Indium-based and iodine-based labeling of HPMA copolymer-epirubicin conjugates: Impact of structure on the in vivo fate.
Recently, we developed 2nd generation backbone degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates which contain enzymatically cleavable sequences (GFLG) in both polymeric backbone and side-chains. This design allows using polymeric carriers with molecular weights above renal threshold without impairing their biocompatibility, thereby leading to significant improvement in therapeutic efficacy. For example, 2nd generation HPMA copolymer-epirubicin (EPI) conjugates (2P-EPI) demonstrated complete tumor regression in the treatment of mice bearing ovarian carcinoma. To obtain a better understanding of the in vivo fate of this system, we developed a dual-labeling strategy to simultaneously investigate the pharmacokinetics and biodistribution of the polymer carrier and drug EPI. First, we synthesized two different types of dual-radiolabeled conjugates, including 1) (111)In-2P-EPI-(125)I (polymeric carrier 2P was radiolabeled with (111)In and drug EPI with (125)I), and 2) (125)I-2P-EPI-(111)In (polymeric carrier 2P was radiolabeled with (125)I and drug EPI with (111)In). Then, we compared the pharmacokinetics and biodistribution of these two dual-labeled conjugates in female nude mice bearing A2780 human ovarian carcinoma. There was no significant difference in the blood circulation between polymeric carrier and payload; the carriers ((111)In-2P and (125)I-2P) showed similar retention of radioactivity in both tumor and major organs except kidney. However, compared to (111)In-labeled payload EPI, (125)I-labeled EPI showed lower radioactivity in normal organs and tumor at 48h and 144h after intravenous administration of conjugates. This may be due to different drug release rates resulting from steric hindrance to the formation of enzyme-substrate complex as indicated by cleavage experiments with lysosomal enzymes (Tritosomes). A slower release rate of EPI(DTPA)(111)In than EPI(Tyr)(125)I was observed. It may be also due to in vivo catabolism and subsequent iodine loss as literature reported. Nevertheless, tumor-to-tissue uptake ratios of both radionuclides were comparable, indicating that drug-labeling strategy does not affect the tumor targeting ability of HPMA copolymer conjugates.


Seroprevalence of cysticercosis in children and young adults living in a helminth endemic community in leyte, the Philippines.
Cysticercosis is a significant public health problem in countries where pigs are raised for consumption and remains an important cause of neurological disease worldwide. The Philippines is considered an endemic area for cysticercosis because cases in both humans and pigs have been reported; however, epidemiologic information stays limited. We conducted a pilot survey of the seroprevalence of human cysticercosis in a village in Leyte, the Philippines, by measuring antibody specific for Taenia solium cyst-fluid antigen. There were 497 subjects aged 7-30 years in our study and most subjects were infected with one or more helminths. The overall cysticercosis seroprevalence in this population was 24.6% (95% CI: 20.82% ~ 28.58%) with no significant difference based on age, sex, or other helminth coinfection status. Although the sample may not be representative of the whole community, the findings suggest that cysticercosis is a significant, but underrecognized public health concern in the Philippines.


Uncovering the genomic and metagenomic research potential in old ethanol-preserved snakes.
Natural history museum collections worldwide represent a tremendous resource of information on past and present biodiversity. Fish, reptiles, amphibians and many invertebrate collections have often been preserved in ethanol for decades or centuries and our knowledge on the genomic and metagenomic research potential of such material is limited. Here, we use ancient DNA protocols, combined with shotgun sequencing to test the molecular preservation in liver, skin and bone tissue from five old (1842 to 1964) museum specimens of the common garter snake (Thamnophis sirtalis). When mapping reads to a T. sirtalis reference genome, we find that the DNA molecules are highly damaged with short average sequence lengths (38-64 bp) and high C-T deamination, ranging from 9% to 21% at the first position. Despite this, the samples displayed relatively high endogenous DNA content, ranging from 26% to 56%, revealing that genome-scale analyses are indeed possible from all specimens and tissues included here. Of the three tested types of tissue, bone shows marginally but significantly higher DNA quality in these metrics. Though at least one of the snakes had been exposed to formalin, neither the concentration nor the quality of the obtained DNA was affected. Lastly, we demonstrate that these specimens display a diverse and tissue-specific microbial genetic profile, thus offering authentic metagenomic data despite being submerged in ethanol for many years. Our results emphasize that historical museum collections continue to offer an invaluable source of information in the era of genomics.


1,2,4-Triazolo[2,3-h]-7,9-thiaza-11-crown-4.
The title compound, 4,7-dioxa-10-thia-1,12,13-triazabicyclo[9.3.0]tetradeca-11,13-diene, C(8)H(13)N(3)O(2)S, contains an 11-membered ring, which appears in a chair conformation and has approximate mirror symmetry. It may be used for the complexation of metal atoms.


Drug-induced liver injury in COVID-19 patients during hospitalization.
Since coronavirus disease 2019 (COVID-19) outbreaks in December 2019 in Wuhan, almost no studies have systematically described drug-induced liver injury (DILI) in COVID-19 patients. This study aimed to assess the characteristics of liver test abnormality or liver injury in patients with COVID-19, and further to explore DILI in COVID-19 patients during hospitalization. It was a single-center retrospective analysis of confirmed severe acute respiratory syndrome coronavirus 2 infected patients in the hospital from January 2020 to March 2020. Univariate and multivariate logistic regression analysis were used to assess the risk factors associated with liver test abnormality or liver injury. At admission, 148 (48.8%, 148/303) patients had abnormal liver test results and 7 (2.4%, 7/303) had liver injury, while 195 (64.4%, 195/303) had abnormal liver test results and 17 (5.6%, 17/303) had liver injury during hospitalization. After excluding these patients with liver disease and liver function abnormalities or liver injury at admission, 15 (11.1%, 15/135) patients developed DILI during hospitalization. Further regression analysis indicated that methylprednisolone (odds ratio = 4.177, 95% confidence interval [1.106-15.771], P = .035), but not Chinese herbal medicine or other used drug, was associated with DILI in patients during hospitalization. Abnormal liver function results were in more than half of patients with COVID-19, and the incidence of DILI in COVID-19 patients was 11.1% during hospitalization. Liver test abnormality or liver injury in patients might be directly caused by the viral infection at admission, but the detrimental effects on liver injury mainly related to certain medications used during hospitalization, particularly methylprednisolone. Severe COVID-19 could increase the occurrence of liver injury (P = .007) during hospitalization, but not a risk factor of liver injury. However, Chinese herbal medicine was a protective factor for liver injury.


Hospital-onset Gram-negative Surveillance Program annual report, 2011.
The Australian Group on Antimicrobial Resistance performs regular period-prevalence studies to monitor changes in antimicrobial resistance in selected enteric Gram-negative pathogens. The 2011 survey focussed on hospital-onset infections, examining isolates from all specimens presumed to be causing disease. In 2011, 1,827 Escherichia coli, 537 Klebsiella species and 269 Enterobacter species were tested using a commercial automated method (Vitek 2, BioMérieux) and results were analysed using Clinical and Laboratory Standards Institute breakpoints from January 2012. Of the key resistances, non-susceptibilty to the third-generation cephalosporin, ceftriaxone, was found in 9.6% of E. coli and 9.5%-12.1% of Klebsiella spp. Non-susceptibility rates to ciprofloxacin were 10.6% for E. coli, 0.0%-8.3% for Klebsiella spp. and 0.0%-5.0% in Enterobacter spp. Resistance rates to gentamicin were 8.6%, 2.9%-10.9%, and 0.0%-15.6% for the same 3 groups respectively. Eight strains, 5 Klebsiella spp. and 3 Enterobacter spp. were shown to harbour a carbapenemase (IMP-4).


Hemorrhagic ascites secondary to endometriosis.
Ascites secondary to endometriosis is extremely uncommon, but curable. We therefore report hemorrhagic ascites in a young woman with this disorder, and provide a literature review and summary of clinical features. The pathogenesis of ascites in this setting is unknown.


Oral rehydration therapy in a rural area, northern Thailand.
A cross-sectional sampling survey of mothers' practice of ORT in Amphoe Bunpotphesai in the northern part of Thailand included 1,619 children under five. Two hundred and six children were reported to have 223 diarrheal episodes. The incidence of diarrhea in children under five was 3.4 episodes per child per year. When children had diarrhea 65.5 per cent of mothers sought help from health providers, 25.2 per cent treated their children with drugs bought from stores, 2.3 per cent used herbal medicine and 6.1 per cent did not treat their children. 50.7 per cent of diarrheal episodes mother gave ORT, using ORS 19.7, commercial electrolytes mixture 16.6 and home available fluid 14.4 per cent. The accuracy of dilution of electrolytes powder from the packets was checked in 80 incidences. 31.8 and 27.8 per cent of mothers made correct dilution of ORS and commercial electrolytes products respectively. Health providers carried both ORS and commercial electrolytes packets. ORS added to a glass of water was found in 13.6 per cent which was 3 times concentrated. Commercial electrolytes products were too dilute in 72.2 per cent. 17.5 per cent of mothers divided electrolytes powder to add in one spoon of water to treat their children as one drug dose. Data showed that the ORT use rate was 50.7 per cent. Home available fluid was used by 14.4 per cent. ORT should be further promoted to control diarrheal diseases and health providers should give instructions to every mother or child minder on how to dispense ORS or electrolytes packets for appropriate dilution and use.


Primary Total Shoulder Arthroplasty is Superior to Hemiarthroplasty for the Treatment of Glenohumeral Arthritis: Analysis of 5-year Outcomes in a Large Surgical Database.
Total shoulder arthroplasty (TSA) is the preferred treatment for glenohumeral arthritis refractory to nonoperative measures. However, some surgeons have argued for a role for hemiarthroplasty (HA) in the setting of a smooth glenoid that articulates appropriately with the humeral head. The purpose of this study is to evaluate long-term revision rates and short-term postoperative complications in patients undergoing either HA or TSA for glenohumeral arthritis. A retrospective review of patients who underwent HA and TSA was conducted using a commercially available national database. Demographics, postoperative complications, risk factors, revision rates, and costs were analyzed using 2 sample t-tests, chi-squared tests, and multivariate logistic regressions. Patients were stratified by operation: (1) HA (n = 1615) or 2) TSA (n = 7845). Patients undergoing primary TSA had higher rates of prior ipsilateral rotator cuff repair and corticosteroid injections. At 2 years, patients who underwent HA, 3.0% of patients had revision surgery, compared to 1.6% of patients who underwent TSA (P = .002); at 5 years, 3.7% of the HA cohort (P < .0001) had revision surgery, compared to 1.9% of patients who underwent TSA. Patients undergoing TSA or RTSA for glenohumeral arthritis had higher preoperative co-morbidities but had no difference in short-term complication rates with a lower risk of revision surgery at both 2-year and 5-year follow-up when compared to HA. Increasing age, female sex, hyperlipidemia, postoperative infection, shoulder instability, and thromboembolism all independently increased odds for revision shoulder arthroplasty for glenohumeral arthritis. III.


