Attenuation of estrogenic effects by dihydrotestosterone in the pig uterus is associated with downregulation of the estrogen receptors.
Androgens are known to attenuate some effects of estradiol-17beta (E) in the uterus. The objectives of the present experiment were to determine effects of 5alpha-dihydrotestosterone (DHT) on estrogenic actions in the pig uterus and its associations with changes in expression of the estrogen receptor (ER) alpha and ERbeta. Postpubertal gilts (120-130 kg of body weight; n = 16) were ovariectomized, and 3-4 weeks later received once-a-day injections (i.m.) of one of the following treatments during four consecutive days: 1) vehicle (corn oil), 2) E (250 microg), 3) E (250 microg) plus 1 mg DHT, or 4) E (250 microg) plus 10 mg DHT. Uterine tissues were collected 24 h after the last treatment. Gilts receiving E or E plus 1 mg DHT had greater uterine wet weight, uterine horn diameter, luminal epithelium thickness, and endometrial gland diameter compared with gilts treated with vehicle or E plus 10 mg DHT. Gilts receiving E or E plus 1 mg DHT were not different in these characteristics. Relative amounts of mRNAs in the endometrium for the cell proliferation marker histone H2a and the E-inducible protein complement component C3 increased in gilts treated with E compared with gilts treated with vehicle. E-induced increases in histone H2a and C3 mRNAs were not altered by cotreatment with E plus 1 mg DHT but were inhibited by E plus 10 mg DHT. Androgen receptor (AR) mRNA in the endometrium increased by treatment with E. Cotreatment of gilts with E and DHT did not alter the E-induced AR mRNA increase. Gilts treated with E plus 10 mg DHT had lesser amounts of immunoreactive ERalpha in cell nuclei of the myometrium and endometrial stroma and a tendency for a decrease in luminal epithelium compared with gilts treated with E. Amounts of immunoreactive ERalpha in glandular epithelium were not influenced by the treatments. Relative amounts of ERalpha and ERbeta mRNAs decreased in the endometrium of gilts treated with E plus 10 mg DHT compared with gilts treated with E. Downregulation of the ERs, particularly ERalpha in the myometrium and endometrial stroma, might be a relevant mechanism in the antagonism of estrogenic effects by DHT in the pig uterus.


Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis.
Clinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce. To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension. A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals. Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 vs 9.85; P < 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG (r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG (r = -0.267, P = 0.007). PlGF levels were higher in CSPH and SPH (P = 0.006; P < 0.0001) whereas Nogo-A levels were lower (P = 0.01; P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 (P = 0.003) and for Nogo-A - 0.67 (P = 0.01); for SPH 0.714 (P < 0.0001) and 0.65 (P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices (P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH. Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.


The Use of Peer Support for Parents and Youth Living with the Trauma of Child Sexual Abuse: An Innovative Approach.
This article describes and reports on an innovative intervention program for parents of sexually abused children and youth. Peer support provided by non-professional staff and volunteers, who have been personally affected by the trauma of child sexual abuse, is an approach with unique advantages. Many of these consumers have not been able to benefit from traditional service delivery approaches. Goals and objectives of the Peer Support Program (PSP) have been developed through inter-agency collaboration initiatives comprised of a coalition of existing social service agencies. This report examines characteristics of service delivery and level of consumer satisfaction of parents and youth who have participated in the peer support program. Implications for interventions with sexually abused youth and parents of sexually abused children are discussed.


Optimal Technique for Performing Invasive Pulmonary Angiography for Chronic Thromboembolic Pulmonary Disease.
High-quality invasive pulmonary angiography is invaluable for the evaluation of chronic pulmonary thromboembolic disease. Optimization of multiple technical factors enables optimal angiography, crucial for identifying both high-grade pulmonary thromboembolic disease warranting surgical resection, and surgically inaccessible disease for interventional and/or targeted medical therapy. Appropriate strategies to address the pitfalls encountered during angiography are highlighted. This manuscript provides detailed guidance in performing hemodynamic assessment and invasive pulmonary angiography for the evaluation of chronic thromboembolic pulmonary disease.


Ruxolitinib treatment in an infant with JAK2+ polycythaemia vera-associated Budd-Chiari syndrome.
Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction commonly seen with myeloproliferative neoplasms (MPNs). Polycythaemia vera (PV) is a very rare MPN in childhood. This is the youngest reported patient diagnosed with PV and BCS secondary to JAK V617F mutation.A 26-month-old girl was admitted with a 5-month history of abdominal distension, hepatosplenomegaly and ascites. Imaging studies revealed occlusion of the right hepatic vein and marked attenuation of the middle and left hepatic veins. BCS was diagnosed after excluding other causes of chronic liver disease. Mandatory prothrombotic workup revealed underlying PV.Partial recanalisation of hepatic veins occurred following anticoagulation therapy and PV was well controlled by pegylated interferon and hydroxycarbamide until she developed nephrotic syndrome, likely secondary to pegylated interferon. Therefore, treatment was modified to ruxolitinib, a novel-JAK-2 inhibitor; the therapy has been effective for almost 20 months with a good response and has no side effects.


Improving the anti-washout property of calcium phosphate cement by introducing konjac glucomannan/κ-carrageenan blend.
Anti-washout calcium phosphate cement (CPC) was prepared by dissolving water-soluble konjac glucomannan (KGM) and κ-carrageenan (KC) blend in the cement liquid. The anti-washout property, setting time, compressive strength and in vitro cytocompatibility of the CPC modified with KGM/KC blend were evaluated. The results indicated that the CPC pastes modified with KGM/KC blend exhibited excellent anti-washout property. The addition of KGM/KC blend shortened the setting time and increased the injectability of CPC. Although the introduction of KGM/KC blend reduced the compressive strength of CPC, the compressive strength still surpassed that of human cancellous bone. The optimal KGM/KC mass ratio was 2:8, with which the modified cement exhibited the most efficient washout resistance and the highest compressive strength. The introduction of KGM/KC blend obviously promoted the proliferation of mouse bone marrow mesenchymal stem cells. This anti-washout CPC modified by KGM/KC blend with excellent in vitro cytocompatibility will have good prospects for application in bone defect repair.


[Capsular sack-fixed IOL implantation in pediatric cataract. Visual prognosis and complications].
The aim of the study was to evaluate results of visual acuity and binocularity and complications after cataract surgery with primary capsular bag-fixated IOL implantation in children. Thirty-three children [mean age (+/- SEM) 6.9 +/- 2.9 years, range 3-12 years] accounting for 43 eyes, were examined before and after surgery (15 traumatic, 19 developmental, and 9 congenital cataracts, of the latter two groups 9 unilateral and 19 bilateral cataracts). All eyes had a best corrected postoperative visual acuity of 0.5 +/- 0.05. The postoperative visual acuity of the traumatic cataracts was 0.6 +/- 0.07, of the developmental cataracts 0.5 +/- 0.07, and of the congenital cataracts 0.2 +/- 0.05. Of the 43 eyes, 17 (40%) showed a best corrected visual acuity of 0.5 or better. There was a positive correlation between morphology (lamellar versus subcapsular opacification) and visual acuity (0.7 +/- 0.07 versus 0.5 +/- 0.05; P < 0.05). Bilateral cataracts had a better postoperative visual acuity than unilateral cataracts (0.7 +/- 0.07 versus 0.2 +/- 0.05 P< 0.001) Stereopis was found postoperatively in 62% of the children. In one eye a capsular bag-fixated IOL implantation was not possible, and so the IOL was inserted in the sulcus. Four children presented with postoperative fibrin formation. Posterior capsule opacification occurred in 19% of the eyes in which a primary posterior capsulotomy had been performed. The prognosis of visual acuity and the results of stereopsis in children older than 3 years following capsular bag-fixated IOL implantation are very good. Both the intraoperative and postoperative complication rates were low.


[Neonatal meningitis. Epidemiological study of the Grupo de Hospitales Castrillo].
A prospective multicenter study was designed to assess the incidence, etiology, risk factors and outcomes of vertically transmitted and nosocomial meningitis in neonates over a two-year period. Cases of neonatal meningitis diagnosed between January 1, 1997 and December 31, 1998 in the neonatology departments of 28 acute-care hospitals in Spain ("Grupo de Hospitales Castrillo") were prospectively studied. Bacteriological meningitis was considered confirmed when cerebrospinal fluid culture (CSF) was positive for bacteria, virus or fungi, probable when CSF culture was negative but blood culture was positive, and unconfirmed when both cultures were negative. During the study period, 151 cases of meningitis were diagnosed. Transmission was vertical in 84 cases and nosocomial in 67. The incidence of vertically transmitted meningitis was 0.51 of live births, and was significantly higher in very low birth weight (VLBW) infants. Confirmed bacteriological meningitis was diagnosed in 66 patients (78.6 %). No risk factors were identified in 46.4 % of the patients. Group B Streptococcus (agalactiae) was isolated in 48.5 % of cases of confirmed meningitis and Escherichia coli was isolated in 18.2 %. In 69.7 % of cases the results of blood culture were in agreement with those of CSF culture. The overall mortality rate was 8.3 %; mortality was significantly higher in VLBW infants (33.3 % vs 4.2 % in infants weighing 1,500 g). Thirteen percent of survivors had sequelae. The incidence of meningitis of nosocomial transmission was 0.2 % of admissions and was more frequent in VLBW infants. Confirmed bacteriological meningitis was diagnosed in 49 patients (73.1 %). Two or more risk factors were present in 62.7 % of patients. E. coli was isolated in 26.5 % of cases of nosocomial meningitis and Staphylococcus epidermidis was isolated in 24.5 %. In 55 % of patients the results of blood culture agreed with those of CSF culture. The overall mortality rate was 19.4 %. Mortality was significantly higher in VLBW infants and 18.5 % of survivors showed sequelae. The incidence, mortality and sequelae of neonatal meningitis in Spain were similar to those reported in recent studies. The most commonly isolated pathogens were group B Streptococcus in vertically transmitted meningitis and E. coli and S. epidermidis in nosocomial meningitis. We believe the distinction between vertical and nosocomial meningitis to be appropriate because the epidemiology of these diseases is different, which implies a different therapeutic approach. The high percentage of positive blood cultures indicates the need to include lumbar puncture whenever systemic infection is suspected in the neonatal period.


