Amacrine Cells Forming Gap Junctions With Intrinsically Photosensitive Retinal Ganglion Cells: ipRGC Types, Neuromodulator Contents, and Connexin Isoform.
Intrinsically photosensitive retinal ganglion cells (ipRGCs) signal not only centrally to non-image-forming visual centers of the brain but also intraretinally to amacrine interneurons through gap junction electrical coupling, potentially modulating image-forming retinal processing. We aimed to determine (1) which ipRGC types couple with amacrine cells, (2) the neuromodulator contents of ipRGC-coupled amacrine cells, and (3) whether connexin36 (Cx36) contributes to ipRGC-amacrine coupling. Gap junction-permeable Neurobiotin tracer was injected into green fluorescent protein (GFP)-labeled ipRGCs in Opn4Cre/+; Z/EG mice to stain coupled amacrine cells, and immunohistochemistry was performed to reveal the neuromodulator contents of the Neurobiotin-stained amacrine cells. We also created Opn4Cre/+; Cx36flox/flox; Z/EG mice to knock out Cx36 in GFP-labeled ipRGCs and looked for changes in the number of ipRGC-coupled amacrine cells. Seventy-three percent of ipRGCs, including all six types (M1-M6), were tracer-coupled with amacrine somas 5.7 to 16.5 µm in diameter but not with ganglion cells. Ninety-two percent of the ipRGC-coupled somas were in the ganglion cell layer and the rest in the inner nuclear layer. Some ipRGC-coupled amacrine cells were found to accumulate serotonin or to contain nitric oxide synthase or neuropeptide Y. Knocking out Cx36 in M2 and M4 dramatically reduced the number of coupled somas. Heterologous gap junction coupling with amacrine cells is widespread across mouse ipRGC types. ipRGC-coupled amacrine cells probably comprise multiple morphologic types and use multiple neuromodulators, suggesting that gap junctional ipRGC-to-amacrine signaling likely exerts diverse modulatory effects on retinal physiology. ipRGC-amacrine coupling is mediated partly, but not solely, by Cx36.


Vascular depression: where do we go from here?
Vascular depression has been the topic of many studies since its revival at the end of the last century. Several important conclusions can be drawn from this research. First, from a conceptual point of view, it is a potentially valuable eiotological based new entity. Second, vascular depression encompasses not only depression with small vessel disease of the brain, but also poststroke depression, and depression related to myocardial infarction should be placed in this same category of vascular depression. Third, the treatment outcome and natural course of vascular depression have been much worse than that of the nonvascular depression. Fourth, more research on vascular depression is needed, especially on interventions. Poststroke antidepressant and psychoeducation therapy and vascular preventive interventions can probably improve outcome.


An evaluation of the effectiveness of water iodinator system to supply iodine to selected schools in Terengganu, Malaysia.
This is a cross-sectional study conducted from January to September 2004 in a group of school children aged 8 -10 years old. The schools and study subjects were selected using stratified systematic sampling technique. A total of 44 schools and 1100 subjects were selected from schools with iodinator and schools without iodinator. Samples collected were spot urine and drinking water. Dietary and iodised water consumption data were obtained from interviews. A total of 931 subjects (84.6%) responded; 558 (50.7%) from schools with iodinator and 373 (33.9%) from schools without iodinator. Results showed that in more than half (53.8%) of the schools with iodinators, mean water iodine level was below 25 microg/L. The study population in Terengganu was found to be mildly iodine deficient with an overall median urine iodine concentration (uIC) of 74 microg/L. Based on WHO criteria, 4.1% with uIC <20 microg/L (severe), 19.5% with uIC between 20-49 microg/L (moderate), 49.2% with uIC between 50-99 microg/L (mild) and 27.2% was iodine sufficient with uIC >100 microg/L. Majority of the study subjects were found to have high seafood intake (> 90%) and low in goitrogen food intake. This study suggests water iodinator system may not be a suitable method of supplying iodine and an alternative is needed in order to eradicate the iodine deficiency problem seen in some parts of Malaysia.


Biomechanical properties of bone and cartilage in growing femoral head following ischemic osteonecrosis.
Legg-Calve-Perthes disease (LCPD) is one of the most common causes of a permanent deformity of the femoral head among pediatric hip disorders. Mechanical loading of the osteonecrotic femoral head undergoing repair is thought play a significant role in the development of the femoral head deformity. This study measured the mechanical properties in uniaxial unconfined compression tests of epiphyseal bone and cartilage from immature femoral heads following surgical induction of osteonecrosis using an established piglet model. Both the modulus and yield strength of bone cores from the infarcted heads were significantly lower by 50%-60% than those of the contralateral normal control heads by 2 weeks after surgery and they remained this low for 8 weeks. No consistent difference in the bone mineral or collagen content per dry weight in the bone cores was observed. Cartilage modulus and yield strength were significantly lower at 2 weeks and remained low for 8 weeks. Cartilage collagen and glycosaminoglycan content per dry weight did not differ significantly between control and infarcted heads at any time point. However, the relative proportion of chondroitin 6-sulfate increased significantly over the 8-week postoperative period, which correlated with an increase in cartilage thickness. These results indicate that the deterioration of the mechanical properties of the epiphyseal bone and cartilage likely plays a significant role in the pathogenesis of the femoral head deformity in LCPD. (


Breast imaging: A survey.
Breast cancer is the second leading cause of death in women. It occurs when cells in the breast start to grow out of proportion and invade neighboring tissues or spread throughout the body. Mammography is one of the most effective and popular modalities presently used for breast cancer screening and detection. Efforts have been made to improve the accuracy of breast cancer diagnosis using different imaging modalities. Ultrasound and magnetic resonance imaging have been used to detect breast cancers in high risk patients. Recently, electrical impedance imaging and nuclear medicine techniques are also being widely used for breast cancer screening and diagnosis. In this paper, we discuss the capabilities of various breast imaging modalities.


Venous thromboprophylaxis in gastrointestinal bleeding.
To study the use of venous thromboembolism (VTE) prophylaxis and the incidence of thrombotic events in patients with acute gastrointestinal (GI) bleeding. Individuals admitted with a primary diagnosis of a GI bleed along with any endoscopically confirmed source (over a two-year period) were included. Patient comorbidity and data regarding anticoagulation or antiplatelet agent use before hospitalization were collected, in addition to type of VTE prophylaxis and duration of treatment. The primary end point was the development of VTE (deep vein thrombosis or pulmonary embolism) within one year of presentation. Data from 504 patients admitted with GI bleeding were eligible for review. The total number of VTE events was 20 (4%) while the mortality rate during hospitalization was 4.6%; 397 patients were not given VTE prophylaxis during their hospitalization. Of the patients who were given VTE prophylaxis, 68 received prophylactic heparin or heparin derivatives during their admission. One hundred sixty-five patients had at least one other significant risk factor for VTE including recent or subsequent surgery, past thrombotic event or malignancy. The incidence of thrombosis in those with significant risk factors for VTE was significantly higher than those without (8.5% versus 1.8%; P=0.0009). Overall, there was no significant difference in thrombotic events between individuals receiving pharmacological prophylaxis (1.2%) and those who did not (2.8%) (P=0.4). Overall, VTE prophylaxis did not significantly affect thrombotic events in patients admitted for an active GI bleed.


Effects of bis(maltolato)oxovanadium(IV) are distinct from food restriction in STZ-diabetic rats.
In association with the insulin-mimetic properties, vanadium and related compounds have been shown to normalize hyperphagia associated with diabetes mellitus. The objective of this study was to clarify the effects of an organic vanadium compound, bis(maltolato)oxovanadium(IV) (BMOV), vs. food restriction on the metabolic abnormalities that occur in diabetes. BMOV was administered daily in drinking water to streptozotocin (STZ)-diabetic rats for 6 wk. Pair-fed groups were fed based on the intake for their respective counterparts from the previous day. Plasma parameters were measured weekly after a carefully controlled 5-h fasting period. BMOV reduced plasma glucose (diabetic = 31.2 +/- 1.9, diabetic treated = 10.2 +/- 1.8, and diabetic pair fed = 34.2 +/- 1.1 mM), triglyceride, and cholesterol levels to normal without a concomitant increase in plasma insulin levels. There was no body weight gain in the diabetic pair-fed group compared with all other groups. BMOV but not pair feeding was effective in preventing the decreased cardiac function observed in STZ-diabetic rats. These data suggest that the glucose-lowering properties of BMOV are independent of the effects of dietary restriction and reinforce the efficacy of BMOV as an effective antihyperglycemic agent.


Prediction approaches to sequentially searching for an optimal dose.
The search for an optimal dose of a drug has been investigated in a sequential setting to ensure the safety level by Eichhorn and Zacks (1973, Journal of the American Statistical Association 68, 594-598; 1981, Communications in Statistics--Theory and Methods A10, 931-953), Eichhorn (1974, Communications in Statistics 3, 263-271), and Robinson (1978, Biometrika 65, 75-78). In this paper the procedure proposed by Robinson is given a new interpretation in terms of mean coverage tolerance prediction, and a new procedure in terms of guaranteed coverage tolerance prediction is proposed. The new procedure has better properties and is more stringent, and hence more desirable for safety consideration.