Inhibitory effects of aryl trans-4-(aminomethyl)cyclohexanecarboxylate and aryl trans-4-(guanidinomethyl)cyclohexanecarboxylate on serine proteases, and their antiallergic effects.
Since serine protease in involved in histamine release from mast cells, we attempted to prepare new protease inhibitors, trans-4-(guanidinomethyl)cyclohexanecarboxylic acid (GmcHX-CO2H) esters, and examined their inhibitory effects on typical serine proteases and on histamine release induced by compound 48/80. We compared their effects with those of trans-4-(aminomethyl)cyclohexanecarboxylic acid (AmcHx-CO2H) esters. AmcHxCO2H and GmcHxCO2H esters inhibited the esterolytic activity of trypsin, but GmcHx-CO2H esters had little or no inhibitory effect on caseinolytic activity whereas AmcHxCO2H esters strongly inhibited the latter. AmcHCO2H esters strongly inhibited plasmin but had no effect on chymotrypsin. GmcHxCO2H esters strongly inhibited the esterolytic activity of chymotrypsin, but had no effect on chymotrypsin-induced caseinolysis. Both GmcHxCO2H an AmcHxCO2H esters inhibited urokinase. Of the esters of AmcHxCO2H and GmcHxCO2H tested, only GmcHxCO2H p-tert-butylphenyl ester (GmcHxCOOPhBut) at low concentration (27 microM) strongly inhibited histamine release from rat mast cells induced by compound 48/80. GmcHxCOOPhBut was effective in preventing active systemic anaphylaxis and passively sensitized guinea pigs. Its effectiveness in preventing anaphylactic phenomena might be due to its strong inhibitory effects on histamine release from mast cells.


A biophysical view on von Willebrand factor activation.
The process of hemostatic plug formation at sites of vascular injury crucially relies on the large multimeric plasma glycoprotein von Willebrand factor (VWF) and its ability to recruit platelets to the damaged vessel wall via interaction of its A1 domain with platelet GPIbα. Under normal blood flow conditions, VWF multimers exhibit a very low binding affinity for platelets. Only when subjected to increased hydrodynamic forces, which primarily occur in connection with vascular injury, VWF can efficiently bind to platelets. This force-regulation of VWF's hemostatic activity is not only highly intriguing from a biophysical perspective, but also of eminent physiological importance. On the one hand, it prevents undesired activity of VWF in intact vessels that could lead to thromboembolic complications and on the other hand, it enables efficient VWF-mediated platelet aggregation exactly where needed. Here, we review recent studies that mainly employed biophysical approaches in order to elucidate the molecular mechanisms underlying the complex mechano-regulation of the VWF-GPIbα interaction. Their results led to two main hypotheses: first, intramolecular shielding of the A1 domain is lifted upon force-induced elongation of VWF; second, force-induced conformational changes of A1 convert it from a low-affinity to a high-affinity state. We critically discuss these hypotheses and aim at bridging the gap between the large-scale behavior of VWF as a linear polymer in hydrodynamic flow and the detailed properties of the A1-GPIbα bond at the single-molecule level.


Seroprevalence to Leptospira interrogans serovar hardjo in merino stud rams in South Australia.
A serological survey of 2160 Merino stud rams on 36 farms detected positive reactions greater than or equal to 1/100 in 42% of animals using the microscopic agglutination test (MAT) to Leptospira interrogans serovar hardjo. Twenty flocks had seroprevalence values greater than 30% with 15 flocks having values > or = 60%. The enzyme-linked immunosorbent assays showed that 47% and 3% of rams on the 36 farms were positive for IgG and IgM antibodies, respectively. Forty-five percent of hardjo reactions were in rams that had not been exposed to cattle. Significant correlations were found between IgM reactors and creek/dam water pumped into troughs, and between MAT/IgG reactors and total flock size. No statistical relationships were detected between positive reactors and two different annual average rainfall gradients, the time of the year in which samples were obtained, or agricultural regions of South Australia. Infections with an organism of the Sejroe serogroup is widespread in Merino stud rams.


Transcriptome Responses to Dexamethasone Depending on Dose and Glucocorticoid Receptor Sensitivity in the Liver.
Tissue sensitivity to glucocorticoids is a key factor dictating outcome of their homeostatic and therapeutic action, whereby liver represents one of the major peripheral targets. Here, we used pigs carrying a natural gain-of-function glucocorticoid receptor (GR) variant Ala610Val (GRAla610Val) as a model to identify genes and pathways related to differential glucocorticoid sensitivity. Animals with different GRAla610Val genotypes were treated either with saline or two different doses of dexamethasone. Genome-wide transcriptional responses depending on treatment, genotype, and their interaction in the liver were investigated using mRNA sequencing. Dexamethasone induced vast transcriptional responses, with more than 30% of present genes being affected. Functional annotation of genes differentially expressed due to dexamethasone treatment suggested that genes related to inflammation respond more sensitively, despite absence of an immune stimulus. In contrast, genes involved in glucose metabolism and cancer appeared to be less sensitive. Analysis of genotype and genotype × treatment interaction revealed that clustered protocadherins, particularly PCDHB7, are most prominently affected by GRAla610Val, mainly depending on dose. GRAla610Val influenced also expression of a set of glucose metabolism related genes, including PPARGC1A and CEBPB, in the absence of dexamethasone though no differences in basal plasma glucose level were observed. This might represent an adaptive response, keeping balance between receptor sensitivity, and level of circulating endogenous glucocorticoids. Administration of low dexamethasone dose changed their expression pattern and induced higher glucose response in carriers of the hypersensitive Val receptor. Our findings suggest that GRAla610Val modulates tissue responses to glucocorticoids dynamically, depending on their circulating level.


A hybrid knowledge based system for therapy adjustment in gestational diabetes.
This poster describes a system to analyze self-monitoring data of gestational diabetic patients, for obtaining an assessment of their metabolic control with the final goal of supporting decision-making in therapy adjustment. The system is able to manage incomplete data and to make temporal reasoning under uncertainty, the two most important constraints when analyzing ambulatory monitoring data. Two different formalism have been used to represent and manage the knowledge: a dynamic Bayesian network and a production system based on rules. The outcomes provided by the whole system are: information on possible patient transgressions of the prescribed treatment and recommendations of treatment adjustments.


[Therapeutic use of ultraviolet irradiation in medicine--scientific principles and clinical results].
Sunshine is one of mankind's oldest remedies. Merely forgotten, UV light treatment came back recently due to (1) technological progress, providing particular UV wavelengths (2) basic research, discovering mode of action at molecular level, and (3) rising knowledge about skin as the primary target. Human skin is a rather difficult organ, possessing a considerable part of the immune system, the so-called skin associated lymphoid tissue. Different biological effects are caused by UV irradiation at different wavelengths. UV radiation alone as well as together with a photosensitizer also can cause systemic effects. Dealing with these, results of basic research and their application on modern treatment of some skin diseases, transplantation medicine, non-specific resistance system, and treatment of cardiovascular diseases are discussed.


Taming Electron Transfers: From Breaking Bonds to Creating Molecules.
The electron is the ultimate redox reagent to build and reshape molecular structures. Understanding and controlling the parameters underlying dissociative electron transfer (DET) reactivity and its coupling with proton transfer is crucial for combining selectivity, kinetics and energy efficiency in molecular chemistry. Reactivity understanding and mechanistic elements in DET processes are traced back and key examples of current research efforts are presented, demonstrating a large variety of applications. The involvement of DET pathways indeed encompasses a broad range of processes such as photoredox catalysis, CO2 reduction and alcohol oxidation. Interplay between these experimental examples and fundamental mechanistic study provides a powerful path to the understanding of driving force-rate relationships, which is crucial for the development of future generations of energy efficient catalytic schemes in redox organic chemistry.


Effects of fluorouracil and fluorouridine on protein synthesis in rabbit retina.
5-Fluorouracil (5-FU) and its active metabolite 5-fluorouridine (FUR) are currently being evaluated for the treatment of proliferative vitreoretinopathy and the control of scarring after glaucoma filtering procedures. To test for retinal toxicity, the authors examined the effect of intravitreal injections of 5-FU and FUR on protein synthesis in rabbit retinal photoreceptors and ganglion cells. In addition, the toxic effect of subconjunctival 5-FU injections, after a trephine filtering procedure, on ganglion cell protein synthesis was examined. Albino rabbit eyes were given either unilateral intravitreal injections of 1 mg of 5-FU, 2.5 mg of 5-FU, or 0.1 mg of FUR, or subconjunctival injections of 3 mg of 5-FU twice daily after a trephine procedure. Quantitative autoradiography was used to study ganglion cells and photoreceptor outer segment renewal, and scintillation counting was used to quantify newly synthesized protein transported axonally from ganglion cell bodies to the superior colliculus (SC). Marked reduction of labeled protein reaching the SC was noted after either intravitreal 0.1 mg of FUR (41% inhibition after a single injection and 53% after two injections) or 2.5 mg of 5-FU (41% after one injection and 26% after two injections). This reduction was still present after 8 days in eyes receiving 0.1 mg of FUR (32%) and 2.5 mg of 5-FU (22%). Quantitative autoradiography of retinal photoreceptors and ganglion cells corroborated these data, demonstrating inhibition of outer segment renewal after one or two injections of either 0.1 mg of FUR or 2.5 mg of 5-FU. This inhibitory effect was statistically significant using the paired t-test for both drugs. No mean inhibition was observed after intravitreal 1 mg of 5-FU injections or after subconjunctival injections of 5-FU.


Postpartum psychiatric illness: the role of the pediatrician.
PPD occurs in 10% to 20% of postpartum women. Maternal depression can affect a child's development significantly. Pediatricians can screen for maternal psychiatric illness with little effort; of all the health care professionals, they may be in the best position to do so. Pediatricians can help affected mothers obtain appropriate treatment and help mobilize social resources. This simple process can minimize morbidity to pediatric patients.