Usability and acceptability by a younger and older user group regarding a mobile robot-supported gait rehabilitation system.
The aim of the study was to identify differences regarding usability, acceptability, and barriers of usage of a robot-supported gait rehabilitation system between a younger and older group of patients with gait impairments. A mobile robot-supported gait rehabilitation prototype was tested on a group of geriatric patients aged 60 and above, and on a group of young patients aged 59 and below in a clinical setting during five therapy sessions. The involved therapists received 2 days training with the system and could test it profoundly. Data on usability, acceptability, and barriers to system usage were collected with questionnaires and structured interviews with the patients. The robotic system received overall moderate usability and good acceptability ratings; it was rated as clearly structured, practical, and safe. Analyses identified a few barriers, such as time-intensive setup of the system or tight leg shells, which can be minimized with regular training and system adaptations. Differences between the two user groups could be revealed and will be used for future investigation. This study showed the potential of the mobile robot-supported system for gait rehabilitation, but also pointed out further need for action. Efficacy studies are the next step in the evaluation process.


Evaluation and treatment of gastrointestinal tract hemorrhage in patients with AIDS.
Hemodynamically significant gastrointestinal tract hemorrhage is infrequently seen among patients with AIDS. During a 35-month period, we evaluated 37 AIDS patients with substantial gastrointestinal tract bleeding: 13 patients had upper gastrointestinal disease; 24 patients had colorectal disease. AIDS-associated lesions were identified as the etiology of the hemorrhage in 8 of 13 patients with upper and 9 of 24 patients with lower gastrointestinal tract bleeding.


H1 histone synthesis by implanting pig blastocysts.
Histones were isolated from pig conceptuses on Days 8-18 of pregnancy, Acid-urea polyacrylamide gel electrophoresis (PAGE) was performed on samples of total histone and on PCA-soluble histone fractions (primarily histone H1). Conceptuses were also incubated for 24 h in vitro in the presence of [3H]lysine, and the histones analysed by autofluorography after PAGE. A minimum of two H1 histone bands was resolved in stained gels by these techniques. The autofluorographs indicate that both H1 histones are synthesized throughout the developmental period analysed. No shift in H1 histone subtype, as encountered in sea urchin development, was observed. The results suggest that such a shift, if it occurs, may have been made before Day 8.


A comparative study of human and zebrafish glucocorticoid receptor activities of natural and pharmaceutical steroids.
The action of environmental steroids on the human glucocorticoid receptor (hGR) has been pointed out with the risk to impair physiological immune and metabolic processes regulated by this nuclear receptor. However, there is still a lack of mechanistic information regarding their ability to interact with GR in aquatic species. To investigate ligand activation differences between hGR and zebrafish GR (zfGR), we tested several natural and synthetic steroids using reporter cell lines expressing hGR or zfGR. Almost all the glucocorticoids tested (dexamethasone, cortisol, bimedrazol, medrol, cortivazol and fluticasone) are agonists of the two receptors with similar potencies. The dissociated glucocorticoids, RU24782 and RU24858 are agonists of both zfGR and hGR but with a better potency for the latter. On the other hand, the synthetic glucocorticoid forbimenol and the mineralocorticoid aldosterone are agonist on hGR but antagonist on zfGR. The other steroids tested, androgens and progestins, are all antagonists of both GRs with equal or lower potency on zfGR than on hGR. Surprisingly, the lower efficacy and potency on zfGR of aldosterone, forbimenol and the dissociated glucocorticoids is not related to their affinity for the receptors which would suggest that it could be related to less efficacious recruitment of coactivators by zfGR compared to hGR.


Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study.
Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.


Veterans Administration medical center policies and procedures for handling injectable antineoplastic drugs.
Policies and procedures for handling injectable antineoplastic agents in Veterans Administration medical centers ( VAMCs ) were surveyed. The chiefs of pharmacy of 158 VAMCs received a questionnaire that covered (1) methods of preparation, administration, and disposal of injectable antineoplastic medications, (2) precautions in the handling of these drugs, and (3) general information about the institutions. Representatives of 136 (86.1%) of the VAMCs responded, representing more than 72,000 hospital beds with 1203 designated as oncology beds. Approximately half of these institutions had written policies and procedures for the preparation, administration, and disposal of the agents. Only 22 VAMCs had a formal training program for their employees. Sixty-two percent indicated that the pharmacy had complete responsibility for the preparation of injectable antineoplastics, while 33% still claimed nursing involvement. Only five institutions stated tests were performed to evaluate harmful effects. Only half used vertical laminar-airflow hoods exclusively for the preparation of these agents. Two thirds of the VAMCs stated that they had special methods for segregating antineoplastic waste; 81% employed incineration. The survey identified areas involving the handling of injectable antineoplastics in which hospitals need to develop policies.


Morphological and immunohistochemical investigations of the utriculus prostaticus from the fetal period up to adulthood.
We investigated the utriculus prostaticus from the fetal period up to adulthood in 148 prostates. During the second half of gestation the utriculus had a simple tubular or a cystic form and was lined with metaplastic squamous epithelium which showed immunohistochemical positivity for different keratins, carcinoembryonic antigen, and peanut agglutinin binding sites. After birth, alveolar outgrowths of the utriculus developed. After puberty, the utriculus had become a complicated and variable structure. The epithelium no longer differed from that of the prostate glands either morphologically or immunohistochemically. Within the epithelium numerous endocrine cells were found containing neuron-specific enolase, chromogranin, and serotonin. The utriculus and ejaculatory ducts were embedded in a fibrous stroma with, after birth, numerous plexus-like blood vessels. This fibrous zone was peripherally bordered by a layer of smooth muscle. There was no evidence for a function of the utriculus differing from that of the prostate glands. Since the epithelium of both structures is identical immunohistochemically, the epithelium of the sinus urogenitalis most likely particpates in the lining of the utriculus during embryogenesis.


[Effect of lyophilization on the nitrogenase activity of Azotobacter vinelandii].
The activity of nitrogenase in the cells of Azobacter vinelandii grown from lyophilized and non-lyophilized cultures depends on the donor of hydrogen and the concentration of oxygen in the gaseous phase. The lyophilized cells are more sensitive to oxygen (O2 optimum for nitrogen fixation is ca. 1 percent) than the non-lyophilized cells (ca. 5 percent). The determination of acetylene reduction in the course of the culture growth has shown that nitrogen fixation in the lyophilized cells takes place after a lag-period (about six hours) at a rate lower than that of the non-lyophilized cells. The results obtained suggest that lyophilization increases the sensitivity of the cells to oxygen and decreases their nitrogenase activity which is however restored after a while.


The predictive potential of hyponatremia for glioblastoma patient survival.
Glioblastoma is a devastating malignancy with a dismal survival rate. Currently, there are limited prognostic markers of glioblastoma including IDH1, ATRX, MGMT, PTEN, EGFRvIII, and others. Although these biomarkers for tumor prognosis are available, a surgical biopsy must be performed for these analyses, which has morbidity involved. A non-invasive and readily available biomarker is sought after which provides clinicians prognostic information. Sodium is an electrolyte that is easily and quickly obtained through analysis of a patient's serum. Hyponatremia has been shown to have a predictive and negative prognostic indication in multiple cancer types, but the role of glioblastoma patients' serum sodium at the time of diagnosis in predicting glioblastoma patient survival has not been determined. We assessed whether hyponatremia at the time of glioblastoma diagnosis correlates to patient survival and show that in our cohort of 200 glioblastoma patients, sodium, at any level, did not significantly correlate to glioblastoma survival, unlike what is seen in multiple other cancer types. We further demonstrate that inducing hyponatremia in an orthotopic murine model of glioblastoma has no effects on tumor progression and survival.


Pediatric liver transplantation: patient evaluation and selection, infectious complications, and life-style after transplantation.
Liver transplantation is an increasingly accepted treatment for children with end-stage liver disease. Evaluation of the patient and appropriate patient selection for transplantation will become increasingly important issues as more and more children come to transplantation and compete for available organs. Numerous complications occur after transplantation, including infections. We have summarized our experience with bacterial, fungal, and viral infections in these patients and emphasize the need for continued improvement in immune suppressive drugs and regimens to minimize such complications. And finally, information presented on 65 pediatric patients followed 2 to 5 years suggests that, despite numerous complications and often prolonged hospitalization for transplantation, life-style after transplantation appears to be significantly improved.


Photophobic and phototropic movement of a self-oscillating gel.
A photosensitive self-oscillating gel that incorporates the Belousov-Zhabotinsky reaction can undergo rhythmic mechanical oscillations. We exploit the dependence of the oscillation frequency on light intensity to generate both photophobic and phototropic movement of the gel under differential illumination. Our findings may be used in designing intelligent sensors that can execute biomimetic behaviours.


Information entropy and temperature of binary Markov chains.
We propose two different approaches for introducing the information temperature of binary Nth-order Markov chains. The first approach is based on a comparison of Markov sequences with equilibrium Ising chains at given temperatures. The second approach uses probabilities of finite-length subsequences of symbols occurring, which determine their entropies. The derivative of the entropy with respect to the energy gives the information temperature measured on the scale of introduced energy. For the case of a nearest-neighbor spin-symbol interaction, both approaches give similar results. However, the method based on the correspondence of the N-step Markov and Ising chains appears to be very cumbersome for N>3. We also introduce the information temperature for the weakly correlated one-parametric Markov chains and present results for the stepwise and power memory functions. An application of the developed method to obtain the information temperature of some literary texts is given.


