P2 purinoceptor-mediated cardioprotection in ischemic-reperfused mouse heart.
P2 purinoceptor modulation of injury during ischemia-reperfusion was studied in murine hearts. Effects of P2 agonism or antagonism, and interstitial accumulation of P2 agonists (UTP, ATP, and ADP), were assessed in Langendorff perfused hearts during 20 min of ischemia and 45 min of reperfusion. In control hearts, ventricular pressure development recovered to 68 +/- 4 mm Hg (63 +/- 3% baseline), diastolic pressure remained elevated (23 +/- 2 mm Hg), and 26 +/- 4 U/g lactate dehydrogenase (LDH) was released during reperfusion, evidencing necrosis. Treatment with 250 nM UTP improved pressure development (85 +/- 5 mm Hg, or 77 +/- 2%) and reduced diastolic contracture (by approximately 70%, to 7 +/- 1 mm Hg) and LDH loss (by approximately 60%, to 11 +/- 2 U/g). In contrast, P2Y1 agonism with 50 nM 2-methyl-thio-ATP (2-MeSATP) was ineffective. In the presence of the P2Y antagonist suramin (10 or 200 microM), UTP no longer improved postischemic outcomes. Ischemia also substantially elevated interstitial [UTP], [ATP], and [ADP], potentially activating P2 receptors. This was supported in part by effects of antagonists: 200 microM suramin worsened LDH efflux (53 +/- 9 IU/g) and contractile dysfunction (41 +/- 2 mm Hg diastolic pressure; 28 +/- 3 mm Hg developed pressure), as did P2Y antagonism with either 10 or 100 microM reactive blue 2. However, a 10 microM concentration of suramin failed to alter outcome. P2X antagonism with 10 microM pyridoxal phosphate-6-azo-(benzene-2,4-disulfonic acid and P2X1-selective pyridoxal-alpha5-phosphate-6-phenylazo-4'-carboxylic acid (MRS2159) (30 microM) was ineffective. Data collectively support cardioprotection with low concentrations of UTP, and they are consistent with P2Y2 involvement. Endogenous nucleotides may also play a protective role, as evidenced by effects of P2 antagonists, although this warrants further investigation.


Detection of dopamine receptors in homogenates of rat hippocampus and other brain areas.
The binding of [3H]spiperone (24-26 pM) specifically to the dopaminergic (DAergic) D2 site has been investigated in homogenates of rat hippocampus, pineal gland and cerebellum. It was found that specific binding in hippocampal homogenates was heat-labile and for a part pH-sensitive. Like striatal tissue, binding to the dopaminergic D2 site in hippocampal and cerebellar homogenates was greatly reduced by (pre)incubation with the iron chelator o-phenanthroline. The binding characteristics in hippocampus and cerebellum have been compared to those in the striatum. In all tissues tested, low (74-138 times fewer than in striatum) but significant numbers of DAergic D2 sites were found. The DAergic D2 site in the hippocampus, as far as measured in cerebellum and pineal gland exhibited similar binding characteristics to that in the striatum.


Charge reversal yolk-shell liposome co-loaded JQ1 and doxorubicin with high drug loading and optimal ratio for synergistically enhanced tumor chemo-immunotherapy via blockade PD-L1 pathway.
Antitumor immunotherapy has become a powerful therapeutic modality to identify and kill various malignant tumors by harnessing the immune system. However, it is hampered by the immunosuppressive microenvironment and poor immunogenicity in malignant tumors. Herein, in order to achieve multi-loading of drugs with different pharmacokinetic properties and targets, a charge reversal yolk-shell liposome co-loaded with JQ1 and doxorubicin (DOX) into the poly (D,L-lactic-co-glycolic acid) (PLGA) yolk and the lumen of the liposome respectively was engineered to increase hydrophobic drug loading capacity and stability under physiological conditions and further enhance tumor chemotherapy via blockade programmed death ligand 1 (PD-L1) pathway. This nanoplatform could release less JQ1 compared to traditional liposomes to avoid drug leakage under physiological conditions due to the protection of liposomes on JQ1 loaded PLGA nanoparticles while the release of JQ1 increased in an acidic environment. In the tumor microenvironment, released DOX promoted immunogenic cell death (ICD), and JQ1 blocked the PD-L1 pathway to strengthen chemo-immunotherapy. The in vivo antitumor results demonstrated the collaborative treatment of DOX and JQ1 in B16-F10 tumor-bearing mice models with minimized systemic toxicity. Furthermore, the orchestrated yolk-shell nanoparticle system could enhance the ICD effect, caspase 3 activation, and cytotoxic T lymphocyte infiltration while inhibiting PD-L1 expression, provoking a strong antitumor effect, whereas yolk-shell liposomes encapsulating only JQ1 or DOX showed modest tumor therapeutic effects. Hence, the cooperative yolk-shell liposome strategy provides a potential candidate for enhancement of hydrophobic drug loading and stability, showing potential for clinic application and synergistic cancer chemo-immunotherapy.


Development of the circadian rhythm of body temperature in rats.
Seven male and seven female rat pups, all from separate litters of 10 pups each, had biotelemetry thermistors implanted into their peritoneal cavities when they were 10-15 days old. Body temperatures (Tb) were recorded by an Apple computer every 10 minutes until the rats were 60-75 days old so that the development of the circadian temperature rhythm (CTR) could be studied. The data were compared with eight parameters taken from adult CTRs. All rats were maintained on a 12 hr light/12 hr dark photoperiod. The results indicate that the CTR begins to develop after thermoregulatory mechanisms mature to produce an adult like daily range of TbS around day 24. From days 25 to 45, there was a steady increase in the percentage of TbS greater than the daily mean occurring in the dark. This process organized Tb into the characteristic sinusoidal waveform of the adult. Proper phasing of the trough and peak relative to the light/dark cycle took place between days 30-36. By day 42, 90% of TbS higher than the daily mean were occurring in the dark, while those lower than the mean were in the light. This is the typical adult pattern. The waveform's appearance continued to develop until day 50.


Acute effects of propylthiouracil on hemodynamics and oxygen content in patients with alcoholic cirrhosis.
The antithyroid drug propylthiouracil has been suggested for the treatment of alcoholic liver disease. Its beneficial effects could be due to either a decrease in hepatic oxygen consumption or an increase in hepatic blood flow. The aim of this study was to test these two hypotheses in patients with proven alcoholic cirrhosis. The pharmacokinetic parameters after intravenous administration of 300 mg of propylthiouracyl were first determined in four patients. Then, the effects on systemic and splanchnic hemodynamics, and oxygen content were measured 45 and 90 min after the intravenous administration of 300 mg (n=6) or 600 mg (n=6) of propylthiouracil. Systemic hemodynamics (heart rate, arterial pressure, cardiac output and systemic vascular resistance) and splanchnic hemodynamics (hepatic venous pressure gradient, hepatic and azygos blood flows) were not modified 45 and 90 min after the administration of 300 mg or 600 mg of propylthiouracil. Moreover, neither oxygen content in the radial artery, pulmonary artery or hepatic vein, nor systemic oxygen uptake was modified after propylthiouracyl administration. The absence of effect of propylthiouracyl administration was also confirmed in patients with cirrhosis with proven acute alcoholic hepatitis (n=7). In patients with alcoholic cirrhosis, acute administration of propylthiouracyl has no effect on systemic and splanchnic hemodynamics or on oxygen contents. The presence of acute alcoholic hepatitis does not modify these results.


FGFR1 copy number in breast cancer: associations with proliferation, histopathological grade and molecular subtypes.
FGFR1 is located on 8p11.23 and regulates cell proliferation and survival. Increased copy number of FGFR1 is found in several cancers including cancer of the breast. ZNF703 is located close to FGFR1 at 8p11-12 and is frequently expressed in the luminal B subtype of breast cancer. Using tissue samples from a well-described cohort of patients with breast cancer with long-term follow-up, we studied associations between FGFR1 copy number in primary breast cancer tumours and axillary lymph node metastases, and proliferation status, molecular subtype and prognosis. Furthermore, we studied associations between copy number increase of FGFR1 and copy number of ZNF703. We used fluorescence in situ hybridisation for FGFR1 and the chromosome 8 centromere applied to tissue microarray sections from a series of 534 breast cancer cases. We found increased copy number (≥4) of FGFR1 in 74 (13.9%) of tumours. Only 6 of the 74 cases with increased copy number were non-luminal. Increased FGFR1 copy number was significantly associated with high Ki-67 status, high mitotic count and high histopathological grade, but not with prognosis. Forty-two (7.9%) cases had mean copy number ≥6. Thirty of these showed ZNF708 copy number ≥6. Our results show that FGFR1 copy number increase is largely found among luminal subtypes of breast cancer, particularly luminal B (HER2-). It is frequently accompanied by increased copy number of ZNF703. FGFR1 copy number increase is associated with high histopathological grade and high proliferation. However, we did not discover an association with prognosis.


MicroRNA-126: Dual Role in Angiogenesis Dependent Diseases.
MicroRNA-126, a microRNA implicated in blood vessel integrity and angiogenesis is significantly up/down regulated in different physiological and pathological conditions related to angiogenesis such as cardiovascular formation and angiogenesis dependent diseases. MicroRNA-126 plays a critical role in angiogenesis via regulating the proliferation, differentiation, migration, and apoptosis of angiogenesis related cells such as endothelial cells. The aim of this review is to investigate the molecular mechanisms and the effects of microRNA-126 on the process of angiogenesis in pathophysiological conditions. To conduct this review, related articles published between 2001 and 2019 were collected from the PubMed, Web of Science, Google Scholar, Scopus and Scientific Information Database using search terms such as microRNA-126, angiogenesis, cardiovascular disorders, hypoxia, VEFG-A, endothelial cells, VEGF pathway, and gene silencing. Then, the qualified articles were reviewed. MicroRNA-126 regulates the response of endothelial cells to VEGF, through directly repressing multiple targets, including Sprouty-related EVH1 domain-containing protein 1 (SPRED1) and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-b). MicroRNA-126 -3p and microRNA-126 -5p have cell-type and strandspecific functions and also various targets in angiogenesis that lead to the regulation of angiogenesis via different pathways and consequently diverse responses. MicroRNA-126 can bind to multiple targets and potentially be both positive and negative regulators of gene expression. Thus, microRNA-126 could cause the opposite biological effects depending on the context. As a result, understanding the different cellular pathways through which microRNA-126 regulates angiogenesis in various situations is a critical aspect in the development of novel and effective treatments for diseases with insufficient angiogenesis.