Inhibiting cholinergic signalling in the cerebellar interpositus nucleus impairs motor behaviour.
The role of neuromodulators in the cerebellum is not well understood. In particular, the behavioural significance of the cholinergic system in the cerebellum is unknown. To investigate the importance of cerebellar cholinergic signalling in behaviour, we infused acetylcholine receptor antagonists, scopolamine and mecamylamine, bilaterally into the rat cerebellum (centred on interpositus nucleus) and observed the motor effects through a battery of behavioural tests. These tests included unrewarded behaviour during open field exploration and a horizontal ladder walking task and reward-based beam walking and pellet reaching tasks. Infusion of a mix of the antagonists did not impair motor learning in the horizontal ladder walking or the reaching task but reduced spontaneous movement during open field exploration, impaired coordination during beam walking and ladder walking, led to fewer reaches in the pellet reaching task, slowed goal-directed reaching behaviour and reduced reward pellet consumption in a free access to food task. Infusion of the muscarinic antagonist scopolamine on its own resulted in deficits in motor performance and a reduction in the number of reward pellets consumed in the free access to food task. By contrast, infusion of the nicotinic antagonist mecamylamine on its own had no significant effect on any task, except beam walking traversal time, which was reduced. Together, these data suggest that acetylcholine in the cerebellar interpositus nucleus is important for the execution and coordination of voluntary movements mainly via muscarinic receptor signalling, especially in relation to reward-related behaviour.


Genetically modified baculoviruses: a historical overview and future outlook.
The concept of using genetic engineering to improve the natural insecticidal activity of baculoviruses emerged during the 1980s. Both academic and industrial laboratories have since invested a great deal of effort to generate genetically modified (GM) or recombinant baculoviruses with dramatically improved speeds of kill. Optimal production methodologies and formulations have also been developed, and the safety and ecology of the recombinant baculoviruses have been thoroughly investigated. Unfortunately, the initial excitement that was generated by these technologies was tempered when industry made a critical decision to not complete the registration process of GM baculoviruses for pest insect control. In this chapter, we summarize the developments in the field from a historical perspective and provide our opinions as to the current status and future potential of the technology. We will argue that GM baculoviruses are valuable and viable tools for pest insect control both alone and in combination with wild-type viruses. We believe that these highly effective biopesticides still have a bright future in modern agriculture as public awareness and acceptance of GM organisms, including GM baculoviruses, increases.


Muscle strength and history of heavy manual work among elderly trained women and randomly chosen sample population.
The association between a history of heavy work and muscle strength was studied among 51 physically active women aged 66-85 years trained in sports and 41 women aged 70-81 years selected randomly from the population register. Maximal isometric muscle strength of hand grip, arm flexion, leg extension and trunk flexion and extension were measured using specially constructed dynamometers. The capacity of the abdominal muscles was evaluated by means of a sit-up test. The study included an interview dealing with the subjects' histories of heavy manual employment. The mean histories of heavy work for the trained and untrained women were 24 and 36 years, respectively. The trained women showed significantly greater maximal isometric muscle strength and abdominal muscle capacity than the untrained women. Among the trained women there was no correlation between the amount of heavy work and muscle performance. Among the untrained women the amount of heavy work correlated positively with maximal isometric trunk extension strength. The results would suggest that among elderly women, whether physically active or not, a history of heavy work has no systematic association with muscle strength.


Noncalcemic Vitamin D Hydroxyderivatives Inhibit Human Oral Squamous Cell Carcinoma and Down-regulate Hedgehog and WNT/β-Catenin Pathways.
The hormonally-active form of vitamin D, 1,25(OH)2D3, demonstrated activity against oral squamous cell carcinoma (OSCC). Cytochrome P450scc (CYP11A1)-derived vitamin D hydroxyderivatives, such as 20(OH)D3 and 1,20(OH)2D3, have overlapping beneficial effects with 1,25(OH)2D3 without causing hypercalcemia. This study sought to determine (i) whether 20(OH)D3 and 1,20(OH)2D3 exhibit antitumor effects against OSCC comparable to those of 1,25(OH)2D3 and (ii) whether these effects may stem from down-regulation of sonic hedgehog (SHH) or WNT/β-catenin signaling pathways. Effects on CAL-27 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt and spheroid assays. Signaling pathways were assessed by immunofluorescence and western blotting. 20(OH)D3 and 1,20(OH)2D3 inhibited the growth of CAL-27 and demonstrated inhibition of WNT/β-catenin and the SHH signaling as evidenced by down-regulation of nuclear translocation of glioma-associated oncogene 1(GLI1) and β-catenin. Noncalcemic vitamin D hydroxyderivatives demonstrated antitumor activities against OSCC comparable to those of 1,25(OH)2D3 Their activities against SHH and the WNT/β-catenin pathways provide insight for a possible target for OSCC treatment.


Penetration of cefoperazone into surgical wound drainage in patients undergoing head and neck surgery.
Cefoperazone penetration into skeletal muscle and wound drainage in patients undergoing major surgery of the head and neck was measured by high-pressure liquid chromatography. Cefoperazone (2 g) was infused over 30 min before surgery and every 8 h for three postoperative doses. Simultaneous samples of serum and sternomastoid muscle were collected in 18 patients at 135 to 480 min after infusion. Mean cefoperazone concentrations in muscle tissue were 17.1% of those in simultaneously collected serum. Steady-state wound drainage concentrations after the fourth dose of cefoperazone averaged 55.2 micrograms/ml at 1 to 2 h and 62.1 micrograms/ml at 2 to 3 h. Simultaneous steady-state serum and wound fluid samples were obtained at regular intervals in six patients. In all patients, the peak level in wound fluid exceeded 25 micrograms/ml. Thus, cefoperazone reaches interstitial fluid concentration in soft tissue that exceeds the MICs required to inhibit the usual pathogens found at the site of wound infection after head and neck surgery.


High-sensitivity bolometers from self-oriented single-walled carbon nanotube composites.
In this work, films of horizontally aligned single-walled carbon nanotubes were thermally and electrically characterized in order to determine the bolometric performance. An average thermal time constant of τ = 420 μs along with a temperature coefficient of resistance of TCR = -2.94% K(-1) were obtained. The maximum voltage responsivity and detectivity obtained were R(V) =230 V/W and D* = 1.22 × 10(8) cm Hz(1/2)/W, respectively. These values are higher than the maximum voltage responsivity (150 V/W) and maximum temperature coefficient of resistance (1.0% K(-1)) previously reported for carbon nanotube films at room temperature. The maximum detectivity was obtained at a frequency of operation of 1.25 kHz.


Seasonal distributions and migrations of Northwest Atlantic swordfish: inferences from integration of pop-up satellite archival tagging studies.
Data sets from three laboratories conducting studies of movements and migrations of Atlantic swordfish (Xiphias gladius) using pop-up satellite archival tags were pooled, and processed using a common methodology. From 78 available deployments, 38 were selected for detailed examination based on deployment duration. The points of deployment ranged from southern Newfoundland to the Straits of Florida. The aggregate data comprise the most comprehensive information describing migrations of swordfish in the Atlantic. Challenges in using data from different tag manufacturers are discussed. The relative utility of geolocations obtained with light is compared with results derived from temperature information for this deep-diving species. The results show that fish tagged off North America remain in the western Atlantic throughout their deployments. This is inconsistent with the model of stock structure used in assessments conducted by the International Commission for the Conservation of Atlantic Tunas, which assumes that fish mix freely throughout the North Atlantic.


Writers' cramp.
At least 4000 people suffer from writers' cramp in the UK. While diagnosis is straightforward, treatment is difficult and many therapies are unsatisfactory. This article reviews the various manifestations of writers' cramp, the physiological evidence indicating that it is a neurological disease and the therapeutic techniques available.


Social environment and headache in 8- to 9-year-old children: a follow-up study.
We studied the occurrence of migraine and nonmigrainous headache and the factors associated with headache in a group of 3580 children. These children belong to a 1-year age cohort which has been followed since birth. When the children were 8 to 9 years old, data on their headaches were gathered through a postal questionnaire. Ninety-five of the children (2.7%) had migraine and 977 (27.3%) reported non-migrainous headache at the age of 8 to 9 years. Thirty-four percent of the children with migraine had already had headache at the age of 5 years. Children with migraine and children with nonmigrainous headache both reported more often being bullied in school, stress in school, and problems in getting along with other children than children without headache. The association of stress in school with headache was strongest in girls with migraine, even though they reported the least difficulties in school subjects. As many as one third of the boys with migraine reported that they had problems with peer relationships.


The molecular weight forms of rat growth hormone secreted in response to growth hormone-releasing factor.
The different molecular weight forms of immunoreactive growth hormone (irGH) secreted by the anterior pituitary of rats were evaluated during basal and stimulated secretion in vitro and in vivo. Anterior pituitary cells maintained in a monolayer culture system secreted only a 22,000-Da form of GH based on Sephacryl S-200 column chromatography. This was also true for the irGH secreted in response to growth hormone-releasing factor and prostaglandin E2 stimulation. In contrast, the molecular weight forms of irGH found in plasma under basal conditions included an approximately 90,000-Da form as well as the expected 22,000-Da form. The concentrations of both forms increased following growth hormone-releasing factor stimulation although there was a shift in the ratio of the forms secreted. These results suggest that the larger molecular weight forms of rat GH observed in plasma may be the result of some postsecretory process which occurs in blood and suggests a possible regulatory function for the larger molecular weight forms as it pertains to the bioavailability of GH in vivo.


Nuclear localization of glutamate-cysteine ligase is associated with proliferation in head and neck squamous cell carcinoma.
Glutathione (GSH) is the keystone of the cellular response toward oxidative stress. Elevated GSH content correlates with increased resistance to chemotherapy and radiotherapy of head and neck (HN) tumors. The purpose of the present cross-sectional study was to evaluate whether the expression of glutamate-cysteine ligase (GCL) accounts for the increased GSH availability observed in HN squamous cell carcinoma (SCC). For that purpose, the messenger (m)RNA levels of the modifier (M) and catalytic (C) subunits of GCL and its putative regulators (namely, nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) were monitored in 35 surgical resections of untreated HNSCC. The localization of GCLM was evaluated using in situ hybridization and immunohistochemistry. GCLM expression was significantly increased in tumor samples, compared with normal mucosa, both at the mRNA and protein level (P=0.029), but the pathway of GCLM activation remains to be elucidated. Protein expression of GCLM was detected in the cytoplasm and nucleus. GCLM and the proliferation marker Ki-67 displayed a similar distribution, being both mainly expressed at the periphery of tumor lobules. The present study reported increased expression of GCL and the rate-limiting enzyme of GSH synthesis, within HNSCC. The nuclear localization of GCLM and the concomitant expression of Ki-67 suggested that the localization of GSH synthesis contributes to the protection against oxidative stress within hotspots of cell proliferation.