Can CS gas induce myocardial infarction?
"2-chlorobenzylidene malononitrile" also named CS gas is the most used riot-control agent in the world. Its reputation as the least toxic tear gas explains its large use by different authorities. Early exposure to CS spray commonly induces visual irritation, skin reactions, with increased mucous secretion in order to temporarily incapacitate targeted people. However, there is a large agreement that safety data of this product is limited and further studies need to be performed since serious problems could occur after heavy exposure such as loss of consciousness, laryngospasm, pulmonary edema and hemorrhage... Herein, we report a case of a young man who had acute myocardial infarction with serious cardiac sequelae after exposure to tear gas. To our knowledge, this is the second case since forty years in the literature that directly links documented acute heart infarction to CS gas exposure.


Biosynthesis of the wall teichoic acid in Bacillus licheniformis.
1. The biosynthesis of the wall teichoic acid, poly(glycerol phosphate glucose), has been studied with a particulate membrane preparation from Bacillus licheniformis A.T.C.C. 9945. The precursor CDP-glycerol supplies glycerol phosphate residues, whereas UDP-glucose supplies only glucose to the repeating structure of the polymer. 2. Synthesis proceeds through polyprenol phosphate derivatives, and chemical studies and pulse-labelling techniques show that the first intermediate is the phosphodiester, glucose polyprenol monophosphate. CDP-glycerol donates a glycerol phosphate residue to this to give a second intermediate, (glycerol phosphate glucose phosphate) polyprenol. 3. The glucose residue in the lipid intermediates has the beta configuration, and chain extension in the synthesis of polymer occurs by transglycosylation with inversion of anomeric configuration at two stages.


[Vascular risk factors in patients with ischaemic stroke. Distribution according to age, sex and stroke subtype].
Cardiovascular diseases are one of the leading health problems in developed countries. This term covers conditions such as coronary vascular disease, cerebrovascular diseases and peripheral vascular disease. Ischaemic cerebrovascular disease accounts for 80% of all cerebrovascular diseases. From a clinical point of view it is interesting to distinguish between modifiable and non-modifiable vascular risk factors. To analyse the prevalence of modifiable vascular risk factors and their different combinations in a case-control study on ischaemic cerebrovascular disease in the Spanish population, and also the differences in the distribution of the risk factors according to the type of stroke (TOAST classification), age and sex. The study was conducted on 308 patients with ischaemic stroke who were paired by age (+/- 5 years) and sex, with 307 controls with no prior history of thrombosis. The statistical analysis was performed using the software application SAS v. 9.1. The results suggest that the risk factors are subject to an adding effect, as well as pointing to the presence of a specific profile of these factors depending on the subtype of stroke that is developed. The addition of cardiovascular risk factors is associated with an increased risk of vascular events. The distribution of the modifiable vascular risk factors differs according to the type of stroke and the patient's sex and age.


Protein-Based Fiber Materials in Medicine: A Review.
Fibrous materials have garnered much interest in the field of biomedical engineering due to their high surface-area-to-volume ratio, porosity, and tunability. Specifically, in the field of tissue engineering, fiber meshes have been used to create biomimetic nanostructures that allow for cell attachment, migration, and proliferation, to promote tissue regeneration and wound healing, as well as controllable drug delivery. In addition to the properties of conventional, synthetic polymer fibers, fibers made from natural polymers, such as proteins, can exhibit enhanced biocompatibility, bioactivity, and biodegradability. Of these proteins, keratin, collagen, silk, elastin, zein, and soy are some the most common used in fiber fabrication. The specific capabilities of these materials have been shown to vary based on their physical properties, as well as their fabrication method. To date, such fabrication methods include electrospinning, wet/dry jet spinning, dry spinning, centrifugal spinning, solution blowing, self-assembly, phase separation, and drawing. This review serves to provide a basic knowledge of these commonly utilized proteins and methods, as well as the fabricated fibers' applications in biomedical research.


Suitable reference genes for real-time PCR in human HBV-related hepatocellular carcinoma with different clinical prognoses.
Housekeeping genes are routinely used as endogenous references to account for experimental differences in gene expression assays. However, recent reports show that they could be de-regulated in different diseases, model animals, or even under varied experimental conditions, which may lead to unreliable results and consequently misinterpretations. This study focused on the selection of suitable reference genes for quantitative PCR in human hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with different clinical outcomes. We evaluated 6 commonly used housekeeping genes' expression levels in 108 HBV-related HCCs' matched tumor and non-tumor tissue samples with different clinical outcomes and 26 normal liver specimens by real-time PCR. The expression stability of the 6 genes was compared using the software programs geNorm and NormFinder. To show the impact of reference genes on data analysis, we took PGK1 as a target gene normalized by each reference gene, and performed one-way ANOVA and the equivalence test. With the geNorm and NormFinder software programs, analysis of TBP and HPRT1 showed the best stability in all tissue samples, while 18s and ACTB were less stable. When 18s or ACTB was used for normalization, no significant difference of PGK1 expression (p > 0.05) was found among HCC tissues with and without metastasis, and normal liver specimens; however, dramatically differences (p < 0.001) were observed when either TBP or the combination of TBP and HPRT1 were selected as reference genes. TBP and HPRT1 are the most reliable reference genes for q-PCR normalization in HBV-related HCC specimens. However, the well-used ACTB and 18S are not suitable, which actually lead to the misinterpretation of the results in gene expression analysis.


Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma.
Conjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo. The objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma. We evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo. In ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation. Dupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS. NCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).


Evaluation of a novel wind tunnel for the measurement of the kinetics of odour emissions from piggery effluent.
A novel laboratory wind tunnel, with the capability to control factors such as air flow-rate, was developed to measure the kinetics of odour emissions from liquid effluent. The tunnel allows the emission of odours and other volatiles under an atmospheric transport system similar to ambient conditions. Sensors for wind speed, temperature and humidity were installed and calibrated. To calibrate the wind tunnel, trials were performed to determine the gas recovery efficiency under different air flow-rates (ranging from 0.001 to 0.028m3/s) and gas supply rates (ranging from 2.5 to 10.0 L/min) using a standard CO gas mixture. The results have shown gas recovery efficiencies ranging from 61.7 to 106.8%, while the average result from the trials was 81.14%. From statistical analysis, it was observed that the highest, most reliable gas recovery efficiency of the tunnel was 88.9%. The values of air flow-rate and gas supply rate corresponding to the highest gas recovery efficiency were 0.028 m3/s and 10.0 L/min respectively. This study suggested that the wind tunnel would provide precise estimates of odour emission rate. However, the wind tunnel needs to be calibrated to compensate for errors caused by different air flow-rates.


The transcription factor FcWRKY40 of Fortunella crassifolia functions positively in salt tolerance through modulation of ion homeostasis and proline biosynthesis by directly regulating SOS2 and P5CS1 homologs.
Although some WRKYs have been characterized, regulatory roles of most WRKYs remain poorly understood. Herein, we elucidated function of FcWRKY40 from Fortunella crassifolia in salt tolerance via overexpression and virus-induced gene silencing (VIGS) and unraveled its target genes. Overexpression of FcWRKY40 enhanced salt tolerance in transgenic tobacco and lemon, while silencing of FcWRKY40 increased salt susceptibility. Homolog genes of Salt Overly Sensitive 2 (SOS2) and Δ-1-pyrroline-5-carboxylate synthetase 1 (P5CS1) were dramatically up-regulated in transgenic lemon but down-regulated in VIGS line. Consistently, transgenic lemon displayed lower Na+ and higher proline concentrations, whereas the silenced line accumulated more Na+ but less proline. Treatment of transgenic lemon with 24-epi-brassinolide compromised salt tolerance, while supply of exogenous proline partially restored salt tolerance of the VIGS line. FcWRKY40 specifically binds to and activates promoters of FcSOS2 and FcP5CS1. FcWRKY40 was up-regulated by ABA and salt, and confirmed as a target of ABA-responsive element binding factor 2 (FcABF2). Moreover, salt treatment up-regulated FcABF2 and FcP5CS1, and elevated proline concentrations. Taken together, our findings demonstrate that FcWRKY40 participates in the ABA signaling pathway and as a positive regulator functions in salt tolerance by regulating genes involved in ion homeostasis and proline biosynthesis.


AMPK: guardian of metabolism and mitochondrial homeostasis.
Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy. This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.


Emissions of pesticides in the European Union: a new regional-level dataset.
We present a European Union (EU)-wide dataset of estimated quantities of active substances of plant protection product applied on crops (also called "emissions"). Our estimates are derived from data reported by eight EU countries and extrapolated to encompass all EU regions using regression models. These models consider both climate and agricultural land use data. This allows us to spatially represent pesticide use at NUTS Level 3 of the European statistical mapping units, and within various agricultural land cover classes in each region. We compare our estimates with aggregated data provided by EUROSTAT and with independent, detailed data for the United Kingdom, highlighting an error typically within one order of magnitude. Our estimates can provide insights into the distribution and patterns of pesticide use in the EU around the year 2015. The estimate is most reliable for Western and Southern Europe. Outside these regions, data scarcity makes extrapolation more uncertain, potentially limiting the ability to accurate depict regional variations in pesticide use.