VPg of murine norovirus binds translation initiation factors in infected cells.
Norovirus genomic and subgenomic RNAs are covalently linked at the 5' nucleotide to a 15 kD protein called VPg. VPg of two human norovirus strains binds translation initiation factor eIF3 and other eIFs in vitro, suggesting VPg functions in initiation of protein synthesis on viral RNA. Human norovirus strains are not cultivable, and thus experimental evidence of interactions between VPg and eIFs in infected cells has been lacking. We used the cultivable murine norovirus MNV-1 as a model to study interactions between VPg and eIFs in infected cells. As shown previously for human norovirus VPg, MNV-1 VPg bound eIF3, eIF4GI, eIF4E, and S6 ribosomal protein in cell extracts by GST pull-down assay. Importantly, MNV-1 VPg co-precipitated eIF4GI and eIF4E from infected macrophages, providing evidence that VPg interacts with components of the translation machinery in norovirus infected cells. The interactions between MNV-1 VPg and eIFs completely mimic those reported for the human norovirus VPg, illustrating the utility of MNV-1 as a relevant molecular model to study mechanisms of human norovirus replication.


Amino acid sequence of polypeptide chain IIB of extracellular hemoglobin from the polychaete Tylorrhynchus heterochaetus.
The giant extracellular hemoglobin from the polychaete Tylorrhynchus heterochaetus consists of two types of subunits: a "monomeric" chain (chain I) and a disulfide-bonded trimer of chains IIA, IIB, and IIC. The complete amino acid sequence of chain IIB was determined. This chain has 148 amino acid residues and a molecular weight of 17,236 including a heme group. Of the residues in chain IIB, 74 (50%) and 34 (30%) were found to be identical with those in the corresponding positions in Tylorrhynchus chains IIC and I, respectively (Suzuki, T., Furukohri, T., and Gotoh, T. (1985) J. Biol. Chem. 260, 3145-3154). Marked differences were found between the chains of Tylorrhynchus and Lumbricus in the COOH-terminal regions. Significant differences were predicted between the monomeric chain I and the "trimeric" chains (IIB and IIC) in the hydropathy profiles and alpha-helical contents.


Individuals redistribution based on differential evolution for covariance matrix adaptation evolution strategy.
Among population-based metaheuristics, both Differential Evolution (DE) and Covariance Matrix Adaptation Evolution Strategy (CMA-ES) perform outstanding for real parameter single objective optimization. Compared with DE, CMA-ES stagnates much earlier in many occasions. In this paper, we propose CMA-ES with individuals redistribution based on DE, IR-CMA-ES, to address stagnation in CMA-ES. We execute experiments based on two benchmark test suites to compare our algorithm with nine peers. Experimental results show that our IR-CMA-ES is competitive in the field of real parameter single objective optimization.


Quantified electroencephalographic correlates of depression in Alzheimer's disease.
While depression is one of the most frequent psychiatric problems among patients with probable Alzheimer's disease (AD), its mechanism is not well known. We performed quantified EEGs in a consecutive series of seven patients with mild dementia and depression, six patients with mild dementia and no depression, eight patients with moderate dementia and depression, and eight patients with moderate dementia and no depression. Regardless of the severity of dementia, depressed patients had a significantly higher percent theta in posterior brain areas. Moreover, depressed patients with mild AD showed a similar theta frequency as non-depressed patients with moderate AD. These findings suggest that the presence of depression may contribute to the qEEG changes of AD.


Texture analysis of contrast-enhanced magnetic resonance imaging predicts microvascular invasion in hepatocellular carcinoma.
Microvascular invasion is one of the important risk factors of postoperative recurrence of hepatocellular carcinoma. Texture analysis uses mathematical methods to analyze the gray's quantitative value and distribution of images, for quantifying the heterogeneity of tissues. To investigate the feasibility of predicting MVI in HCC by analyzing the texture features of hepatic MR-enhanced images. 110 patients with HCC who underwent MR-enhanced examinations were included in this study, were divided into MVI-positive group (n = 52) and MVI-negative group (n = 58) according to postoperative pathology. Clinical, pathological data and MR imaging features were collected. 11 texture parameters were selected from the gray histogram and gray level co-occurrence matrix (GLCM). Texture parameters of MR-enhanced images were calculated for statistical analysis. There were statistically significant differences in tumor size, location, degree of differentiation, AFP level, signal, pseudocapsule, margin, peritumoral enhancement and intratumoral artery between MVI-positive group and MVI-negative group (P < 0.05). The AUC value of combining MR image features in prediction of MVI was 0.693(sensitivity and specificity: 53.8 %, 82.8 %, respectively). There were statistically significant differences in the texture parameters of GLCM between two groups (P < 0.05). The AUC value of combining texture parameters in prediction of MVI was 0.797 (sensitivity and specificity: 88.2 %, 62.7 %, respectively). MR image features and texture analysis have certain predictive effect on MVI, which are mutually verified and complementary. The texture parameters of GLCM could reflect tumor heterogeneity, which have great potential to help with preoperative decision. The combination of MR image features and texture analysis may improve the efficiency in prediction of MVI.


Production of purified hepatitis B surface antigen from Alexander hepatoma cells grown in artificial capillary units.
An artificial capillary system was devised for growth of hepatoma cells that yields very high titers of hepatitis B surface antigen (HBsAg). High yield of antigen was facilitated by slowing cellular metabolism through reduction of incubation temperature and addition of 0.1 mM caffeine. Deletion of serum from the medium did not reduce the yield of antigen. HBsAg prepared from the culture fluid by affinity chromatography and additional chemical and enzymatic steps was essentially pure and was indistinguishable from HBsAg prepared from infected human plasma. Preparation of HBsAg from the cell culture source presents advantages over that of human plasma and might be a source of HBsAg for vaccine preparation.


Toxicity and occupational health hazards of coal fly ash (CFA). A review of data and comparison to coal mine dust.
Coal fly ashes (CFA) are complex particles of a variable composition, which is mainly dependent on the combustion process, the source of coal and the precipitation technique. Toxic constituents in these particles are considered to be metals, polycyclic aromatic hydrocarbons and silica. The purpose of this review was to study the in vitro and in vivo data on coal fly ash and relate the studied endpoints to the role of (crystalline) silica, considering its recent classification as a human carcinogen. For most of the effects coal mine dust was chosen as a reference, since it contains up to 10% of crystalline silica (alpha-quartz) and is well studied both in vivo and in vitro. Most studies on fly ash toxicity were not designed to elucidate the effect of its silica-content nor did they include coal mine dust as a reference. Taking this into account, both in vitro and in vivo experimental studies show lower toxicity, inflammatory potential and fibrogenicity of CFA compared to silica and coal mine dust. Although in vitro and in vivo studies suggest genotoxic effects of fly ash, the data are limited and do not clarify the role of silica. Epidemiological studies in fly ash exposed working populations have found no evidence for effects commonly seen in coal workers (pneumoconiosis, emphysema) with the exception of airway obstruction at high exposure. In conclusion, the available data suggest that the hazard of coal fly ash is not to be assessed by merely adding the hazards of individual components. A closer investigation of 'matrix' effects on silica's toxicity in general seems an obligatory step in future risk assessment on fly ashes and other particles that incorporate silica as a component.


Effect of dual PPAR-α/γ agonist saroglitazar on diabetic retinopathy and oxygen-induced retinopathy.
Diabetic retinopathy is a serious complication of diabetes, marked by retinal vascular damage, inflammation, and angiogenesis. This study's objective was to assess the potential benefits of saroglitazar, a peroxisome proliferator-activated receptor-alpha/gamma (PPAR-α/γ) agonist in diabetic retinopathy. Diabetic retinopathy was induced by streptozotocin in Sprague Dawley rats. The effect of saroglitazar was also assessed in the oxygen-induced retinopathy model in newborn rats and VEGF-induced angiogenesis in the chick chorioallantoic membrane (CAM) assay. Treatment of saroglitazar (1 and 4 mg/kg, oral) for 12 weeks significantly ameliorated retinal vascular leakage and leukostasis in the diabetic rats. Saroglitazar decreased oxidative stress, VEGF receptor signalling, NF-κBp65, and ICAM-1 in the retina of diabetic rats. The beneficial effects of saroglitazar (1 and 4 mg/kg, oral) were also observed on the neovascularization in oxygen-induced retinopathy in newborn rats. Saroglitazar also reduced VEGF-induced angiogenesis in CAM assay. This study reveals that saroglitazar has the potential to prevent the progression of retinopathy in diabetic patients.


Analytical method to derive environmental policy effects in an endogenous growth model with leisure.
There is deep-rooted opposition to strict environmental regulations, stating that they will lead to job losses and production contraction. Identifying environmental policies compatible with economic growth and pollution reduction is necessary to promote sustainable development. Using an R&D-based model with an endogenous labor supply, we examine the positive effect of an environmental policy on economic growth and welfare, where the policy reduces pollution emissions. The results show a substitution effect, where a reduction in pollution permit levels causes households to substitute labor for leisure and move their labor from production to R&D activities. This policy increased consumption. Thus, reducing pollution permit levels increases the growth rate and welfare via the substitution effect. This methodology can be applied to facilitate the complete analysis of environmental policy effects in an R&D-based growth model. Additionally, applying this analytical approach to other endogenous growth models and simulation analyzes can reveal the mechanisms of various environmental policy effects. In summary, this method facilitates the following steps:•Analysis of growth and welfare effects of environmental policies.•Understanding the process of deriving these effects in a basic R&D-based growth model.•A framework that can be applied to the simulation analysis of these effects was provided.