Morphological and phylogenetic evidence for two new species of Russula subg. Heterophyllidia from Guangdong Province of China.
Two new species of Russulasubg.Heterophyllidia from Guangdong Province of China were described and illustrated based on morphological characters, and their identity supported by molecular phylogeny. R.luofuensis is morphologically characterized by a grayish yellow to brownish orange pileus center with a purplish gray to grayish magenta margin, a surface that is cracked and broken into small golden-brown patches, subglobose to broadly ellipsoid basidiospores with warts fused in short or long chains and a suprapellis composed of hyphal extremities with inflated, ellipsoid or globose cells and attenuated terminal cell. R.subbubalina is distinguished by the blanched almond to dark salmon pileus that is cracked with age, subglobose to broadly ellipsoid basidiospores with wart fused in short or long chains and frequently connected by line connections, a suprapellis with hyphal ends composed of inflated or ellipsoid cells and attenuated terminal cell, and pileocystidia that are mainly clavate and sometimes with round or ellipsoid appendage. The phylogenetic analyses based on ITS-nrLSU-mtSSU-TEF1 dataset were performed using maximum likelihood and Bayesian analysis. In terms of morphological features and molecular data, the former species belongs to subsect. Virescentinae, whereas the latter comes under subsect. Heterophyllinae.


Magnetic resonance diffusion tensor imaging of optic nerve and optic radiation in healthy adults at 3T.
To investigate the diffusion characteristics of water of optic nerve and optic radiation in healthy adults and its related factors by diffusion tensor imaging (DTI) at 3T. A total of 107 healthy volunteers performed head conventional MRI and bilateral optic nerve and optic radiation DTI. The primary data of DTI was processed by post-processing software of DTI studio 2.3, obtaining fractional anisotropy value, mean diffusivity value, principal engine value, orthogonal engine value by measuring, and analyzed by the SPSS13.0 statistical software. The bilateral optic nerve and optic radiation fibers presented green color in directional encoded color (DEC) maps and presented high signal in fractional anisotropy (FA) maps. The FA value of the left optic nerve was 0.598±0.069 and the right was 0.593±0.065; the mean diffusivity (MD) value of the left optic nerve was (1.324±0.349)×10(-3)mm(2)/s and the right was (1.312±0.350)×10(-3)mm(2)/s; the principal engine value (λ‖) of the left optic nerve was (2.297±0.522)×10(-3)mm(2)/s and the right was (2.277±0.526)×10(-3)mm(2)/s; the orthogonal engine value (λ⊥) of the left optic nerve was (0.838±0.285)×10(-3)mm(2)/s and the right was (0.830±0.280)×10(-3)mm(2)/s; the FA value of the left optic radiation was 0.636±0.057 and the right was 0.628±0.056; the mean diffusivity (MD) value of the left optic radiation was (0.907±0.103)×10(-3)mm(2)/s and the right was (0.889±0.125)×10(-3)mm(2)/s; the principal eigenvalue (λ‖) of the left optic radiation was (1.655±0.210)×10(-3)mm(2)/s and the right was (1.614±0.171)×10(-3)mm(2)/s; the orthogonal enginvalue (λ⊥) of the left optic radiation was (0.531±0.103)×10(-3)mm(2)/s and the right was (0.524±0.152)×10(-3)mm(2)/s. There was no obvious difference between the FA, MD, λ‖, λ⊥ of the bilateral optic radiation and the bilateral optic nerve (P>0.05) and no obvious difference between male and female group. The FA, MD, λ‖, λ⊥ of the bilateral optic radiation and the bilateral optic nerve had no obvious correlations to the age. DTI is sensitive to the optic nerve and radiation and the relevant DTI parameters of the optic nerve and radiation are established preliminarily in this study.


Balancing the dilution and oddity effects: decisions depend on body size.
Grouping behaviour, common across the animal kingdom, is known to reduce an individual's risk of predation; particularly through dilution of individual risk and predator confusion (predator inability to single out an individual for attack). Theory predicts greater risk of predation to individuals more conspicuous to predators by difference in appearance from the group (the 'oddity' effect). Thus, animals should choose group mates close in appearance to themselves (eg. similar size), whilst also choosing a large group. We used the Trinidadian guppy (Poecilia reticulata), a well known model species of group-living freshwater fish, in a series of binary choice trials investigating the outcome of conflict between preferences for large and phenotypically matched groups along a predation risk gradient. We found body-size dependent differences in the resultant social decisions. Large fish preferred shoaling with size-matched individuals, while small fish demonstrated no preference. There was a trend towards reduced preferences for the matched shoal under increased predation risk. Small fish were more active than large fish, moving between shoals more frequently. Activity levels increased as predation risk decreased. We found no effect of unmatched shoal size on preferences or activity. Our results suggest that predation risk and individual body size act together to influence shoaling decisions. Oddity was more important for large than small fish, reducing in importance at higher predation risks. Dilution was potentially of limited importance at these shoal sizes. Activity levels may relate to how much sampling of each shoal was needed by the test fish during decision making. Predation pressure may select for better decision makers to survive to larger size, or that older, larger fish have learned to make shoaling decisions more efficiently, and this, combined with their size relative to shoal-mates, and attractiveness as prey items influences shoaling decisions.


Ewing's sarcoma of the proximal phalanx of the foot: A rare case report.
Ewing's sarcoma localized to foot is extremely rare. Local control is mandatory because of the aggressive nature of the tumor. Therapeutic options for these local tumors include neoadjuvant chemotherapy followed by surgery. A 17-year-old female patient presented with a 6-month history of progressive swelling and intermittent pain of the left great toe. Plain radiography and magnetic resonance imaging revealed an expansile mass that had originated from the proximal phalanx of the great toe and was destructing and surrounding the distal phalanx. Her erythrocyte sedimentation rate and serum lactate dehydrogenase levels were slightly elevated. Distant metastasis was not detected. The patient underwent an open biopsy, which confirmed the diagnosis of Ewing's sarcoma. She was treated with neoadjuvant chemotherapy and disarticulation above the metatarsophalangeal joint. She received adjuvant chemotherapy following the operation. The patient died 50 months after the operation as a result of disseminated disease. The distal phalanx of the foot is an extremely rare site for the development of Ewing's sarcoma. As local control is important to avoid dissemination of the disease, neoadjuvant chemotherapy followed by amputation or disarticulation of the affected digit and subsequently adjuvant chemotherapy may be favorable modality for increasing the patient's duration of survival. Hippokratia 2015, 19 (1): 82-84.


Swift and definite serotyping for isolated Listeria monocytogenes strains.
The serotype is most important for molecular epidemiological analysis of Listeria monocytogenes (L.m.) contaminating marketed meats. An improvement on the traditional method was thus attempted in the present study because of the requirement of swift and definite serotyping. In the determination of O-antigen, definite judgement was allowed by an immediate cooling at 80 degrees C after autoclaving the bacteria. In the determination of H-antigen, use of a culture plate without Craigie's tube yielded the active bacteria only by single culture. The stable and clear agglutination in many samples was also obtained with a microplate using less antiserum. The availability was confirmed with 123 strains and the serovar 1/2b was dominant in the Japanese strains.


Molecular Mechanisms for the Coupling of Endocytosis to Exocytosis in Neurons.
Neuronal communication and brain function mainly depend on the fundamental biological events of neurotransmission, including the exocytosis of presynaptic vesicles (SVs) for neurotransmitter release and the subsequent endocytosis for SV retrieval. Neurotransmitters are released through the Ca2+- and SNARE-dependent fusion of SVs with the presynaptic plasma membrane. Following exocytosis, endocytosis occurs immediately to retrieve SV membrane and fusion machinery for local recycling and thus maintain the homeostasis of synaptic structure and sustained neurotransmission. Apart from the general endocytic machinery, recent studies have also revealed the involvement of SNARE proteins (synaptobrevin, SNAP25 and syntaxin), synaptophysin, Ca2+/calmodulin, and members of the synaptotagmin protein family (Syt1, Syt4, Syt7 and Syt11) in the balance and tight coupling of exo-endocytosis in neurons. Here, we provide an overview of recent progress in understanding how these neuron-specific adaptors coordinate to ensure precise and efficient endocytosis during neurotransmission.


Curriculum resources for cultural diversity education.
As part of the 2001 Coalition for Allied Health Leadership, a review of curriculum resources for teaching diversity courses in allied health programs was conducted. A synopsis of the most relevant resources and an example of a generic diversity course for programs preparing entry-level allied health professionals, are presented.


New advances on the functions of epidermal growth factor receptor and ceramides in skin cell differentiation, disorders and cancers.
Recent advances in understanding of the biological functions of the epidermal growth factor and epidermal growth factor receptor (EGF-EGFR) system and ceramide production for the maintenance of skin integrity and barrier function are reported. In particular, the opposite roles of EGFR and ceramide cascades in epithelial keratinocyte proliferation, migration and terminal differentiation are described. Moreover, the functions of ceramides in the epidermal permeability barrier are reviewed. The alterations in EGFR signaling and ceramide metabolism, which might be involved in the etiopathogenesis of diverse skin disorders and cancers, are described. New progress in understanding of skin organization, which might provide the basis for the design of new transcutaneous drug delivery techniques as well as for the development of new therapies of skin disorders and cancers, are reported.


Stimulated intrauterine insemination in women with unilateral tubal occlusion.
To investigate the value of stimulated intrauterine insemination (IUI) in women with unilateral tubal occlusion. Superovulation and IUI was performed during 2003-2010 and the medical records were reviewed retrospectively. Thirty-seven infertile women (52 cycles) with unilateral tubal occlusion diagnosed by hysterosalpingography and without other causes of infertility were selected. One-hundred fourteen patients with unexplained infertility served as a control group (182 cycles). The main outcome was the clinical pregnancy rate per cycle. The pregnancy rate per cycle was similar, 17.3% for the unilateral tubal occlusion group and 16.5% for the unexplained infertility group. The rate of miscarriage (11.1% vs. 23.3%) and ectopic pregnancy (11.1% vs. 6.7%) was similar between the two groups. The pregnancy rate was higher in patients with proximal occlusion (25.0%) compared with distal occlusion (13.9%) or unexplained infertility, but not statistically significant. Stimulated IUI can be suggested as the initial treatment option in women with unilateral proximal or distal tubal occlusion.