Prioritization of schizophrenia risk genes from GWAS results by integrating multi-omics data.
Schizophrenia (SCZ) is a polygenic disease with a heritability approaching 80%. Over 100 SCZ-related loci have so far been identified by genome-wide association studies (GWAS). However, the risk genes associated with these loci often remain unknown. We present a new risk gene predictor, rGAT-omics, that integrates multi-omics data under a Bayesian framework by combining the Hotelling and Box-Cox transformations. The Bayesian framework was constructed using gene ontology, tissue-specific protein-protein networks, and multi-omics data including differentially expressed genes in SCZ and controls, distance from genes to the index single-nucleotide polymorphisms (SNPs), and de novo mutations. The application of rGAT-omics to the 108 loci identified by a recent GWAS study of SCZ predicted 103 high-risk genes (HRGs) that explain a high proportion of SCZ heritability (Enrichment = 43.44 and [Formula: see text]). HRGs were shown to be significantly ([Formula: see text]) enriched in genes associated with neurological activities, and more likely to be expressed in brain tissues and SCZ-associated cell types than background genes. The predicted HRGs included 16 novel genes not present in any existing databases of SCZ-associated genes or previously predicted to be SCZ risk genes by any other method. More importantly, 13 of these 16 genes were not the nearest to the index SNP markers, and them would have been difficult to identify as risk genes by conventional approaches while ten out of the 16 genes are associated with neurological functions that make them prime candidates for pathological involvement in SCZ. Therefore, rGAT-omics has revealed novel insights into the molecular mechanisms underlying SCZ and could provide potential clues to future therapies.


High correlation between Framingham equations with BMI and with lipids to estimate cardiovascular risks score at baseline in HIV-infected adults in the Temprano trial, ANRS 12136 in Côte d'Ivoire.
Data on cardiovascular risk (CVR) score among HIV-infected patients in sub-Saharan Africa are scarce. Our first objective was to compare the CVR score of Framingham utilizing BMI and lipids at baseline, and secondary to assess evolution of CVR score over time at Month 30 in the Temprano trial. HIV-infected adults with CD4 <800/mm3 without criteria for initiating ART were included and followed for 30 months in the Temprano trial, which assessed the benefits and risks of early antiretroviral treatment (ART) vs deferred ART. CVR score was estimated at baseline and Month-30 using Framingham equations with either BMI or lipids and classified as high (>20%), moderate (10-20%), and low risk (<10%). At baseline, we compare these two estimations utilizing the Pearson correlation test and analyze the increasing CV risk score over time by Proportional odds cumulative logit models for people attending the Month-30 (M30) visit. Among the 2056 patients, 78% were women, median age was 35 years, and median CD4 count was 464/mm3, 6.8% were obese, 6.3% had hypertension, 7.8% were smokers (1.8% women, 26.8% men), 19% had Total Cholesterol (TC) >5mmol/L, and 1% diabetes at baseline. At baseline the concordance between the two Framingham equations was excellent (r = 0.95; p<0.0001). Among the 1700 patients who attended M30 visit and with available data, 1.3% had a high CV risk score at baseline and 3.1% at M30 visit using Framingham equation with BMI. Adjusted odds ratio (aOR) of being at a higher CV risk score at M30 visit compared to a higher CV risk score at M0 visit was 1.35 (CI 95% 1.17-1.57). Stratified by sex, the increasing CV risk score was OR 1.73 (CI 95%: 1.30-2.29) for women and OR 1.24 (CI 95%: 1.02-1.50) for men. Early ART was not associated with an increasing CV risk score (p = 0.88). Results for the 1422 patients with Framingham equation using lipids were similar. In a large trial evaluating early ART for HIV infection in Côte d'Ivoire, Framingham equation with BMI and lipids were highly correlated and CV risk score increases over time. Early ART was not significantly associated with this increasing CV risk score.


5-Aminosalicylic acid inhibits leukotriene B4 omega-hydroxylase activity in human polymorphonuclear leukocytes.
omega-Oxidation is regarded as the major pathway for the metabolism and inactivation of leukotriene B4 (LTB4). To investigate the action of 5-aminosalicylic acid (5-ASA) on LTB4 omega-hydroxylase activity, we incubated human polymorphonuclear leukocytes (PMNLs) with 3H-labeled LTB4 after pre-incubation with various concentrations of 5-ASA. omega-oxidation metabolites were separated by high performance liquid chromatography and each radioactivity was measured by a liquid scintilation counter. LTB4 omega-hydroxylase activity was inhibited by 5-ASA in a concentration-dependent fashion. The 50% inhibitory dose was about 50 mumol/l, which is within the concentration range found in the colonic mucosa. Our findings may be valuable in elucidating the potentially critical aspect of 5-ASA treatment in ulcerative colitis (UC).


Periodontal practice and referral profile of general dentists in Nova Scotia, Canada.
In contrast to an expected increase in demand for periodontal services with aging of the population, it appears that referrals to periodontists are declining. To determine the extent to which general dentists in Nova Scotia, Canada, provide periodontal and surgical implant therapies and to determine the factors influencing a dentist's decision to provide treatment or refer patients to a specialist. A cross-sectional survey study was performed. The survey questionnaire was mailed to all 443 general dentists practising in Nova Scotia in summer 2009. The questionnaire presented several clinical scenarios and asked respondents whether they would treat the patient in the office or refer to a specialist. The data were analyzed by logistic regression. Of the 279 (63.0%) dentists responding to the survey, 272 (61.4% of the total) were eligible for inclusion in the analysis. The majority of dentists reported rendering nonsurgical periodontal therapy, including scaling (98.5%; 262/266), periodontal maintenance (95.9%; 255/266), and treatment for bruxism (95.1%; 252/265). The most common surgical procedures performed by dentists were frenectomy (29.4%; 78/265), gingivectomy (29.3%; 77/263) and crown-lengthening procedures (17.0%; 46/271). Eleven factors significantly influenced dentists' decisions to treat or refer patients. The most common criteria used in selecting a periodontist were satisfaction of previous patients, previous success with the treatment, and the personality of and good communications with the periodontist. In this study, dentists reported rendering nonsurgical periodontal therapy on a wide scale, whereas their involvement in oral or periodontal and implant surgical therapies was limited.


Enzyme histochemistry of the small intestinal mucosa in experimental infections of calves with rotavirus and enterotoxigenic Escherichia coli.
The effect of rotavirus and enterotoxigenic Escherichia coli, administered in different sequences, on alkaline and acid phosphatase, leucinaminopeptidase, beta-galactosidase, and succinicdehydrogenase of the intestinal mucosa of cesarian-derived, colostrum-deprived calves was investigated. Decrease in enzyme activity was most prominent in dual infections; it also occurred in parts of the small intestine in monoinfected animals. Increases in enzyme activity involved totally either one or all tissue compartments (crypt, basal villus area, villus tips). Increased activity was present in enteric mucosae that were either not affected or were only slightly affected by rotavirus or enterotoxigenic E. coli. We interpret the increase in enzyme activity as an adaptation of the enteric mucosa to maintain the absorptive function.


Healthy lifestyles through an Adaptive Living Program: a pilot study.
This study examined the effects of an Adaptive Living Program (ALP) on quality of life and life satisfaction of 19 low-income adults living in a city-subsidized apartment complex in Michigan. The ALP included 12 modules and three community outings over a 12-week period, two times a week, with each session lasting 1.5 hours. Occupational therapy students conducted the groups under faculty supervision. The RAND SF-36 and a non-standardized tool were used to collect data. Results obtained from the participants' RAND SF-36 pre-test and post-test scores demonstrated no significant difference in the physical, social and emotional health variables. Qualitative information gathered in a 60-minute semi-structured focus group held on the final day of the programme indicated that participants reported that they had increased their quality of life and life satisfaction through developing better social skills, increased knowledge of nutrition and improved interpersonal skills. Methodological limitations included a small sample, limited ethnic population, occasional absences during the group sessions, abbreviated length of programme and application of a non-standardized assessment. Recommendations include a larger sample size of diverse ethnic population with varying ages, an established cut-off date for new evaluations, a lengthened programme, a standardized qualitative questionnaire and alternative quantitative assessment.


Integration of Hybridization Strategies in Pyridine-Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights.
Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound 8a, specifically, exhibited an impressive GI50 value of 0.06 μM against the MCF7 cancer cell line, while compound 8h displayed the highest cytotoxic activity against the HCT116 cell line, with a GI50 of 0.33 ± 0.042 μM. Notably, compounds 8a, 8h, and 8i demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors.


Oxytetracycline Inhibits Mucus Secretion and Inflammation in Human Airway Epithelial Cells.
Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 μg/mL) significantly inhibited TNF-α-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1β gene expression and IL-1β protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases.


Gastrointestinal tract development in red deer (Cervus elaphus) calves from 1 to 12 months of age.
This study provides a detailed description of the development of the gastrointestinal tract (GIT) of farmed red deer (Cervus elaphus) calves over the first 12 months of age. GIT development was measured using a combination of computerised tomography (CT) scanning and traditional slaughter plus dissection techniques. Red deer calves of a known birth date were randomly assigned to two treatment groups. A group of five animals were repeatedly CT scanned at 31, 63, 92, 135, 207, 275 and 351 days of age to identify GIT organs and determine their volume. From a group of 20 animals, subsets of four individuals were also scanned at corresponding ages (except 135 days of age). They were immediately euthanised and dissected after CT scanning to compare CT-scanned results with actual anatomical measurements. Individual organ weights were compared with their respective organ volumes determined by CT scanning and were found to have a strong, positive relationship. The combined rumen and reticulum (RR) CT-scanned volume was compared with its volume determined by the water-displacement technique and this also showed good correlation between the two techniques (R = 0.92). The allometric growth rates of organs, relative to animal live weight gains, in descending order, were the rumen, omasum, reticulum, abomasum, caecum blind sac, kidneys, spleen and liver. The red deer GIT was continuing to grow and develop when the last measurement was taken at 351 days of age. The greatest growth of the RR, when expressed in terms of empty weight, was between 31 and 92 days of age. Compared with sheep and cattle, it appears that the red deer have a similar or greater rate of RR development up until approximately 60 to 90 days of age; however, the final increments of GIT maturity in deer may take longer to complete, with the empty weight of the RR gaining 7.5 g/day between 275 and 351 days of age. CT scanning was validated in this study as a viable technique to follow GIT development in the same animals over time, and it provided novel information on allometric organ growth. The success of CT scanning highlights the potential future use of diagnostic imaging for GIT development studies.