Infection prevention and control standards and associated factors: Case study of the level of knowledge and practices among nurses in a Saudi Arabian hospital.
Healthcare-associated infection is a significant public health issue in both developed and developing countries. This study was performed to assess the knowledge and practices of infection prevention and control (IPC) of nurses working in a Saudi hospital, and to examine their associations with the nurses' sociodemographic characteristics and work/training experience. A self-administered questionnaire survey was conducted with participation of male and female nurses of all nationalities who had direct contact with patients while providing healthcare services at King Abdulaziz Medical City-Riyadh (KAMC-R). Sociodemographic characteristics, and work/training experience were reported; IPC knowledge and practices were assessed by questionnaire. Data of 308 valid responses were analyzed. Percentage of correct responses to nine IPC knowledge questions and frequent adherence to 11 IPC practices were calculated. IPC knowledge and practice scores were developed by using principal component analyses; individual scores were classified into high/low level of knowledge or practices by the median of the scores. Logistic regression analysis was performed to evaluate associations between IPC knowledge or practice scores and sociodemographic or work/training variables. Majority of the participants were females (89.3%). Significant associations between high education level and high level of IPC knowledge (AOR = 2.72, 95% CI = 1.45-5.10) and practices (AOR = 3.66, 95% CI = 1.90-7.05) were observed, after controlling the influence of sociodemographic and work/training variables. High scores for IPC knowledge and IPC practices were independently associated with nurses' high level of education, regardless of their nationality or previous working experience. Further studies to develop effective programs for IPC regardless of the nurses' educational attainment are recommended.


Massage therapy for skin conditions in young children.
Two studies are reviewed that highlight the positive effects of massage therapy on skin conditions in young children. In the first study children being treated on a burn trauma unit received 30-minute massages before debridement or dressing change. The children who received massage therapy were more relaxed during the procedure. In the study on children with eczema, those who were massaged during the application of their skin medication showed less anxiety after the massage sessions. Across the massage period the children also showed an improved clinical condition including less redness, lichenification, scaling, excoriation, and pruritus.


[Clinical dose finding study of indocyanine green to detect choroidal neovascularization in patients with exudative age-related macular degeneration].
To evaluate the proper clinical dosage of indocyanine green(ICG) in angiography for detecting choroidal neovascularization(CNV) of exudative age-related macular degeneration(AMD). Indocyanine green angiography (IA) was performed using a randomized crossover method with two different doses on two occasions. Ease of detection, side effects and clinical serum data were also evaluated. Among the 39 eyes, detection of CNV using 12.5 mg and 25 mg was most effective in 21 and 31 eyes respectively, showing a statistically significant difference. Slight vomiting was observed temporarily in one patient who had taken 25 mg. A dose of 25 mg is appropriate for detection of CNV of exudative AMD and this dosage raises no safety concerns.


Kalmyks from Republic of Kalmykia, Russia.
NGS typing reveals 2 novel alleles amongst 206 class I and class II alleles.


A comparison study of different facial soft tissue analysis methods.
The purpose of this study was to evaluate several different facial soft tissue measurement methods. After marking 15 landmarks in the facial area of 12 mannequin heads of different sizes and shapes, facial soft tissue measurements were performed by the following 5 methods: Direct anthropometry, Digitizer, 3D CT, 3D scanner, and DI3D system. With these measurement methods, 10 measurement values representing the facial width, height, and depth were determined twice with a one week interval by one examiner. These data were analyzed with the SPSS program. The position created based on multi-dimensional scaling showed that direct anthropometry, 3D CT, digitizer, 3D scanner demonstrated relatively similar values, while the DI3D system showed slightly different values. All 5 methods demonstrated good accuracy and had a high coefficient of reliability (>0.92) and a low technical error (<0.9 mm). The measured value of the distance between the right and left medial canthus obtained by using the DI3D system was statistically significantly different from that obtained by using the digital caliper, digitizer and laser scanner (p < 0.05), but the other measured values were not significantly different. On evaluating the reproducibility of measurement methods, two measurement values (Ls-Li, G-Pg) obtained by using direct anthropometry, one measurement value (N'-Prn) obtained by using the digitizer, and four measurement values (EnRt-EnLt, AlaRt-AlaLt, ChRt-ChLt, Sn-Pg) obtained by using the DI3D system, were statistically significantly different. However, the mean measurement error in every measurement method was low (<0.7 mm). All measurement values obtained by using the 3D CT and 3D scanner did not show any statistically significant difference. The results of this study show that all 3D facial soft tissue analysis methods demonstrate favorable accuracy and reproducibility, and hence they can be used in clinical practice and research studies.


Enhanced dynamic range in a genetically encoded Ca2+ sensor.
Genetically encoded fluorescence resonance energy transfer (FRET) indicators are powerful tools for real-time detection of second messenger molecules and activation of signal proteins. However, these fluorescent protein-based sensors typically display marginal FRET efficiency. To improve their FRET efficiency for optical imaging and screening, we developed a number of fluorescent protein mutants based on cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP). To improve FRET ratios, which were initially within a narrow dynamic range, we used DNA shuffling to develop a new FRET pair called 3xCFP/Venus. The optimized 3xCFP/Venus pair exhibited higher FRET ratios than CyPet/YPet, which has one of the greatest dynamic ranges of protein-based FRET pairs. We converted this FRET pair to a Ca(2+) FRET indicators using circular permutation Venus (cpVenus) linked with 3xCFP to form 3xCFP/cpVenus, which displayed an ∼11-fold change in dynamic range in response to Ca(2+) binding. The enhanced dynamic range for Ca(2+) concentration detection using 3xCFP/cpVenus was confirmed in PC12 cells using previously established indicators (TN-XXL, ECFP/cpCitrine). To our knowledge, this FRET pair displays the largest dynamic range so far among genetically-encoded sensors, and can be used for sensitive FRET detection.


Diagnosis and treatment of hereditary tyrosinemia in Japan.
Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I-III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long-term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good.


Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-M™.
The usefulness of the synthetic membrane, Strat-M™ as an alternative to human and animal skins was evaluated by estimating the skin permeabilities of chemical compounds. Thirteen chemical compounds with molecular weights (M.W.) of 152-289 and lipophilicities (log Ko/w) of -0.9 to 3.5 were selected. Strat-M™, excised human skin, or hairless rat skin was set in a Franz-type diffusion cell and a saturated solution of each chemical compound was applied to determine membrane permeation profiles. The obtained permeability coefficients (log P) were compared among these membranes. Elevations were observed in log P for Strat-M™ with an increase in the log Ko/w of the applied compounds, and similar results were observed with the human and hairless rat skins. A correlation was obtained in log P values between Strat-M™ and human or hairless rat skin. Furthermore, the diffusion and partition parameters of chemicals in Strat-M™ were similar to those in the excised human and rat skins. These results suggest that Strat-M™ could be used as an alternative to animal or human skin in permeation studies.


Inhaler technique and asthma: feasability and acceptability of training by pharmacists.
Poor inhaler technique is frequent in asthma, but its long-term consequences have been seldom assessed. Pharmacists are ideally positioned to teach inhaler technique. This prospective observational study evaluated the feasibility of inhaler training by pharmacists in patients receiving inhaled corticosteroids by pressurised metered-dose inhaler (pMDI) or breath-actuated MDI. In parallel, the relationships between inhaler technique, adherence, and asthma control, and their modulation one month after training were assessed. Of 727 patients receiving training at pharmacies (n=123), 61% were prescribed a pMDI; 35%, an Autohaler(®); and 5%, an Easi-Breathe(®) inhaler. Poor asthma control (Asthma Control Questionnaire score ≥ 1.5) at baseline was significantly (p<0.05) and independently associated with poor inhaler technique and poor self-reported adherence (Morisky score ≥ 3). The percentage of patients with optimal inhaler technique rose from 24% before to 79% after training (p<0.001). Median training session length was 6 min. At 1 month, mean (SD) ACQ score had improved from a baseline score of 1.8 (1.2) to 1.4 (1.1), (p<0.001). Importantly, greater change was observed in patients with improved inhaler technique versus those without. Similar results were observed for Morisky score. Inhaler technique is associated with adherence and influences asthma control. Inhaler training by pharmacists is feasible and seams to improve inhaler technique, asthma control and adherence.


Anthropometric indicators of insulin resistance.
During recent years, there have been numerous published reports associating increased circumferences of certain regions of the human body with insulin resistance or increased risk of cardiovascular disease. In the present review, we summarize the findings and conclusions of some of these publications.


Renin modulates HIV replication in T cells.
HIV is known to subvert cellular machinery to enhance its replication. Recently, HIV has been reported to enhance TC renin expression. We hypothesized that HIV induces and maintains high renin expression to promote its own replication in TCs. Renin enhanced HIV replication in TCs in a dose-dependent manner. (P)RR-deficient TCs, as well as those lacking renin, displayed attenuated NF-κB activity and HIV replication. TCs treated with renin and Hpr displayed activation of the (P)RR-PLZF protein signaling cascade. Renin, HIV, and Hpr activated the PI3K pathway. Both renin and Hpr cleaved Agt (a renin substrate) to Ang I and also cleaved Gag polyproteins (protease substrate) to p24. Furthermore, aliskiren, a renin inhibitor, reduced renin- and Hpr-induced cleavage of Agt and Gag polyproteins. These findings indicate that renin contributes to HIV replication in TCs via the (P)RR-PLZF signaling cascade and through cleavage of the Gag polyproteins.


Clinical and individual features associated with maternal stress in young adolescents with autism spectrum disorder.
Parents of people with autism spectrum disorder experience both negative stressful and positive events. Several clinical and socio-demographic features of children on the autism spectrum have been associated with parenting stress in their families. However, there have been few studies that focus on adolescents and the role of cognitive impairment has rarely been addressed. The main aim of the present research is to explore associations between autism symptoms, cognitive impairment, emotional and behavioral problems, socio-demographic features, and maternal stress in a sample of young adolescents with Autism Spectrum Disorder with and without cognitive impairment. Cognitive impairment and emotional and behavioral problems are associated with maternal stress, while autism symptoms seem to play a minor role. Maternal education and occupation are only associated with maternal stress in the group with cognitive impairment, while maternal age is stress-associated in the group of adolescents without cognitive impairment. Age-related implications for intervention and future research directions are discussed. LAY SUMMARY: Parents of individuals on the autism spectrum are exposed to both negative stressful and enriching experiences during their parenthood. While the influence of several child characteristics and socio-demographic features on parental stress during childhood has been widely explored in past studies, studies on teenagers are limited. The aim of the present research is to explore the influence of several characteristics on maternal stress levels in families with teenagers on the autism spectrum. We found that cognitive impairment and emotional and behavioral problems are associated with maternal stress, while autism symptoms seem to play a minor role. Socio-demographic features are not associated with maternal stress. Broadly speaking, the subjective perception of parental distress in both groups is less related to teenagers' characteristics then the perception of having a difficult interaction with the teenagers. We divided our participants into two groups (one group with cognitive impairment and the other group without). We found that mothers of teenagers with cognitive impairment are generally more stressed compared to the other group. Furthermore, we confirm that emotional and behavioral problems seem to play a major role in maternal stress (especially in the group without cognitive impairment), while autism symptoms seem to play a minor role. Furthermore, we found that maternal education/occupation and maternal age are associated with maternal stress in the group with and the group without cognitive impairment respectively. This research highlights the association between several variables and stress in mothers of adolescents on the spectrum. Results are discussed in the framework of previous findings highlighting the lack of adequate care and support services for families, especially for those of adolescents on the spectrum with cognitive impairment.