A Novel Approach to Atomistic Molecular Dynamics Simulation of Phenolic Resins Using Symthons.
Materials science is beginning to adopt computational simulation to eliminate laboratory trial and error campaigns-much like the pharmaceutical industry of 40 years ago. To further computational materials discovery, new methodology must be developed that enables rapid and accurate testing on accessible computational hardware. To this end, the authors utilise a novel methodology concept of intermediate molecules as a starting point, for which they propose the term 'symthon'[a] rather than conventional monomers. The use of symthons eliminates the initial monomer bonding phase, reducing the number of iterations required in the simulation, thereby reducing the runtime. A novel approach to molecular dynamics, with an NVT (Canonical) ensemble and variable unit cell geometry, was used to generate structures with differing physical and thermal properties. Additional script methods were designed and tested, which enabled a high degree of cure in all sampled structures. This simulation has been trialled on large-scale atomistic models of phenolic resins, based on a range of stoichiometric ratios of formaldehyde and phenol. Density and glass transition temperature values were produced, and found to be in good agreement with empirical data and other simulated values in the literature. The runtime of the simulation was a key consideration in script design; cured models can be produced in under 24 h on modest hardware. The use of symthons has been shown as a viable methodology to reduce simulation runtime whilst generating accurate models.


Air medical transportation in India: Our experience.
Long distance air travel for medical needs is on the increase worldwide. The condition of some patients necessitates specially modified aircraft, and monitoring and interventions during transport by trained medical personnel. This article presents our experience in domestic and international interhospital air medical transportation from January 2010 to January 2014. Hospital records of all air medical transportation undertaken to the institute during the period were analyzed for demographics, primary etiology, and events during transport. 586 patients, 453 (77.3%) males and 133 (22.6%) females of ages 46.7 ± 12.6 years and 53.4 ± 9.7 years were transported by us to the institute. It took 3030 flying hours with an average of 474 ± 72 min for each mission. The most common indication for transport was cardiovascular diseases in 210 (35.8%) and central nervous system disease in 120 (20.4%) cases. The overall complication rate was 5.3% There was no transport related mortality. Cardiac and central nervous system ailments are the most common indication for air medical transportation. These patients may need attention and interventions as any critical patient in the hospital but in a difficult environment lacking space and help. Air medical transport carries no more risk than ground transportation.


Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis.
Isoniazid is the most effective and widely used antituberculosis drug. The metabolism of isoniazid is noninducible and the primary metabolic route determining the rate at which isoniazid is eliminated from the body is acetylation. There are large diffrences between individuals in the rates at which isoniazid and certain other hydrazides and some sulfonamides are acetylated. The acetylation of isoniazid is inherited in a simple Mendelian fashion, individuals being either slow, heterozygous rapid, or homozygous rapid acetylators. Improved methods of discriminating between the different phenotypes have recently been described that are also more convenient to use. The proportion of slow acetylators among Japanese and Eskimos is about 10%; among Chinese about 20%; among Caucasians, Negroes, and South Indians about 60%. The results of a series of meticulously controlled clinical trials carried out in India, East Africa, Hong Kong, Singapore, Czechoslovakia, and Britain have shown the isoniazid acetylator status of tuberculosis patients treated with isoniazid-containing regimens is of no prognostic significance when treatment is given on daily basis. It may, however, be of significance when twice-weekly regimens are employed, especially in circumstances in which only a short period of initial daily chemotherapy is given, and where the companion drug employed during the twice-weekly continuation phase is relatively weak. The acetylator phenotype is, however, extremely important in once-weekly treatment, rapid acetylators always having fared considerably worse than slow acetylators on all the regimens evaluated so far. Experimental studies of the action of isoniazid against Mycobacterium tuberculosis in vitro and in vivo have enabled these findings to be understood.


Nonlinear theophylline pharmacokinetics. A preventable cause of iatrogenic theophylline toxic reactions.
When theophylline is used for the treatment of patients with obstructive pulmonary diseases, most clinicians attempt to maintain serum levels between 55 and 110 mumol/L because higher levels are associated with an increased risk of serious toxic effects. Nonlinear theophylline kinetics are known to occur in animals, in some pediatric patients, and at very high toxic levels in adults. However, within the usual therapeutic range of serum levels, first-order kinetics are assumed to operate, and, thus, a one-compartment model or a model-independent approach is routinely used for dose adjustments. We have recently encountered two adult patients in whom nonlinear theophylline kinetics existed within the subtherapeutic and therapeutic range of serum levels. In both cases this was not immediately recognized by the clinician, resulting in prolonged use of subtherapeutic doses of theophylline. In addition, in one case our empiric attempts to achieve therapeutic serum levels resulted in serious theophylline toxicity. We present only the data from this latter patient to be used as a case study. Based on this example and a review of the literature, we propose that to avoid such a potentially fatal complication the following steps should be taken when dealing with a patient in whom serum theophylline levels fail to rise as expected with increasing oral doses: (1) supervised administration of oral theophylline to rule out noncompliance; (2) discontinuation of further empirical increases of the oral dose of theophylline; (3) obtention of steady-state serum levels on at least two different oral doses of theophylline; and (4) calculation of the appropriate maintenance dose of theophylline for that individual patient using any of the methods cited in this report.


Giant inflammatory variant of well differentiated liposarcoma: a case report of a rare entity.
An inflammatory liposarcoma is a rare variant of a well-differentiated liposarcoma. A case of a giant variety of an inflammatory well-differentiated liposarcoma is being reported. CT scan revealed a large abdomino-pelvic mass which had displaced the gut loops to left and posteriorly and urinary bladder and uterus to right. FNAC yielded mature adipocytes with no evidence of atypical cells. The large bossilated and irregular fibro-fatty mass which weighed 23 kg was excised. Microscopy revealed mature adipocytes with foci of fibrosis and abundant inflammatory cell infiltrates of eosinophils, lymphocytes, plasma cells and few neutrophils, along with few atypical cells. Only a few cases of a giant inflammatory variant of a well-differentiated liposarcoma have been reported in the world literature and this is first of its kind from the Indian sub-continent. A rare giant variant of a inflammatory well-differentiated liposarcoma with abundant eosinophils is being reported here, along with review of literature.


[Fasting serum glucose and subsequent liver cancer risk in a Korean prospective cohort].
Chronic infections with hepatitis B or C and alcoholic cirrhosis are three well-known major risk factors for liver cancer. Diabetes has also been suggested as a potential risk factor. However, the findings of previous studies have been controversial in terms of the causal association. Therefore, the aim of this study was to evaluate the association between serum glucose levels and liver cancer development in a Korean cohort. Thirty-six liver cancer cases were identified in the Korean Multi-Center Cancer Cohort (KMCC). Baseline information on lifestyle characteristics was obtained via questionnaire. Serum glucose levels were measured at the study's enrollment. Relative risks (RRs) were estimated using a Cox proportional hazard regression model. The adjusting variables included age, gender, smoking history, alcohol consumption, body mass index, and hepatitis B surface antigen (HBsAg) seropositivity. The RRs of serum glucose for liver cancer were 1.20 (95% CI = 0.48-2.99) for the category of 100 to 125 mg/dL of serum glucose and 2.77 (95% CI = 1.24-6.18) for the > 126 mg/dL serum glucose category (both compared to the < 100 mg/dL category). In a subgroup analysis, the RR of serum glucose among those who were both HBsAg seronegative and non-drinkers was 4.46 (95% CL = 1.09-18.28) for those with glucose levels > 100 mg/dL. The results of this study suggest that a high level of serum glucose can increase liver cancer risk independently of hepatitis infection and drinking history in Koreans. This study implies that glucose intolerance may be an independent risk factor for liver cancer.


MIR100 host gene-encoded lncRNAs regulate cell cycle by modulating the interaction between HuR and its target mRNAs.
Long non-coding RNAs (lncRNAs) regulate vital biological processes, including cell proliferation, differentiation and development. A subclass of lncRNAs is synthesized from microRNA (miRNA) host genes (MIRHGs) due to pre-miRNA processing, and are categorized as miRNA-host gene lncRNAs (lnc-miRHGs). Presently, the cellular function of most lnc-miRHGs is not well understood. We demonstrate a miRNA-independent role for a nuclear-enriched lnc-miRHG in cell cycle progression. MIR100HG produces spliced and stable lncRNAs that display elevated levels during the G1 phase of the cell cycle. Depletion of MIR100HG-encoded lncRNAs in human cells results in aberrant cell cycle progression without altering the levels of miRNA encoded within MIR100HG. Notably, MIR100HG interacts with HuR/ELAVL1 as well as with several HuR-target mRNAs. Further, MIR100HG-depleted cells show reduced interaction between HuR and three of its target mRNAs, indicating that MIR100HG facilitates interaction between HuR and target mRNAs. Our studies have unearthed novel roles played by a MIRHG-encoded lncRNA in regulating RNA binding protein activity, thereby underscoring the importance of determining the function of several hundreds of lnc-miRHGs that are present in human genome.