Breast carcinoma metastatic to the orbit: an unusually late presentation.
An 83-year-old woman, diagnosed with breast carcinoma 28 years earlier, presented with left hyperglobus and limitation of extraocular motility. CT and MRI showed bilateral nodular thickening of extraocular muscles. Left orbital biopsy disclosed metastatic breast carcinoma. Subsequent positron-emission tomography/CT revealed diffuse metastatic disease. To the authors' knowledge, this case represents the longest reported interval from the diagnosis of primary breast cancer to the presentation of orbital metastasis.


Using dihydropyridine-release strategies to enhance load effects in engineered human bone constructs.
We report on the development of a novel biodegradable scaffold capable of enhancing mechanical signals for tissue-engineering applications. It has been shown that mechanotransduction enhances bone formation in vitro and in vivo; in tissue-engineering applications, this phenomenon is exploited through the use of mechanical bioreactors to generate bone tissue. The dihydropyridine agonist Bay K8644 (Bay) acts to increase the opening time of mechanosensitive voltage-operated calcium channels (VOCCs), specifi- cally L-type VOCCs, which are known to play a fundamental role in the early mediation of mechanotransduction. We have produced porous 3-dimensional, Bay-encapsulated biodegradable poly(L-lactide) acid scaffolds using a solvent-casting and salt-leaching technique. The effects of the released Bay on osteoid production and mineralization in human bone cell-seeded constructs following incubation in a perfusion-compression bioreactor in vitro was investigated using Western blotting techniques and a calcium assay protocol developed in our lab. Our newly developed scaffolds act by slowly releasing the calcium channel agonist Bay K8644 as observed using ultraviolet spectroscopy, maintaining the open state of mechanosensitive VOCCs responding to load, which augments the load signal at sites of strain across the scaffold. Our results demonstrate that, in the presence of physiological loading regimes in vitro, release of Bay enhances collagen I protein production and osteoid calcification more than non-Bay control constructs do. Osteopontin and alpha2delta1 VOCC subunit protein levels were also higher as a result of perfusion-compression conditioning. These results indicate that Bay-encapsulated scaffolds can be used in the presence of load to enhance the production of load-bearing engineered tissue.


Suspicious Behavior Detection with Temporal Feature Extraction and Time-Series Classification for Shoplifting Crime Prevention.
The rise in crime rates in many parts of the world, coupled with advancements in computer vision, has increased the need for automated crime detection services. To address this issue, we propose a new approach for detecting suspicious behavior as a means of preventing shoplifting. Existing methods are based on the use of convolutional neural networks that rely on extracting spatial features from pixel values. In contrast, our proposed method employs object detection based on YOLOv5 with Deep Sort to track people through a video, using the resulting bounding box coordinates as temporal features. The extracted temporal features are then modeled as a time-series classification problem. The proposed method was tested on the popular UCF Crime dataset, and benchmarked against the current state-of-the-art robust temporal feature magnitude (RTFM) method, which relies on the Inflated 3D ConvNet (I3D) preprocessing method. Our results demonstrate an impressive 8.45-fold increase in detection inference speed compared to the state-of-the-art RTFM, along with an F1 score of 92%,outperforming RTFM by 3%. Furthermore, our method achieved these results without requiring expensive data augmentation or image feature extraction.


Comparing Two Independent Satellite-Based Algorithms for Detecting and Tracking Ash Clouds by Using SEVIRI Sensor.
The Eyjafjallajökull (Iceland) volcanic eruption of April-May 2010 caused unprecedented air-traffic disruption in Northern Europe, revealing some important weaknesses of current operational ash-monitoring and forecasting systems and encouraging the improvement of methods and procedures for supporting the activities of Volcanic Ash Advisory Centers (VAACs) better. In this work, we compare two established satellite-based algorithms for ash detection, namely RSTASH and the operational London VAAC method, both exploiting sensor data of the spinning enhanced visible and infrared imager (SEVIRI). We analyze similarities and differences in the identification of ash clouds during the different phases of the Eyjafjallajökull eruption. The work reveals, in some cases, a certain complementary behavior of the two techniques, whose combination might improve the identification of ash-affected areas in specific conditions. This is indicated by the quantitative comparison of the merged SEVIRI ash product, achieved integrating outputs of the RSTASH and London VAAC methods, with independent atmospheric infrared sounder (AIRS) DDA (dust-detection algorithm) observations.


Transit of hormonal and EGF receptor-dependent signals through cholesterol-rich membranes.
The functional consequences of changes in membrane lipid composition that coincide with malignant growth are poorly understood. Sufficient data have been acquired from studies of lipid binding proteins, post-translational modifications of signaling proteins, and biochemical inhibition of lipidogenic pathways to indicate that growth and survival pathways might be substantially re-directed by alterations in the lipid content of membranes. Cholesterol and glycosphingolipids segregate into membrane patches that exhibit a liquid-ordered state in comparison to membrane domains containing relatively lower amounts of these classes of lipids. These "lipid raft" structures, which may vary in size and stability in different cell types, both accumulate and exclude signaling proteins and have been implicated in signal transduction through a number of cancer-relevant pathways. In prostate cancer cells, signaling from epidermal growth factor receptor (EGFR) to the serine-threonine kinase Akt1, as well as from IL-6 to STAT3, have been demonstrated to be influenced by experimental interventions that target cholesterol homeostasis. The recent finding that classical steroid hormone receptors also reside in these microdomains, and thus may function within these structures in a signaling capacity independent of their role as nuclear factors, suggests a novel means of cross-talk between receptor tyrosine kinase-derived and steroidogenic signals. Potential points of intersection between components of the EGFR family of receptor tyrosine kinases and androgen receptor signaling pathways, which may be sensitive to disruptions in cholesterol metabolism, are discussed. Understanding the manner in which these pathways converge within cholesterol-rich membranes may present new avenues for therapeutic intervention in hormone-dependent cancers.


Design of multisegmented freeform lens for LED fishing/working lamp with high efficiency.
A novel LED fishing/working light is proposed to enhance the lighting efficiency of a fishing boat. The study is focused on the freeform secondary lens design so as to create a lamp that attracts fish and sheds light on the deck for the crew's work. The experimental results show that the proposed multisegmented freeform lens can deliver the proposed aim, giving 3 times as much illuminating power as the traditional high-intensity discharge fishing lamp does with the same input of electrical power.


Cloning, expression, and characterization of an oligoxyloglucan reducing end-specific xyloglucanobiohydrolase from Aspergillus nidulans.
An oligoxyloglucan reducing end-specific xyloglucanobiohydrolase from the filamentous fungus Aspergillus nidulans was cloned and expressed in Pichia pastoris as a secreted histidine-tagged protein and purified by affinity chromatography. The enzyme acts on xyloglucan oligomers and releases the first two glycosyl residue segments from the reducing end, provided that neither the first glucose nor the xylose attached to the third glucose residue from the reducing end is not further substituted. The enzyme has a specific activity of 7 U/mg at the pH optimum of 3 and at the temperature optimum of 42 degrees C.


Outstanding Resistance of H2S-Modified Cu/TiO2 to SO2 for Capturing Gaseous Hg0 from Nonferrous Metal Smelting Flue Gas: Performance and Reaction Mechanism.
The utilization of H2SO4, produced using SO2 from nonferrous metal smelting flue gas as a source of S, is extremely restricted due to Hg contamination; therefore, there is great demand to remove Hg0 from smelting flue gas. Although the ability of Cu/TiO2 to capture Hg0 is excellent, its resistance to H2O and SO2 is very poor. In this study, Cu/TiO2 was treated with H2S to improve its resistance to H2O and SO2 for capturing Hg0. The chemical adsorption of Hg0 on Cu/TiO2 was primarily through the HgO route, which was almost suppressed by H2O and SO2 due to the transformation of CuO into CuSO4. Besides the HgO route, the HgS route also contributed to the chemical adsorption of Hg0 on modified Cu/TiO2. As the CuS on modified Cu/TiO2 was inert to H2O and SO2, the chemical adsorption of Hg0 on modified Cu/TiO2 through the HgS route was barely inhibited. Meanwhile, the HgS route was predominant in the chemical adsorption of Hg0 on modified Cu/TiO2. Therefore, modified Cu/TiO2 exhibited an excellent resistance to H2O and SO2, and its Hg0 capture capacity from simulated flue gas was up to 12.7 mg g-1 at 100 °C.


Laparoscopic lower anterior rectal resection using a curved stapler: original technique and preliminary experience.
Laparoscopic low anterior rectal resection (LLAR), allowing better visualization and rectal mobilization, can reduce postoperative pain and recovery. A contour curved stapler (CCS) is a very helpful device because of its curved profile that consents better access into the pelvic cavity and allows to perform rectal closure and section in one shot, especially in the presence of a narrow pelvis, complex anatomy, or large tumors. We developed an original technique of laparoscopic rectal resection using CCS. Between 2005 and 2009, in 36 cases, we performed LLAR with a three-trocar technique, starting with mobilization of left colonic flexure followed by the section of inferior mesenteric vessels. The rectum was prepared up to the levator ani with total mesorectal excision. The Lapdisc was inserted trough a suprapubic midline incision, allowing the CCS stapler placement into the pelvic cavity. After the rectal section, the anastomosis was then performed with a circular stapler. Ileostomy was performed if neoadjuvant radiotherapy and chemotherapy have been carried out or if the anastomosis was below 4 cm from the anal verge. Mean operative time was 135 minutes and no intra- or postoperative bleeding occurred. In 27 patients we performed temporary ileostomy. In two cases we observed anastomotic leakage; one of these patients already had ileostomy. No anastomotic stenosis occurred after one-year follow-up. This procedure simplifies the section of the lower rectum, reduces leaking rate resulting from technical difficulties, and does not nullify the benefits of laparoscopy.