Mediastinal histoplasmosis with esophageal abscess. Two case reports.
Two patients were seen with Histoplasma capsulatum infection of mediastinal nodes which had eroded into the esophagus to produce dysphagia. Fungal serologies were of value in the diagnosis in one of the patients. Both patients responded well to amphotericin B therapy. A traction diverticulum was noted to follow healing in 1 patient.


Demonstration of the histopathological and immunohistochemical effects of a novel hemostatic agent, Ankaferd Blood Stopper, on vascular tissue in a rat aortic bleeding model.
Ankaferd Blood Stopper® (ABS) is a folkloric medicinal plant extract used as a hemostatic agent in traditional Turkish medicine. This experimental study investigated the histopathological and immunohistochemical effects of ABS on vascular tissue in a rat model of aortic bleeding. Four groups of 11 Wistar albino rats were used. The abdominal aortas of the rats were wounded; an ABS-soaked tampon was applied to rats in Groups 1 and 3, and a plain gauze tampon was applied to rats in Groups 2 and 4 until the bleeding stopped. The bleeding time was recorded. Immediately following sacrificing, the arteriotomy sites from Groups 1 and 2 were removed. The abdominal incisions in Groups 3 and 4 were closed following hemostasis. On Day 7 of the study, Group 3 and 4 rats were sacrificed and the abdominal aorta arteriotomy sites were removed for histopathological and immunohistochemical evaluation. The mean bleeding time in 15 animals in Groups 2 and 4 was 4.9 ± 0.6 s, and in 22 animals in Groups 1 and 3 was 3.1 ± 0.6 s. Distal aortic occlusion was not observed on either Day 1 or 7 in any group. Significantly more widespread and dense endothelial nitric oxide synthase (eNOS) staining was observed in Group 1 animals than Group 2. On Days 1 and 7 after application of ABS, histopathological changes, consisting of necrosis, inflammation, and endothelial cell loss, in the rat abdominal aortas did not differ between Groups 1 and 2. The basophilic discoloration in the ABS group on the operation day was a result of a foreign body reaction and hemosiderin-loaded histiocyte accumulation, which occurred on Day 7. In this study, hemostasis was successfully achieved with ABS in rat abdominal aortas. No histopathological change was found in the rat abdominal aortas between the ABS and control groups on Days 1 and 7. Further studies on the long-term effects of foreign body reactions and hemosiderin-loaded histiocyte accumulation are required.


Experimental evaluation of atrial function in right atrium--pulmonary artery conduit operation for tricuspid atresia.
Right ventricular bypass operations were performed in dogs by right atrium--pulmonary artery (RA-PA) conduits with closure of the tricuspid valve. Atrial fibrillation (AF) was induced in prebypass (control) and postbypass (postconduit) studies. Six dogs tolerated the procedure and had postoperative sinus rhythm (SR). In the postconduit studies, AF resulted in significant decline in both mean arterial pressure (73 +/- 2 to 65 +/- 2 mm Hg [mean +/- SEM], p less than 0.05) and pulmonary blood flow (1,050 +/- 160 to 880 +/- 110 ml/min, p less than 0.05). However, there were no significant differences between the magnitude of these changes and those during control studies. Mean right atrial pressure was markedly elevated (17.3 +/- 1.3 mm Hg) during SR after the conduit operations, but it did not increase significantly with AF. In volume load studies, pulmonary blood flow increased in proportion to rises between 15 and 30 mm Hg in mean right atrial pressure. The results suggest that right atrial contraction is not critical to the maintenance of pulmonary blood flow following RA-PA conduit operations.


Inorganic arsenic speciation analysis of water samples by trapping arsine on tungsten coil for atomic fluorescence spectrometric determination.
Arsine trapping on resistively heated tungsten coil was investigated and an analytical method for ultratrace arsenic determination in environmental samples was established. Several chemical modifiers, including Re, Pt, Mo, Ta and Rh, were explored as permanent chemical modifiers for tungsten coil on-line trapping and Rh gave the best performance. Arsine was on-line trapped on Rh-coated tungsten coil at 640 degrees C, then released at 1930 degrees C and subsequently delivered to an atomic fluorescence spectrometer (AFS) by a mixture of Ar and H(2) for measurement. In the medium of 2% (v/v) HCl and 3% (m/v) KBH(4), arsine can be selectively generated from As(III). Total inorganic arsenic was determined after pre-reduction of As(V) to As(III) in 0.5% (m/v) thiourea-0.5% (m/v) ascorbic acid solution. The concentration of As(V) was calculated by difference between the total inorganic arsenic and As(III), and inorganic arsenic speciation was thus achieved. With 8 min on-line trapping, the limit of detection was 10 ng L(-1) for As(III) and 9 ng L(-1) for total As; and the precision was found to be <5% R.S.D. (n=7) for 0.2 ng mL(-1) As. The proposed method was successfully applied in total arsenic determination of several standard reference materials and inorganic arsenic speciation analysis of nature water samples.


Folic acid deficiency exacerbates the inflammatory response of astrocytes after ischemia-reperfusion by enhancing the interaction between IL-6 and JAK-1/pSTAT3.
To demonstrate the role of IL-6 and pSTAT3 in the inflammatory response to cerebral ischemia/reperfusion following folic acid deficiency (FD). The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured primary astrocytes were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to emulate ischemia/reperfusion injury in vitro. Glial fibrillary acidic protein (GFAP) expression significantly increased in astrocytes of the brain cortex in the MCAO group compared to the SHAM group. Nevertheless, FD did not further promote GFAP expression in astrocytes of rat brain tissue after MCAO. This result was further confirmed in the OGD/R cellular model. In addition, FD did not promote the expressions of TNF-α and IL-1β but raised IL-6 (Peak at 12 h after MCAO) and pSTAT3 (Peak at 24 h after MCAO) levels in the affected cortices of MCAO rats. In the in vitro model, the levels of IL-6 and pSTAT3 in astrocytes were significantly reduced by treatment with Filgotinib (JAK-1 inhibitor) but not AG490 (JAK-2 inhibitor). Moreover, the suppression of IL-6 expression reduced FD-induced increases in pSTAT3 and pJAK-1. In turn, inhibited pSTAT3 expression also depressed the FD-mediated increase in IL-6 expression. FD led to the overproduction of IL-6 and subsequently increased pSTAT3 levels via JAK-1 but not JAK-2, which further promoted increased IL-6 expression, thereby exacerbating the inflammatory response of primary astrocytes.


Drug transport across the blood--brain barrier. I. Anatomical and physiological aspects.
This review describes various aspects of the transport of drugs across the blood-brain barrier and comprises three parts. In this first part, the anatomical and physiological aspects of blood-brain transport are discussed. It appears that the blood-brain barrier has an anatomical basis at the endothelium of the capillary wall. This endothelium is characterized by the presence of very tight junctions. As a result, the transport by passive diffusion of drugs with a low lipophilicity, is restricted. For certain classes of closely related relatively hydrophilic compounds, however, the presence of specialized carrier systems has been demonstrated which may facilitate transport. Also evidence is presently available, that the permeability of the blood-brain barrier may be under active regulatory control. It is expected that improved knowledge of the anatomical and physiological aspects of the blood-brain barrier and its regulation will provide a scientific basis for the development of strategies to improve the transport of drugs into the central nervous system.


Induction of attenuated Nocardia seriolae and their use as live vaccine trials against fish nocardiosis.
Nocardia seriolae, a Gram-positive facultative intercellular pathogen, has been identified as the causative agent of fish nocardiosis, causing substantial mortality and morbidity of a wide range of fish species. Looking into that fact, the effective vaccine against this pathogen is urgently needed to control the significant losses in aquaculture practices. In order to induct attenuated strains for developing the potential live vaccines, the mutagenic N. seriolae strain S-250 and U-20 were obtained from wild-type strain ZJ0503 through continuous passaging and ultraviolet (UV) irradiation, respectively. Additionally, the biological characteristic, virulence, stability, mediating immune response and supplying protective efficacy to hybrid snakehead of the S-250 and U-20 strains were determined in the present study. The results showed that U-20 strain displayed dramatic changes in morphological characteristic and significant decreased in the virulence to hybrid snakehead, while that of S-250 strain had no obvious different in comparison to ZJ0503 strain. When hybrid snakehead were intraperitoneally injected with ZJ0503, S-250 and U-20 strains at their respective sub-clinical dosage, the non-specific immunity parameters (serum LYZ, POD, ACP, AKP and SOD activities), specific antibody (IgM) titers production and immune-related genes (CC1, CC2, IL-1β, IL-8, TNFα, IFNγ, MHCIα, MHCIIα, CD4, CD8α, TCRα and TCRβ) expression were up-regulated, indicating that they were able to trigger humoral and cell-mediated immune responses. Furthermore, the protective efficacy in hybrid snakehead after vaccination with ZJ0503, S-250 and U-20 strains, in terms of relative percentage survival (RPS), were 28.85%, 56.89% and 89.65% respectively. Taken together, two attenuated N. seriolae strains S-250 and U-20 were obtained successfully and they could elicit strong immune response and supply protective efficacy to hybrid snakehead against N. seriolae, which suggested that these two attenuated strains were the potential candidates for live vaccine development to control fish nocardiosis in aquaculture.