Effects of stress and social support on mothers and premature and full-term infants.
This study examined the relationships of stress and social support to maternal attitudes and early mother-infant interactive behavior. 52 mother-premature infant pairs and 53 mother-full-term infant pairs were seen for structured home interviews at 1 month, and behavioral interactions at 4 months. Maternal life stress, social support, life satisfaction, and satisfaction with parenting were assessed at the 1-month home visit. Although no group differences were found, both stress and support significantly predicted maternal attitudes at 1 month and interactive behavior at 4 months when data were pooled. Mothers with greater stress were less positive in their attitudes and behavior, while mothers with greater support were significantly more positive. Intimate support proved to have the most general positive effects. Additionally, social support moderated the adverse effects of stress on mother's life satisfaction and on several behavioral variables. Maternal social support was further found to have several significant effects on infant interactive behavior. Results are discussed in terms of the ecological significance of social support to parenting and infants' early development.


[Spirometry in general practice in Northern Norway].
The Ministry of Health and Care Services developed an action plan for COPD (chronic obstructive pulmonary disorder) in 2006. General practitioners (GPs) have a central role in this plan and use of spirometry for measurement of lung function is important. We wished to study general practitioners' use of spirometry in the three northern counties of Norway. A questionnaire was sent by post to all the GP offices in the region. Those who did not return the questionnaire were contacted by telephone and the researcher filled in the form based on the conversation. The Norwegian Labour and Welfare Administration provided information about the doctors' use of fee categories. We found that 91 % of the GP offices had a spirometer. Support staff did the spirometric measurements in 66 % of the offices and physicians in the rest. Personnel using spirometry had been trained during the last two years in 86 % of the centres. Spirometry is much used in GP offices and support personnel usually do these measurements. Measures to improve the quality of spirometry should be directed towards both doctors and support staff.


Women with high plasma levels of PBDE-47 are at increased risk of preterm birth.
Nearly 100% of North American women have detectable levels of flame retardants such as polybrominated diphenyl ethers (PBDEs) in their plasma. These molecules have structural homology to thyroid hormones and may function as endocrine disruptors. Thyroid dysfunction has previously been associated with increased risk for preterm birth. Therefore, we conducted a multi-center, case-cohort study to evaluate if high plasma concentrations of a common PBDE congener in the first trimester increases the risk of preterm birth and its subtypes. Pregnant women were recruited at the onset of initiation of prenatal care at Kaiser-Permanente Southern California (KPSC)-West Los Angeles and KPSC-San Diego medical centers. Plasma samples from women whose pregnancies ended preterm and random subset of those delivering at term were assayed for PBDE-47 and thyroid-stimulating hormone (TSH) by immunoassay. Quartile cutoffs were calculated for the patients at term and used to determine if women with exposures in the 4th quartile are at increased risk for preterm birth using logistic regression. We found that high concentrations of PBDE-47 in the first trimester significantly increased the odds of both indicated (adjusted odds ratio, adjOR=2.35, 95% confidence interval [CI]: 1.31, 4.21) and spontaneous (adjOR=1.76, 95% CI: 1.02, 3.03) preterm birth. Regardless of pregnancy outcome, TSH concentrations did not differ between women with high and low concentrations of PBDE-47. These results suggest that high plasma concentrations of PBDE-47 in the first trimester, increases the risk of indicated and spontaneous preterm birth.


Restriction fragment length polymorphisms of constant region genes of immunoglobulin lambda chains in Venezuelan patients with systemic lupus erythematosus.
Previous studies suggest a potential association between human immunoglobulin (Ig) genes and susceptibility to systemic lupus erythematosus (SLE). Ig allotypic determinants seem to confer an increased risk for the disease in various ethnic patient populations. In this study we have examined the pattern of restriction fragment length polymorphisms (RFLP) of constant region lambda (C lambda) light chain genes in a group of 78 Venezuelan patients with SLE and 70 healthy controls. The frequency of the 8-kb allele and the 8/8 genotype was significantly lower in normal Venezuelan controls as compared to healthy British Caucasians (P = 0.0002 and 0.0007 respectively). In turn, Venezuelan controls showed a higher frequency of the 18-kb allele and the 18/18 genotype (P = 0.0002 and 0.0052 respectively). However, there were no statistically significant differences in either parameter between Venezuelan SLE patients and healthy controls. Our study argues against a role for lambda light chain constant region genes in predisposition to SLE.


The Lipomyces starkeyi gene Ls120451 encodes a cellobiose transporter that enables cellobiose fermentation in Saccharomyces cerevisiae.
Processed lignocellulosic biomass is a source of mixed sugars that can be used for microbial fermentation into fuels or higher value products, like chemicals. Previously, the yeast Saccharomyces cerevisiae was engineered to utilize its cellodextrins through the heterologous expression of sugar transporters together with an intracellular expressed β-glucosidase. In this study, we screened a selection of eight (putative) cellodextrin transporters from different yeast and fungal hosts in order to extend the catalogue of available cellobiose transporters for cellobiose fermentation in S. cerevisiae. We confirmed that several in silico predicted cellodextrin transporters from Aspergillus niger were capable of transporting cellobiose with low affinity. In addition, we found a novel cellobiose transporter from the yeast Lipomyces starkeyi, encoded by the gene Ls120451. This transporter allowed efficient growth on cellobiose, while it also grew on glucose and lactose, but not cellotriose nor cellotetraose. We characterized the transporter more in-depth together with the transporter CdtG from Penicillium oxalicum. CdtG showed to be slightly more efficient in cellobiose consumption than Ls120451 at concentrations below 1.0 g/L. Ls120451 was more efficient in cellobiose consumption at higher concentrations and strains expressing this transporter grew slightly slower, but produced up to 30% more ethanol than CdtG.


Identifying kinase targets of PPARγ in human breast cancer.
Breast cancer is the most common cancer in women. Despite advances in screening women for genetic predisposition to breast cancer and risk stratification, a majority of women carriers remain undetected until they become affected. Thus, there is a need to develop a cost-effective, rapid, sensitive and non-invasive early-stage diagnostic method. Kinases are involved in all fundamental cellular processes and mutations in kinases have been reported as drivers of cancer. PPARγ is a ligand-activated transcription factor that plays important roles in cell proliferation and metabolism. However, the complete set of kinases modulated by PPARγ is still unknown. In this study, we identified human kinases that are potential PPARγ targets and evaluated their differential expression and gene pair correlations in human breast cancer patient dataset TCGA-BRCA. We further confirmed the findings in human breast cancer cell lines MCF7 and SK-BR-3 using a kinome array. We observed that gene pair correlations are lost in tumours as compared to healthy controls and could be used as a supplement strategy for diagnosis and prognosis of breast cancer.


Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor.
The α7 nicotinic acetylcholine receptor (nAChR) belongs to the family of pentameric ligand-gated ion channels and is involved in fast synaptic signaling. In this study, we take advantage of a recently identified chimera of the extracellular domain of the native α7 nicotinic acetylcholine receptor and acetylcholine binding protein, termed α7-AChBP. This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X-ray crystallography to identify allosteric binding sites. One allosteric site is surface-exposed and is located near the N-terminal α-helix of the extracellular domain. Ligand binding at this site causes a conformational change of the α-helix as the fragment wedges between the α-helix and a loop homologous to the main immunogenic region of the muscle α1 subunit. A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human α7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. This work presents a structural framework for different allosteric binding sites in the α7 nAChR and paves the way for future development of novel allosteric modulators with therapeutic potential.


Use of extract of Ruscus aculeatus in venous disease in the lower limbs.
The effectiveness and tolerability of a venotropic drug (RAES) composed of an extract of Ruscus aculeatus (16.5 mg), hesperidin (75 mg) and ascorbic acid (50 mg) were evaluated in 40 patients (30 female, 10 male) aged between 28 and 74 years, suffering from chronic phlebopathy of the lower limbs. The cross-over, double-blind trial involved two periods of treatment of 2 months with the drug (2 capsules, 3 times/day) or with placebo, and an interim period of 15 days for wash-out. An overall tendency for improvement occurred that was more distinct during the periods of treatment with the drug. In fact, symptoms and plethysmographic parameters (in particular MVIV 40 and 60) immediately changed significantly in correspondence with the administration of RAES. The biological and clinical tolerability were excellent.


Comparison of the side effects of antivirals in chronic hepatitis B patients: a single-center experience.
Entecavir (ETV), Tenofovir Disoproxil Fumarate (TDF), and Tenofovir Alafenamide (TAF) have been approved for treating Chronic Hepatitis B (CHB) and recommended due to their high safety profile and high resistance barriers. This study aimed to evaluate the kidney functions, bone, and metabolic parameters in CHB patients receiving ETV, TDF, and TAF treatment. In this retrospective cohort study, a total of 469 CHB patients who were treated with TDF (n = 256), ETV (n = 184), or TAF (n = 129) for at least six months between March 2012 and March 2022, were enrolled. No significant difference was observed between three groups regarding ALT normalization, HBV DNA suppression, and HBs Ag seroconversion (p = 0.15, p = 0.26, p = 0.72). After the treatment, there was a significant decrease in GFR values in the TDF, ETV, and TAF groups (p<0.01, p = 0.01, p = 0.01, respectively). No significant improvement was observed in the GFR values after TAF treatment in 77 patients who had switched from TDF to TAF (p = 0.51). Moreover, no significant decrease in bone mineral densities was observed in the TDF, ETV, and TAF groups (p = 0.24, p = 0.41, p = 0.95, respectively). There was no significant difference between the three groups in metabolic parameters (serum glucose, lipid profile, calcium and phosphorus levels, etc.) when the data were adjusted for underlying comorbidities. ETV, TDF, and TAF are comparably safe and effective antiviral agents against CHB.