Illuminating political clarity in culturally relevant science instruction.
Failure to improve achievement in K-12 science for racially minoritized students and students living in poverty continues to challenge the inclusionary rhetoric of science for all. Science education researchers, teacher educators, and educators must consider the racialized and classed inequalities that continue to limit students' opportunities to learn. To achieve this, we must be able to conceptualize sociopolitical pedagogical approaches and learn from empirical examples of science teachers who consciously attend to their students' realities in empowering rather than deficit-oriented ways. We argue for the importance of utilizing culturally relevant pedagogy (CRP) and attending to and theorizing an educator's sociopolitical consciousness and enactments of political clarity in science instruction. Our analysis highlights how an African American male science teacher responds to his middle school students' realities and identities as African American youth and children growing up contexts with limited economic resources. Through classroom observations and interviews with the teacher, we nuance our understanding of sociopolitical consciousness, the third tenet of CRP, as reliant upon a teacher's political clarity and examine how, through instruction, science teachers can position students and their realities as consonant with knowing and doing science and being scientists.


A contextualised e-cigarette testing strategy shows flavourings do not impact lung toxicity in vitro.
Vaping has the potential to reduce the individual health risks associated with smoking and e-cigarette flavours have been reported to help smokers' transition from cigarettes. In this manuscript, we provide evidence to support the reduced risk potential of e-cigarette aerosols and flavours by assessing commercially available e-liquids (Vuse ePod - Manufactured by British American Tobacco) in a 2D in vitro screening approach. We also analysed selected flavours using a more physiologically relevant 3D (MucilAir) whole aerosol exposure model, measuring toxicity and functional endpoints such as Trans Epithelial Electrical Resistance, Cilia Beat Frequency and Active Area. To contextualise responses, we have compared e-cigarette aerosol to cigarette smoke (1R6F research cigarette) and calculated the percentage reduction using a point of departure approach. We show that aerosolised flavoured e-liquids, (appropriately stewarded) do not increase the overall measured aerosol toxicity when compared to cigarette smoke. In fact, we demonstrate that the measured in vitro cellular toxicity of flavoured e-cigarette products remains > 95% reduced when compared to cigarette smoke toxicity, using point of departure (IC80) approach. These data indicate that the overall product toxicity is not increased in a flavour dependent manner and that flavoured e-cigarette products can potentially play a role in tobacco harm reduction.


Cytotoxicity of Hybrid Noble Metal-Polymer Composites.
The aim of the present research was to assess the cytotoxicity of gold and silver nanoparticles synthesized into dextran-graft-polyacrylamide (D-PAA) polymer nanocarrier, which were used as a basis for further preparation of multicomponent nanocomposites revealed high efficacy for antitumor therapy. The evaluation of the influence of Me-polymer systems on the viability and metabolic activity of fibroblasts and eryptosis elucidating the mechanisms of the proeryptotic effects has been done in the current research. The nanocomposites investigated in this study did not reduce the survival of fibroblasts even at the highest used concentration. Our findings suggest that hybrid Ag/D-PAA composite activated eryptosis via ROS- and Ca2+-mediated pathways at the low concentration, in contrast to other studied materials. Thus, the cytotoxicity of Ag/D-PAA composite against erythrocytes was more pronounced compared with D-PAA and hybrid Au/polymer composite. Eryptosis is a more sensitive tool for assessing the biocompatibility of nanomaterials compared with fibroblast viability assays.


Development of mRNA vaccines against respiratory syncytial virus (RSV).
Respiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that is the primary etiologic pathogen of bronchitis and pneumonia in infants and the elderly. Currently, no preventative vaccine has been approved for RSV infection. However, advances in the characterization, and structural resolution, of the RSV surface fusion glycoprotein have revolutionized RSV vaccine development by providing a new target for preventive interventions. In general, six different approaches have been adopted in the development of preventative RSV therapeutics, namely, particle-based vaccines, vector-based vaccines, live-attenuated or chimeric vaccines, subunit vaccines, mRNA vaccines, and monoclonal antibodies. Among these preventive interventions, MVA-BN-RSV, RSVpreF3, RSVpreF, Ad26. RSV.preF, nirsevimab, clesrovimab and mRNA-1345 is being tested in phase 3 clinical trials, and displays the most promising in infant or elderly populations. Accompanied by the huge success of mRNA vaccines in COVID-19, mRNA vaccines have been rapidly developed, with many having entered clinical studies, in which they have demonstrated encouraging results and acceptable safety profiles. In fact, Moderna has received FDA approval, granting fast-track designation for an investigational single-dose mRNA-1345 vaccine against RSV in adults over 60 years of age. Hence, mRNA vaccines may represent a new, more successful, chapter in the continued battle to develop effective preventative measures against RSV. This review discusses the structure, life cycle, and brief history of RSV, while also presenting the current advancements in RSV preventatives, with a focus on the latest progress in RSV mRNA vaccine development. Finally, future prospects for this field are presented.


Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis.
Constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway has been shown to be involved in the resistance of tumor cells to apoptosis in several human malignancies of the hematopoietic lineage. By using electrophoretic mobility shift assay (EMSA) and confocal microscopic analysis, we demonstrate that NF-kappaB is constitutively activated in cutaneous T-cell lymphoma (CTCL) cell lines HuT-78, MyLa, and SeAx and in peripheral blood lymphocytes (PBLs) from patients with Sézary syndrome (SS) presenting a high ratio of tumor cells, with evidence of p50 and RelA/p65 in DNA-linked complexes. Transfection of SeAx line with a kappaB/luciferase reporter plasmid showed that translocated NF-kappaB complexes were functional. Selective inhibition of NF-kappaB, by transfecting CTCL cell lines with a super-repressor form of IkappaB alpha, led to apoptosis. We evidenced down-regulation of NF-kappaB activation and induction of CTCL cell apoptosis in the presence of proteasome 26S inhibitors ALLN, MG132, and bortezomib. Bortezomib at nanomolar concentrations inhibited constitutive activation of NF-kappaB and induced apoptosis of CTCL cells, with evidence of an upregulation of Bax expression. These results demonstrate the key role played by NF-kappaB in the resistance of CTCL to apoptosis and suggest that bortezomib might be useful for the treatment of patients with advanced stages of CTCL refractory to standard antineoplastic chemotherapy.


IL-1β dysregulates cGMP signaling in the newborn lung.
Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1β regulates the expression of the α1-subunit of soluble guanylate cyclase (sGCα1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1β were discovered to rapidly decrease sGCα1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGCα1 expression inhibition appeared to be at a transcriptional level; IL-1β treatment did not alter sGCα1 mRNA stability, although it reduced sGCα1 promoter activity. Transforming growth factor-β (TGFβ)-activated kinase-1 (TAK1) was determined to be required for IL-1β's regulation of sGCα1 expression; TAK1 knockdown protected sGCα1 mRNA expression in IL-1β-treated IMR-90 cells. Moreover, heterologously expressed TAK1 was sufficient to decrease sGCα1 mRNA levels in those cells. Nuclear factor-κB (NF-κB) signaling played a critical role in the IL-1β-TAK1-sGCα1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-κB subunit (RelA) binding to the sGCα1 promoter after IL-1β treatment unless treated with an IκB kinase-2 inhibitor. Also, this NF-κB signaling inhibition protected sGCα1 expression in IL-1β-treated fibroblasts. Lastly, using transgenic mice in which active IL-1β was conditionally expressed in lung epithelial cells, we established that IL-1β expression is sufficient to stimulate TAK1 and decrease sGCα1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1β inhibits cGMP signaling in the newborn lung.


Vision impairment and traffic safety outcomes in low-income and middle-income countries: a systematic review and meta-analysis.
Road traffic injuries are a major public health concern and their prevention requires concerted efforts. We aimed to systematically analyse the current evidence to establish whether any aspects of vision, and particularly interventions to improve vision function, are associated with traffic safety outcomes in low-income and middle-income countries (LMICs). We did a systematic review and meta-analysis to assess the association between poor vision and traffic safety outcomes. We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials in the Cochrane Library from database inception to April 2, 2020. We included any interventional or observational studies assessing whether vision is associated with traffic safety outcomes, studies describing prevalence of poor vision among drivers, and adherence to licensure regulations. We excluded studies done in high-income countries. We did a meta-analysis to explore the associations between vision function and traffic safety outcomes and a narrative synthesis to describe the prevalence of vision disorders and adherence to licensure requirements. We used random-effects models with residual maximum likelihood method. The systematic review protocol was registered on PROSPERO, CRD-42020180505. We identified 49 (1·8%) eligible articles of 2653 assessed and included 29 (59·2%) in the various data syntheses. 15 394 participants (mean sample size n=530 [SD 824]; mean age of 39·3 years [SD 9·65]; 1167 [7·6%] of 15 279 female) were included. The prevalence of vision impairment among road users ranged from 1·2% to 26·4% (26 studies), colour vision defects from 0·5% to 17·1% (15 studies), and visual field defects from 2·0% to 37·3% (ten studies). A substantial proportion (range 10·6-85·4%) received licences without undergoing mandatory vision testing. The meta-analysis revealed a 46% greater risk of having a road traffic crash among those with central acuity visual impairment (risk ratio [RR] 1·46 [95% CI 1·20-1·78]; p=0·0002, 13 studies) and a greater risk among those with defects in colour vision (RR 1·36 [1·01-1·82]; p=0·041, seven studies) or the visual field (RR 1·36 [1·25-1·48]; p<0·0001, seven studies). The I2 value for overall statistical heterogeneity was 63·4%. This systematic review shows a positive association between vision impairment and traffic crashes in LMICs. Our findings provide support for mandatory vision function assessment before issuing a driving licence. None.