Strong association of glaucoma with atherosclerosis.
Carbonic anhydrases (CAs) catalyze the synthesis of HCO3- from H2O and CO2. The dysfunction of CAs leads to aqueous humor secretion and high intraocular pressure to cause glaucoma pathogenesis. Methazolamide (MTZ), a CA inhibitor, can effectively treat glaucoma by reducing aqueous humor secretion. We previously reported that carbonic anhydrase I (CA1), a CA family member, was highly expressed in atherosclerotic tissues of the aorta and stimulated atherosclerosis (AS) by promoting calcification. MTZ showed therapeutic and preventive effects on AS in a mouse model. The above findings suggest a relationship between AS and glaucoma. This study explored the possible association between AS prevalence and glaucoma prevalence and the therapeutic effect of MTZ on AS by analyzing medical records. Among 10,751 patients with a primary diagnosis of glaucoma, 699 (6.5%) were also diagnosed with AS. However, the incidences of AS in patients with keratitis and scleritis, which are also ophthalmic diseases, were 2.5% (206/8383 patients) and 3.5% (46/1308 patients), respectively. In the population without ophthalmic records, the AS prevalence was only 1.9% (99,416/5,168,481 patients) (all p values between each group were below 0.001). Among 152,425 patients with a primary diagnosis of AS, 1245 (0.82%) were also diagnosed with glaucoma. Among 199,782 patients with a primary diagnosis of hypertension (excluding AS), 1149 (0.57%) were diagnosed with glaucoma, and among 5,313,433 patients without AS or hypertension, 9513 (0.18%) were diagnosed with glaucoma (all p values between each group were below 0.001). Additionally, among 14 patients who suffered from both AS and glaucoma and were treated with MTZ to cure their glaucoma, 9 of them showed reduced low-density lipoprotein (LDL) levels, the main index of AS, within 3 months after medication use (2.81 ± 0.61 mmol/L vs. 2.38 ± 0.58 mmol/L, p = 0.039). The above findings demonstrated a strong relation between AS and glaucoma and suggested that AS patients with glaucoma were more likely to suffer from angle-closure glaucoma.


Material model of lung parenchyma based on living precision-cut lung slice testing.
We describe a novel constitutive model of lung parenchyma, which can be used for continuum mechanics based predictive simulations. To develop this model, we experimentally determined the nonlinear material behavior of rat lung parenchyma. This was achieved via uni-axial tension tests on living precision-cut rat lung slices. The resulting force-displacement curves were then used as inputs for an inverse analysis. The Levenberg-Marquardt algorithm was utilized to optimize the material parameters of combinations and recombinations of established strain-energy density functions (SEFs). Comparing the best-fits of the tested SEFs we found Wpar = 4.1 kPa(I1-3)2 + 20.7 kPa(I1 - 3)3 + 4.1 kPa(-2 ln J + J2 - 1) to be the optimal constitutive model. This SEF consists of three summands: the first can be interpreted as the contribution of the elastin fibers and the ground substance, the second as the contribution of the collagen fibers while the third controls the volumetric change. The presented approach will help to model the behavior of the pulmonary parenchyma and to quantify the strains and stresses during ventilation.


Antler cannibalism in reindeer.
Prion diseases constitute a class of invariably fatal and degenerative encephalopathies. Chronic Wasting Disease (CWD) is a contagious prion disease among cervids, which is spreading and causing marked population declines in USA and Canada. The first outbreak of CWD in Europe was discovered in a reindeer population in Norway in 2016. In the worst-case scenario with continental-wide spreading of CWD in Eurasia, an annual harvest of around 4 million cervids is at stake only in Europe, with huge economic and cultural significance. An in situ origin of CWD was suspected, and it appear urgent to identify the likely cause to prevent future emergences. Here, we document the novel phenomenon of extensive antler cannibalism prior to shedding among reindeer in the CWD-infected population. The extent of antler cannibalism increased over the last decades when CWD emerged, and included ingestion of vascularized antlers. Ingestion of tissues from conspecifics is a risk factor for the emergence of prion diseases, where the presence of extensive antler cannibalism opens the intriguing possibility of a 'Kuru-analogue' origin of CWD among the reindeer in Europe. Based on general insight on pathology of prion diseases and strain selection processes, we propose an hypothesis for how contagious CWD may emerge from sporadic CWD under the unique epidemiological conditions we document here. More research is required to document the presence of prions in reindeer antlers, and whether antler cannibalism actually led to a strain selection process and the emergence of a contagious form of CWD from a sporadic form of CWD.


Age-dependent insulin resistance in male mice with null deletion of the carcinoembryonic antigen-related cell adhesion molecule 2 gene.
Cc2 -/- mice lacking the gene encoding the carcinoembryonic-antigen-related cell adhesion molecule 2 (Cc2 [also known as Ceacam2]) exhibit hyperphagia that leads to obesity and insulin resistance. This starts at 2 months of age in female mice. Male mutants maintain normal body weight and insulin sensitivity until the last age previously examined (7-8 months), owing to increased sympathetic tone to white adipose tissue and energy expenditure. The current study investigates whether insulin resistance develops in mutant male mice at a later age and whether this is accompanied by changes in insulin homeostasis. Insulin response was assessed by insulin and glucose tolerance tests. Energy balance was analysed by indirect calorimetry. Male Cc2 -/- mice developed overt metabolic abnormalities at about 9 months of age. These include elevated global fat mass, hyperinsulinaemia and insulin resistance (as determined by glucose and insulin intolerance, fed hyperglycaemia and decreased insulin signalling pathways). Pair-feeding experiments showed that insulin resistance resulted from hyperphagia. Indirect calorimetry demonstrated that older mutant male mice had compromised energy expenditure. Despite increased insulin secretion caused by Cc2 deletion, chronic hyperinsulinaemia did not develop in mutant male mice until about 9 months of age, at which point insulin clearance began to decline substantially. This was probably mediated by a marked decrease in hepatic CEACAM1 expression. The data demonstrate that at about 9 months of age, Cc2 -/- male mice develop a reduction in energy expenditure and energy imbalance which, combined with a progressive decrease in CEACAM1-dependent hepatic insulin clearance, causes chronic hyperinsulinaemia and sustained age-dependent insulin resistance. This represents a novel mechanistic underpinning of age-related impairment of hepatic insulin clearance.


Injury patterns in traffic accidents and suggested preventive measures.
A short survey is given of the main patterns of injuries sustained in traffic accidents. The following injuries are accounted for: ruptures of the parasagittal bridging veins and gliding contusions of the brain, axis fractures, and aortic and pelvic injuries.


The effect of environmental photoperiodicity on indole rhythms and locomotor activity in sighted and eye covered chickens.
Direct (via the skull) and indirect (via the eyes) light on the rate of adaptation of circadian rhythms of pineal, retina and serum indoleamines and of locomotor activity was examined by observing photoperiod reversal in eye covered and normally sighted chickens. Eye covering did not affect indoleamine levels nor locomotor activity on the regular light:dark (L:D) cycle. However, following photoperiod reversal, the eye covered chickens showed slower rates of adaptation of retinal melatonin and locomotor activity to the new L:D cycle than did the normal sighted chickens. Pineal and serum indole levels were unaffected by eye covering. Our results in birds indicate that 1) light to the eye has a role in governing retinal melatonin and locomotor activity, 2) the pineal is directly photosensitive, and 3) the endogenous rhythm of pineal melatonin may play a role in the entrainment of the locomotor rhythm in the chicken.


The kinetic mechanism of the glutamate-aspartate carrier in rat intestinal brush-border membrane vesicles: the role of potassium.
The sodium dependent transport system for L-glutamate and L-aspartate localized in the apical part of rat enterocytes has previously been kinetically characterized (Prezioso, G., and Scalera, V. (1996). Biochim. Biophys. Acta 1279, 144-148). In this paper the mechanism by which the potassium cation specifically activates the L-glutamate-sodium cotransport process is investigated. Potassium has been found to act as an activator when it is present inside the membrane vesicles, while its presence outside is ineffective, and the effect is saturable. The kinetic parameters with respect to sodium and glutamate have been compared in the presence and in the absence of the activator. The results indicate that the ordered sodium-sodium glutamate mechanism is not altered by potassium, and that the activation is probably exerted on both the rate determining steps of the transport process. It is proposed that (1) a specific binding site for potassium is present on the inside hydrophilic part of the membrane carrier, (2) the binding of the effector accelerates the intramembrane rearrangement steps of both the disodium glutamate-carrier complex and the free carrier, (3) the affinity of the carrier is lowered with respect to sodium whereas it is increased for glutamate, and (4) K+ antiport is not performed by this carrier.


Venous thromboembolism incidence associated with pegylated asparaginase (ASP) compared to the native L-ASP: A retrospective analysis with an ASP-based protocol in adult patients with acute lymphoblastic leukaemia.
Venous thromboembolism (VTE) is a well-known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)-based chemotherapy, including the ASP-intensive Dana-Farber Cancer Institute (DFCI) 91-01 protocol for adults. Since 2019, native L-ASP is no longer available in Canada and was replaced by pegylated (PEG)-ASP. To determine whether the incidence of VTE has changed since switching from L-ASP to PEG-ASP, we conducted a single-centred retrospective cohort study. We included 245 adult patients with Philadelphia chromosome negative ALL between 2011 and 2021, with 175 from the L-ASP group (2011-2019) and 70 from the PEG-ASP group (2018-2021). During Induction, 10.29% (18/175) of patients who received L-ASP developed VTE, whereas 28.57% (20/70) of patients who received PEG-ASP developed VTE (p = 0.0035; odds ratio [OR] 3.35, 95% confidence interval [CI] 1.51-7.39), after adjusting for line type, gender, history of VTE, platelets at diagnosis. Similarly, during Intensification, 13.64% (18/132) of patients had VTE on L-ASP while 34.37% (11/32) of patients on PEG-ASP developed VTE (p = 0.0096; OR 3.96, 95% CI 1.57-9.96 with multivariable analysis). We found that PEG-ASP is associated with a higher incidence of VTE compared to L-ASP, both during Induction and Intensification, despite the administration of prophylactic anticoagulation. Further VTE mitigation strategies are needed in particular for adult patients with ALL receiving PEG-ASP.


The effect of plantar fascia release on strain in the spring and long plantar ligaments.
The effect of plantar fascia release on strain in the spring and long plantar ligaments was investigated in 11 cadaveric feet. Strain gauges were placed in the spring and long plantar ligaments of each specimen, and cyclic axial loading was applied until reproducible hysteresis curves were observed in the ligaments before and after plantar fascia release. After release of the plantar fascia, the average strain observed in the spring ligaments at 920N of axial load increased by 52% (p < .001) and in the long plantar ligaments by 94% (p = .04). Longer resting lengths of the ligaments were also observed. Release of the plantar fascia significantly changed force distributions in the foot which may explain the development of deformities and symptoms observed clinically following this procedure.