The nature of affect attunement used by disability support workers interacting with adults with profound intellectual and multiple disabilities.
The interactions experienced by adults with profound intellectual and multiple disabilities (PIMD) with their disability support workers (DSWs) may have a large impact on life quality. However, defining good-quality interaction has presented challenges for this group. It has been suggested that in typically developing infant-mother dyads, the presence of affect attunement may be an indicator of quality. Affect attunement refers to the recasting of one person's affect by another with emphasis. The presence and nature of affect attunement in interactions between 21 pairs of adults with PIMD and their DSWs were explored in this study. Natural interactions were videorecorded for 21 pairs of adults with PIMD and their DSWs. The recordings were analysed for the presence and nature of affect attunement incidents, and analysed using descriptive statistics. Affect attunement incidents were observed in 16 of the pairs. The DSW's attunement behaviour was in response to subtle, short duration behaviours of participants with PIMD. These brief moments of connection may be a basis of good-quality interaction.


An Engineered Kinetic Amplification Mechanism for Single Nucleotide Variant Discrimination by DNA Hybridization Probes.
Even a single-nucleotide difference between the sequences of two otherwise identical biological nucleic acids can have dramatic functional consequences. Here, we use model-guided reaction pathway engineering to quantitatively improve the performance of selective hybridization probes in recognizing single nucleotide variants (SNVs). Specifically, we build a detection system that combines discrimination by competition with DNA strand displacement-based catalytic amplification. We show, both mathematically and experimentally, that the single nucleotide selectivity of such a system in binding to single-stranded DNA and RNA is quadratically better than discrimination due to competitive hybridization alone. As an additional benefit the integrated circuit inherits the property of amplification and provides at least 10-fold better sensitivity than standard hybridization probes. Moreover, we demonstrate how the detection mechanism can be tuned such that the detection reaction is agnostic to the position of the SNV within the target sequence. in contrast, prior strand displacement-based probes designed for kinetic discrimination are highly sensitive to position effects. We apply our system to reliably discriminate between different members of the let-7 microRNA family that differ in only a single base position. Our results demonstrate the power of systematic reaction network design to quantitatively improve biotechnology.


Feeding during High-Flow Nasal Cannula for Bronchiolitis: Associations with Time to Discharge.
High-flow nasal cannula (HFNC) is increasingly used to treat children hospitalized with bronchiolitis; however, the best practices for feeding during HFNC and the impact of feeding on time to discharge and adverse events are unknown. The study objective was to assess whether feeding exposure during HFNC was associated with time to discharge or feeding-related adverse events. This retrospective cohort study included inpatients aged 1-24 months receiving HFNC for bronchiolitis at an academic children's hospital from January 1, 2015 to March 1, 2017. Feeding exposures during HFNC were categorized as fed or not fed. Among fed children, we further evaluated mixed (oral and tube) or exclusive oral feeding. The primary outcome was time to discharge after HFNC cessation. Secondary outcomes were aspiration, intubation after HFNC, and seven-day readmission. Of 123 children treated with HFNC, 45 (37 %) were never fed. A total of 78 children (63%) were fed; 50 (41%) were exclusively orally fed and 28 (23 %) had mixed feeding. Median (interquartile range) time to discharge after HFNC was 29.5 hours (23.5-47.9) and 39.8 hours (26.4-61.5) hours in the fed and not fed groups, respectively. In adjusted models, time to discharge was shorter with any feeding (hazard ratio [HR] 2.17; 95% CI: 1.34-3.50) and with exclusive oral feeding (HR 2.13; 95% CI: 1.31-3.45) compared with no feeding. Time to discharge from HFNC initiation was shorter for exclusive oral feeding versus not feeding (propensity weighted HR 1.97 [95% CI: 1.13-3.43]). Adverse events (one intubation, one aspiration pneumonia, one readmission) occurred in both groups. Assessment of feeding exposure did not account for quantity and duration. Children fed while receiving HFNC for bronchiolitis may have shorter time to discharge than those not fed. Feeding-related adverse events were rare regardless of the feeding method. Controlled prospective studies addressing residual confounding are needed to justify a change in the current practice.


Cyclodextrin-based supramolecular nanoparticles for biomedical applications.
Supramolecular host-guest interactions are ideal for engineering supramolecular nanoparticles (SNPs), because their modular character offers the possibility of using the same basic SNPs made of very similar building blocks in a variety of applications. The most widely used host is cyclodextrin (CD), therefore, this review will focus on SNPs involving CD as the host entity. In the first part, particle formation and size control are described, and the forces that induce the assembly between the different components and, therefore, result in the formation of stable and controllable nanoparticles. In the second part, the use of CD-based SNPs for diagnostics and therapeutics is described. Here, the emphasis is on how the therapeutic agent/imaging component is included in the system and how it is released at the target site. CD-based SNPs provide great possibilities for the formulation of nanoparticles for biomedical applications because of their high flexibility, stability, modular character, and biocompatibility.


[Plasmapheresis in the complex therapy of patients with acute pyelonephritis and urologic infection].
In 19 urological patients with pyointoxication and urosepsis 49 plasmaphereses for the purpose of detoxication were performed in the complex with other therapeutic measures. The causes for the pyoseptic complications were as follows: urolithiasis in connection with acute pyelonephritis, acute pyelonephritis (among others in pregnancy, cystic renal dysplasia, carcinoma of the urinary bladder), renal insufficiency in the terminal stage. The treatment of these diseases with haemodialysis and haemoperfusion was complicated by a pyosepsis. Two methods of the plasmapheresis were used: the intermitting plasmapheresis with use of a refrigeration centrifuge K-70 (GDR) and the permanent membrane plasma separation with the device A2008 RG of the firm "Fresenius" (FRG). The plasma perfusion was experimentally proved and in 5 cases used on 5 columns with activated charcoal. The efficacy of the plasmapheresis and the plasma perfusion was apart from the clinical condition judged according to the values of the middle molecules in the blood, or urea, creatinine and the normalisation of the hypoproteinaemia as well as of the humoral immunity. To this are added the increase of diuresis, the normalisation of the haematological parameters and the bacteriological findings of blood and urine. Furthermore, several pathogenetic mechanisms of the positive effect of the plasmapheresis were analysed (mechanic removal of bacteria and their toxins, effect of "deplasmation" with tissue dehydration, improvement of the functional state of the kidneys within the first 3-4 days: reduction of the azotaemic intoxication, the DWS-syndrome, improvement of the rheological properties of the blood and of the microcirculation, increase of the antitoxic function of the liver).(ABSTRACT TRUNCATED AT 250 WORDS)


The role of Basal cortisol in predicting change in mental health problems across the transition to middle school.
The period in which the transition to middle school occurs is marked by major changes in social context, social rules, and scholastic responsibilities. Some adolescents thrive during this period whereas others are overwhelmed and fail to cope adequately with their changing environment. We investigated basal cortisol upon waking as a predictor of change in mental health problems across the transition to middle school. By taking into account the transition experience, we extend prior findings that high basal cortisol predicts deteriorated mental health after the transition. In individuals with high awakening cortisol, we expected mental health problems to increase after negative transition experiences and to decrease after positive transition experiences, reflecting differential susceptibility. Evidence for the former but not the latter would suggest diathesis-stress. Data from 1,664 subjects were obtained from two measurement waves (mean ages, 11 and 13.5 years) of the TRacking Adolescents' Individual Lives Survey. Using linear regression, we investigated effects of awakening cortisol level, school transition experience, and their hypothesized interaction on change in mental health problems. We found that a negative but not a positive experience was predictive of change in mental health. Importantly, our results showed that a negative experience predicts deteriorated mental health only in adolescents with high awakening cortisol but not in adolescents with low awakening cortisol. This finding was robust across informants. The converse, high awakening cortisol predicting decreasing mental health problems after a positive transition was not found. These results support the diathesis-stress model but not the differential susceptibility hypothesis.