Carotenoid-biofortified maize maintains adequate vitamin a status in Mongolian gerbils.
Efforts to biofortify maize with provitamin A carotenoids have been successful, but the impact on vitamin A (VA) status has not been determined. We conducted two studies that investigated the bioefficacy of provitamin A carotenoids from maize and compared maize percentage and carotenoid concentrations on VA status in VA-depleted Mongolian gerbils (Meriones unguiculatus). Gerbils (n = 40/study) were fed a white maize diet 4 wk prior to treatment. In study 1, treatments (n = 10/group) included oil control, 60% high-beta-carotene maize, and beta-carotene or VA supplements (matched to high-beta-carotene maize). In study 2, gerbils were fed 30 or 60% orange or yellow maize diets. Gerbils were killed after 4 wk. In study 1, liver VA concentrations, compared with the high-beta-carotene maize group (0.25 +/- 0.15 micromol/g), were higher in the VA group (0.56 +/- 0.15 micromol/g, P < 0.05), lower in the control (0.10 +/- 0.04 micromol/g, P < 0.05), and did not differ in the beta-carotene group (0.25 +/- 0.08 micromol/g). Bioconversion was approximately 3 microg beta-carotene to 1 mug retinol (1.5 mol beta-carotene to 1 mol retinol). The liver beta-carotene content was greater in the high-beta-carotene maize group (26.4 +/- 6.0 nmol) than in the beta-carotene supplement group (14.1 +/- 6.0 nmol; P < 0.05). In study 2, the gerbils' VA status improved with increasing dietary beta-carotene. Liver VA in gerbils fed orange maize was greater than in those fed yellow maize, regardless of maize percentage (P < 0.05). Biofortified maize adequately maintained VA status in Mongolian gerbils and was as efficacious as beta-carotene supplementation. In populations consuming maize as a staple food, using orange instead of white maize could dramatically affect VA status.


Evaluation of culture, histological examination, serology and the rapid urease test for diagnosis of Helicobacter pylori in patients with dyspepsia in Bangladesh.
Helicobacter pylori, a gram-negative, microaerophilic bacterium, has been established to have a causal association with chronic gastritis, peptic ulcer, gastric adenocarcinoma, and low-grade lymphoma. The present study was undertaken to evaluate the efficacy of culture, histological examination, the rapid urease test, and serology for the diagnosis of H. pylori infection. A total of 45 consecutive subjects with various upper gastrointestinal symptoms were included in this study. The rates of diagnosis of H. pylori infection were 51.1%, 55.6%, 82.2%, and 93.3%, by culture, rapid urease test (RUT), histological examination, and serology, respectively. The sensitivity, specificity, and positive and negative predictive values were 95.5%, 82.6%, 84.0%, and 95.0%, respectively for RUT; 95.5%, 30.4%, 56.8%, and 87.5% for histological examination; 100%, 13.6%, 54.8% and 100% for serology.


Physiological and production responses to feeding schedule in lactating dairy cows exposed to short-term, moderate heat stress.
The objective of this research was to characterize the production responses of lactating dairy cows during and after short-term, moderate heat exposure, and to determine whether evening (p.m.) feeding would alleviate the associated production losses. In a two-period, cross-over design, eight mature lactating cows were fed a total mixed ration at either 0830 or 2030 h. Each 15-d period consisted of a 5-d thermoneutral phase, a 5-d heat stress phase and a 5-d thermoneutral recovery phase. Mean daily vaginal temperature and respiration rate increased by 0.6 +/- 0.04 degrees C and 27 +/- 1.3 breaths/min, respectively, during short-term heat exposure. Daily dry matter intake, milk yield and solids-not-fat were depressed by 1.4 +/- 0.13 kg, 1.7 +/- 0.32 kg and 0.07 +/- 0.023%, respectively, during heat exposure. During the recovery phase, dry matter intake remained depressed, milk protein declined by 0.05 +/- 0.020%, and daily milk yield exhibited a further decline of 1.2 +/- 0.32 kg. Time of feeding had no effect on vaginal temperature, respiration rate, dry matter intake, water intake, milk yield, fat-corrected milk, protein percent, solids-non-fat percent or somatic cell count during heat exposure or during the recovery period that followed. Fat percent was, however, significantly lower in p.m.-fed animals. These data indicate that short-term, moderate heat stress, which occurs during the spring and summer months in Canada and the Northern United States, will significantly decrease production in the lactating cow. Shifting from morning to evening feeding did not alleviate production losses associated with this type of heat stress.


Participation of contrasting changes in IL-10 and IL-12 production in the reduction of Th1-predominance by Hachimi-jio-gan in autoimmune MRL/MP-lpr/lpr mice.
Hachimi-jio-gan (Chinese name: Ba-Wei-Di-Huang-Wan, HMG), a traditional Japanese herbal medicine, has been used for disorders accompanying aging. Our previous studies suggested that HMG ameliorated Thl-predominant autoimmune diseases in MRL/lpr mice through inhibition of IL-12 production. In the present study, the oral administration of HMG down-regulated phosphorylated STAT4 and up-regulated phosphorylated STAT6 in CD4 T cells. In the T cells, IL-12Rbeta1 and IL-12Rbeta2 mRNA expression levels were suppressed. In antigen-presenting cells (CD45R- MHC class II+ cells) which control Th1 and Th2 immune responses, the total cell number and the percentage of cells expressing co-stimulatory molecules decreased in the HMG-treated group. In addition, the levels of IL-12 and 18 mRNA expression increased and conversely, IL-10 mRNA expression decreased. Further, the production of IL-10 was up-regulated and that of IL-12 was down-regulated by HMG in the presence of anti-CD40 antibody. These results suggest that the opposite effects on IL-10 production and, IL-12 or IL-18 production in antigen-presenting cells of oral administration of HMG are due a decline in IL-12R expression, and consequently, amelioration of MRL/lpr autoimmune diseases occurs through the suppression of Th1 predominance via STAT4/STAT6 signaling.


Efficient Ni/Au Mesh Transparent Electrodes for ITO-Free Planar Perovskite Solar Cells.
Indium thin oxide (ITO)-free planar perovskite solar cells (PSCs) were fabricated at a low temperature (150 °C) in this work based on the transparent electrode of photolithography processed nickel/gold (Ni/Au) mesh and the high conductivity polymer, PH1000. Ultrathin Au was introduced to increase the conductivity of metal mesh, and the optimal hexagonal Ni (30 nm)/Au (10 nm) mesh (line width of 5 μm) shows a transmittance close to 80% in the visible light region and a sheet resistance lower than 16.9 Ω/sq. The conductive polymer PH1000 not only smooths the raised surface of the metal mesh but also enhances the charge collection ability of metal mesh. The fabricated PSCs have the typical planar structure (glass/Ni-Au mesh/PH1000/PEDOT:PSS/MAyFA1-yPbIxCl3-x/PCBM/BCP/Ag) and the champion PSC (0.09 cm2) obtains a power conversion efficiency (PCE) of 13.88%, negligible current hysteresis, steady current density and PCE outputs, and good process repeatability. Its photovoltaic performance and stability are comparable to the reference PSC based on the ITO electrodes (PCE = 15.70%), which demonstrates that the Ni/Au mesh transparent electrodes are a promising ITO alternative to fabricate efficient PSCs. The relatively lower performance of Ni/Au based PSC results from the relatively slower charge extraction and stronger charge recombination than the ITO based PSC. Further, we tried to fabricate the large area (1 cm2) device and achieve a PCE over 6% with negligible hysteresis and steady current density and PCE outputs. The improvements of perovskite film quality and interface modification should be an effective approach to further enhance the device performance of Ni/Au based PSCs, and the Ni/Au mesh electrode may find wider applications in PSCs and flexible devices.


Winner of the AlbertTrillat Young Investigator Award. The effects of aggressive notchplasty on the normal knee in dogs.
We assessed the possible association between an aggressive intercondylar notchplasty and histopathologic, radiographic, and gait changes to the knee. Three groups of six adult greyhounds were observed for 6 months. Group I dogs had a sham operation. Group II dogs had a 4-mm notchplasty of the lateral femoral condyle where it articulates with the lateral tibial spine. Group III dogs had a 7- to 8-mm notchplasty of the lateral femoral condyle to simulate the long-term effects of an overly aggressive notchplasty. Force plate gait analyses were not significantly different for any dogs at 3 and 6 months. Histopathologic studies (hematoxylin and eosin and safranin O stains) revealed notchplasty area remodeling with a thin layer of lamellar bone covered by fibrous connective tissue. Both Group II and III dogs had significant loss of lateral femoral condyle and trochlear groove articular surface proteoglycans. The radiographic notch width index remained unchanged throughout the study for Group I; the indexes increased immediately after surgery in Groups II and III because of the notchplasty, but after 6 months these values returned to near-preoperative measurements. An aggressive intercondylar notchplasty caused articular cartilage histopathologic changes at 6 months consistent with those found in knees with early degenerative arthritis. Significant refilling of a non-impinged notchplasty occurred by 6 months after surgery. Our results raise concern about the effects of aggressive intercondylar notch widening in humans.


Medicaid and Uninsured Hepatocellular Carcinoma Patients Have More Advanced Tumor Stage and Are Less Likely to Receive Treatment.
To evaluate the impact of insurance status on tumor stage at diagnosis, treatment received, and overall survival among adults with hepatocellular carcinoma (HCC). Insurance status affects access to care, which impacts timely access to cancer screening for early detection and treatment. Using the 2007 to 2012 Surveillance, Epidemiology, and End Results (SEER) database, we retrospectively evaluated US adults with HCC. Insurance status included Medicare/commercial insurance (MC), Medicaid (MA), and no insurance (NI). HCC tumor stage was evaluated using SEER staging system and Milan criteria. HCC treatment and survival were evaluated using multivariate logistic regression and Cox proportional hazards models. Among 32,388 HCC patients (71.2% MC, 23.9% MA, and 4.9% NI), patients with MA or NI were significantly less likely to have localized tumor stage at time of diagnosis compared with MC [NI vs. MC; odds ratio, 0.41; 95% confidence interval (CI), 0.78-0.92; P<0.001]. MA and NI patients were less likely to receive treatment, and specifically less likely to receive surgical resection or liver transplantation compared with MC patients, even after correcting for tumor stage at diagnosis (odds of surgical resection or liver transplant in NI vs. MC: odds ratio, 0.26; 95% CI, 0.21-0.33; P<0.001). NI patients (hazard ratio, 1.39; 95% CI, 1.29-1.50; P<0.001) had significantly lower survival compared with MC patients. Among US adults with HCC, MA, or NI patients had more advanced tumor stage at diagnosis, lower rates treatment, and significantly lower overall survival. Ensuring equal insurance coverage may improve access to care and mitigate some disparities in HCC outcomes.