Enzymatic Profile of 'Willamette' Raspberry Leaf and Fruit Affected by Prohexadione-Ca and Young Canes Removal Treatments.
The influence of growth regulator prohexadione-Ca (ProCa) concurrently with young canes removal on the modification of photosynthetic pigments content and antioxidant enzymes (peroxidase, POD; catalase, CAT; polyphenol oxidase, PPO; superoxide dismutase, SOD) activities in leaves and fruits of raspberry (Rubus idaeus L.) cultivar 'Willamette' was studied. ProCa increased while canes removal decreased chlorophylls and carotenoids content compared to control. POD, CAT, and PPO activities in leaves after removal of young canes were higher compared to control (2-4 times) which was visually confirmed for POD by isoelectrofocusing. Removal of young canes slithly increased, while ProCa significantly enhanced SOD activity in leaves compared to control (475.10 and 218.38 nkat mg-1 prot, respectively). Pattern of SOD activity in fruit was similar as in leaf with substantial increase compared to control (about 15 times). Combination of implemented measures increased activity of all enzymes in the leaves and fruits. Our study could provide a better knowledge of the ProCa and canes removal influences on the action of enzymes in order to regulate their activities in fruit products.


[Association analysis between sex hormone levels and all-cause mortality in Hainan female centenarians].
Objective: To investigate the distribution characteristics of sex hormones and their relationship with all-cause mortality in Hainan female centenarians. Methods: All the subjects were from China Hainan Centenarian Cohort Study. A total of 717 female centenarians were included in the final analysis. Kaplan-Meier method was used to draw the survival curve, and Cox proportional hazard regression was used to analyze the relationship between sex hormones and survival time. Results: The M(Q1, Q3) of estradiol and progesterone among female centenarians was 32.60 (18.40, 58.70) pmol/L and 0.62 (0.32, 1.01) nmol/L. The estradiol (pmol/L) and progesterone (nmol/L) in the survival and death groups were 26.65 vs.37.80, 0.54 vs.0.69, respectively, with statistical differences (P<0.05). Cox multivariate analysis showed that estradiol and progesterone were significantly associated with death (P<0.05), the hazard ratio (HR) of estradiol Q4 was 1.58 (95%CI: 1.17-2.15), and the HR of progesterone Q3 was 1.53 (95%CI: 1.10-2.12), HR for Q4 was 1.63 (95%CI: 1.15-2.32). Subgroup and cross-analysis showed that estradiol was statistically significant with hypertension, diabetes, and low high-density lipoprotein cholesterol (P<0.05), and progesterone interacted with diabetes (P=0.016), while testosterone interacted with low high-density lipoprotein cholesterol (P=0.034). Conclusion: It is suggested that the estrogen levels of female centenarians in Hainan were associated with a higher mortality risk and an increased risk of cardiovascular metabolic disease (such as diabetes, hypertension, and abnormal lipid metabolism).


Acidic patch histone mutations and their effects on nucleosome remodeling.
Structural and biochemical studies have identified a histone surface on each side of the nucleosome disk termed 'the nucleosome acidic patch' that acts as a regulatory hub for the function of numerous nuclear proteins, including ATP-dependent chromatin complexes (remodelers). Four major remodeler subfamilies, SWI/SNF, ISWI, CHD, and INO80, have distinct modes of interaction with one or both nucleosome acidic patches, contributing to their specific remodeling outcomes. Genome-wide sequencing analyses of various human cancers have uncovered high-frequency mutations in histone coding genes, including some that map to the acidic patch. How cancer-related acidic patch histone mutations affect nucleosome remodeling is mainly unknown. Recent advances in in vitro chromatin reconstitution have enabled access to physiologically relevant nucleosomes, including asymmetric nucleosomes that possess both wild-type and acidic patch mutant histone copies. Biochemical investigation of these substrates revealed unexpected remodeling outcomes with far-reaching implications for alteration of chromatin structure. This review summarizes recent findings of how different remodeler families interpret wild-type and mutant acidic patches for their remodeling functions and discusses models for remodeler-mediated changes in chromatin landscapes as a consequence of acidic patch mutations.


New targets for the mechanism of action of antibiotics active against gram-positive cocci.
The main mechanisms of resistance to beta-lactams in gram-positive cocci include either the production of beta-lactamases or alterations in the molecular targets of these antibiotics, the penicillin binding proteins (PBPs). In spite of the appearance of new beta-lactams, more stable to the hydrolytic activity of beta-lactamases or with higher affinity for PBPs, no substantial progress in improving the activity against gram-positive has been achieved. In addition to the search for new beta-lactams it would be of interest to find molecules directed against new targets of the cell wall of gram-positive bacteria (i.e. teichoic acids and lipoteichoic acid) of which up to now no specific inhibitor is known. These two wall polymers are thought to be essential for cell survival within the host. Among new inhibitors a new antibiotic belonging to the class of acid lipopeptides called daptomycin (LY146032), and active against gram-positive seems of particular interest. Our studies demonstrate that daptomycin is a specific inhibitor of lipoteichoic acid synthesis.


Influence of Water on the Interfacial Nanostructure and Wetting of [Rmim][NTf2] Ionic Liquids at Mica Surfaces.
The effect of water concentration on the interfacial nanostructure and wetting behavior of a family of ionic liquids (ILs), 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, [Rmim][NTf2], at the surface of mica was investigated by contact angle measurement and atomic force microscopy (AFM). AFM reveals that interfacial layers of ILs observed at the surface of mica for "dry" ILs are not present for water-saturated ILs. The interaction of the IL ions of [Rmim][NTf2] with water molecules through hydrogen bonding is suspected to disrupt IL ion layering and precursor film growth on mica. Without the IL precursor film, contact angle relaxation of "wet" ILs on mica is less significant and ambient vapor adsorption becomes more important in determining the macroscopic wetting behavior.


Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors.
Cysteine proteinases are widely distributed among living organisms. According to the most recent classifications (Rawlings and Barrett, 1993, 1994), they can be subdivided on the basis of sequence homology into 14 or even 20 different families, the most important being the papain and the calpain families. The papain-like cysteine proteinases are the most abundant among the cysteine proteinases. The family consists of papain and related plant proteinases such as chymopapain, caricain, bromelain, actinidin, ficin, and aleurain, and the lysosomal cathepsins B, H, L, S, C and K. Most of these enzymes are relatively small proteins with Mr values in the range 20000-35000 (reviewed in Brocklehurst et al., 1987; Polgar, 1989; Rawlings and Barrett, 1994; Berti and Storer, 1995), with the exception of cathepsin C, which is an oligomeric enzyme with Mr approximately 200000 (Metrione et al., 1970; Dolenc et al., 1995). A number of cysteine proteinases are located within lysosomes. Four of them, cathepsins B, C, H and L, are ubiquitous in lysosomes of animals, whereas cathepsin S has a more restricted localisation (Barrett and Kirschke, 1981; Kirschke and Wiederanders, 1994). The enzymes, except cathepsin C, are endopeptidases (reviewed in Kirschke et al., 1995), although cathepsin B was found also to be a dipeptidyl carboxypeptidase (Aronson and Barrett, 1978) and cathepsin H also an aminopeptidase (Koga et al., 1992). Cathepsin C is a dipeptidyl aminopeptidase, but at higher pH it exhibits also dipeptidyl transferase activity (reviewed in Kirschke et al., 1995). Among the lysosomal cysteine proteinases, cathepsin L was found to be the most active in degradation of protein substrates, such as collagen, elastin and azocasein (Barrett and Kirschke, 1981; Maciewicz et al., 1987; Mason et al., 1989), arid cathepsin B the most abundant (Kirschke and Barrett, 1981). All the enzymes are optimally active at slightly acidic pH, although their pH optima for degradation of synthetic substrates vary from 5.5 for cathepsin L to 6.8 for cathepsin H (reviewed in Kirschke et al., 1995). Several other lysosomal cysteine proteinases, such as cathepsins N, T and K, are known, although their properties are less well characterised (reviewed in Kirschke et al., 1995). In particular cathepsin K has attracted recent interest (Bromme et al., 1996; Shi et al., 1995; Bossard et al., 1996; Drake et al., 1996) and was found to be expressed specifically in osteoclasts (Drake et al., 1996) with properties similar to cathepsin L (Bossard et al., 1996).


A radioautographic study of the incorporation of iron 55 by the ameloblasts in the zone of maturation of rat incisors.
This study was designed to study the time course of the incorporation of 55Fe into the ameloblasts of maturation in rat incisors. Male Sherman rats (100 +/- 5 gm) were injected intravenously with 0.9 mCi of 55Fe and sacrificed in pairs by perfusion at various time intervals from 5 min to 7 days after injection. The incisors were demineralized in 4.13% disodium EDTA, postfixed in 1% osmium tetroxide in veronal acetate buffer, and embedded in Epon. Incisors from control rats injected with only physiological saline were treated in the same way. Sections from blocks of tissue in the zone of maturation were prepared for light microscope radioautographic observations. The greatest incorporation of iron occurred at 9 mm within the zone; at this site the ameloblasts contained few pigment granules. About 5 mm deeper into the zone the activity fell off to zero, as observed at 2.5 hr after injection of 55Fe. Between 1 day and 7 days after injection the 55Fe labeling was found over the cells containing many pigment granules, while the initial labeling over the cells within 9 mm of the zone had diminished. These data have shown that at any given time, from 30 min to 4 hr, the iron enters the maturation ameloblasts over a wide extent of the zone, reaching a maximum at about 9 mm from the onset of maturation. However, at longer times (1 day to 7 days) the labeling curve shifts and shows the greatest activity beyond 9 mm within the zone.