Factors associated with elevated ALT in an international HIV/HBV co-infected cohort on long-term HAART.
Previous studies have demonstrated that hepatitis B virus (HBV) infection increases the risk for ALT elevations in HIV-HBV co-infected patients during the first year of HAART; however, there is limited data on the prevalence of ALT elevations with prolonged HAART in this patient group. To identify factors associated with ALT elevations in an HIV-HBV co-infected cohort receiving prolonged HAART, data from 143 co-infected patients on HAART enrolled in an international HIV-HBV co-infected cohort where ALT measurements were obtained every 6 months was analysed. A person-visit analysis was used to determine frequency of ALT elevation (≥ 2.5×ULN) at each visit. Factors associated with ALT elevation were determined using multivariate logistic regression with generalized estimating equations to account for correlated data. The median time on HAART at the end of follow-up was 5.6 years (range 0.4-13.3) years. During follow-up, median ALT was 36 U/L with 10.6% of person-visits classified as having ALT elevation. Most ALT elevations were grade 2 (86.5%), with only 13.5% of all ALT elevations grade 3 or higher. Univariate associations with ALT elevation (p<0.05) included history of AIDS, HBV DNA ≥ 2,000 IU/ml, HBeAg positive, study visit CD4 <200 cells/ml and nadir CD4 <200 cells/ml. In the multivariate analysis, only study visit CD4 <200 cells/ml (OR 2.07, 95%CI 1.04-4.11, p = 0.04) and HBeAg positive status (OR 2.22, 95%CI 1.03-4.79, p = 0.04) were independently associated with ALT elevation. In this HIV-HBV co-infected cohort, elevated ALT after >1 year of HAART was uncommon, and severe ALT elevations were rare. HIV-HBV co-infected patients on long-term HAART who are either HBeAg positive or have a CD4 count of <200 cells/ml are at increased risk for ALT elevations.


Early childhood caries.
Dental caries is one of the most common childhood diseases, and people continue to be susceptible to it throughout their lives. Although dental caries can be arrested and potentially even reversed in its early stages, it is often not self-limiting and progresses without proper care until the tooth is destroyed. Early childhood caries (ECC) is often complicated by inappropriate feeding practices and heavy infection with mutans streptococci. Such children should be targeted with a professional preventive program that includes oral hygiene instructions for mothers or caregivers, along with fluoride and diet counseling. However, these strategies alone are not sufficient to prevent dental caries in high-risk children; prevention of ECC also requires addressing the socioeconomic factors that face many families in which ECC is endemic. The aim of this paper is to systematically review information about ECC and to describe why many children are suffering from dental caries.


Outcome of pigs with short gut syndrome submitted to orthotopic intestinal transplantation.
To evaluate the current model of small bowel resection and intestinal transplantation in pigs. Forty two Large White pigs were distributed in five groups: G1(n=6), G2(n=6) and G3(n=6) were submitted to 80%,100% and 100% plus right colon resection respectively and G4(n=7) and G5(n=5) to 100% SBR plus IT without and with immunosuppression based on Tacrolimus and Mycophenolic acid. Evaluation included weight control, clinical status, biochemical analysis and endoscopies for graft biopsies. Follow-up in G1 and 2 was 84 days, while in G3, four and five was ± three weeks. G1 increased weight suggesting adaptation while G2 and 3 loused weight and inadequate adaptation. G4 and 5 died of acute cellular rejection (ACR) and sepses respectively. Overall survival in G1, 2, 3, 4 and 5 at 30 days was 100, 100, 0 and 20 %, respectively. Medium survival in G4 and 5 was 14 and 16 days. The resection of 80% of small intestine in pigs is not suitable for short bowel syndrome induction. Intestinal transplantation with the proposed immunosuppression protocol was effective in prevent the occurrence of severe acute rejection, but inappropriate to increase recipients survival.


Study design for the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial: A double-blind randomized controlled trial of intravenous glucose, insulin, and potassium for acute coronary syndromes in emergency medical services.
Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation. The IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI. The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms.


Trends and knowledge gaps in field research investigating effects of anthropogenic noise.
Anthropogenic noise is a globally widespread sensory pollutant, recognized as having potentially adverse effects on function, demography, and physiology in wild animals. Human population growth and associated changes in urbanization, transportation, and resource extraction all contribute to anthropogenic noise and are predicted to increase in the coming decades. Wildlife exposure to anthropogenic noise is expected to rise correspondingly. Data collected through field research are uniquely important in advancing understanding of the real-world repercussions of human activity on wildlife. We, therefore, performed a systematic review of literature published from 2008 to 2018 that reported on field investigations of anthropogenic noise impacts. We evaluated publication metrics (e.g., publication rates and journal type), geographical distribution of studies, study subject, and methods used. Research activity increased markedly over the assessment period. However, there was a pronounced geographical bias in research, with most being conducted in North America or Europe, and a notable focus on terrestrial environments. Fewer than one-fifth of terrestrial studies were located in rural areas likely to experience urbanization by 2030, meaning data on ecosystems most likely to be affected by future changes are not being gathered. There was also bias in the taxonomic groups investigated. Most research was conducted on birds and aquatic mammals, whereas terrestrial mammals, reptiles, amphibians, fish, and invertebrates received limited attention. Almost all terrestrial studies examined diurnal species, despite evidence that nocturnality is the prevailing animal activity pattern. Nearly half the studies investigated effects of road or urban noise; the bulk of research was restricted to functional, rather than physiological or demographic consequences. Few experimental studies addressed repercussions of long-term exposure to anthropogenic noise or long-term postexposure effects, and multiple noise types or levels were rarely compared. Tackling these knowledge gaps will be vital for successful management of the effects of increasing wildlife exposure to anthropogenic noise.


Screening and identification of post-traumatic stress-related serum factors in children with Wilms' tumors.
Wilms' tumors are one of the most common malignant, solid intra-abdominal tumors observed in children. Although potential tumor markers have been found, inflammatory cytokines interfere with the process of specific protein identification. The present study was undertaken to identify post-traumatic stress-related factors of Wilms' tumors and to verify the accuracy of early-stage tumor-specific serum protein markers. Serum samples were screened for differentially-expressed proteins using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). Potential markers were isolated and purified using solid-phase extraction (SPE) and SDS-PAGE. Following enzymatic digestion of the protein samples, the peptide fragments were detected with high performance liquid chromatography-mass spectrometry. The obtained peptide mass fingerprint was searched in the Swiss-Prot protein sequence database via the Mascot search engine. Differentially-expressed proteins were verified using western blot analysis. Differentially-expressed proteins with a mass/charge of 5,816 were screened out using SELDI-TOF-MS, and significant differences between the tumor and control groups, and the trauma and control groups were observed. Target proteins were isolated and purified using SPE and SDS-PAGE. Thioredoxin 1 (Trx1) was found to be differentially expressed. In the serum of children with Wilms' tumors, there was an increase in the level of the post-traumatic stress-related inflammatory factor, Trx1, as compared with the normal control group. Thus, the results of this study indicate that Trx1 presents a potential post-traumatic stress-related factor of Wilms' tumors.


Competitive dendrite growth during directional solidification of a transparent alloy: Modeling and experiment.
A two-dimensional (2-D) cellular automaton-finite difference method (CA-FDM) model and in situ observation experiments of directional solidification using a transparent alloy of SCN-2wt.% ACE are employed to investigate various microstructural evolution of columnar dendrites during directional solidification. In the present model, the growth of columnar dendrites is simulated using a CA technique. The solute diffusion is solved using the FDM. The model is capable of visualizing the interaction between the formation of dendrite arrays with identical or different growth orientations, and the evolving solute concentration field. Several dendritic competitive growth modes between two converging and diverging dendrite arrays are reproduced. The simulation results agree well with the experimental observations. The simulations are also performed to study the effects of temperature gradient and cooling rate on the growth morphology of diverging dendrites. It is found that with the increase of temperature gradient and cooling rate, the tertiary branches produced from the well-developed side branches of the unfavorably oriented grain at the divergent grain boundaries are more likely to become the new primary dendrite arms.


Interview with a quality leader: Kate Goonan on performance excellence. Interview by Pamela K. Scarrow.
Kathleen Jennison Goonan, MD, is Executive Director of the Mongan Institute for Health Policy, Center for Performance Excellence (CPE) at Massachusetts General Hospital. CPE guides transformational change in healthcare management and helps leaders, administrators, and practitioners in the healthcare workforce nationwide achieve and sustain performance excellence (http://www.mghcpe.org). An internist trained at the Massachusetts General Hospital, she has more than two decades' experience leading healthcare quality assessment and improvement initiatives. Before joining the CPE in 2002, she held a number of senior executive positions, including Senior Vice President of the Institute for Healthcare Improvement. Dr. Goonan has served as a judge for the Malcolm Baldrige National Quality Award, the Joint Commission's Codman Award, and for the American Hospital Association's McKesson Quest for Quality Award. She teaches extensively about achieving organizational performance excellence. Dr. Goonan co-authored Journey to Excellence: How the Baldrige Health Care Leaders Succeed, authored The Juran Prescription: Clinical Quality Management, and has written numerous articles and book chapters on performance improvement in healthcare. Dr. Goonan was faculty for the Harvard School of Public Health Leadership Development Program for Physicians from Academic Health Centers (1995-2007) and the Institute for Healthcare Improvement (1999-2005).