Homogeneity and heterogeneity of toxins produced by Clostridium botulinum type C and D strains.
Five Clostridium botulinum strains were used in the present work, two of type C, C-Stockholm (C-ST) and C-CB19, and three of type D, D-South African (D-SA), D-1873, and D-CB16. The toxins, except for those of C-CB19 and D-CB16, were purified, and antisera were prepared in rabbits. To clarify the antigenicity of the toxins, neutralization and agar gel double-diffusion tests were performed. Anti-C-ST toxin serum neutralized two kinds of type C(1) toxin to a similar extent. Antisera against D-SA and D-1873 toxins, however, showed different neutralizing activity toward three type D toxins. Precipitin lines formed between D-SA and D-1873 toxins, and their antisera spurred to each other. From anti-D-SA toxin serum, two neutralizing fractions, one which neutralized D-SA, D-1873, and D-CB16 and one which neutralized only D-SA, were obtained. These results indicate that the antigenicities of D-SA and D-1873 toxins are not identical. Anti-C-ST toxin serum produced cross-neutralization on type D toxins, although the neutralization titer differed depending on the kind of toxin used. A precipitin line was formed with D-SA toxin, but not with D-1873; the developed line spurred to the C-ST toxin precipitin line. Two anti-D toxin sera also caused cross-neutralization on type C(1) toxins. However, the neutralizing activity of each serum to the same type C(1) toxin was different, and only anti-D-SA toxin serum developed a precipitin line with C-ST toxin which spurred to the D-SA toxin precipitin line. From anti-D-SA toxin serum, two different fractions capable of neutralizing C(1) and D toxins were obtained; one neutralized C-ST, C-CB19, and D-SA toxins, but not D-1873 and D-CB16, and the other neutralized all five toxins. There may be at least two common parts among C-ST, C-CB16, and D-SA toxin molecules.


Benefits of prolonged angiotensin-converting enzyme inhibition in congestive heart failure.
Normal individuals have time-dependent variations in cardiovascular function, most of which are circadian (once daily). They include changes in heart rate, systemic arterial blood pressure, cardiac output, blood volume, and viscosity. There are also changes in neuroendocrine function, including the sympathetic and parasympathetic nervous systems and the renin-angiotensin system. These variations have important consequences for the heart, since haemodynamic and neuroendocrine alterations determine cardiac work load; heart rate, blood pressure, and sympathetic nervous system activity are highest during the waking hours and lowest during sleep. Cardiovascular mortality and morbidity are associated with these changes. Patients with congestive heart failure undergo changes in neurohumoral cardiovascular regulation that increase the work load of the heart as a result of increases in heart rate and peripheral vascular resistance. Moreover, a normal circadian variation is lost, causing blood pressure and heart rate to remain increased at night, depriving the heart of a period of rest. In addition, these patients have an ability to increase blood flow to exercising skeletal muscle, limiting exercise tolerance, as well as the consequences of elevated ventricular filling pressures. These time-dependent variations in the pathophysiological processes of congestive heart failure have implications for pharmacological therapy. In particular, vasodilator therapy should be administered to provide optimal unloading of the heart throughout the day. Vasodilator therapy should also provide antagonism to those factors that limit blood flow to working skeletal muscle, so that the physical ability is not intermittently compromised during the trough effect of the drug. Criteria for establishing the efficacy of drugs for the treatment of congestive heart failure should include an analysis of peak and trough effects.


A simple set of validation steps identifies and removes false results in a sandwich enzyme-linked immunosorbent assay caused by anti-animal IgG antibodies in plasma from arthritis patients.
Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are chronic diseases characterized by activation of the immune system and production of antibodies. Thus, rheumatoid factor, anti-animal IgG antibodies and heterophilic antibodies in plasma samples from arthritis patients can interfere with immunoassays such as sandwich enzyme-linked immunosorbent assay (ELISA) systems often used in arthritis research. However, standard methodologies on how to test for false results caused by these antibodies are lacking. The objective of this study was to design a simple set of steps to validate a sandwich ELISA before using it for measuring analytes in plasma from arthritis patients. An interleukin-24 (IL-24) sandwich ELISA system was prepared with a monoclonal mouse capture antibody and a polyclonal goat detection antibody and tested for interference by rheumatoid factor, anti-animal IgG antibodies and heterophilic antibodies. Plasma samples from 23 patients with RA and SpA were used. No differences were found between plasma samples measured in wells coated with anti-IL-24 specific antibody and in wells coated with isotype control antibody (false positive results), and recombinant human IL-24 was not recovered in spiked samples (false negative results). This interference was removed after preincubating the plasma samples from patients with arthritis with goat or bovine IgG, suggesting that anti-animal IgG antibodies found in the plasma of the arthritis patients caused the false results. Additional testing showed that the signal-to-noise ratio could be increased by titration of the capture and detection antibodies and by using the ELAST amplification system. Finally, the calculated concentration of IL-24 was increased in ethylenediaminetetraacetic acid (EDTA) plasma compared to heparin plasma and serum and decreased with repetitive freeze/thaw cycles of the samples illustrating how sample handling could additionally contribute to the variations reported by different laboratories in measurement of the same analyte. This study proposes a simple set of validation steps to evaluate and optimize a sandwich ELISA before using it for measuring analytes in plasma from arthritis patients. Anti-animal IgG antibodies are also present in healthy individuals, suggesting that validation of ELISA systems for measuring non-arthritis samples could also be improved by this simple set of validation steps.


Photoinhibition of 2-amino-2-carboxybicyclo[2,2,1]heptane transport by O-diazoacetyl-L-serine. An initial step in identifying the L-system amino acid transporter.
Neutral amino acid uptake into mammalian cells occurs predominantly through the L, A, and ASC carrier-mediated transport systems. The proteins responsible for transport by these systems have not been isolated, and the three pathways presently are defined by their amino acid specificity and physiologic parameters. We have found that the amino acid derivative, O-diazoacetyl-L-serine (azaserine), is a potentially useful probe for identification of the L-(leucine-favoring) system transporter in human T-lymphocytes. Uptake of azaserine competitively inhibits the uptake of the prototype L-system amino acid, 2-amino-2-carboxybicycloheptane (BCH). Azaserine undergoes photolytic cleavage with 365 nm incident light to yield a highly reactive carbene intermediate and free N2. Following photolysis of [14C]azaserine in a suspension of lymphocytes, the 14C label is detectable within a crude cytoplasmic membrane preparation, and this process is inhibited by a 50-fold excess of unlabeled azaserine or 2-amino-2-carboxybicycloheptane, suggesting that the 14C-product is associated with the membranes at or near the L-system transport site. Furthermore, photolysis of azaserine in the presence of lymphocytes results in specific irreversible inhibition of L-system transport. Thus, photolysis of azaserine provides an initial step toward the identification of the L-system transporter.


[Examining the effects of dissonance-based primary prevention of Internet and computer-game addiction on attitudes toward gaming among grade 5 pupils: A pilot study].
Examining the effects of dissonance-based primary prevention of Internet and computer-game addiction on attitudes toward gaming among grade 5 pupils: A pilot study Abstract. Objective: To date, childhood has hardly been considered in the development of effective prevention and intervention programs for gaming disorder and Internet addiction. PROTECTdissonance was therefore designed as a 1-hour dissonance-based, universal primary prevention program for grade 5 high-school students. This pilot study examines the immediate effects of dissonance induction on attitudes toward gaming. Method: A single-arm A+B design with three measurement points (T0, T1, T2) assessed attitudes toward gaming using the Gaming Attitude Test (GAT). The baseline sequence (sequence A, T0 to T1, subsample) included N = 83 high-school students (age: M = 10.27; SD = 0.48) and the intervention sequence (sequence B, T1 to T2, total sample) included N = 200 pupils (age: M = 10.24; SD = 0.47). Acceptance and satisfaction were recorded after the intervention. Results: Hierarchical linear growth models showed a significant reduction of GAT symptoms through the intervention, both in the total GAT score and on the subscale "Trivialization of Negative Consequences." There were no changes in the natural course (baseline sequence A). Pupils correspondingly reported a high rate of satisfaction with PROTECTdissonance. Conclusions: A brief, targeted dissonance-induction exercise shows immediate effects on an attitudinal measure of gaming. To follow up on this promising approach, future studies should investigate whether reduced trivialization of negative consequences of gaming is actually reflected in behavioral change.


DNA-Templated Aptamer Probe for Identification of Target Proteins.
Using aptamers as molecular probes for biomarker discovery has attracted a great deal of attention in recent years. However, it is still a big challenge to accurately identify those protein markers that are targeted by aptamers under physiological conditions due to weak and noncovalent aptamer-protein interactions. Herein, we developed an aptamer based dual-probe using DNA-templated chemistry and photo-cross-linking technique for the identification of target proteins that are recognized by aptamers. In this system, the aptamer was modified by a single strand DNA as binding probe (BP), and another complementary DNA with a photoactive group and reporter group was modified as capture probe (CP). BP was first added to recruit the binding protein via aptamer recognition, and subsequently CP was added to let the cross-linker close to the target via DNA self-assembly, and then a covalent bond between CP and its binding protein was achieved via photo-cross-linking reaction. The captured protein can be detected or affinity enrichment using the tag, finally identified by MS. By use of lysozyme as a model substrate, we demonstrated that this multiple functionalized probe can be utilized for a successful labeling and enrichment of target protein even under a complicated and real environment. Thus, a novel method to precisely identify the aptamer-targeted proteins has been developed and it has a potential application for discovery of aptamer-based biomarkers.


ES micro-environment enhances stemness and inhibits apoptosis in human limbal stem cells via the maintenance of telomerase activity.
Our previous work had found that telomerase rejuvenated in the cytoplasm of corneal epithelial cells cultured in embryonic stem cell-conditioned medium, the functional properties of stem-like corneal epithelial cells can be enhanced by co-culturing with embryonic stem cells (ESCs) via activation of the integrinβ1-FAK-PI3K/Akt signaling pathway. The goal of this study was to explore the potential molecular mechanisms of the ES micro-environment that enhance the stem cell-like phenotype and inhibit apoptosis in human limbal stem cells (LSC). The LSC were cultured in different media, either CnT-20 medium or CnT-20 +20% ES culture supernatant (ESC-CM). We observed that LSC cultured in ESC-CM had an increased proliferative capacity, greater serial passage capacity, higher colony-forming efficiency (CFE) and higher levels of stem cell-associated marker than those cultured in CnT-20. Compared with CnT-20, ESC-CM enhanced the undifferentiated status and inhibited apoptosis in the LSC by promoting the maintenance of telomerase activity, which could reduce the generation of reactive oxygen species (ROS), maintain the membrane potential (Δψm) at higher levels and reduce the expression of the p21 protein. Our findings indicated that ESC-CM system induced LSC to maintain a stem cell phenotype and inhibit the process of apoptosis. These effects might partially be achieved via the telomerase-p21-mitochondrial axis and the activation of the FAK/Wnt signaling pathways. This study may have high impact and clinic implication on the expansion of LSC in regenerative medicine, especially for ocular surface reconstruction.