Molecular recognition: model studies with convergent functional groups.
Model studies of molecular recognition are reviewed with emphasis on contributions from macrocyclic chemistry. Recent developments concerning new molecular shapes are discussed. The advantages of a molecular cleft are presented. In these structures functional groups converge to create a microenvironment complementary to substrates. Specifically, di-, tri- and tetracarboxylic acids of varying sizes are shown to recognize smaller molecules of complementary shape. The new receptors function by a combination of hydrogen bonding and aryl stacking interactions. Substrates include amines, acids, amino acids, metal ions and nucleotide components. The relationship between functional group orientation and catalysis is explored and two systems capable of concerted acid/base catalysis are introduced.


Expression patterns of mouse Hox genes: clues to an understanding of developmental and evolutionary strategies.
Expression patterns of Antennapedia-like homeogenes in the mouse embryo show many similarities o those of their homologues in Drosophila. It is argued here that homeogenes may regulate development of the body plan in mouse by mechanisms similar to those used in Drosophila. In particular, they may differentially specify positional address of cell groups within lineage compartments along the body axes. In vertebrates, a single ancestral homeogene cluster has become duplicated to give four separate clusters. Comparisons of homeogene expression patterns between different clusters of the mouse suggest ways in which duplication has permitted development of a more complex body plan. Cluster duplication may therefore have provided a selective advantage during vertebrate evolution.


Utilization of catheterization and revascularization procedures in patients with non-ST segment elevation acute coronary syndrome over the last decade.
The degree to which catheterization and revascularization procedures are utilized in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) during hospitalization has broad implications with respect to initial pharmacotherapeutic decisions (upfront therapies), treatment and hospital transfer protocols, guideline recommendations, and allocation of training, material, and financial resources. Analysis of data from multiple trials and registries of patients with NSTE-ACS has the potential to assess more broadly utilization of invasive and revascularization procedures and provide a wide angle or bird's-eye view of the management of such patients, complementing the data obtained from any one trial or registry. We therefore undertook a systematic overview of all large trials and registries of patients with NSTE-ACS conducted over the last decade that were deemed appropriate to provide information on catheterization and revascularization procedures. Although not unexpectedly the percentage of patients with NSTE-ACS managed with cardiac catheterization, percutaneous coronary intervention (PCI), and coronary artery bypass grafting varies in different clinical trials and registries, general findings and trends were still discernable from these studies. During the initial treatment period, the majority of patients were ultimately treated with medical therapy alone (e.g., without revascularization). The percentage of those NSTE-ACS patients undergoing diagnostic cardiac catheterization who were then managed with PCI increased over the last decade and now stands at approximately 50%. Of NSTE-ACS patients who undergo revascularization, the percentage of those patients who are revascularized via PCI similarly increased, and PCI is currently the revascularization procedure utilized in approximately three-fourths of patients undergoing revascularization. The percentages of patients undergoing invasive and revascularization procedures were consistently higher in the U.S. cohorts of study subjects when compared to non-U.S. cohorts of study subjects.


The effect of altered macroclimate on N-fixation by boreal feather mosses.
Plant productivity is predicted to increase in boreal forests owing to climate change, but this may depend on whether N inputs from biological N-fixation also increases. We evaluated how alteration of climatic factors affects N input from a widespread boreal N-fixer, i.e. cyanobacteria associated with the feather moss Pleurozium schreberi. In each of 10 forest stands in northern Sweden, we established climate-change plots, including a control (ambient climate) plot and three plots experiencing a +2°C temperature increase, an approximately threefold reduction in precipitation frequency, and either 0.07, 0.29 or 1.16 times normal summer precipitation. We monitored N-fixation in these plots five times between 2007 and 2009, and three times in 2010 after climate treatments ended to assess their recovery. Warmer temperatures combined with less frequent precipitation reduced feather moss moisture content and N-fixation rates regardless of total precipitation. After climate treatments ended, recovery of N-fixation rates occurred on the scale of weeks to months, suggesting resilience of N-fixation to changes in climatic conditions. These results suggest that modelling of biological N-inputs in boreal forests should emphasize precipitation frequency and evaporative water loss in conjunction with elevated temperature rather than absolute changes in mean precipitation.


A pilot cross-sectional investigation of chronic shame as a mediator of the relationship between subjective social status and self-rated health among middle-aged adults.
Subjective social status (SSS) is an important independent predictor of health outcomes, however, the pathways through which it affects health are poorly understood. Chronic shame has previously been suggested as a potential mechanism but this has never been investigated and the relationship between chronic shame and health is under-researched. The purpose of this pilot study was to explore whether chronic shame explains a significant portion of the association between SSS and self rated health (SRH). Two-hundred American adults aged 30-55 years were recruited via a crowd-sourcing platform and were asked to provide information on their SSS, level of chronic shame, and SRH. Chronic shame significantly mediated the relationship between SSS and SRH. This pilot study provides initial evidence that shame explains a significant portion of the relationship between subjective social status and self-rated health. These findings support the initiation of larger, longitudinal investigations into chronic shame as a mediator of the subjective social status and self-rated health relationship.


Incidence of hidradenitis suppurativa in the United States: A sex- and age-adjusted population analysis.
The true incidence of hidradenitis suppurativa (HS) is unknown. To determine standardized incidence estimates for HS in the United States. We used a retrospective cohort analysis, including incident HS cases identified using electronic health records data for a demographically heterogeneous population-based sample of >48 million unique patients across all 4 census regions. We calculated standardized 1- and 10-year cumulative incidences for the overall population and for sex-, age-, and race-specific groups. There were 5410 new HS diagnoses over a 1-year period, with an incidence of 11.4 (95% confidence interval [CI], 11.1-11.8) cases per 100,000 population. One-year incidence in women was 16.1 (95% CI, 15.5-16.6) per 100,000, more than twice that of men [6.8 (95% CI, 6.5-7.2) per 100,000; P < .0001]. Age group-specific incidence was highest among patients 18 to 29 years of age [22.0 (95% CI, 21.0-23.2) per 100,000]. Incidence among African Americans [30.6 (95% CI, 29.1-32.2) per 100,000] was >2.5 times that of whites [11.7 (95% CI, 11.3-12.2) per 100,000; P < .0001]. The average annual overall incidence over 10 years was 8.6 (95% CI, 8.6-8.7) per 100,000 population. The use of deidentified claims prevented validation for a larger case subset. HS incidence has increased over the past decade and disproportionately involves women, young adults, and African Americans.


Usefulness of multi-parameter opiate analysis in hair of drug users and victims of fatal poisonings.
The results of a multi-parameter analysis of opiates in the hair of drug users and victims of fatal poisonings with these xenobiotics have been presented. The analysis was carried out with the use of liquid chromatography coupled with mass spectrometry (LC-MS). The article discusses the monitoring of the drug users' adherence to pharmacotherapy and the usefulness of hair analysis for medico-legal purposes. The authors evaluate the differences in the contents of particular opiates in the hair as related to the origin of a sample (untreated drug user, drug user in the course of treatment, victim of fatal poisoning). The report presents differences between the Polish and American profiles of abuse, providing confirmation that a great part of drug users undergoing methadone treatment do not abstain from opiates and/or amphetamine, the latter as a rule being very often taken with opiates.


Additive Prognostic Value of Carotid Plaque Score to Enhance the Age, Creatinine, and Ejection Fraction Score in Patients with Acute Coronary Syndrome.
To assess whether combining measurements obtained from carotid ultrasonography in addition to the age, creatinine, and ejection fraction (ACEF) score would improve the predictive ability of outcome in patients with acute coronary syndrome (ACS). We examined 264 patients with ACS (194 men; mean age: 68±11 years) who underwent percutaneous coronary intervention. The carotid plaque score (cPS) and intima-media thickness (cIMT) were determined by carotid ultrasonography. The modified ACEF score was calculated using the following formula: (age/left ventricular ejection fraction) +1 point for every 10 mL/min reduction in creatinine clearance below 60 mL/min per 1.73 m2. The endpoint of this study was major adverse cardiovascular and cerebrovascular events (MACEs), defined as all-cause death, myocardial infarction, stoke, and target vessel revascularization. During the median 4-year follow-up, there were 121 incidents of MACEs. Multivariate Cox proportional hazard regression analysis revealed that cPS ≥9.8 (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.01-2.31) and ACEF score ≥1.20 (HR, 1.62; 95% CI, 1.11-2.39) were significantly associated with MACEs, whereas cIMT was not. When the new combined risk score was calculated by multiplying the cPS by the modified ACEF score, the freedom from MACEs at 5 years was 71% and 31% for the lower and higher scores, respectively (p<0.001). The area under the receiver-operating characteristic curve for MACEs for the ACEF score, cPS, and combined risk score were 0.65, 0.66, and 0.71, respectively (p<0.05). The cPS offers an incremental predictive value when combined to the simple ACEF score in ACS.


PI3K signaling in cancer: beyond AKT.
The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K. Here, we highlight three PI3K-dependent, but AKT-independent, signaling branches that have recently been shown to have important roles in promoting phenotypes associated with malignancy. First, the PDK1-mTORC2-SGK axis can substitute for AKT in survival, migration, and growth signaling and has emerged as a major mechanism of resistance to PI3K and AKT inhibitors. Second, Rac signaling mediates the reorganization of the actin cytoskeleton to regulate cancer cell migration, invasion, and metabolism. Finally, the TEC family kinase BTK has a critical role in B cell function and malignancy and represents a recent example of an effective therapeutic target in cancer. These mechanisms highlight how understanding PI3K-dependent, but AKT-independent, signaling mechanisms that drive cancer progression will be crucial for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.


Modified Technique of Separate Vertical Wiring for the Fixation of Patellar Inferior Pole Fracture.
To evaluate the biomechanical and clinical results of modified separate vertical wiring technique (SVW) for inferior pole patellar fracture repair we conducted a finite element biomechanical study using 2 fixation methods and evaluated a clinical series of eleven patients. The modified SVW technique was an effective, safe and simple method that can provide stable fixation for early exercise with excellent functional results in fixing inferior pole patella fractures.