Mitotic spindle poles are organized by structural and motor proteins in addition to centrosomes.
The focusing of microtubules into mitotic spindle poles in vertebrate somatic cells has been assumed to be the consequence of their nucleation from centrosomes. Contrary to this simple view, in this article we show that an antibody recognizing the light intermediate chain of cytoplasmic dynein (70.1) disrupts both the focused organization of microtubule minus ends and the localization of the nuclear mitotic apparatus protein at spindle poles when injected into cultured cells during metaphase, despite the presence of centrosomes. Examination of the effects of this dynein-specific antibody both in vitro using a cell-free system for mitotic aster assembly and in vivo after injection into cultured cells reveals that in addition to its direct effect on cytoplasmic dynein this antibody reduces the efficiency with which dynactin associates with microtubules, indicating that the antibody perturbs the cooperative binding of dynein and dynactin to microtubules during spindle/aster assembly. These results indicate that microtubule minus ends are focused into spindle poles in vertebrate somatic cells through a mechanism that involves contributions from both centrosomes and structural and microtubule motor proteins. Furthermore, these findings, together with the recent observation that cytoplasmic dynein is required for the formation and maintenance of acentrosomal spindle poles in extracts prepared from Xenopus eggs (Heald, R., R. Tournebize, T. Blank, R. Sandaltzopoulos, P. Becker, A. Hyman, and E. Karsenti. 1996. Nature (Lond.). 382: 420-425) demonstrate that there is a common mechanism for focusing free microtubule minus ends in both centrosomal and acentrosomal spindles. We discuss these observations in the context of a search-capture-focus model for spindle assembly.


Pulmonary and extrapulmonary support for patients with Pneumocystis carinii pneumonia.
Temporary extrapulmonary oxygenation may benefit selected patients with Pneumocystis carinii pneumonia who exhibit severe respiratory insufficiency. Four persons were considered candidates for extrapulmonary oxygenation with a membrane lung while under treatment for pneumocystis pneumonia. In one patient, attempts to institute membrane lung circulation were postponed until his condition was terminal. In another individual, membrane lung support was discontinued prematurely because of complications of anticoagulation. A third patient died of cardiac failure even though her oxygenation had improved during respiratory assistance. In the fourth, the membrane lung was used successfully to maintain the patient through therapy until lung recovery was adequate to resume vital function. The four cases presented are examples of the immunosuppression that creates susceptibility to pneumocystis pneumonia: In two patients, immunodeficiency was caused by lymphoma and combination chemotherapy for the underlying disease; in two others, immunosuppression was induced for the purposes of transplantation. Two patients underwent veno-venous perfusion for prepulmonary oxygenation, and one underwent venoarterial bypass with the membrane lung. Indications for, and techniques of, membrane lung bypass are reviewed. This method of extrapulmonary membrane lung support may save some patients with transient severe pulmonary insufficiency due to P, carinii pneumonia, and the membrane lung may be an adjunct to antimicrobial therapy.


Molecular evidence of post-copulatory inbreeding avoidance in the field cricket Gryllus bimaculatus.
Female promiscuity has broad implications for individual behaviour, population genetics and even speciation. In the field cricket Gryllus bimaculatus, females will mate with almost any male presented to them, despite receiving no recorded direct benefits. Previous studies have shown that female crickets can benefit from polyandry through increased hatching success of their eggs. There is evidence that this effect is driven by the potential of polyandrous females to avoid fertilizing eggs with sperm from genetically incompatible males. We provide direct evidence supporting the hypothesis that polyandry is a mechanism to avoid genetic incompatibilities resulting from inbreeding. Using microsatellite markers we examined patterns of paternity in an experiment where each female mated with both a related and an unrelated male in either order. Overall, unrelated males were more successful in gaining paternity than were related males, but this effect was driven by a much greater success of unrelated males when they were the first to mate.


Preserving correlations between trajectories for efficient path sampling.
Importance sampling of trajectories has proved a uniquely successful strategy for exploring rare dynamical behaviors of complex systems in an unbiased way. Carrying out this sampling, however, requires an ability to propose changes to dynamical pathways that are substantial, yet sufficiently modest to obtain reasonable acceptance rates. Satisfying this requirement becomes very challenging in the case of long trajectories, due to the characteristic divergences of chaotic dynamics. Here, we examine schemes for addressing this problem, which engineer correlation between a trial trajectory and its reference path, for instance using artificial forces. Our analysis is facilitated by a modern perspective on Markov chain Monte Carlo sampling, inspired by non-equilibrium statistical mechanics, which clarifies the types of sampling strategies that can scale to long trajectories. Viewed in this light, the most promising such strategy guides a trial trajectory by manipulating the sequence of random numbers that advance its stochastic time evolution, as done in a handful of existing methods. In cases where this "noise guidance" synchronizes trajectories effectively, as the Glauber dynamics of a two-dimensional Ising model, we show that efficient path sampling can be achieved for even very long trajectories.


Understanding men's aggression in bars: development of the Beliefs and Attitudes toward Male Alcohol-Related Aggression (BAMARA) inventory.
While several qualitative studies suggest that beliefs and attitudes are important in explaining men's alcohol-related aggression, no quantitative instrument measuring men's beliefs and attitudes about male alcohol-related aggression has been developed. The purpose of this study was to develop and test a theoretically based multidimensional inventory measuring Beliefs and Attitudes toward Male Alcohol-Related Aggression (BAMARA) consisting of 9 dimensions: (i) expected negative consequences; (ii) expected positive consequences; (iii) personal approval; (iv) perceived male peer approval; (v) perceived female peer approval; (vi) perceived normality; (vii) relaxed norms when drinking; (viii) alcohol as an excuse; and (ix) male honor/protection of masculinity. A random sample of 1,343 young adult male college and university students participated in an online survey. Item analyses using confirmatory factor analytic (CFA) and item-response theory (IRT) procedures were conducted to select a refined pool of items promoting high internal consistency and discriminant validity of the 9 scales. We evaluated the criterion validity of the 9 scales, the BAMARA total score (BAMARA-Total), and a short form of the inventory (BAMARA-SF) in terms of their association with experiences of barroom aggression and other theoretically linked constructs. CFA and IRT analyses resulted in a 53-item inventory consisting of the 9 scales with adequate model fit and good internal consistency indices. Criterion validity was demonstrated, with the BAMARA scales correlating well with reports of actual experiences of aggression in bars. BAMARA-Total and BAMARA-SF were found to be significantly associated with barroom aggression controlling for a number of important control variables. This new instrument is expected to have many important applications in the male aggression literature, with the full BAMARA being employed for the assessment of specific beliefs and attitudes and the BAMARA-SF used as a general attitudinal measure.


Item-based analysis of delayed reward discounting decision making.
Delayed reward discounting (DRD) is a behavioral economic index of time preference, referring to how much an individual devalues a reward based on its delay in time, and has been linked to a wide array of health behaviors. It is commonly assessed using a task that asks participants to make dichotomous choices between two monetary rewards, one available immediately and the other after a delay. This study sought to shorten an extended iterative DRD assessment to increase its versatility and efficiency. Data were drawn from two young adult samples, an exploratory sample (N=130) and a confirmatory sample (N=247). In the exploratory sample, eight items were identified as predicting the majority of the variance in the full task area under the curve (AUC) (R(2)=.821; p<.001). In the confirmatory sample, the same eight items similarly predicted the majority of variance in the full task AUC (R(2)=.844, p<.001). These results provide initial support for the validity of a brief 8-item assessment of DRD. Priorities for further validation and potential applications are discussed.


Mutations in the netrin-1 gene cause congenital mirror movements.
Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.


Young Children's Development of Fairness Preference.
Fairness is one of the most important foundations of morality and may have played a key role in the evolution of cooperation in humans beings. As an important type of fairness concern, inequity aversion is the preference for fairness and the resistance to inequitable outcomes. To examine the early development of fairness preference in young children, sixty 2- and 3-year-old children were recruited to examine young children's preferences for fairness using a forced choice paradigm. We tested how toddlers acted when they took charge of distributing resources (two candies) to themselves and others and when they were the recipients of both other-advantageous distribution and self-advantageous distribution. Different alternative options were paired with the same fair option in the two conditions. In the other-advantageous condition, children had fewer resources in the alternative options than others, whereas their resources in the alternative options were greater than others' in the self-advantageous condition. The results showed that more children displayed fairness preferences when they distributed resources between two friends than when they distributed resources between a friend and themselves. In both scenarios, 3-year-old children were more likely to demonstrate fairness preference than 2-year-old children. The findings suggest that inequity aversion develops in young children and increases with age over the course of early childhood. When they were recipients, there was a trend in young children's preference for fairness in the other-advantageous condition compared with the self-advantageous condition. This suggests that children might tend to be more likely to display inequity aversion when they are in a disadvantageous position.


Simulating the T-jump-triggered unfolding dynamics of trpzip2 peptide and its time-resolved IR and two-dimensional IR signals using the Markov state model approach.
We proposed a computational protocol of simulating the T-jump peptide unfolding experiments and the related transient IR and two-dimensional IR (2DIR) spectra based on the Markov state model (MSM) and nonlinear exciton propagation (NEP) methods. MSMs partition the conformation space into a set of nonoverlapping metastable states, and we can calculate spectra signal for each of these states using the NEP method. Thus the overall spectroscopic observable for a given system is simply the sum of spectra of different metastable states weighted by their populations. We show that results from MSMs constructed from a large number of simulations have a much better agreement with the equilibrium experimental 2DIR spectra compared to that generated from straightforward MD simulations starting from the folded state. This indicates that a sufficient sampling of important relevant conformational states is critical for calculating the accurate spectroscopic observables. MSMs are also capable of simulating the unfolding relaxation dynamics upon the temperature jump. The agreement of the simulation using MSMs and NEP with the experiment not only provides a justification for our protocol, but also provides the physical insight of the underlying spectroscopic observables. The protocol we developed has the potential to be extended to simulate a wide range of fast triggering plus optical detection experiments for biomolecules.