The effects of aspartame on the HTR8/SVneo extravillous trophoblast cell line.
Extravillous trophoblasts (EVTs) are a key cell type involved in placentation. Aspartame is an artificial sweetener with a widespread use. In rodents, aspartame ingestion during pregnancy was found to cause a reduction in placental and fetal weights, but its effect in placentation at a cellular level has not been studied. Aspartame is completely hydrolyzed in the gastrointestinal tract into L-phenylalanine, L-aspartic acid, and methanol. We aimed to study the effects of aspartame and its metabolites on placentation related characteristics of EVTs. For this, we exposed HTR-8/SVneo cells to aspartame (0.001, 0.01, 0.1, 0.5 and 1 mM), L-phenylalanine (0.14 and 0.5 mM), L-aspartic acid (0.82, 2.8 and 10 mM) or methanol (0.14 and 0.8 mM) for 24 h. Aspartame had an anti-proliferative effect, decreased the number of metabolically active cells and glucose cellular uptake and increased the number of cells arrested in S phase. L-aspartic acid significantly reduced glucose uptake and whole-cell protein content. L-phenylalanine had an anti-proliferative effect and increased the number of metabolically active cells. Interestingly, methanol exerted very marked effects on HTR8/SVneo cells: it showed an anti-proliferative effect, decreased glucose uptake, the migratory ability and the number of cells in the G2/M phase and increased oxidative stress levels, in concentrations corresponding to the blood levels after the 99th percentile of projected daily ingestion of aspartame. Overall, our results demonstrate that aspartame and its metabolites can affect several characteristics of EVTs and support the conclusion that the effect of aspartame in the placenta should be further evaluated.


Mitigation of emerging pollutants and pathogens in decentralized wastewater treatment processes: A review.
Emerging pollutants (such as micropollutants, microplastics) and pathogens present in wastewater are of rising concern because their release can affect the natural environment and drinking water resources. In this decade, with increasing numbers of small-scale decentralized wastewater systems globally, the status of emerging pollutant and pathogen mitigation in the decentralized wastewater treatment processes has received more attention. This state-of-the-art review aims to discuss the mitigation efficiencies and mechanisms of micropollutants, microplastics, and pathogens in single-stage and hybrid decentralized wastewater treatment processes. The reviewed results revealed that hybrid wastewater treatment facilities could display better performance compared to stand-alone facilities. This is because the multiple treatment steps could offer various microenvironments, allowing incorporating several mitigation mechanisms (such as sorption, degradation, filtration, etc.) to remove complicated emerging pollutants and pathogens. The factors (such as system operation conditions, environmental conditions, wastewater matrix) influencing the removals of emerging pollutants from wastewater in these systems have been further identified. Nevertheless, it was found that very limited research work focused on synergised or conflicted effects of operation conditions on various emerging pollutants naturally present in the wastewater. Meanwhile, effective, reliable, and rapid analysis of the emerging pollutants and pathogens in the complicated wastewater matrix is still a major challenge.


A region-specific clustering approach to investigate risk-factors in mortality rate during COVID-19: comprehensive statistical analysis from 208 countries.
Since the outbreak of the novel coronavirus, COVID-19 has continuously spread across the globe briskly. However, since its existence, the symptoms of the disease have been varying widely; thus, developing an urgent need to stratify high-risk categories of people who show more propensity to be affected by this deadly virus will be beneficial for health care. Using the open-access data and machine learning algorithms, this paper aims to cluster countries in groups with similar profiles with respect to the country level pre COVID-19 pandemic parameters. The purpose of performing the data analysis is to measure the extent to which these major risk factors determine the mortality rate due to the coronavirus disease 2019. An unsupervised machine learning model (k-means) was employed for two hundred and eight countries to define data-driven clusters based on thirteen country-level parameters. After performing the one-way ANOVA for comparing the clusters in terms of total cases, total deaths, total cases per population, total deaths per population, and death rate, the paradigm with four and seven clusters showed the best ability to stratify the countries according to total cases per population and death rate with p-values of less than 0.05 and 0.001, respectively. However, the model could not stratify countries in total deaths/cases and total deaths per population.


Effects of clomipramine and desipramine on a C-fiber reflex in rats.
A C-fiber nociceptive reflex evoked by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in urethane anesthetized rats. Intravenously administered clomipramine and desipramine produced a dose-dependent depression of the C-fiber reflex. High doses of intrathecal desipramine also inhibited the C-fiber reflex, while similar intrathecal doses of clomipramine produced only a modest inhibition of the response. Intracerebroventricular administration of clomipramine decreased dose-dependently the C-fiber reflex whereas intracerebroventricular desipramine increased this reflex. These findings suggest that tricyclic antidepressants with noradrenergic selectivity, as desipramine, inhibit the spinal processing of C inputs by acting directly at the spinal cord level, while those with serotonergic spectra, as clomipramine, depress the C-fiber-evoked spinal reflex by acting at a supraspinal modulatory site.


Understanding the Delivery of Patient-Centered Survivorship Care Planning: An Exploratory Interview Study With Complex Cancer Survivors.
Understanding key elements of the survivorship care planning process, such as patient-centered communication (PCC) and health self-efficacy, are critical for delivering patient-centered survivorship care to cancer survivors with multiple chronic conditions ("complex cancer survivors"). Building upon our team's recent research efforts to examine the survivorship care planning process from a patient-centered lens, this exploratory study leveraged an ongoing quasi-experimental trial to elucidate the experience of complex cancer survivors with survivorship care planning and post-treatment management. We conducted a hypothesis-generating thematic content analysis on 8 interview transcripts. Survivors reported positive experiences communicating with their oncology care team but the presence of multiple chronic conditions in addition to cancer creates additional barriers to patient-centered survivorship care. These findings support the need for further in-depth research aimed at improving PCC across all care teams and enabling self-management by delivering more personalized survivorship care planning that aligns with survivor's needs, values, and preferences.


Evaluation of groundwater contamination in Chandigarh: Source identification and health risk assessment.
The major objective of the current study is to estimate the groundwater quality and identify the likely sources of contamination in Chandigarh, India. Total 80 groundwater samples were collected from different locations and at various depths. Further, physcio-chemical analysis was done to estimate pH, electrical conductivity (EC), total dissolved solids, total hardness (TH), total alkalinity (TA), Na+, K+, Cl-, SO42-, PO43- and NO3-. The groundwater samples collected from shallow water sources contain higher concentration of total dissolved salts. EC, TA, Cl-, TH, Na+, and K+ were found relatively higher in the shallow aquifer (<150 ft). Based on the location of pollution sources at the surface and consecutive geo-statistical distribution of physicochemical characteristics, this study suggests that non-scientific disposal of municipal solid waste, dumping of industrial waste and agricultural activities, in the nearby areas lead to the deterioration of groundwater of shallow aquifer. These observations were also confirmed using various water quality indices and outcomes of multivariate modeling, including principal component analysis. Health risk assessment for nitrates indicated that 29 groundwater samples pose non-carcinogenic health risk for children due to dermal and oral exposure. Hence, there is a need to establish a system for regularly assessing the groundwater quality to minimize public health risks.


Detection of dengue using PAMAM dendrimer integrated tapered optical fiber sensor.
The exponential escalation of dengue cases has indeed become a global health crisis. This work elaborates on the development of a biofunctionalized tapered optical fiber (TOF) based sensor with the integration of polyamidoamine (PAMAM) dendrimer for the detection of dengue E protein. The dimension of the TOF generated an evanescent field that was sensitive to any changes in the external medium while the integration of PAMAM promoted more adhesion of bio-recognition molecules; anti-DENV II E protein antibodies; that were complementary to the targeted protein. This in return created more active sites for the absorption of DENV II E proteins onto the tapered region. The resolution and detection limit of the sensor are 19.53 nm/nM and 1 pM, respectively with Kd = 1.02 × 10-10 M.


Second-generation tricyclic pyrimido-pyrrolo-oxazine mTOR inhibitor with predicted blood-brain barrier permeability.
Highly selective mTOR inhibitors have been discovered through the exploration of the heteroaromatic ring engaging the binding affinity region in mTOR kinase. Compound 11 showed predicted BBB permeability in a MDCK-MDR1 permeability in vitro assay, being the first pyrimido-pyrrolo-oxazine with potential application in the treatment of neurological disorders.


Effect of theβ-D-galactoside-binding lectin on cell to substratum and cell to cell adhesion of cells from the extraembryonic endoderm of the early chick blastoderm.
Cells from the extraembryonic endoderm of the gastrulating chick embryo contain a β-D-galactoside-binding lectin inhibited by thiodigalactoside (TDG). When cell suspensions are cultured in stationary culture in the presence of exogenously added purified blastoderm lectin or TDG, their attachment to the substratum is delayed and decreased compared to controls. The cells take on a fibroblastic-like morphology and cell to cell contact becomes limited to localized areas of the cell surface. Many lectin or TDG-treated cells appear to be migrating over the substratum. This is in contrast to control cultures where the cells appear epithelial in morphology and tend to maximize their areas of apposition. These data suggest that the endogenous lectin may have a role to play in cell to substratum and cell to cell adhesion.


The correlation between excessive vitreal protein levels, prostaglandin E2 levels, and the blood retinal barrier.
Changes in vitreal protein and prostaglandin E2 (PGE2) concentrations, as well as chorioretinal in vitro PGE2 production, were studied in rabbit eyes following Neodymium (Nd):YAG laser retinal exposure. Laser exposure was associated with an enhanced vitreal PGE2 concentration throughout a two-week observation period, with highest levels on days 1 and 7 after exposure (a 5.3 and 4.7 increase above baseline, respectively). A transitory 50% elevation above baseline in vitreal protein levels was observed in the laser-exposed eyes during the second week after exposure. Laser exposure was also associated with an enhancement in the in vitro chorioretinal PGE2 production, which varied throughout the observation period, and was more pronounced during the first week after exposure, when levels were four times higher than baseline. Initially PGE2 vitreal levels were closely related to excessive in vitro production. However, during the second week after exposure, evidence of such correlation was lacking, but PGE2 vitreal levels coincided with a small increase in vitreal protein levels. It is suggested that disruption of the blood retinal barrier by the long-term exposure to mildly elevated vitreal PGE2 levels was accountable for protein leakage, which might have affected PGE2 removal mechanisms.


