition, a significant increase in the RSV was observed for searches related to alcohol withdrawal (p<0.001), how to extract alcohol from sanitizer (p = 0.002), alcohol home delivery online (p<0.001), alcohol home delivery (p<0.001), and sleeping pills (p = 0.006). The trends suggested a decrease in general interest in alcohol but increased demand, and a possible connection with changes in policy measures. State-level RSV and alcohol use prevalence did not reveal a significant relationship. Google trend is a potential source of rapid feedback to policymakers about population responses to an abrupt change in alcohol policies.


Magnesium and the control of cell proliferation: looking for a needle in a haystack.
Experimental evidence supports the important role of magnesium in the process of cellular proliferation, even though cell magnesium homeostasis is not completely clarified. We were the first to describe some molecular characteristics of the magnesium-dependent regulation of the cell cycle, and others proposed a mechanism for the magnesium-dependent regulation of protein synthesis occurring in the early phases of cell proliferation. We will attempt to relate such mechanisms with pathologic conditions whereby cell proliferation is severely disregulated, as in the case of tumors. It is interesting to note that recently some efforts have been made to correlate magnesium transport systems with its functions within the cells. Few, but stimulating new data are emerging which relate molecularly defined ion channels with magnesium homeostasis and its functions. Old and new data are now being merged and corroborated by diverse experimental approaches including molecular genetics, proteomics, electrophysiology and biochemistry. This, together with the development of new techniques to measure cell magnesium content and distribution, will hopefully pave the way to unravel the intimate mechanisms of such an essential though undefined metabolic regulator. New and deeper appreciation of magnesium homeostasis will help in delineating the key role of this cation in the regulation of normal or pathologic cell proliferation.


Investigation of the structural stability of the human acidic fibroblast growth factor by hydrogen-deuterium exchange.
The conformational stability of the human acidic fibroblast growth factor (hFGF-1) is investigated using amide proton exchange and temperature-dependent chemical shifts, monitored by two-dimensional NMR spectroscopy. The change in free energy of unfolding (DeltaG(u)) of hFGF-1 is estimated to be 5.00 +/- 0.09 kcal.mol(-)(1). Amide proton-exchange rates of 74 residues (in hFGF-1) have been unambiguously measured, and the exchange process occurs predominately according to the conditions of the EX2 limit. The exchange rates of the fast-exchanging amide protons exposed to the solvent have been measured using the clean SEA-HSQC technique. The amide proton protection factor and temperature coefficient estimates show reasonably good correlation. Residues in beta-strands II and VI appear to constitute the stability core of the protein. Among the 12 beta-strands constituting the beta-barrel architecture of hFGF-1, beta-strand XI, located in the heparin binding domain, exhibits the lowest average protection factor value. Amide protons involved in the putative folding nucleation site in hFGF-1, identified by quench-flow NMR studies, do not represent the slow-exchanging core. Residues in portions of hFGF-1 experiencing high conformational flexibility mostly correspond to those involved in receptor recognition and binding.


Alterations in neuropeptide Y levels and Y1 binding sites in the Flinders Sensitive Line rats, a genetic animal model of depression.
Previously, we observed specific alterations of neuropeptide Y (NPY) and Y1 receptor mRNA expression in discrete regions of the Flinders Sensitive Line rats (FSL), an animal model of depression. In order to clarify the correlation between mRNA expression and protein content, radioimmunoassay and receptor autoradiography were currently performed. In the FSL rats, NPY-like immunoreactivity (NPY-LI) was decreased in the hippocampal CA region, while Y1 binding sites were increased; NPY-LI was increased in the arcuate nucleus. Fluoxetine treatment elevated NPY-LI in the arcuate and anterior cingulate cortex and increased Y1 binding sites in the medial amygdala and occipital cortex in both strains. No differences were found regarding the Y2 binding sites. The results demonstrate a good correlation between NPY peptide and mRNA expression, and sustain the possible involvement of NPY and Y1 receptors in depression.


Development of a standardized mucositis and osteoradionecrosis animal model using external radiation.
Although the side effects of radiation therapy vary from mucositis to osteomyelitis depending on the dose of radiation therapy, to date, an experimental animal model has not yet been proposed. The aim of this study was to develop an animal model for assessing complications of irradiated bone, especially to quantify the dose of radiation needed to develop a rat model. Sixteen Sprague-Dawley rats aged seven weeks with a mean weight of 267.59 g were used. Atraumatic extraction of a right mandibular first molar was performed. At one week after the extraction, the rats were randomized into four groups and received a single dose of external radiation administered to the right lower jaw at a level of 14, 16, 18, or 20 Gy, respectively. Clinical alopecia with body weight changes were compared and bony volumetric analysis with micro-computed tomography (CT), histologic analysis with H&E were performed. The progression of the skin alopecia was different depending on the irradiation dose. Micro-CT parameters including bone volume, bone volume/tissue volume, bone mineral density, and trabecular spaces, showed no significant differences. The progression of osteoradionecrosis (ORN) along with that of inflammation, fibrosis, and bone resorption, was found with increased osteoclast or fibrosis in the radiated group. As the radiation dose increases, osteoclast numbers begin to decrease and osteoclast tends to increase. Osteoclasts respond more sensitively to the radiation dose, and osteoblasts are degraded at doses above 18 Gy. A standardized animal model clinically comparable to ORN of the jaw is a valuable tool that can be used to examine the pathophysiology of the disease and trial any potential treatment modalities. We present a methodology for the use of an experimental rat model that incorporates a guideline regarding radiation dose.


Piloting a logic-based framework for understanding organisational change process for a health IT implementation.
This paper describes how a method for evaluating organisational change based on the theory of logical types can be used for classifying organisational change processes to understand change after the implementation of an electronic documentation system in a residential aged care facility. In this instance we assess the organisational change reflected by care staff's perceptions of the benefits of the new documentation system at one site, at pre-implementation, and at 12 months post-implementation. The results show how a coherent view from the staff as a whole of the personal benefits, the benefits for others and the benefits for the organization create a situation of positive feedback leading to embeddedness of the documentation system into the site, and a broader appreciation of the potential capabilities of the electronic documentation system.