Cross-linking and O-acetylation of newly synthesized peptidoglycan in Staphylococcus aureus H.
Staphylococcus aureus H growing exponentially was labelled with N-acetyl[14C]glucosamine, which became incorporated into the peptidoglycan. The portion of peptidoglycan not linked to teichoic acid (60-75% of the whole) was degraded with Chalaropsis muramidase to yield disaccharide-peptide monomers and dimers, trimers and oligomers formed by biosynthetic cross-linking of the monomers. The degree of O-acetylation of these fragments was also examined. Pulse-chase experiments showed that the proportion of label initially in the monomer fraction immediately after the 1 min pulse declined rapidly during a 3 min chase, while the oligomer fraction (fragments greater than trimer) gained the radioactivity proportionately. The radioactivity of the dimer and trimer fractions remained virtually unchanged. At 4 min after the commencement of labelling (i.e. approx. one-tenth of a generation time) final values had been reached. The O-acetylation of all fragments had achieved final values even at 1 min, except for the monomer fraction, which showed an increase from 40% to 60% during the first 3 min of chase. Although O-acetylation was clearly a very rapid process, no O-acetylated peptidoglycan lipid-intermediates could be detected.


Nitrous oxide from integrated fixed-film activated sludge membrane bioreactor: Assessing the influence of operational variables.
The influence of the main operational variables on N2O emissions from an Integrated Fixed Film Activated Sludge University of Cape Town membrane Bioreactor pilot plant was studied. Nine operational cycles (total duration: 340days) were investigated by varying the value of the mixed liquor sludge retention time (SRT) (Cycles 1-3), the feeding ratio between carbon and nitrogen (C/N) (Cycles 4-6) and simultaneously the hydraulic retention time (HRT) and the SRT (Cycles 7-9). Results show a huge variability of the N2O concentration in liquid and off-gas samples (ranged from 10-1μgN2O-NL-1 to 103μgN2O-NL-1). The maximum N2O concentration (1228μgN2O-NL-1) in the off-gas samples occurred in the anoxic reactor at the lowest C/N value confirming that unbalanced C/N promotes the N2O emission during denitrification. The aerated reactors (aerobic and MBR) have been the major N2O emitters during all the three Phases.


Association between physical activity levels and anxiety or depression among college students in China during the COVID-19 pandemic: A meta-analysis.
This meta-analysis aimed to investigate the links between the level of physical activity and the risk of anxiety or depression among college students in China during the Coronavirus Disease 2019 pandemic. Eligible studies were searched from the PubMed, Embase, and Web of Science databases. The associations between them were assessed with odd ratio (OR) and 95% confidence interval (CI). The heterogeneity of the included studies was evaluated and subgroup analysis was performed. Sensitivity analysis was executed using leave-one-out method. Publication bias of included studies was evaluated. Ten studies with moderate quality were included. Physical activity levels of college students were associated with reduced risk of depression (OR [95%CI] = 0.69 [0.58, 0.82], P < .001) and anxiety (OR [95%CI] = 0.71 [0.62, 0.80], P < .001). The measurement scale of depression or anxiety and whether multi-factor correction was performed or not did not influence the pooled results. The pooled results of depression and anxiety were stable and were not significantly influenced by a single study. No publication bias was observed in the included studies reporting depression and anxiety. The physical activity level of college students is negatively correlated with anxiety and depression in China during the pandemic. During the Coronavirus Disease 2019 pandemic, it is necessary to strengthen the construction of university physical education courses. As an organized form of physical activity, physical education classes are a necessary and effective way to increase physical activity among college students.


Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer's disease mouse model.
Cognitive decline in Alzheimer's disease is attributed to loss of functional synapses, most likely caused by synaptotoxic, oligomeric forms of amyloid-β. Many treatment options aim at reducing amyloid-β levels in the brain, either by decreasing its production or by increasing its clearance. We quantified the effects of immunotherapy directed against oligomeric amyloid-β in Tg2576 mice, a mouse model of familial Alzheimer's disease. Treatment of 12-month-old mice with oligomer-specific (A-887755) or conformation-unspecific (6G1) antibodies for 8 weeks did not affect fibrillar plaque density or growth. We also quantified densities of DLG4 (previously known as PSD95) expressing post-synapses and synapsin expressing presynapses immunohistochemically. We found that both pre- and post-synapses were strongly reduced in the vicinity of plaques, whereas distant from plaques, in the cortex and hippocampal CA1 field, only post-synapses were reduced. Immunotherapy alleviated this synapse loss. Synapse loss was completely abolished distant from plaques, whereas it was only attenuated in the vicinity of plaques. These results suggest that fibrillar plaques may act as reservoirs for synaptotoxic, oligomeric amyloid-β and that sequestering oligomers suffices to counteract synaptic pathology. Therefore, cognitive function may be improved by immunotherapy even when the load of fibrillar amyloid remains unchanged.


[The construction of cancer as an object of scientific study and sanitary problem in Argentina: discourses, experimental practices and institutional initiatives, 1903-1922].
This article analyzes the construction of cancer as a sanitary problem and an object of scientific inquiry in Argentina in the first two decades of the twentieth century. It considers the acquisition and circulation of foreign knowledge on the subject, the context in which the first experimental developments arose, the institutional initiatives promoted by the medical profession and the way in which state authorities and civil society were enlisted to further these initiatives. There is a detailed examination of the process of creating the Instituto de Medicina Experimental, a center wholly devoted to the study and treatment of cancer, which was inaugurated in 1922, symbolically ending the first phase of constructing cancer as a problem in the country.


Efficacy of sodium hyaluronate in the management of chemical and radiation cystitis.
Onset of cystitis in patients receiving immuno-chemotherapeutic agents by intravesical instillation for non-muscle invasive transitional cell carcinoma of the bladder or after radiotherapy for prostatic cancer is frequent and problematic, since it responds poorly and slowly to the usual symptomatic treatments. This iatrogenic complication often means that cancer therapy has to be interrupted on account of the bladder pathology symptoms and of course this has further clinical implications. The symptoms resemble those of the urgency/frequency and painful bladder syndromes, so we tested the treatment used for these disorders to see whether it helped in this difficult clinical situation. This prospective study therefore enrolled 69 male consecutive patients, between 54 to 81 years of age, with iatrogenic acute cystitis; in 15 the symptoms had appeared after radiotherapy for prostatic cancer, in 24 after intravesical BCG, in 30 after instillation of Mitomycin C (with Synergo thermotherapy for 12 of them). All patients were given intravesical instillations of sodium hyaluronate, 40 mg/50 mL, weekly for from 8 to 24 weeks, depending on how the symptoms released. In the first four weeks dexamethasone 32 mg was mixed in as a "cocktail", on account of its prompt and effective topical antiinflammatory action and good mucosal penetration. Longer use of cortisone is contraindicated because of the high risk of sensitization and it provided no evidence of any ability to overcome the severe urinary disturbances with lasting effect. In order to allow patients with marked overactive bladder to keep these drugs within the bladder, we instilled lidocaine 2% 30 mL, 30 minutes before. Patients recorded their bladder capacity (BC) by filling a micturition diary. Pain was assessed using a Visual Analog Scale (VAS) from 0 to 10 for the chemical cystitis cases at the beginning and end of treatment. After only four weeks BC increased in all patients, and urgency and pain disappeared. Treatment was continued, however, for another four weeks, even in patients with total remission of their symptoms as we had seen earlier that if it was stopped too soon the symptoms could return. In the chemical cystitis group the VAS score dropped from an initial mean of 8.6 to 0.9 at the end of treatment (P<0.0001). Mean BC rose from 58.4 to 283.7 mL in the chemical cystitis cases (P<0.0001), and from 85 to 243.3 mL (P<0.0001) in the radiotherapy patients. Overall 67 patients (97%) reported complete relief of dysuria and pain. Two treatment failures were due to a reduced compliance to treatment by the patients themselves. No adverse reactions were observed related to the catheters or drugs used. Patients with non-invasive bladder tumors were able to restart their cancer therapy. For cystitis induced by intravescical immuno-chemotherapy or pelvic radiotherapy this approach appears to achieve an effective and rapid cure with no adverse reactions, allowing the conclusion of treatments for non-invasive transitional cell-bladder cancer. Patients with chemical cystitis responded a little better than those who had received radiotherapy. Subsequent urinary cytology and cystoscopy ruled out bladder cancer progression in these cases after temporary postponement of the oncological treatment. Intravescical sodium hyaluronate seems a valid and quick therapeutic solution for iatrogenic cystitis from chemo or radiotherapy. After review literature, this strategy does not appear to have been used before for this particular problem.