Identification, characterization, and quantitative measurement of cyclic AMP receptor proteins in cytosol of various tissues using a photoaffinity ligand.
Two protein bands, present in cytosol fractions from each of seven rat tissues examined, specifically incorporated 32P-labeled 8-azidoadenosine 3':5'-monophosphate (8-N3-[32P]cAMP), a photoaffinity label for cAMP-binding sites. These proteins had apparent molecular weights of 47,000 and 54,000 on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis system. These two proteins were characterized in three of the tissues, namely, heart, uterus, and liver, by the total amount of 8-N3-[32P]cAMP incorporation, by the dissociation constant (Kd) for 8-N3-[32P]cAMP, and by the nucleotide specific inhibition of 8-N3-[32P]cAMP incorporation. Several lines of evidence were obtained that the protein with an apparent molecular weight of 47,000 represents the regulatory subunit of a type I cAMP-dependent protein kinase, while the protein with an apparent molecular weight of 54,000 represents the regulatory subunit of a type II cAMP-dependent protein kinase. Almost all of the cAMP receptor protein found in the cytosol of these tissues, as measured by 8-N3-[32P]cAMP incorporation, was associated with these two protein kinases, in agreement with the idea that most effects of cAMP are mediated through protein kinases. The photoaffinity labeling with 8-N3-[32P]cAMP can be used to estimate quantitatively the amounts of regulatory subunit of type I and type II cAMP-dependent protein kinases in various tissues.


The detection and characterization of vesicoureteral reflux in the child.
Voiding cystourethrography or radionuclide cystography should be performed in the child in whom it is important to know whether reflux is present. Voiding cystourethrography is more accurate in characterizing and grading reflux, and monitoring is intermittent. Conversely, radionuclide cystography uses a lower radiation dose and its continuous monitoring leads to fewer false negative results but its ability to characterize reflux is poor. The performance of voiding cystourethrography or radionuclide cystography to detect reflux is an art as well as a science. These tests are done best by those who are experienced and interested in imaging the urinary tract of the child. At our hospital we perform voiding cystourethrography in all young children with urinary tract infection to detect and precisely characterize reflux to enable intelligent planning of management. In older patients, when it is less likely that reflux is present but it is still desirable to ensure that reflux is not occurring, radionuclide cystography is performed. If reflux is present, then a decision is made on an individual basis as to whether additional characterization by voiding cystourethrography is needed. Radionuclide cystography is also used for family screening, for periodic followup of reflux being managed nonoperatively and to ensure that reflux has been eliminated after antireflux surgery.


Synthesis and anticonvulsant activity of racemic 2-amino-N-substituted succinimide derivatives.
Several derivatives of (R,S)-2-amino-N-substituted succinimides were synthetized and evaluated in mice against seizures produced by electroshock and pentylenetetrazol. The most active compound against both electroshock- and pentylenetetrazol-induced seizures was (R,S)-N-benzyl-2-(methanesulfamido)succinimide.


Raman and photoluminescence spectroscopy analysis of gamma irradiated human hair.
Preliminary study has been made of black human hair, carbon concentration of some 53%, a model in examining the potential of hair of the human head in retrospective and emergency biodosimetry applications, also offering effective atomic number near to that of water. The hair samples were exposed to [Formula: see text]Co gamma rays, delivering doses from 0 to 200 Gy. Structural alterations were observed, use being made of Raman and photoluminescence (PL) spectroscopy. Most prominent among the features observed in the first-order Raman spectra are the D and G peaks, appearing at 1370 [Formula: see text] and 1589 [Formula: see text] respectively, the intensity ratio [Formula: see text] indicating dose-dependent defects generation and annealing of structural alterations. The wavelengths of the PL absorption and emission peaks are found to be centred at [Formula: see text] nm and [Formula: see text] nm, respectively. The hair samples mean band gap energy ([Formula: see text]) post-irradiation was found to be [Formula: see text] eV, of the order of a semiconductor and approximately two times the [Formula: see text] of other carbon-rich materials reported via the same methodology.


CD147 promotes proliferation and migration of oral cancer cells by inhibiting junctions between E-cadherin and β-catenin.
Although association between oral squamous cell carcinoma (OSCC) with epithelial-mesenchymal transition (EMT) has been demonstrated, we found CD147, one transmembrane protein we previously studied in oral submucous fibrosis, was correlated with E-cadherin, one marker of EMT. Here, we investigated CD147 expression in the different stages of OSCC and assessed its association with epithelial-mesenchymal transition (EMT). CD147 and E-cadherin expression in tissue microarrays containing 48 OSCC specimens and matched adjacent tissues was analysed using immunohistochemistry. CD147 was overexpressed or knocked down using exogenous cloning vector and RNA interference, respectively, in OSCC cell lines. Cell proliferation and migration were measured using the CCK8 assay and scratch test, respectively. The expression and localization of EMT-associated proteins was analysed by Western blotting and immunofluorescence. CD147 expression in OSCC tissues was significantly higher than that in adjacent tissues and was markedly higher in cancer tissues with metastasis (P < .05). CD147 expression showed significant negative correlation with E-cadherin expression. CD147 overexpression downregulated E-cadherin and inhibited its complex with β-catenin and then upregulated N-cadherin and vimentin. Additionally, alterations in CD147 protein expression affected proliferation and migration ability in OSCC cells and were related to β-catenin nuclear translocation. CD147 plays an important role in tumorigenesis and metastasis by promoting EMT progression in OSCC. It may be considered as a novel potential diagnostic and therapeutic target for OSCC.


Foreign material in the capsules around breast prostheses and the cellular reaction to it.
Thirteen capsules which had formed around breast prostheses were examined, using the technique of splitting the capsule wall. A foreign material in droplet form was present in all the capsules. The foreign material was taken up by phagocytes, and the cytological evidence is that it has cytotoxic activity. It was shown that the material migrates to the vessels in the outer layer of the capsule and may reach the lumen of those vessels. On the basis of the microscopic appearance and the results of infrared spectrum analysis, the foreign material in the capsules was assumed to be silicone.


Cellular assessment of the extract of bambangan (Mangifera pajang) as a potential cytoprotective agent for the human hepatocellular HepG2 cell line.
This study was conducted to investigate the potential of bambangan (Mangifera pajang) fruit extracts in the protection against oxidative damage caused by tert-butyl hydroperoxide in the human hepatocellular HepG2 cell line. Proteins which might be involved in the cytoprotective mechanism were investigated using western blotting technique. Quercetin was used as a positive control. The results showed that only the kernel extract of M. pajang and quercetin displayed cytoprotective activity in HepG2 cells, with EC(50) values of 1.2 and 5.3μg/ml, respectively. Expression of quinone reductase, glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by quercetin, suggesting their involvement in the cytoprotective activity of quercetin. However, expressions of only glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by the kernel extract, again suggesting their involvement in the cytoprotective activity of bambangan kernel extract. Future study is needed to investigate the involvement of other cytoprotective proteins in the cytoprotection mechanism.


Updates on conservative management of endometrial cancer in patients younger than 45 years.
Endometrial cancer is the most common gynecologic malignancy in developed country. Women under the age of 40 represent 5% of all endometrial cancer and the majority are nulliparous at the time of diagnosis. The aim of this review was to compare oncologic and fertility outcomes among different fertility-preserving therapies in patients under 45 years of age with grade 1 or 2 endometrial cancer. A systematic review was conducted, the MEDLINE, EMBASE, and CINAHL databases were searched for articles published during the period from January 2010 through January 2020 in accordance with PRISMA guidelines, using the terms endometrial cancer, fertility sparing treatment and conservative treatment. A total of 661 patients in 38 studies were included. The median age was 32.3 years (range 13--43). Regardless of the primary treatment, it is always accompanied by systemic or local hormonal treatment. The median follow-up time was 47.92 months (range 1-412), 54.9 months (range 3.4-412) for the progesterone group, 38.97 months (range 3-172) for the hysteroscopic resection group and 23.11 months (range 1-115.5) for the Levonorgestrel Intrauterine Device group. The overall complete response rate was 79.4%, [Hysteroscopic Resection: 90%, hormonal treatment: 77.7%, and Levonorgestrel Intrauterine Device: 71.3%] The p = 0.02 when the primary treatment is Hysteroscopic resection, always followed by hormonal therapy either oral progesterone or Levonorgestrel Intrauterine Device. Patients who had tumor resection had lower progression than those who received hormonal treatment or Levonorgestrel Intrauterine Device 3.5% vs. 12.1% vs. 19.5% respectively (p = 0.03). The complete response time was higher in the Hysteroscopic Resection group (p = 0.04) with fewer patients undergoing hysterectomy (p = 0.0001). Patients who underwent Hysteroscopic Resection had higher pregnancy rates compared to medical treatment or Levonorgestrel Intrauterine Device, 34.5%, 27.6% and 18.4%, respectively (p = 0.002). CONCLUSION: Patients who underwent Hysteroscopic Resection followed progestogens agent was associated to a better complete response, high pregnancy rates and minor numbers of hysterectomies.


A Highly Efficient Agrobacterium-Mediated Method for Transient Gene Expression and Functional Studies in Multiple Plant Species.
Although the use of stable transformation technology has led to great insight into gene function, its application in high-throughput studies remains arduous. Agro-infiltration have been widely used in species such as Nicotiana benthamiana for the rapid detection of gene expression and protein interaction analysis, but this technique does not work efficiently in other plant species, including Arabidopsis thaliana. As an efficient high-throughput transient expression system is currently lacking in the model plant species A. thaliana, we developed a method that is characterized by high efficiency, reproducibility, and suitability for transient expression of a variety of functional proteins in A. thaliana and 7 other plant species, including Brassica oleracea, Capsella rubella, Thellungiella salsuginea, Thellungiella halophila, Solanum tuberosum, Capsicum annuum, and N. benthamiana. Efficiency of this method was independently verified in three independent research facilities, pointing to the robustness of this technique. Furthermore, in addition to demonstrating the utility of this technique in a range of species, we also present a case study employing this method to assess protein-protein interactions in the sucrose biosynthesis pathway in Arabidopsis.


Long lasting changes in the spontaneous activity of hippocampal neurons following stimulation of the entorhinal cortex.
The spontaneous activity of hippocampal and denate units was investigated in acute and chronic experiments on adult rats. Spontaneous unitary discharges from both regions were measured before and after brief tetanic stimulation of the entorhinal cortex. An increase in the frequency of spontaneous unit activity was obtained in units recorded from the dentate gyrus and CA3 field of the hippocampus for up to 20 min following stimulation. In chronic recordings of physiologically identified dentate units from freely moving rats similar results were obtained. The findings are discussed with reference to long lasting potentiation of synaptic activity in the perforant path-dentate granule cell connection.


[Use of PCR and nucleotide sequence analysis of the VP7 gene for detection of bovine rotaviruses and identification of their G serotypes].
A Vp7 gene fragment PCR protocol was developed to detect the bovine rotaviruses and to identify their G serotypes. The most widespread bovine rotaviruses of G serotypes (G6, G8 and G10) can be distinguished on the basis of the PCR fragment size, while other G serotypes can be differentiated through a comparative analysis of the VP7 gene fragment nuclcotide sequence. Twenty-four bovine rotavirus field isolates were detected, and their G stereotypes were determined by using the method in question. Fourteen isolates were shown to be of G6 serotype; four of them were of G8, five--of G10, and one isolate was of G11 serotype. A possibility of detecting more than one isolate by this method was shown. Finally, a feasibility of using the method for searching for rotaviruses of new bovine rotavirus G serotypes and for rotaviruses, which do not belong to a so far described G serotypes, is discussed.


Halothane modifies oxygen free radical activity on the voltage-sensitive calcium channels in canine myocardial membranes.
The functional derangements in the myocyte cell membrane, the sarcolemma, during short myocardial ischaemia and reperfusion are attributed to excessive influx of Ca2+ ions via the voltage-sensitive calcium channels (VSCC) and to the free radical-related injury. However, it is unclear whether the primary changes in the VSCC should be attributed to the ischaemic effect or to free radical action on channel constituents. Under these circumstances of ischaemia and reperfusion, volatile anaesthetics have exhibited protective properties on the myocardium. The present study is aimed at characterizing the effect of artificially-generated oxygen free radicals on the VSCC in canine sarcolemma, independently of the effect of ischaemia, and the effect of halothane on the membranes during the surge of the free radicals. Selective production of free radicals (O2-, CO2-) was made by gamma irradiation of isolated sarcolemma membranes with 137 Cesium (Cs), in the presence of 20 mM sodium formate. Control studies were performed without formate in the aqueous solution. In an additional group, liquid halothane (3 microl. 1.9 vol%) was added to the sarcolemma / formate preparation immediately prior to irradiation. The effects of free radicals on the VSCC was evaluated by redioligand binding studies of the calcium channel blocker [3H] isradipine to the sarcolemma. In six control studies, the rediolytic aqueous species produced by 137 Cs irradiation resulted in unchanged [3 H] isradipine binding. In the presence of formate [n=9], the free radicals have caused a 23% to 25% decrease, both, in density and dissociation constant (P=0.05) of [3 H]isradipine to the VSCC binding sites. When superoxide radicals were generated in the presence of 1.9% halothane and formate (n=6), a significant increase in maximal binding capacity (by 55% +/- 2; P<0.01) and in the dissociation constant (by 209% +/- 35, P<0.01) occurred. Oxidative free radicals which are generated by gamma irradiation exerted minimal changes on the normal function of the VSCC as reflected by the non-significant changes in [3 H] isradipine specific binding. Introduction of halothane into free radical generating system causes acute perturbations to the VSCC kinetics, and does not provide protection to the cardiac membranes.


The efficacy of myofunctional therapy in patients with atypical swallowing.
The myofunctional treatment (MFT) is a conventional therapy in the treatment of oral disease like atypical swallowing (AS). Functional (standardized surface electromyographic analysis-ssEMG) and clinical ("orofacial muscular evaluation with score" protocol-OMES) analyses were conducted to detect the effects of MFT (10 weeks session) in a group of patients with AS. ssEMG was performed to analyze the activity of masseter (MM), temporalis (TA), and submental (SM) muscles before (T1) and after (T2) the MFT in a group of 15 patients. OMES was completed at the same timepoints. A Student-t test was carried out to detect differences between T1 and T2 for ssEMG data, and a signed RANK test was used for OMES ones. One-way ANOVA variance test was performed to detect any differences between the different couples of muscles at each timepoint. After MFT, patients showed a shorter duration of the whole act of swallowing (p < .0001), higher intensity of the SM activity (p < .01) than at T1. At T2 masticatory muscles showed lower values for the activation index (ANOVA, p < .0001) and for the spike position (ANOVA, p < .01) than SM. The OMES protocol showed a significant increase for the total evaluation score (p < .01), appearance-posture (p < .01) and functions (p < .001). MFT permits a shortening of the muscular activation pattern and an increase in SM activity. The improvement of oral functionalities is possible and identifiable thanks to the use of standardized protocols.


The effects of endothelin-1 on human dermal fibroblast growth and synthetic activity.
Endothelin-1 (ET-1) is the most potent vasoconstricting substance known, and is believed to have a fundamental role in the regulation of blood flow. It is a peptide produced and secreted by endothelial cells in response to hypoxia and injury, as well as by macrophages. These properties suggest that ET-1 may play a role during tissue repair. In this study, we have examined the effects of ET-1 on the growth and synthetic activity of human dermal fibroblasts. ET-1 stimulated DNA synthesis in serum-deprived cultures: this effect reached a mean value of 64% more than control (P < 0.01) at 2.5 ng/ml (10(-9) M) of ET-1. In contrast, the addition of ET-1 to fibroblasts at different densities and in 0, 3, or 10% fetal bovine serum (FBS) failed to increase cell counts. In 1% FBS, a 41% mean increase in cell counts compared to control values was observed in cultures treated with 2.5 ng/ml of ET-1 (P < 0.01). Incubation of dermal fibroblast cultures at 37 degrees C for 1 hr with increasing concentrations of 125I-ET-1 resulted in saturable binding and a half-maximal specific binding of 27.5 pM. Scatchard plot analysis of the binding showed a Kd of 224 pM and 11,400 high-affinity binding sites per cell. ET-1 had no effect on [14C]-glucosamine incorporation by fibroblasts and caused no increase in collagen synthesis, as measured by collagenase-sensitive [3H]proline incorporation and by salt precipitation of 3H-labeled collagen at acid and neutral pH successively.(ABSTRACT TRUNCATED AT 250 WORDS)


Legislator voting and behavioral science theory: a systematic review.
To examine the application of behavioral science theories to explain the voting behavior of legislators for public health policies. We conducted a systematic review to identify studies that examined factors associated with legislator support, intention to vote, or actual votes on public health policies, emphasizing those grounded in behavior science theory. Twenty-one papers met our inclusion criteria, and 6 were explicitly grounded in a behavioral science theory. Behavioral science theories, and the theory of planned behavior in particular, provide a framework for understanding legislator voting behavior and can be used by advocates to advance pro-health policies.


Heterogeneity in the size of the apical surface of cortical progenitors.
The apical surface (AS) of epithelial cells is highly specialized; it is important for morphogenetic processes that are essential to shape organs and tissues and it plays a role in morphogen and growth factor signaling. Apical progenitors in the mammalian neocortex are pseudoepithelial cells whose apical surface lines the ventricle. Whether changes in their apical surface sizes are important for cortical morphogenesis and/or other aspects of neocortex development has not been thoroughly addressed. Here we show that apical progenitors are heterogeneous with respect to their apical surface area. In Efnb1 mutants, the size of the apical surface is modified and this correlates with discrete alterations of tissue organization without impacting apical progenitors proliferation. Altogether, our data reveal heterogeneity in apical progenitors AS area in the developing neocortex and shows a role for Ephrin B1 in controlling AS size. Our study also indicates that changes in AS size do not have strong repercussion on apical progenitor behavior.


On/Off O2 Switchable Photocatalytic Oxidative and Protodecarboxylation of Carboxylic Acids.
Photoredox catalysis in recent years has manifested a powerful branch of science in organic synthesis. Although merging photoredox and metal catalysts has been a widely used method, switchable heterogeneous photoredox catalysis has rarely been considered. Herein, we open a new window to use a switchable heterogeneous photoredox catalyst which could be turned on/off by changing a simple stimulus (O2) for two opponent reactions, namely, oxidative and protodecarboxylation. Using this strategy, we demonstrate that Au@ZnO core-shell nanoparticles could be used as a switchable photocatalyst which has good catalytic activity to absorb visible light due to the localized surface plasmon resonance effect of gold, can decarboxylate a wide range of aromatic and aliphatic carboxylic acids, have multiple reusability, and are a reasonable candidate for synthesizing both aldehydes/ketones and alkane/arenes in a large-scale set up. Some biologically active molecules are also shown via examples of the direct oxidative and protodecarboxylation which widely provided pharmaceutical agents.


Effective passivation of lead by phosphate solubilizing bacteria capsules containing tricalcium phosphate.
Phosphate solubilizing bacteria (PSBs) shows high potential to be used for lead passivation in sediments due to the abilities of releasing phosphate and the subsequent formation of insoluble Pb-phosphate compounds. In this research, microbial capsules implemented with sodium alginate and CaCl2, containing Leclercia adecarboxylata L15 (a lead resistant PSB) and Ca3(PO4)2, were developed and the performance on lead passivation under different conditions was examined. The optimal concentrations of sodium alginate and CaCl2 for formulating the capsules were determined to be 0.3% and 10%, respectively. The removal efficiency of Pb2+ by capsules containing L15 and Ca3(PO4)2 was up to 98% with a capsule dosage of 2%, initial Pb2+ concentration of 1mM and pH of 3.0, which was better than that of free L15 (18%) and capsules containing only L15 (34%). Lead was immobilized via the formation of Pb5(PO4)3Cl on the surface and Pb3(PO4)2 in the interior of the capsules. The simulated sediment remediation experiments showed that the acid soluble fraction of lead reduced from 28% to 14% and transformed into more stable fractions after 10 days. The experiment results indicated that PSBs capsules coupled with phosphate materials have a great promise for application in remediation of lead contaminated sediments.