Acute paracetamol toxicity-induced inflammatory and oxidative effects are relieved by Aleppo galls: a novel experimental study.
Paracetamol (acetaminophen) is an over-the-counter non-steroidal anti-inflammatory drug that may cause acute toxic overdosage particularly in neuropsychiatric patients. Paracetamol is also very commonly prescribed as an analgesic and antipyretic agent. Paracetamol toxicity causes decreased reduced glutathione and oxidative tissue damage. Aleppo galls is a promising natural remedy exerting antioxidant and tissue-protective effects that may combat acetaminophen-induced oxidative tissue damage. Biochemical and toxicological effects of a toxic dose of paracetamol (250 mg/kg) were investigated for three consecutive days versus the tissue-protective effects of Aleppo galls. Eighteen white albino mice were randomly allocated in this study and divided into three experimental groups (six mice per group): negative control (received intraperitoneal sterile water injection), paracetamol toxicity group (received intraperitoneal paracetamol injection) and the third group (received paracetamol injection at 250 mg/kg/day together with oral Aleppo galls treatment at 250 mg/kg/day for 3 consecutive days). All mice were sacrificed by the end of the study. Our data revealed that paracetamol toxicity exerted significant oxidative stress damaging effects (high serum malondialdehyde, decreased serum catalase and decreased total antioxidant capacity), and significant inflammatory effects (high serum IL-6) and significant tissue-damaging effects (high serum LDH). Aleppo galls treatment significantly protected against acetaminophen toxicity-induced oxidative stress effects (P<0.001), inflammatory effects (P<0.001) and tissue-damaging effects (P<0.001). Aleppo galls are promising for future drug therapeutics and for the synthesis of natural remedies for treating paracetamol toxicity. We recommend formulating Aleppo galls extract as a pharmaceutical nutrition and to be given to those who need to take large doses of paracetamol.


Comparative Evaluation on the Effects of Three Pediatric Syrups on Microhardness, Roughness and Staining of the Primary Teeth Enamel: An In-Vitro Study.
Introduction One of the most prevalent oral diseases is dental caries. Syrups are commonly used by children who have difficulty swallowing tablets and capsules. Some medications can make dental caries worse and cause the enamel to erode. Most of the time, parents are unaware that a number of foods, drinks, and syrup-formulated pediatric drugs include sugar, which can cause erosion of primary teeth, resulting in plaque accumulation and dental caries. Henceforth, the aim of this study is to assess the effects of pediatric syrups on the microhardness, roughness, and staining ability of primary tooth enamel as a result of daily intake of syrup. Methods Eighty primary teeth, including both anterior and posterior, that required extraction due to pre-shedding mobility were randomly divided into four groups of twenty samples each. Samples were exposed to multivitamin syrup (Rudimin), iron syrup (C Pink), and diuretic syrup (Furosemide). The samples were submerged in 10 mL of the respective medication once daily for five minutes for 21 days. On days 0 and 21, enamel surfaces were assessed for changes in microhardness, roughness, and staining. The microhardness was assessed using a Micro Vickers microhardness tester machine; the roughness was assessed using a Mitutoyo surface roughness tester; and the staining ability was assessed using a spectrophotometer, and data processing was done using the analysis of variance (ANOVA) test and Tukey's post hoc analysis. Results The changes in enamel surface for microhardness, roughness, and staining were assessed twice, at days 0 and 21. Group 4 (Furoped) showed a significant difference in surface microhardness and staining ability of enamel surfaces with a statistically significant p-value (<0.05). When roughness was compared, all three interventions had a significant difference from the control group, whereas there was no statistically significant difference between the intervention groups. Conclusion This study concludes that pediatric syrups can significantly weaken the enamel of primary teeth, resulting in loss of enamel surface microhardness and roughness making them vulnerable to caries. Since frequent consumption of these syrups is correlated with tooth decay, certain precautions like oral hygiene maintenance and rinsing with water after taking the syrup should be done to prevent dental caries, as consumption of medicinal syrups by children cannot be avoided.


Atorvastatin-induced osteoclast inhibition reduces orthodontic relapse.
The statin class of drugs enhances osteogenesis and suppresses bone resorption, which could be a plausible biologic mechanism for mitigation of orthodontic relapse. We aimed to determine whether atorvastatin (ATV) might affect orthodontic relapse and osteoclastogenesis by modulating expression of RANKL and osteoprotegerin (OPG), crucial molecules involved in bone turnover. Furthermore, we analyzed the adverse effects of ATV on femur turnover and endochondral ossification. Wistar rats were subjected to orthodontic tooth movement for 21 days, followed by removal of the appliance and ATV or saline solution administration. Up to 7, 14, and 21 days of ATV administration, tooth relapse was measured, and maxilla and femur sections were obtained and prepared for hematoxylin and eosin, TRAP, and immunohistochemical (RANKL and OPG) staining. ATV decreased tooth relapse (P = 0.03) and osteoclast counts (P = 0.04), which were positively correlated (P = 0.006). Statin administration increased periodontal expression of OPG (P = 0.008), but not of RANKL protein. ATV administration also enhanced growth plate cartilage thickness. Statin-induced OPG overexpression reduces relapse after orthodontic tooth movement, in a phenomenon correlated with decreased osteoclast counts. This phenomenon sheds light on OPG as a molecular target that modulates maxillary bone metabolism and orthodontic relapse.


Respiratory system mechanics during laparoscopic cholecystectomy.
The influence of laparoscopic cholecystectomy (LC) on the mechanical properties of the respiratory system (RS) was examined using multiple regression analysis (MRA). Measurements of airway pressure (PaO) and flow (V') were obtained from 32 patients at four distinct stages of the LC procedure: 1) Immediately before the application of pneumoperitoneum (PP) at supine position, 2) 5 min after the induction of PP at Trendelenburg position, 3) 5 min after the patients position at reverse Trendelenburg, and 4) 5 min after the end ofthe surgical procedure with the patient again in supine position. Evaluated parameters were the RS elastance (Ers), resistance (Rrs), impedance (Zrs), the angle theta indicating the balance between the elastic and resistive components of the impedance, as well as the end-expiratory elastic recoil pressure (EEP). Ers and Zrs increased considerably during PP and remained elevated immediately after abolishing PP Rrs, on the contrary, returned to pre-operative levels right after the operation. Change of body position from Trendelenburg (T) to reverseTrendelenburg (rT) mainly induced a significant change in theta, thus indicating an increased dominance of the elastic component of Zrs on changing fromT to rT. There was no evidence of increased End-Expiratory Pressure during PP


(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel ATP-sensitive potassium channel opener: hemodynamic comparison to ZD-6169, WAY-133537, and nifedipine in the anesthetized canine.
The therapeutic utility of KATP channel opening agents (KCOs) in the treatment of overactive bladder may be limited by hypotension as a result of insufficient selectivity in vivo for bladder versus vasculature smooth muscle. Recently, we demonstrated that the putative uroselective KCOs, A-278637, ZD-6169, and WAY-133537 suppress unstable bladder contraction in an in vivo pre-clinical pig model of detrusor instability secondary to partial outlet obstruction. In the present study in the anesthetized dog we targeted plasma concentrations 3-, 10-, and 30-fold above a common index of in vivo efficacy (EC35) for suppression of unstable bladder contraction in pigs, to provide a comprehensive cardiovascular profile of these compounds. When compared at similar multiples of efficacy, dose-dependent reductions in SVR were greater in ZD-6169 and WAY-133537-treated animals versus A-278637. A-278637, unlike ZD-6169 or WAY-133537, produced no effect on MAP at concentrations 10-fold above the EC35. At concentrations 30-fold above the EC35, MAP in A-278637-treated animals was reduced -11% from baseline versus -24% and -42% for ZD-6169 and WAY-133537. Accordingly, at plasma concentrations approximately 30-fold above the EC35 reflex-mediated increases in HR were modest for A-278637-treated animals (15% above baseline) versus ZD-6169 (22%) or WAY-133537 (35%). Increases in both dP/dt and cardiac output occurred at lower therapeutic multiples and were greater in magnitude for animals treated with WAY-133537 (66% and 64% above baseline, respectively, 60 minutes into compound infusion) and ZD-6169 (10% and 13%) versus A-278637 (-2% and 6%). Thus, A-278637 exerted lesser effects on cardiovascular function at equivalent multiples of the EC35 than either ZD-6169 or WAY-133537. These data suggest that A-278637 possesses a greater functional selectivity for urinary bladder versus vascular smooth muscle in vivo and that A-278637 may exhibit a more favorable therapeutic index than either ZD-6169 or WAY-133537.


Development and Evaluation of Maze-Like Puzzle Games to Assess Cognitive and Motor Function in Aging and Neurodegenerative Diseases.
There is currently a need for engaging, user-friendly, and repeatable tasks for assessment of cognitive and motor function in aging and neurodegenerative diseases. This study evaluated the feasibility of a maze-like Numberlink puzzle game in assessing differences in game-based measures of cognition and motor function due to age and neurodegenerative diseases. Fifty-five participants, including young (18-31 years, n = 18), older (64-79 years, n = 14), and oldest adults (86-98 years, n = 14), and patients with Parkinson's (59-76 years, n = 4) and Huntington's disease (HD; 35-66 years, n = 5) played different difficulty levels of the Numberlink puzzle game and completed usability questionnaires and tests for psychomotor, attentional, visuospatial, and constructional and executive function. Analyses of Numberlink game-based cognitive (solving time and errors) and motor [mean velocity and movement direction changes (MDC)] performance metrics revealed statistically significant differences between age groups and between patients with HD and older adults. However, patients with Parkinson's disease (PD) did not differ from older adults. Correlational analyses showed significant associations between game-based performance and movement metrics and performance on neuropsychological tests for psychomotor, attentional, visuospatial, and constructional and executive function. Furthermore, varying characteristics of the Numberlink puzzle game succeeded in creating graded difficulty levels. Findings from this study support recent suggestions that data from a maze-like puzzle game provide potential "digital biomarkers" to assess changes in psychomotor, visuoconstructional, and executive function related to aging and neurodegeneration. In particular, game-based movement measures from the maze-like puzzle Numberlink games are promising as a tool to monitor the progression of motor impairment in neurodegenerative diseases. Further studies are needed to more comprehensively establish the cognitive validity and test-retest reliability of using Numberlink puzzles as a valid cognitive assessment tool.


Mutations in HlyD, part of the type 1 translocator for hemolysin secretion, affect the folding of the secreted toxin.
HlyD, a member of the membrane fusion protein family, is essential for the secretion of the RTX hemolytic toxin HlyA from Escherichia coli. Random point mutations affecting HlyA secretion were obtained, distributed in most periplasmic regions of the HlyD molecule. Analysis of the secretion phenotypes of different mutants allowed the identification of regions in HlyD involved in different steps of HlyA translocation. Four mutants, V349-I, T85-I, V334-I and L165-Q, were conditionally defective, a phenotype shown to be linked to the presence of inhibitory concentrations of Ca2+ in extracellular medium. Hly mutant T85-I was defective at an early stage in secretion, while mutants V334-I and L165-Q appeared to accumulate HlyA in the cell envelope, indicating a block at an intermediate step. Mutants V349-I, V334-I, and L165-Q were only partially defective in secretion, allowing significant levels of HlyA to be transported, but in the case of V349-I and L165-Q the HlyA molecules secreted showed greatly reduced hemolytic activity. Hemolysin molecules secreted from V349-I and V334-I are defective in normal folding and can be reactivated in vitro to the same levels as HlyA secreted from the wild-type translocator. Both V349-I and V334-I mutations mapped to the C-terminal lipoyl repeat motif, involved in the switching from the helical hairpin to the extended form of HlyD during assembly of the functional transport channel. These results suggest that HlyD is an integral component of the transport pathway, whose integrity is essential for the final folding of secreted HlyA into its active form.


Effect of exercise training on the rates of fatty acid synthesis in mice.
The present study has investigated the respective effects of training and exercise on the rates of fatty acid synthesis in mice. Male C57B1 10ScSn mice were trained by forced swimming in a tank at 36 degrees C for 2 h each day for a 28-day period. Rates of fatty acid synthesis were determined in vivo by measuring the incorporation of tritium from 3H2O into tissue fatty acids. At the end of the training programme, both sedentary and trained mice were assigned to either exercising or resting groups. The results obtained show that both training and exercise affected the rates of fatty acid synthesis, regardless of whether the results are expressed per gram of tissue or per whole tissue. Training led to significant decreases in the rates of synthesis in the liver, interscapular brown adipose tissue, epididymal white adipose tissue, and the remaining carcass, particularly in resting mice. The rates of fatty acid synthesis in the major lipogenic tissues were also lower during exercise than under sedentary conditions. The reduction in synthesis in brown adipose tissue was noteworthy in view of the high capacity of this tissue for fatty acid synthesis. In conclusion, it is suggested that in exercise-trained mice carbohydrate is shunted away from the synthesis of lipid in favour of energy storage as glycogen.


The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women.
Fabry disease is a rare X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A (alpha-Gal A) resulting in the storage of glycosphingolipids, especially globotriaosylceramide (Gb3), in cells throughout the body, causing life-threatening renal, cardiac, and cerebrovascular complications in hemizygous males and some heterozygous females. Disease manifestations in heterozygotes are being recognized increasingly, but quantitative prospective data on their extent and severity are limited. Prospective clinical and laboratory assessments were performed in a 7-day study of 61 women with signs and symptoms of Fabry disease. Analyses included medical history and physical, neurologic, cardiac, and ophthalmologic assessments; laboratory assessments; renal function tests; magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head; and Fabry-related blood and urine tests, including Gb3 levels in blood and urine, skin biopsies, and DNA genotype analysis of the alpha-Gal A gene to identify causative mutations. Quality of life, pain and concomitant medication were documented using validated questionnaires and diaries. All patients had normal Gb3 levels in plasma; only 1 patient had visible storage material in the superficial dermal vascular endothelial cells. Cardiac, renal, or cerebrovascular abnormalities were documented in 52 of the 57 patients (91%) with confirmed Fabry genotypes. These included electrocardiographic abnormalities in 38 of 52 patients (73%), echocardiographic abnormalities in 8 of 57 (14%), proteinuria (>150 g protein/24-h urine) in 23 of 38 (61%), low estimated glomerular filtration rate (<90 mL/min per 1.73 m) in 24 of 57 (42%), abnormal MRI in 4 of 54 (7%), and abnormal MRA in 10 of 50 patients (20%). Angiokeratomas and corneal epitheliopathy were documented in 63% and 82% of the 57 patients, respectively. Despite the virtual absence of storage material in plasma and skin vascular endothelial cells, this population of women with Fabry disease exhibited a wide spectrum of clinical abnormalities. Useful outcome measures for assessment of specific therapies need to be developed. Studies limited to homogeneously affected subjects may be possible.


Evaluation of National Research Council amino acid recommendations for large white turkeys.
Two trials of identical experimental design were conducted to evaluate the NRC (1994) amino acid requirements for growing turkeys. Diets were formulated for 4-wk age intervals using intact ingredients and amino acid supplements to provide 85, 90, 95, 100, 105, 110, 115, and 120% of the suggested requirements. Formulation was done in a manner to minimize excess levels of as many essential amino acids as possible. Day-old male poults of a commercial Large White strain were grown to 20 wk on the test diets with body weight and feed conversion determined at intervals throughout the test; representative samples of birds were processed to determine carcass composition and parts yield. Results suggested that diets formulated to provide 105% of the suggested NRC requirements were needed to provide maximum body weight gain, feed conversion, and breast meat yield. Ambient temperatures in the present study frequently exceeded 27 C and may have contributed to the need for somewhat greater amino acid needs than the present NRC (1994) suggestions.


A novel signature of aging-related genes associated with lymphatic metastasis for survival prediction in patients with bladder cancer.
The predominant and most prevalent form of metastatic bladder cancer (BCa) is lymphatic metastasis, which is associated with a highly dismal prognosis for patients. Aging-related genes (ARGs) are believed to contribute significantly to tumor development. However, the effect of ARGs on lymphatic metastasis of BCa is unclear. This research sought to establish a prognosis model based on ARGs associated with lymphatic metastasis in BCa. We downloaded BCa data from the TCGA and GEO databases and ARGs from the Aging Atlas database. The least absolute shrinkage and selection operator (LASSO) approach was applied to obtain the characteristic ARGs of risk signature in the TCGA cohort. Verification was done using the GSE13507 dataset. The R package 'ConsensusClusterPlus' was employed to identify the molecular subtypes based on the characteristic ARGs. Protein-Protein interaction network, MCODE analysis, enrichment analysis (KEGG, GO, GSEA), and immune infiltration analysis were performed to investigate underlying mechanisms. EdU, migration and invasion assays, wound healing assays, immunofluorescence staining, and quantitative polymerase chain reaction were conducted to evaluate the impact of ELN on the proliferative, migratory, and invasive capacities of BCa cells. We identified 20 differently expressed ARGs. A four ARGs risk signature (EFEMP1, UCHL1, TP63, ELN) was constructed in the TCGA cohort. The high-risk group (category) recorded a reduced overall survival (OS) rate relative to the low-risk category (hazard ratio, 2.15; P <0.001). The risk score could predict lymphatic metastasis in TCGA cohort (AUC=0.67). The GSE13507 dataset was employed to verify the validity of this risk score. Based on the four ARGs, two distinct aging profiles (Cluster 1 and Cluster 2) were discovered utilizing the ConsensusClusterPlus, and Cluster 2 possessed a favorable OS in contrast with Cluster 1 (hazard ratio, 0.69; P =0.02). Classical tumor signaling pathways, ECM-associated signaling pathways, and immune-related signaling pathways participate in BCa progression. ELN recombinant protein affected the expression of collagen and increased migration and invasiveness in BCa cells. We constructed a four-ARG risk signature and identified two aging molecular subtypes. This signature could serve as an effective survival predictor for patients with BCa.


Modulation of histamine release from human basophils in vitro by physiological concentrations of zinc.
Zinc, at physiologic concentrations, inhibits in vitro histamine release from human basophils induced by several immunologic (i.e., antigen and anti-immunoglobulin E (IgE) and nonimmunologic [Ca++ ionophore A23187 and formylated tripeptide formyl-methionyl-leucyl-phenylalanine (f-met peptide)] stimuli in a dose-dependent manner. Inhibition begins at about 10(-6) (ionophore A23187, anti-IgE and antigen) or 10(-5) M (f-met peptide) and is maximum at 10(-4) M (80--100% inhibition of histamine release). The activity of zinc is about 25-fold greater with respect to ionophore A23187 (ID50 = 1.1 x 10(-6) M) than to f-met peptide-induced (ID50 = 4 x 10(-5) M) histamine release. Its activity on IgE-mediated histamine release is intermediate between these two extremes (ID50 = 9.7 x 10(-6) M). Zinc does not affect the first stage of histamine release but acts on the calcium-dependent second stage. It is a competitive antagonist of the action of Ca++ in histamine secretion induced by antigen, anti-IgE and f-met peptide (but not by A23187) with a dissociation constant of about 1.2 x 10(-5) M. The addition of colchicine with zinc fails to increase the inhibition caused by the ion alone, suggesting the two compounds work via a common mechanism of action. Deuterium oxide reversed, in a dose-dependent manner, the inhibition of histamine release caused by zinc. These results suggest that the effect of zinc on histamine release from human basophils may be related to its influence on the microtubule system, directly or via its interaction with calcium.