Non-epithelial tumors of the larynx: case series of 12 years.
Laryngeal neoplasms are almost always epithelial in origin and squamous cell carcinoma is the most common tumor of the larynx. Non-epithelial tumors make a small subset of laryngeal neoplasms. We present the experience of a single institution to define clinical presentations and outcomes. The pathology archives and clinical records of our center with the diagnosis of laryngeal tumors between the 2005 and 2018 were reviewed. Age, gender, symptoms, location of the tumor, histopathological diagnosis, treatment modality and disease status were discussed. 657 patients were diagnosed with laryngeal tumor between 2005 and 2018 and 13 patients with non-epithelial tumors were identified. The majority of the patients were male. The age ranged between 13 and 93 years. The most common tumor localizations were vocal cords and subglottis. Seven patients were diagnosed with malignant tumors and six patients had benign tumors. Chondrosarcoma was the most common malignant mesenchymal tumor. Others were leiomyosarcoma, fibrosarcoma and liposarcoma. The most common benign non-epithelial tumors were schwannoma and hemangioma. Plexiform neurofibroma and granular cell tumor were the other benign tumors. Eleven patients underwent excisional biopsy. One patient underwent partial laryngectomy and one had total laryngectomy. Three cases presented with recurrent tumor. Among the recurrent cases, two were malignant tumors. Non-epithelial tumors of the larynx are rare and have a wide histological diversity. Immunohistochemical studies are of great importance in the diagnosis of these tumors. Primary mesenchymal tumors of the larynx should be kept in mind in differential diagnosis.


[Outcomes of an Independent Clinical Study to Compare Branded and Generic Formulations of Sustained-Release Oxycodone].
To evaluate the potential for the adoption of a generic formulation of sustained-release oxycodone(Oxycodone SR Capsules), an independent clinical study was planned to accurately evaluate the efficacy and safety during a 9-day period. After a 3-day pretreatment period, the generic formulation was administered to patients with progressive cancer, who had been treated with a branded formulation(OxyContin®Tablets)of the drug for 5 days at the same dose. This was followed by a 1- day observation period. Drug administration to 3 patients with pulmonary cancer achieved the primary(dose, pain level, and adverse drug reactions)and secondary(rescue dose frequency and quality of life)endpoints, as well as safety goals. The merits of adopting a different dosage form were also noted. Independent data collection using an appropriate evaluation method consequently promoted the understanding of generic opioids in the clinical setting.


Body image and weight control in young adults: international comparisons in university students from 22 countries.
Young women in the United States and Western Europe are notoriously concerned about weight but less is known about attitudes to weight in other regions of the world. This study explores the associations between body mass index (BMI), weight perceptions, and attempts to lose weight in male and female university students from 22 countries. Data were collected from 18,512 university students, using standardised methods, as part of the International Health Behaviour Survey. Measures included weight, height, perception of overweight, and weight loss status. BMI was calculated from weight and height, but was categorised into gender and country-standardised deciles rather than the conventional weight categories in response to the inaccuracy of self-reports. Perceived overweight and weight loss status were plotted against country-standardised BMI deciles. The 22 countries were grouped into five geopolitical/economic areas for regional analyses: North-Western Europe and the USA, Central and Eastern Europe, the Mediterranean, Pacific Asia, South America. Perceived overweight compared across the five regions. Perceived overweight increased systematically across BMI deciles in all countries. More women than men felt overweight at any decile. Women had low levels of perceived overweight in the lowest decile but rates rapidly increased to 50% by the 5th decile. Men, even in the highest deciles, were less aware that they are overweight and few of them were trying to lose weight. Women had a faster rise of weight loss attempts over the BMI deciles but nevertheless the proportion trying to lose in the highest decile did not exceed 75%. Perceived overweight profiles across BMI deciles were similar across all regions, suggesting that perceptions of overweight derive from local comparisons. The patterning for trying to lose weight was more diverse, with men and women from Asian countries showing higher levels of trying to lose weight at all deciles. This study shows the international consistency in perceptions of overweight in educated young men and women across diverse regions of the world. It confirms the patterning of women's overestimation of weight at lower BMI deciles and men's underestimation of weight at the higher deciles. Perceptions of overweight and attempts to lose weight were highest in the group of Asian countries where body weights are generally low, suggesting that local culture and norms could moderate attitudes to weight.


[Effects of intravenous aprindine on hemodynamics in patients with cardiac dysfunction and its pharmacodynamics in patients with premature ventricular contractions].
The effects of aprindine, 100 mg iv, on hemodynamics, and the relationship between its inhibitory effect on PVC and its levels in the blood were determined in patients with diminished cardiac function. PVC was inhibited in 7 of 13 patients (54%), compared with a 50% inhibition rate in controls. The levels of aprindine in the blood after intravenous administration, rapidly decreased from 1.78 +/- 1.09 micrograms/ml immediately after administration, to 0.80 +/- 0.25 micrograms/ml after 15 min, to 0.65 +/- 0.23 micrograms/ml after 30 min and to 0.56 +/- 0.19 micrograms/ml after 1 hour. The duration of blood levels of 0.55 +/- 0.35 micrograms/ml, which are the levels presumed to be effective, was one hour after administration. The mean elimination half-life of aprindine was 18.9 +/- 8.4 hours. Aprindine produced relatively little effect on hemodynamics in patients with moderate to severe heart failure, but when its effects in individual cases were studied, it was found that aprindine elicited such changes as reduction in cardiac index, stroke volume index and stroke work index, and elevation in pulmonary arterial diastolic pressure. These findings suggest that care should be exercised in aprindine therapy in patients with diminished cardiac function. At least there should be monitoring of blood pressure and heart rate at appropriate times after intravenous administration.


The role of heat shock proteins (HSPs) in type 2 diabetes mellitus pathophysiology.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by sustained hyperglycemia caused by impaired insulin signaling and secretion. Metabolic stress, caused by an inappropriate diet, is one of the major hallmarks provoking inflammation, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Heat shock proteins (HSPs) are a group of highly conserved proteins that have a crucial role in chaperoning damaged and misfolded proteins to avoid disruption of cellular homeostasis under stress conditions. To do this, HSPs interact with diverse intra-and extracellular pathways among which are the insulin signaling, insulin secretion, and apoptosis pathways. Therefore, HSP dysfunction, e.g. HSP70, may lead to disruption of the pathways responsible for insulin secretion and uptake. Consistently, the altered expression of other HSPs and genetic polymorphisms in HSP-producing genes in diabetic subjects has made HSPs hot research in T2DM. This paper provides a comprehensive overview of the role of different HSPs in T2DM pathogenesis, affected cellular pathways, and the potential therapeutic strategies targeting HSPs in T2DM.


Low Daily Step Count Associated with Small Erector Spine Muscle Area and Sarcopenia in Idiopathic Pulmonary Fibrosis.
Objective The daily step count is associated with mortality in idiopathic pulmonary fibrosis (IPF). However, the factors associated with this phenomenon are not yet fully understood. We therefore clarified its association with clinical parameters. Methods Fifty-nine patients with IPF with available data for daily step counts; 6-minute walk distance (6MWD); chest, abdominal, and pelvic computed tomography (CT); pulmonary function; psychological evaluations; and sarcopenia assessments were prospectively enrolled. The daily step count was measured continuously for seven consecutive days. The cross-sectional areas of the erector spinae muscles at the level of the 12th vertebra (ESMCSA) and psoas major muscle volume (PMV) obtained by CT were assessed. Results The average age of the patients was 73.3±8.1 years old, and the percent predicted forced vital capacity was 81.6% ±15.8%. The average daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESMCSA, and PMV were 413±97 m, 25.5±6.7 cm2, and 270±75.6 cm3, respectively. A linear regression analysis for daily step count showed that the ESMCSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESMCSA, and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusions A lower daily step count was associated with a smaller erector spinae muscle area and sarcopenia in patients with IPF. Further studies are warranted to confirm the importance of physical therapy for muscle strengthening in patients with IPF.


Establishment and characterization of a new canine mast cell tumor cell line.
A new cell line (CoMS) was established from a 3-year-old male mongrel dog with mast cell tumor of the oral mucosa. CoMS cells grow in suspension with a doubling time of 27.0 +/- 0.7 hr. The cytoplasmic granules were formalin-sensitive, showed diverse appearances in their ultrastructural findings and contained heparin proteoglycan and neutral protease chymase. Calcium ionophore A23187, substance P and concanavalin A caused significant histamine release from CoMS cells, while compound 48/80 failed to release histamine. This cell line will make an available source for studies on canine mast cell tumors.


In silico target fishing for the potential targets and molecular mechanisms of baicalein as an antiparkinsonian agent: discovery of the protective effects on NMDA receptor-mediated neurotoxicity.
The flavonoid baicalein has been proven effective in animal models of parkinson's disease; however, the potential biological targets and molecular mechanisms underlying the antiparkinsonian action of baicalein have not been fully clarified. In the present study, the potential targets of baicalein were predicted by in silico target fishing approaches including database mining, molecular docking, structure-based pharmacophore searching, and chemical similarity searching. A consensus scoring formula has been developed and validated to objectively rank the targets. The top two ranked targets catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) have been proposed as targets of baicalein by literatures. The third-ranked one (N-methyl-d-aspartic acid receptor, NMDAR) with relatively low consensus score was further experimentally tested. Although our results suggested that baicalein significantly attenuated NMDA-induced neurotoxicity including cell death, intracellular nitric oxide (NO) and reactive oxygen species (ROS) generation, extracellular NO reduction in human SH-SY5Y neuroblastoma cells, baicalein exhibited no inhibitory effect on [(3) H]MK-801 binding study, indicating that NMDAR might not be the target of baicalein. In conclusion, the results indicate that in silico target fishing is an effective method for drug target discovery, and the protective role of baicalein against NMDA-induced neurotoxicity supports our previous research that baicalein possesses antiparkinsonian activity.


Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease.
We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations.