C-H ... O hydrogen bonding in solutions of methylated nucleic acid base analogs as revealed by NMR.
Formation and thermodynamic characteristics of C-H ... O hydrogen bonding of methylated uracils and caffeine have been studied by nmr along two lines. 1. The concentration and temperature dependencies of the PMR spectra of 1,3-dimethyluracil (m2 1,3Ura), 1,3-dimethylthymine (m2 1,3Thy), and 1,3,6-trimethyluracil (m3 1,3,6Ura) in chloroform at high concentrations of base analogs indicated the self-association of m2 1,3Ura and m2 1,3Thy via C(6)H ... O hydrogen bonding and the competitive formation of C-H ... O bonds between carbonyl oxygens and chloroform. The intermolecular interaction energy and the arrangement of molecules in the local minima of various m2 1,3Ura dimers were calculated by the method of atom-atom potentials. The deepest minimum for the m2 1,3Ura coplanar dimer corresponds to a C(6)-H ... O hydrogen-bond formation. 2. At low concentration of m2 1,3Ura and caffeine in CCl4, C(6)-H ... O bonding for m2 1,3Ura and C(8)-H ... O bonding for caffeine with oxygens of dimethyl sulfoxide (DMSO) and acetone were observed. The association constants of these complexes were obtained at different temperatures. The enthalpies delta H, of the m2 1,3Ura-DMSO, m2 1,3Ura-accetone, caffeine-DMSO, and caffeine-acetone complexes were -2 +/- 0.1 kcal/mol. The calculations showed that the deepest minimum of the caffeine-acetone coplanar complex corresponds to C(8)-H ... O bonding with energy of -3.5 kcal/mol and that of the m2 1,3Ura-acetone complexes corresponds to C(6)-H ... O bonding with energy of -3.4 kcal/mol. The approximate correction for the solvent effect provides good agreement of the experimental data with the calculations.


Increase in water temperature increases acute toxicity of sumithion causing nuclear and cellular abnormalities in peripheral erythrocytes of zebrafish Danio rerio.
Global warming and indiscriminate usages of pesticides are notable concern to all. The present study has been conducted to evaluate the effects of high temperature on acute toxicity of sumithion in adult zebrafish. A 2-day renewal bioassay system was used to determine the 96 h LC50 value of sumithion at three temperature regimes, such as 25 °C, 30 °C, and 35 °C. Blood glucose (mg/dL) level was measured in control (0.0 mg/L) and low concentration (1.0 mg/L) of sumithion during the determination of LC50 in three temperature conditions. In addition, micronucleus (MN), erythrocytic nuclear abnormalities (ENA), and erythrocytic cellular abnormalities (ECA) tests were performed in the blood erythrocytes. The 96 h LC50 value of sumithion for zebrafish was significantly lower at 35 °C, which indicates that the toxicity of sumithion increases at higher temperature. Blood glucose level was significantly increased by sumithion in all temperature conditions, while it was significantly higher in the highest (35 °C) temperature compared to the lowest (25 °C) temperature in both control and sumithion-treated fish. Similarly, frequencies of MN, ENA, and ECA were elevated by sumithion in all temperature conditions, whereas it was significantly raised in the highest (35 °C) temperature compared to the lowest (25 °C) temperature in both control and sumithion treated fish. With increasing temperature in exposure to sumithion, dissolved oxygen decreased significantly, whereas free CO2 increased significantly. On the other hand, no distinct changes were observed in pH and total alkalinity during the experimental period. Therefore, it can be inferred that increasing temperature enhances the toxicity of sumithion in the zebrafish.


The impact of a community screening program on psychiatric hospital admissions.
A rural CMHC screening program significantly reduced admission rates to a state hospital compared with hospital-based screening. Personnel from CMHCs in three counties evaluated each potential admission to the hospital to evaluate their need for hospitalization. Hospital staff screened admissions from the remaining counties of the state. Both community and hospital screening resulted in significant reductions in admissions with community screening producing larger declines. Additional possible advantages of community screening for improved treatment outcomes, efficient utilization of community resources, and reduced costs are discussed.


Dyadic effects of social support, illness uncertainty on anxiety and depression among lung cancer patients and their caregivers: a cross-sectional study.
To explore the dyadic relationships between perceived social support, illness uncertainty, anxiety, and depression among lung cancer patients and their family caregivers. To examine the potential mediating role of illness uncertainty and the moderating role of disease stage in lung cancer patient-caregiver dyads. A total of 308 pairs of lung cancer patients and their family caregivers from a tertiary hospital in Wuxi, China, from January 2022 to June 2022 were included. Participants' perceived social support, illness uncertainty, anxiety, and depression were assessed by corresponding questionnaires. To test for dyadic relationships between the variables, we employed the actor-partner interdependence mediation model. There were actor and partner effects of both patient and caregiver perceived social support on anxiety and depression, and illness uncertainty mediated the effect of perceived social support on anxiety and depression. Lung cancer stage plays a moderating role in lung cancer patient-caregiver dyads. There is an indirect positive partner effect of perceived social support from family caregivers on anxiety and depression in patients with early lung cancer; there is a direct or indirect negative partner effect of social support from family caregivers on anxiety and depression in patients with advanced lung cancer. This study confirmed the dyadic interdependence between perceived social support, illness uncertainty, anxiety, and depression among lung cancer patients and family caregivers. Furthermore, studies on differences between different lung cancer stages may provide a theoretical basis for different dyadic supportive interventions based on lung cancer stages.


Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release.
We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation in vitro and Bcr-Abl+ patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine.


Gene expression profiling of breast cancer.
Gene expression profiling is enabling scientists to understand the heterogeneous nature of breast cancer on a genomic level. Several gene expression profiles for breast cancers have emerged in the initial studies and appear to be generally concordant in their ability to predict poor outcome. Of these profiles, the Oncotype Dx and Mammaprint assays are the best validated and are commercially available. Their role in clinical practice is being refined through ongoing clinical trials. Other efforts are directed at determining host factors that might help identify prognosis as well as response and toxicity of therapy. It is expected that availability of these types of analyses will only increase in the future. It will be imperative that such assays be well validated and have implications for how to modify care for the individual patient.


Shoulder-hand syndrome in patients with intracranial neoplasms.
The diagnosis of Shoulder-Hand Syndrome in patients with cerebral neoplasms is difficult and often overlooked. Three cases are reviewed to illustrate this important clinical association.


Implications of the impact of prevalence on test thresholds and outcomes: lessons from tuberculosis.
With today's rapid advances in technology and understanding of disease, more screening and diagnostic tests have become available in a variety of sociodemographic and clinical settings. This analysis quantifies the impact of varying prevalence rates on test performance for given sensitivity and specificity values. Using a worked example of latent tuberculosis infection, we compared true-positive (TP) and false-positive (FP) results when varying prevalence and test sensitivity and specificity. We used estimates from published literature to estimate two tests' sensitivity (81%, QuantiFERON®-TB Gold In-Tube; 88%, T-SPOT®.TB) and specificity (99%; 88%), and we used World Health Organization data to estimate disease prevalence in five countries. Varying sensitivity impacted outcomes most in high-prevalence settings; change in specificity had greater impact in low-prevalence settings. In switching from QuantiFERON-TB to T-SPOT.TB (higher sensitivity, lower specificity), trade-offs between increasing case identification (TPs) and decreasing unnecessary treatments (FPs) varied dramatically with prevalence. Lower-prevalence settings paid a greater "price" of more FPs for each TP gained, with 37.7 FPs per TP in the United States (5% prevalence) versus 2.5 in the Ivory Coast (55% prevalence). Prevalence affects test performance for given sensitivity and specificity values. To optimize test performance, disease prevalence should be incorporated in testing decisions, and sensitivity and specificity should be set locally, not globally. In lower-prevalence settings, using highly specific assays may optimize outcomes.


`A critical review on current status and environmental sustainability of pre-treatment methods for bioethanol production from lignocellulose feedstocks.
Lignocellulosic biomass resource has been widely used as a natural resource for the synthesis of biofuels and bio-based products through pre-treatment, saccharification and fermentation processes. In this review, we delve into the environmental implications of bioethanol production from the widely utilized lignocellulosic biomass resource. The focus of our study is the critical stage of pre-treatment in the synthesis process, which also includes saccharification and fermentation. By collecting scientific data from the available literature, we conducted a comprehensive life cycle analysis. Our findings revealed substantial differences in the environmental burdens associated with diverse pre-treatment methods used for lignocellulosic biomass. These results highlight the importance of selecting environmentally benign pre-treatment techniques to promote the sustainability of bioethanol production. Future research directions are suggested, emphasizing the optimization of pre-treatment processes to further mitigate their environmental impact.


COVID-19: A review of therapeutic strategies and vaccine candidates.
The world is engulfed by one of the most widespread and significant public health crises in decades as COVID-19 has become among the leading causes of death internationally. The novel SARS-CoV-2 coronavirus which causes COVID-19 has unified the scientific community in search of therapeutic and preventative solutions. The top priorities at the moment are twofold: first, to repurpose already-approved pharmacologic agents or develop novel therapies to reduce the morbidity and mortality associated with the ever-spreading virus. Secondly, the scientific and larger pharmaceutical community have been tasked with the development, testing, and production of a safe and effective vaccine as a longer-term solution to prevent further spread and recurrence throughout the populace. The purpose of this article is to review the most up-to-date published data regarding both the leading pharmacological therapies undergoing clinical trials and vaccine candidates in development to stem the threat of COVID-19.


Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines.
Activation of the MEK/ERK/MAP kinase signaling pathway promotes the proliferation and survival of hematopoietic cells. The kinases MEK-1, MEK-2, ERK-1/MAPK and ERK-2/MAPK are activated by phosphorylation at specific sites, and these events can be monitored using phospho-specific antibodies. In this report we examined the importance of the MEK/ERK/MAP kinase pathway in the monocytic and granulocytic differentiation of myeloid cell lines. Induction of monocytic differentiation in HL-60 cells by treatment with phorbol 12-myristate 13-acetate (PMA) led to rapid and sustained activation of MEK-1/-2, ERK-1/MAPK and ERK-2/MAPK, while induction of granulocytic differentiation by retinoic acid (RA) caused similar activation of MEK-1/-2 and ERK-2/MAPK, but not ERK-1/MAPK. The total levels of these kinases were not affected during the course of differentiation along either pathway. Pretreatment of cells with 5 microM of the MEK-1/-2-specific inhibitor U0126 abrogated PMA- or RA-induced activation of ERK-1/MAPK and ERK-2/MAPK. Importantly, pretreatment of HL-60 cells with U0126 was found to potently inhibit both monocytic and granulocytic differentiation, as assessed by cytochemical staining for non-specific esterase or nitroblue tetrazolium reduction, flow cytometric analysis of myeloid surface markers, and immunoblotting for the cell cycle inhibitor p21 WAF1/Cip1. Similar results were seen in U937 cells, where U0126 inhibited PMA-induced monocytic differentiation, and in 32D cells, where G-CSF-induced granulocytic differentiation was inhibited by U0126 pretreatment. Additional experiments revealed that inhibition of MEK-1/-2 in HL-60 cells resulted in nearly complete inhibition of differentiation-induced cell death during monocytic differentiation. By contrast, U0126 only partially inhibited cell death resulting from granulocytic differentiation. Taken together, our findings demonstrate that the MEK/ERK/MAP kinase signaling pathway is activated, and plays a critical role, during both monocytic and granulocytic differentiation of myeloid cell lines.


Molecular cloning and characterization of a major allergen (Myr p I) from the venom of the Australian jumper ant, Myrmecia pilosula.
Five IgE-binding components were identified in the venom of the Australian jumper ant, Myrmecia pilosula using SDS polyacrylamide gel electrophoresis and Western blotting. A cDNA clone which encodes the entire amino acid sequence of one of the major IgE-binding venom allergens has been nucleotide sequenced. The IgE-binding determinants of this allergen are located in its C-terminal domain. Database searches, however, did not reveal any homology with any other known nucleotide or protein sequence. The sequenced allergenic polypeptide has, according to the convention recommended by the International Union of Immunological Societies (IUIS), been named Myr p I.


Thin-layer chromatography of chlorinated catechols.
The thin-layer chromatography of catechol and six chlorinated catechols has been studied on five adsorbents. Acetic acid in the developing solvent was essential for the production of sharp zones. The best separation of the individual compounds occurred on alumina, whereas silica gel appeared to be good for group separation (clean-up) from other compounds.


Evaluation of maize/peanut intercropping effects on microbial assembly, root exudates and peanut nitrogen uptake.
Legume/cereal intercropping has been widely studied within ecosystem function, owing to its overyield potential, predominantly by dinitrogen (N2) fixation. In our 2-year peanut/maize intercropping field experiment, land equivalent ratio (LER) showed an average yield-increase by 41.48%. Performance index of intercropped peanut (IP) functional leaves exhibited significant improvement (2.02-fold). Moreover, IP increased dry nodule weight by 58.82% as compared to mono-cropped. Also, the ratio of nodules to aboveground biomass in IP reduced by 65.8%. In pot experiment, higher urease activity was found in rhizosphere (22.73%). The abundance of Rhizobium and niƒH gene in the rhizosphere of IP were significantly enhanced by 71.91% and 208%, respectively. To analyze root exudates, we performed hydroponic coculture, the proportion of total isoflavonoids in peanut root exudates were increased distinctly by 22.4%. Our findings certainly helped in filling one the information gaps, that how intercropping increases nitrogen fixation in rhizosphere. Lastly, it can further facilitate to understand functional significance of intercropping system for agricultural ecological sustainability and efficient resource utilization.


Effectiveness of integrated interpretation of exome and corresponding transcriptome data for detecting splicing variants of genes associated with autosomal recessive disorders.
Part of the weakness of exome analysis lies in the inability to detect aberrant splicing. An evaluation of the post-splicing mRNA sequence concurrently with genomic variants could improve the diagnostic rate. We aimed to investigate publicly available exome sequencing data and its matching transcriptomics data of phenotypically normal individuals to identify alternatively spliced variants from known genes associated with autosomal recessive disorders under the premise that some of the subjects could be carriers of such disorders. Aberrant splicing events and their triggering genomic variants were detected with the aid of Bayesian network method "SAVNet" which was originally developed for cancer genomics. Forty aberrant splicing events including exon skipping, the creation of a new splice site, and the use of a cryptic splice site in response to the disruption of the authentic site were detected in 1916 genes among 31 of the 179 subjects from the 1000 Genomes Project. The predicted effects on proteins were either frameshift mutations (30) or large in-frame insertions or deletions (10). Five missense mutations and 2 silent mutations were reinterpreted as triggering major changes in transcript sequences. The detection rate of provisionally truncating pathogenic variants increased by 19%, compared with a conventional exome analysis. The coupling interpretation of exome and transcriptome data enhances the performance of conventional exome analyses through the proper interpretation of intronic variants that are outside of the GT/AG splicing consensus sequences and also allows the reinterpretation of "missense" or "silent" substitutions that can indeed have drastic effects on splicing.


Efficient inhibition of endogenous peroxidase without antigen denaturation in immunohistochemistry.
The immunoperoxidase technique is commonly used for the antigenic characterization of cells and tissues. However, the occurrence of endogenous peroxidase-positive cells frequently complicates such evaluations. In some instances it is impossible to distinguish between these cells and antibody-stained cells. Methods so far described for inhibiting the endogenous peroxidase, are not always satisfactory - either the endogenous peroxidase is not satisfactorily blocked, or the cellular antigens lose their reactivity. A new two-step method is described which involves transient inhibition of endogenous peroxidase by sodium azide and hydrogen peroxide and a final blocking of this enzyme by lowering the pH to 2.3, while antigens remain undamaged. This method may be of value in immunohistochemical studies of various tissues, especially inflammatory tissues which contain many endogenous peroxidase-positive cells.


Calibration and functional analysis of three genetically encoded Cl(-)/pH sensors.
Monitoring of the intracellular concentrations of Cl(-) and H(+) requires sensitive probes that allow reliable quantitative measurements without perturbation of cell functioning. For these purposes the most promising are genetically encoded fluorescent biosensors, which have become powerful tools for non-invasive intracellular monitoring of ions, molecules, and enzymatic activity. A ratiometric CFP/YFP-based construct with a relatively good sensitivity to Cl(-) has been developed (Markova et al., 2008; Waseem et al., 2010). Recently, a combined Cl(-)/pH sensor (ClopHensor) opened the way for simultaneous ratiometric measurement of these two ions (Arosio et al., 2010). ClopHensor was obtained by fusion of a red-fluorescent protein (DsRed-monomer) to the E(2)GFP variant that contains a specific Cl(-)-binding site. This construct possesses pK a = 6.8 for H(+) and K d in the 40-50 mM range for Cl(-) at physiological pH (~7.3). As in the majority of cell types the intracellular Cl(-) concentration ([Cl(-)] i ) is about 10 mM, the development of sensors with higher sensitivity is highly desirable. Here, we report the intracellular calibration and functional characterization of ClopHensor and its two derivatives: the membrane targeting PalmPalm-ClopHensor and the H148G/V224L mutant with improved Cl(-) affinity, reduced pH dependence, and pK a shifted to more alkaline values. For functional analysis, constructs were expressed in CHO cells and [Cl(-)] i was changed by using pipettes with different Cl(-) concentrations during whole-cell recordings. K d values for Cl(-) measured at 33°C and pH ~7.3 were, respectively, 39, 47, and 21 mM for ClopHensor, PalmPalm-ClopHensor, and the H148G/V224L mutant. PalmPalm-ClopHensor resolved responses to activation of Cl(-)-selective glycine receptor (GlyR) channels better than did ClopHensor. Our observations indicate that these different ClopHensor constructs are promising tools for non-invasive measurement of [Cl(-)] i in various living cells.


Long-term effect of phacoemulsification on intraocular pressure after trabeculectomy.
To evaluate the effect of temporal clear corneal phacoemulsification on intraocular pressure (IOP) in eyes that have had trabeculectomy. Department of Ophthalmology, University of Vienna, Vienna, Austria. This retrospective study evaluated the IOP in 48 eyes (35 patients) that had temporal clear corneal phacoemulsification after trabeculectomy. The mean interval between trabeculectomy and phacoemulsification was 27 months +/- 21 (SD) and the mean follow-up after phacoemulsification, 23 +/- 12 months. Intraocular pressure and antiglaucoma therapy before cataract surgery and at the end of follow-up were evaluated. For statistical analysis, the paired t test, Wilcoxon test, and chi-square test were used. Thirty-five eyes (73%) preoperatively and 25 eyes (52%) postoperatively were controlled (IOP < 22 mm Hg) without antiglaucoma therapy. The difference was statistically significant (P =.04, chi-square test). At the end of follow-up, the increase in mean IOP (1.6 mm Hg) and in mean number of antiglaucoma medications (0.4) was statistically significant (P =.002 and P =.05, respectively). Temporal clear corneal phacoemulsification after trabeculectomy was followed by a slight but statistically significant increase in IOP and the need for antiglaucoma medication after 2 years. However, the impairment in IOP control is comparable to that in the natural course of trabeculectomy.


Antibacterial, antibiofilm and anticaries effect of BioXtra® mouthrinse for head and neck cancer (HNC) patients under a microcosm biofilm model.
Considering the lack of studies investigating salivary substitutes to control post-radiation caries for patients with head and neck cancer (HNC), this study aimed to evaluate the antibacterial, antibiofilm, and anticaries effects of BioXtra® on the microcosm biofilm formed on different enamel types (non-irradiated and irradiated) and from distinct saliva sources (control and HNC patients). Non-irradiated and irradiated enamel specimens were treated with BioXtra®, phosphate-buffered-saline (PBS; negative control), or 0.12% chlorhexidine (CHX; positive control) for 1 min. Biofilm was produced from human saliva (healthy participants with normal salivary flow for the control group or irradiated HNC patients with hyposalivation for the HNC group), mixed with McBain saliva, under 0.2% sucrose exposure, daily submitted to the treatments (1 min), for 5 days. Bacterial metabolic activity, biofilm viability, CFU counting, and enamel demineralization were determined. BioXtra® significantly reduced the bacterial metabolic activity for both enamel types and the inoculum sources, being more effective for the irradiated enamel or for the saliva from the control group. Similarly, BioXtra® significantly reduced the biofilm viability, the CFU for total microorganisms, mutans streptococci, and lactobacilli, and was able to significantly reduce the mineral loss and the lesion depth compared to PBS. CHX was an effective treatment to significantly reduce all parameters, performing better than BioXtra® and reinforcing its reliable efficiency as a positive control. Regardless of the enamel type and the inoculum source, BioXtra® presented antibacterial, antibiofilm, and anticaries effects under this experimental model, which should be confirmed in further clinical studies.


Correlates of psychological care strategies for people with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study.
To assess the ways in which healthcare professionals address psychological problems of adults with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study. Approximately 120 primary care physicians, 80 diabetes specialists and 80 nurses and dietitians providing diabetes care participated in each of 17 countries (N=4785). Multiple regression analyses were used to evaluate independent statistically significant associations of respondent attributes concerning psychological care strategies, including assessment of diabetes impact on the patient's life, assessment of depression, provision of psychological assessment and support, and coordination with mental health professionals. Psychological care strategies were positively associated with each other but differed by healthcare practice site and discipline; nurses and dietitians were less likely to assess depression than other healthcare professionals, while primary care physicians were less likely to coordinate with mental health specialists or ask patients how diabetes affects their lives. Psychological care was positively associated with healthcare professionals' beliefs that patients need help dealing with emotional issues and that clinical success depends on doing so, and also with level of psychological care training, multidisciplinary team membership and availability of resources for psychological care. There were significant between-country variations in psychological care strategies, before and after adjustment for individual-level factors, and significant country-by-covariate interactions for almost all individual-level factors investigated. Improvements in training and resources, recognition and assessment of psychological problems, and increased belief in the efficacy of psychological support may enhance healthcare professionals' efforts to address psychological problems in adults with diabetes.


Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins.
The voltage-gated sodium channel isoform NaV1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1-1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting NaV1.7.


No changes in myocardial perfusion following radiation therapy of left-sided breast cancer: A positron emission tomography study.
Adjuvant radiation therapy (RT) for breast cancer has improved overall survival. However, incidental exposure of the heart has been linked to development of radiation-induced heart disease. The aim of this study was, in a cohort of asymptomatic post-irradiation breast cancer patients, to investigate changes in myocardial blood flow (MBF) and presence of perfusion defects in myocardial perfusion positron-emission-tomography (PET) in the irradiated myocardium. Twenty patients treated with RT for left-sided breast cancer underwent 13N-ammonia myocardial perfusion PET 7(± 2) years after breath adapted RT to a total dose of 48 Gy given in 24 fractions. No differences in rest or stress MBF were noted between the irradiated and non-irradiated myocardium (1.29 (± 0.29) vs 1.33 (± 0.29) mL/g/min, ns; 2.74 (± 0.59) vs 2.78 (± 0.66) mL/g/min, ns, respectively). One patient demonstrated a myocardial perfusion defect localized in the irradiated anterior wall myocardium. Although limited by a small sample size, early signs of cardiac injury detected by NH3 myocardial perfusion PET was at least not frequent in our cohort of patients treated with a modern RT technique for left-sided breast cancer, even 7 years after treatment. The findings however, may not rule out subsequent development of myocardial injury.


Reviewing the recent advances in application of pectin for technical and health promotion purposes: From laboratory to market.
Pectin is natural biopolymer derived from various plant sources and its activity is driven by functional groups. Affinity of pectin and chemical interactions of the active sites to chemicals in media determines fate of adjuvant molecules. Pectin is appropriate co-polymer in modulation of drawbacks of other biopolymers such as low glass transition temperature, low water solubility, and susceptibility to human digestive tract. However, functionality of pectin is improved by its optimized complexation with other chemicals especially in food packaging and tissue engineering. In the last decade, several technical and health-related functions of pectin have been studied through which some products designed and marketed progressively. Pectin-based formulations were commercialized in food, medicine, and radioprotection sectors. It is also advised for alleviation of constipation symptoms. Cost-effectiveness of this multifunctional biopolymer compared to the others that are currently used, has introduced it as a potential alternative for the next years.


Adjuvant-enhanced antibody and cellular responses to inclusion bodies expressing FhSAP2 correlates with protection of mice to Fasciola hepatica.
Fasciola hepatica saposin-like protein-2 (FhSAP2) is a protein differentially expressed in various developmental stages of F. hepatica. Recombinant FhSAP2 has demonstrated the induction of partial protection in mice and rabbits when it is administered subcutaneously (SC) in Freund's adjuvant. Because FhSAP2 is overexpressed in bacteria in the form of inclusion bodies (IBs), we isolated IBs expressing FhSAP2 and tested their immunogenicity when administered SC in mice emulsified in two different adjuvants: QS-21 and Montanide TM ISA720. Animals received three injections containing 20 μg of protein two weeks apart and 4 weeks after the third injection, mice were infected with 10 F. hepatica metacercariae by oral route. The percentages of protection induced by FhSAP2-IBs were estimated to be between 60.0 and 62.5% when compared with adjuvant-vaccinated, infected controls. By determining the levels of IgG1 and IgG2a antibodies and IL-4 and IFNγ cytokines in the serum of experimental animals, it was found that both Th1 and Th2 immune responses were significantly increased in the FhSAP2-IBs vaccinated groups compared with the adjuvant-vaccinated, infected control groups. The adjuvant-vaccinated groups had significantly lower IgG1 to IgG2a ratios and lower IL-4 to IFNγ ratios than the FhSAP2-IBs vaccinated animals, which is indicative of higher levels of Th2 immune responses. Irrespective to the adjuvant used, animals vaccinated with FhSAP2-IBs exhibited significantly higher survival percentage and less liver damage than the adjuvant-control groups. This study suggests that FhSAP2 has potential as vaccine against F. hepatica and that the protection elicited by this molecule could be linked to a mechanism driven by the CD4-Th1 cells.


Relationship between the inhibition of receptor-induced increase in cytosolic free calcium concentration and the vasodilator effects of nitrates in patients with congestive heart failure.
Nitroglycerin, isosorbide dinitrate and sodium nitroprusside, like nifedipine, were found to inhibit the receptor-provoked increase of cytosolic free calcium concentration in human platelets loaded with 2-[(2-amino-5-methylphenoxy)methyl]-6-methoxy-8-aminoquinoline-N,N,N',N' - tetraacetate. Sodium nitroprusside and nitroglycerin induced elevation of cyclic guanosine 3',5'-monophosphate content in platelets which correlated with their calcium-blocking activity. Methylene blue and epinephrine decreased the calcium-blocking effect and the influence of nitroglycerin on cyclic guanosine 3'-5'-monophosphate content, but failed to suppress the inhibitory effect of sodium nitroprusside. Ascorbic acid increased the calcium blocking effect of sodium nitroprusside and its influence on cyclic guanosine 3'-5'-monophosphate content, but did not alter the inhibitory effect of nitroglycerin. In order to evaluate the relationship between the mode of action of nitrates at cellular level and their vasodilatory effectiveness, we studied the circulatory response of the forearm to isosorbide dinitrate and the influence of nitroglycerin on free calcium concentration in the platelets in 10 patients with chronic heart failure. We established a significant positive correlation between the basal values for venous tone and its peak decrease after administration of the 10-mg dose of isosorbide dinitrate. A correlation was also found between the deviation of maximal decrease of venous tone by this dose of isosorbide dinitrate from the regression line (the relationship between the basal venous tone and its lowering by the drug) and mean inhibitory concentration values for nitroglycerin in blocking that proportion of the rise of calcium ion concentration in platelets due to blocking of the platelet-activating factor. Thus, nitrates, like calcium antagonists, inhibit the receptor-provoked calcium supply to the contractile system of the cells so neutralizing the effects of increased concentrations of vasoconstrictors. This suggests that the effectiveness of nitrates appears to be positively related to the contribution of receptor-induced increase of cytosolic free calcium concentration in vasoconstriction together with their capacity to raise cyclic guanosine 3',5'-monophosphate.


Sex differences in clinical characteristics, management, and outcomes in patients admitted for ventricular tachycardia: 2016-2018.
The concurrent data on sex disparities in VT management and outcomes have remained unclear. Therefore, our objective was to determine the impact of sex on ventricular tachycardia (VT) management and outcomes in patients admitted with VT, dervied from the US National Inpatient Sample database (NIS). We used data from the US NIS to identify hospitalized adult patients who were admitted with VT between 2016 and 2018. Regression analysis was conducted to evaluate the impact of sex on VT management, in-hospital mortality, complications, length of stay, and hospitalization costs. Of the database, a total of 146 070 patients, who were primarily hospitalized for VT, were approximated. Among these, women comprised 25.5%; they were significantly younger and had fewer comorbidities. Of procedural aspects, women were less likely to receive an angiogram, mechanical support, implantable cardioverter-defibrillator implantation, and VT ablation compared to men. Notably, women were associated with higher do-not-resuscitate rates and in-hospital cardiac arrests than men. No differences in in-hospital mortality and cardiogenic shock were observed between men and women (p > .05). Length of stay was significantly longer for women, while no differences in hospital costs were observed in both sexes. Significant sex disparities in management and outcomes were observed in admitted patients with VT. Our results reflect the need for further studies to explore factors causing such diversities.


Experience with combined video-assisted thoracoscopic surgery (VATS) anterior spinal release and posterior spinal fusion in Scheuermann's kyphosis.
Retrospective. To determine whether anterior endoscopic release and posterior spinal fusion could achieve stable correction in Scheuermann's kyphosis. The initial treatment of choice of Scheuermann's kyphosis is thoracic hyperextension and postural exercises and/or Milwaukee brace. Milwaukee bracing is most efficacious in the early stages when the curvature is flexible and in the skeletally immature. However, it is known that larger curves, vertebral wedging greater than 10 degrees, and skeletally mature patients will not usually respond to this treatment. Surgery is indicated in the skeletally immature with severe deformity where brace treatment has failed to prevent progression. Posterior spinal instrumentation can achieve adequate correction in the less rigid curves. However, the more rigid curves have been shown to be resistant to posterior spinal fusion alone, therefore needing anterior spinal release. Between 1995 and 2001, 19 patients underwent video-assisted thoracoscopic surgery and posterior spinal fusion for the treatment of Scheuermann's kyphosis. The average age was 17.4 years with closed triradiate cartilage in all. Average follow-up was 2.7 years. An average of 8.3 discs were released anteriorly; an average of 13 levels were fused posteriorly. Average preoperative kyphosis was 84.8 degrees. Average postoperative kyphosis was 43.7 degrees. Average kyphosis at follow-up was 45.3 degrees. Only 1.6 degrees of correction loss was noted. No junctional kyphosis was present. Two patients developed pleural effusion; one required thoracocentesis. Two patients developed pneumothorax. One patient underwent revision surgery for inferior hook pullout. One required mechanical ventilation. Combined video-assisted thoracoscopic surgery release and posterior spinal fusion for the treatment of Scheuermann's kyphosis is a viable option for the treatment of the more severe and rigid curves.


Evaluation of products upon the reaction of hypohalous acid with unsaturated phosphatidylcholines.
Myeloperoxidase released from stimulated neutrophils is able to produce hypochlorous and hypobromous acids. The composition of the reaction products of the interaction of hypohalous acid with double bonds of phosphatidylcholines was analysed by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry using reagents enriched in 16O, 18O, 35Cl, 37Cl, 79Br, or 81Br. Two different types of products were assigned according to the mass spectra. First, chlorohydrins as well as bromohydrins were formed whereby the oxygen introduced was derived from water as shown by using H2 16O or H2 18O. In the second product a hydrogen atom was replaced by a halogen. This was clearly evidenced by different mass shifts using chlorine or bromine isotopes and the lack of any effects by oxygen isotopes. These results are consistent with the view that two principal possibilities of stabilisation of pi-complexes formed after binding of Cl(+) or Br(+) to the pi-system of the double bond exist.


Progress in vaccination for histoplasmosis and blastomycosis: coping with cellular immunity.
Human infection with Histoplasma capsulatum or Blastomyces dermatitidis is sufficiently frequent to warrant exploring the development of vaccines. This review examines the advancements that have been accomplished over the last few years. The availability of molecular tools to create recombinant antigens or mutant strains has produced a small number of useful vaccine candidates. More importantly, the studies summarized herein demonstrate that understanding the host response to a protein or mutant fungus is critical to creating a vaccine that may be useful for the immunocompromised patient.


Scaphoid malunion. The significance of rotational malalignment.
Three patients with painful malunions of the scaphoid and significant loss of active wrist extension were treated with an opening wedge multiplanar osteotomy that corrected flexion, ulnar deviation, and pronatory rotational malalignment of the distal fragment. After a minimum follow-up of 4 years, all three patients were satisfied with the procedure and were pain-free. The preoperative range of wrist motion had improved, and they had returned to their preoperative occupations.


Anthropomorphising nature in times of crisis: A serial mediation model from connectedness to nature via anthropomorphism on support for COVID-19 travel restrictions.
The COVID-19 pandemic has resulted in widespread travel restrictions to reduce the spread of the virus. It is therefore necessary to understand factors that lead to support for these imposed travel restrictions. Given the reduced environmental impact (e.g., reduced pollution) resulting from travel restrictions, these restrictions can be viewed through a pro-environmental lens. This study aimed to examine the influence of the well-supported predictor of pro-environmental behaviour, connectedness to nature, on support for COVID-19 travel restrictions. To understand why connectedness to nature may predict support for travel restrictions, mediators of this relationship were examined. Anthropomorphism of nature is reasoned to accompany connectedness to nature, and can involve anthropomorphism in various forms (i.e., generalised, and context-specific anthropomorphism). This study (N=270) examined a mediation model whereby anthropomorphism of nature (general) and anthropomorphism of nature in COVID-19 (context-specific) were serial mediators of the relationship between connectedness to nature and support for travel restrictions. Individual pathways of the model were significant, as were the indirect effects, providing support for the serial mediation model, with these predictors accounting for 13% of the variance in support for COVID-19 travel restrictions. Implications of this research are discussed and include promotion of connectedness to nature as well as considering anthropomorphic message framing.


Drug utilization in a hospital general medical outpatient clinic with particular reference to antihypertensive and antidiabetic drugs.
To examine the prescribing patterns, particularly antihypertensive and antidiabetic drugs, in a hospital outpatient clinic and to evaluate the expenditure incurred. Prescriptions from a general medical outpatient clinic in a teaching hospital were collected for 4 weeks. Drug expenditures were calculated. A total of 622 prescriptions containing 1903 items were collected. Antihypertensive and antidiabetic drugs accounted for 25.9 and 9.1% usage, respectively. Calcium channel blocking agents, angiotensin converting enzyme inhibitors and beta-blocking agents were the most popular antihypertensive drugs used. Sulphonylureas were the most frequently prescribed antidiabetic agents. Amlodipine, doxazosin and sotalol accounted for 4.5% of all prescription items but 27.8% of the total drug expenditure. The use of antihypertensive and antidiabetic drugs accounted for most of the drug usage in this study. Use of newer and more expensive agents has further increased drug expenditure. Monitoring drug usage and their correlations with clinical outcomes are warranted.


The efficiency of different IRESs (internal ribosomes entry site) in monocistronic mRNAS.
The IRES from poliovirus and from encephalomyocarditis virus (EMCV) added between the cap and the AUG initiator codon were strong inhibitors of chloramphenicol acetyltransferase gene expression in three different cell types. The poliovirus IRES also inhibited bGH (bovine growth hormone) cDNA expression in the HC11 mammary cell line when added between the rabbit whey acidic gene promoter and the cDNA whereas the HTLV-1 IRES showed a stimulatory effect in the same situation. RNA stem loops were added before HTLV-1 (SUR) and the BiP (Immunoglobulin heavy-chain Binding Protein) IRESs followed by the firefly luciferase gene under the control of Rous sarcoma virus (RSV) promoter. The RNA loops abolished the expression of the reporter gene almost completely. These data suggest that the different IRESs may favour or inhibit translation of monocistronic mRNA.


Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle.
The purpose of this study was to simultaneously isolate skeletal muscle plasma and microsomal membranes from the hind limbs of male Sprague-Dawley rats perfused either in the absence or presence of 20 milliunits/ml insulin and to determine the effect of insulin on the number and distribution of glucose transporters in these membrane fractions. Insulin increased hind limb glucose uptake greater than 3-fold (2.4 +/- 0.7 versus 9.2 +/- 1.0 mumol/g x h, p less than 0.001). Plasma membrane glucose transporter number, measured by cytochalasin B binding, increased 2-fold (9.1 +/- 1.0 to 20.4 +/- 3.1 pmol/mg protein, p less than 0.005) in insulin-stimulated muscle while microsomal membrane transporters decreased significantly (14.8 +/- 1.6 to 9.8 +/- 1.4 pmol/mg protein, p less than 0.05). No change in the dissociation constant (Kd approximately 120 nm) was observed. K+-stimulated-p-nitrophenol phosphatase, 5'-nucleotidase, and galactosyltransferase specific activity, enrichment, and recovery in the plasma and microsomal membrane fractions were not altered by insulin treatment. Western blot analysis using the monoclonal antibody mAb 1F8 (specific for the insulin-regulatable glucose transporter) demonstrated increased glucose transporter densities in plasma membranes from insulin-treated hind limb skeletal muscle compared with untreated tissues, while microsomal membranes from the insulin-treated hind limb skeletal muscle had a concomitant decrease in transporter density. We conclude that the increase in plasma membrane glucose transporters explains, at least in part, the increase in glucose uptake associated with insulin stimulation of hind limb skeletal muscle. Our data further suggest that these recruited transporters originate from an intracellular microsomal pool, consistent with the translocation hypothesis.


Covalent cross-linking of tRNAGly1 to the ribosomal P site via the dihydrouridine loop.
The dihydrouracil residue at position 20 of Escherichia coli tRNAGly1 has been replaced by the photoaffinity reagent, N-(4-azido-2-nitrophenyl)glycyl hydrazide (AGH). The location of the substituent was confirmed by the susceptibility of the modified tRNA to cleavage with aniline. When N-acetylglycyl-tRNAGly1 derivatized with AGH was bound noncovalently to the P site of E. coli 70 S ribosomes, 5-6% on average was photochemically cross-linked to the ribosomal particles in a reaction requiring poly(G,U), irradiation and the presence of the AGH label in the tRNA. Approximately two-thirds of the covalently attached tRNA was associated with 16 S RNA in the 30 S subunit. This material was judged to be in the P site by the criterion of puromycin reactivity. As partial RNAase digestion of the tRNA-16 S RNA complex produced labeled fragments from both 5' and 3' segments of the rRNA, there appeared to be more than one site of cross-linking in the 30 S subunit. The small amount of N-acetylglycyl-tRNAGly1 associated with the 50 S subunit was also linked mainly to rRNA, but it was not puromycin-reactive.


Factors associated with problematic social media use among a sample of Lebanese adults: The mediating role of emotional intelligence.
To assess the relationship of smoking (cigarettes or waterpipe), alcohol drinking, alexithymia, self-esteem, anxiety, depression, stress, social phobia, emotional intelligence, impulsivity, insomnia, physical health, and loneliness with problematic social media use (PSMU) in a sample of Lebanese citizens. This cross-sectional study enrolled 466 participants (January-May 2019). Higher anxiety, alcohol use disorder, and social phobia were correlated with elevated PSMU, while older age was associated with lower PSMU. Emotional intelligence partially mediated the association between alexithymia and PSMU by 4.55%. Since these manifestations are preventable, spreading awareness through our schools, educational programs, and even healthcare professionals would considerably reduce the pace at which young adults are transforming into anxious and distorted individuals.


Effect of 6-phosphogluconate on phosphoglucose isomerase in rat brain in vitro and in vivo.
The activity of phosphoglucose isomerase, its kinetic properties, and the effect of 6-phosphogluconate on its activity in the forward (glucose 6-phosphate----fructose 6-phosphate) and the reverse (fructose 6-phosphate----glucose 6-phosphate) reactions were determined in adult rat brain in vitro. The activity of phosphoglucose isomerase (in nmol/min/mg of whole brain protein) was 1,865 +/- 20 in the forward reaction and 1,756 +/- 32 in the reverse reaction at pH 7.5. It was 1,992 +/- 28 and 2,620 +/- 46, respectively, at pH 8.5. The apparent Km and Vmax of phosphoglucose isomerase were 0.593 +/- 0.031 mM and 2,291 +/- 61 nmol/min/mg of protein, respectively, for glucose 6-phosphate and 0.095 +/- 0.013 mM and 2,035 +/- 98 nmol/min/mg of protein, respectively, for fructose 6-phosphate. The activity of phosphoglucose isomerase was inhibited intensely and competitively by 6-phosphogluconate, with an apparent Ki of 0.048 +/- 0.005 mM for glucose 6-phosphate and 0.042 +/- 0.004 mM for fructose 6-phosphate as the substrate. With glucose 6-phosphate as the substrate, at concentrations from 0.05 to 0.5 mM, the activity of the enzyme was inhibited completely in the presence of 0.5-2.0 mM 6-phosphogluconate. With 0.05-0.2 mM fructose 6-phosphate as the substrate, it was inhibited greater than or equal to 85% at the same concentrations of the inhibitor. No significant changes were observed in the values of Km, Vmax, and Ki for phosphoglucose isomerase in the brain of 6-aminonicotinamide-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Enhanced photocatalytic performance of auto-combusted nanoparticles for photocatalytic degradation of azo dye under sunlight illumination and hydrogen fuel production.
In this study, an innovative nanomaterial was synthesized for hydrogen production from methanolysis on sodium borohydride (NaBH4) in order to be a solution for future energy problems. The nanocomposite containing FeCo, which does not contain noble metals, and whose support material is Polyvinylpyrrolidone (PVP), was synthesized by means of a thermal method. TEM, XRD and FTIR characterization methods were used for the analysis of the morphological and chemical structure of the nanocomposite. Nanocomposite particle size was found to be 2.59 nm according to XRD analysis, and 5.45 nm according to TEM analysis for scale of 50 nm. For catalytic properties of nanomaterial in the methanolysis reaction of NaBH4, temperature, catalyst, substrate, and reusability experiments were carried out and kinetic calculations were obtained. Among the activation parameters of FeCo@PVP nanoparticles, turnover frequency, enthalpy, entropy and activation energy were calculated as 3858.9 min-1, 29.39 kJ/mol, -139.7 J/mol.K, and 31.93 kJ/mol, respectively. As a result of the reusability test of the obtained FeCo@PVP nanoparticles catalysts, which was carried out for 4 cycles, the catalytic activity was 77%. Catalytic activity results are given in comparison with the literature. In addition, the photocatalytic activity of FeCo@PVP NPs was evaluated against MB azo dye under solar light irradiation for 75 min and was found to be as 94%.


Pathways framework identifies wildfire impacts on agriculture.
Wildfires are a growing concern to society and the environment in many parts of the world. Within the United States, the land area burned by wildfires has steadily increased over the past 40 years. Agricultural land management is widely understood as a force that alters fire regimes, but less is known about how wildfires, in turn, impact the agriculture sector. Based on an extensive literature review, we identify three pathways of impact-direct, downwind and downstream-through which wildfires influence agricultural resources (soil, water, air and photosynthetically active radiation), labour (agricultural workers) and products (crops and livestock). Through our pathways framework, we highlight the complexity of wildfire-agriculture interactions and the need for collaborative, systems-oriented research to better quantify the magnitude of wildfire impacts and inform the adaptation of agricultural systems to an increasingly fire-prone future.


[Heart function studies under stress in hypertonic patients with and without ischemic heart disease].
Recently in patients with hypertension in one third of the cases by haemodynamic investigations in rest a latent heart insufficiency could be proved. It was the aim of the at present performed examinations to test, whether or in which degree the proportion of latent heart insufficiency increases in patients with hypertension affected. In 30 patients with essential hypertension a complex haemodynamic examination program consisting of catheterisation of the right heart, radiocardiography and ergometry was carried out. It could be demonstrated that complex examinations of such a kind are possible also under physical stress and may be used in the judgment of the cardiac function in patients with hypertension.


Engineering-geological comparative analysis of four cases studies of waste landfills.
The aim of the paper is to carry out a comparative engineering-geological study of four different waste landfills using the evaluation criteria for the geological subsoil as a natural sealing barrier. The study evaluates 4 localities (Velké Pavlovice, Kvítkovice, Prakšice and Horní Suchá) using three variants (based on two standards) which approach the geological barrier requirements as a combination of impermeability requirements based on a filtration coefficient limit value. and the required geometry represented by investigation depths. The research was carried out in landfills in Moravia, in the east of the Czech Republic. The study's motivation is to point at the differences in engineering-geological investigations of waste landfills (as for the requirements for impermeable geological subsoil as a natural sealing barrier) when compared with other engineering structures (where the main goal is to evaluate load-bearing capacity and settlement). The purpose of the geological barrier is to prevent the spread of contamination, and the paper shows this can be approached differently, as shown in two different methodologies investigated herein. The first model (Model 1) assumes there is a 3-m-thick subsoil below the landfill's footing bottom, which manifests impermeability characterized by the filtration coefficient Kf ≤ 1.0 * 10-9 m/s, or a 30-m-thick subsoil of Kf ≤ 1.0 * 10-8 m/s. The second model (Model 2) assumes a 1-m thick, impermeable subsoil massif of Kf ≤ 1.0 * 10-9 m/s. We found that none of the landfills in the four selected localities had an impermeable layer in the required depth (a filtration coefficient Kf from 1.8 * 10-9 to 3.9 * 10-9 m/s), and thus did not comply with the limiting conditions. As a result, an anthropogenic technical barrier had to be installed. An important goal of the study from an environmental point of view was to assess the existence of a suitable geological barrier under the proposed landfills. The most important criterion from this point of view is permeability. An additional technical objective of the project was also the assessment of the possible creation of a technical anthropogenic isolation barrier. In the event that the natural sealing barrier would not be sufficient. This was shown in all solved case studies of engineering geological investigations of waste landfills.


Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study.
To assess the safety and effectiveness of eflornithine as first line treatment for human African trypanosomiasis. Cohort study. Control programme in Ibba, southern Sudan. 1055 adults and children newly diagnosed with second stage disease in a 16 month period. Deaths, severe drug reactions, and cure at 24 months. 1055 patients received eflornithine for 14 days (400 mg/kg/day in adults and 600 mg/kg/day in a subgroup of 96 children). Overall, 2824 drug reactions (2.7 per patient) occurred during hospital stay, 1219 (43.2%) after the first week. Severe reactions affected 138 (13.1%) patients (mainly seizures, fever, diarrhoea, and bacterial infections), leading to 15 deaths. Risk factors for severe reactions included cerebrospinal fluid leucocyte counts > or =100x10(9)/l (adults: odds ratio 2.6, 95% confidence interval 1.5 to 4.6), seizures (adults: 5.9, 2.0 to 13.3), and stupor (children: 9.3, 2.5 to 34.2). Children receiving higher doses did not experience increased toxicity. Follow-up data were obtained for 924 (87.6%) patients at any follow-up but for only 533 (50.5%) at 24 months. Of 924 cases followed, 16 (1.7%) died during treatment, 70 (7.6%) relapsed, 15 (1.6%) died of disease, 403 (43.6%) were confirmed cured, and 420 (45.5%) were probably cured. The probability of event free survival at 24 months was 0.88 (0.86 to 0.91). Most (65.8%, 52/79) relapses and disease related deaths occurred after 12 months. Risk factors for relapse included being male (incidence rate ratio 2.42, 1.47 to 3.97) and cerebrospinal fluid leucocytosis: 20-99x10(9)/l (2.35, 1.36 to 4.06); > or =100x10(9)/l (1.87, 1.07 to 3.27). Higher doses did not yield better effectiveness among children (0.87 v 0.85, P=0.981). Conclusions Eflornithine shows acceptable safety and effectiveness as first line treatment for human African trypanosomiasis. Relapses did occur more than 12 months after treatment. Higher doses in children were well tolerated but showed no advantage in effectiveness.


On a novel chromanone-naphthalenetrione rearrangement related to vitamin E.
4-Oxo-alpha-tocopherol (7) was synthesized in an efficient three-step procedure starting from alpha-tocopheryl acetate (1b) and rearranged under physiological conditions into naphthalenetrione 4, a minor vitamin E metabolite. The rearrangement involves a [4 + 2]-cycloaddition as the key step. [reaction: see text]


Efficacy of ripasudil in reducing intraocular pressure and medication score for ocular hypertension with inflammation and corticosteroid.
To investigate the efficacy of ripasudil, a Rho kinase inhibitor, in reducing intraocular pressure (IOP) and medication scores of anti-glaucoma drugs in patients with ocular hypertension with inflammation and corticosteroid. The study included 11 patients diagnosed with ocular hypertension with inflammation and corticosteroid, all of whom were prescribed ripasudil eye drops and followed up for at least 2y after the initiation of treatment. IOP was measured using a non-contact tonometer before enrollment and at each follow-up visit. The medication score of glaucoma eye drops was calculated for each patient. The mean IOP (26.4±2.9 mm Hg before treatment) significantly decreased after ripasudil therapy (13.7±3.3 mm Hg at 3mo) and remained stable in the low-teens during the 2-year follow-up period (P<0.0001). A significant decrease in the medication score was observed at 12mo or later after the initiation of ripasudil therapy (P<0.05). Both baseline medication scores and glaucomatous optic disc change rates were significantly higher in the five eyes that required glaucoma surgery during the 2-year observation period than the 10 eyes that did not require surgery. Our results demonstrate the efficacy of ripasudil, in reducing IOP and the medication score over a 2-year treatment period in patients with ocular hypertension with inflammation and corticosteroid. Our findings also suggest that ripasudil could reduce the IOP in uveitic glaucoma patients with both lower baseline medication score and lower glaucomatous optic disc change rate.


Macular holes: vitreoretinal relationships and surgical approaches.
Idiopathic full-thickness macular holes develop as a result of anteroposterior and tangential traction exerted by the posterior vitreous cortex at the fovea. Vitreoretinal relationships during the development of macular holes can be demonstrated in detail by ocular coherence tomography, facilitating an improved understanding of their pathogenesis and guiding clinical management. Surgical strategies for the repair of macular holes are designed to relieve vitreofoveal traction and to promote flattening and reapposition of the macular hole edges by intraocular gas tamponade. A period of face-down positioning postoperatively is conventionally advised. However, the evidence to support this recommendation is weak and practice varies considerably. Surgical removal of the inner limiting membrane (ILM) is advocated to ensure thorough removal of any tangential tractional components including any residual cortical vitreous. Current evidence suggests that ILM peeling can improve anatomical outcomes but the effect on visual function is less predictable; unsuccessful attempts to peel the ILM can be associated with poor visual outcome. The use of vital dyes can facilitate visualisation of the ILM and help achieve complete, atraumatic peeling. Indocyanine green dye can enable high rates of macular hole closure but has been associated with poorer visual outcomes suggesting a dose-dependent toxicity. Trypan blue dye offers an alternative that may have a more favourable risk profile. An improved understanding of vitreoretinal relationships may facilitate a tailored approach to surgery in individuals with macular holes. Vitrectomy to relieve anteroposterior traction is central in the management of all full-thickness holes. The use of long-acting gases, prolonged face-down positioning, and ILM peeling may be more valuable for larger holes, longstanding holes, and those that have failed to close following conventional surgery.


Myosatellite cells associated with different muscle fibre types in the Atlantic hagfish (Myxine glutinosa, L.).
The incidence of myosatellite cells associated with "white" and "red" muscle fibres of the parietal muscle and "red" fibres of the craniovelar muscle was estimated by quantitative electron microscopy in the Atlantic hagfish (Myxine glutinosa, L.). Myosatellite cell nuclei constitute 3, 11 and 23% of the total number of nuclei inside the basal lamina of the three types of muscle fibres, respectively. However, the total number of nuclei is highest in "white" fibres, most of the nuclei belonging to striated muscle cells. Myosatellite cell profiles in transverse sections constitute 23, 41 and 61% of the number of muscle fibre profiles of the three types, respectively. The intervals between adjacent myosatellite cells are approximately 135 micrometer in "white" fibres, approximately 55 micrometer in "red" parietal fibres, and only approximately 25 micrometer in craniovelar fibres. Since craniovelar fibres are also comparatively thin, myosatellite cells constitute a significant fraction of the volume inside the basal lamina in these fibres. The myosatellite cells are approximately 30-50 micrometer long and up to 5 micrometer thick. Some myosatellite cells possess few organelles, whereas others appear to contain many free ribosomes, granular endoplasmic reticulum, prominent Golgi apparatus and lysosome-like bodies.


Author Correction: Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


The role of surgery in meningiomas involving the optic nerve sheath.
Clinical presentation, radiological appearance and treatment options of patients with optic nerve sheath meningiomas (ONSM) vary. To provide a baseline for treatment of this tumour entity a series of 24 patients with ONSM is presented. Clinical charts of the patients including surgical and histological records, imaging studies as well as meticulously focusing questionnaires of clinical outcome were reviewed. Twenty four patients with ONSM were treated at the Neurosurgical Department from 1981 to 2002. Mean age at diagnosis was 44 years (14-69) with a female:male ratio of 7:1. The preoperative duration of symptoms was negatively correlated with the preoperative visual acuity. The microsurgical approach consisted of pterional craniotomy, intra-/extradural subtotal excision of the meningioma and bony decompression of the optic canal. Surgical results showed low surgical morbidity and preserved or even improved vision in 8/16 patients (50%) all of whom had rapid visual decline preoperatively. In the long-term, visual loss occur again occurred due to recurrence in about 20% of cases. Microneurosurgery for treatment of ONSMs is still reserved for cases with intracranial extension, disfiguring proptosis and patients with rapid visual deterioration. Radiotherapy should be considered as treatment option in all other cases as it prolongs the time for functional vision in the affected eye with low morbidity.


Cervicovaginal fetal fibronectin testing in threatened preterm labour--translating research findings into clinical practice.
A retrospective audit was undertaken involving 70 women with a singleton pregnancy who attended hospital with symptoms of threatened preterm labour prior to 34 weeks' gestation and who had a bedside fetal fibronectin (FFN) Membrane Immunoassay Kit Test (Adeza Biomedical) performed. The aim of the study was to determine if the results of the FFN test when used in routine clinical practice would be similar to those of a previous research study (1) that was performed at the same centre, and whether or not knowledge of the result of the FFN test might influence clinical management. The audit revealed that the sensitivity of the FFN test in the prediction of delivery prior to 34 weeks' gestation was 90%, the specificity was 82%, whilst the positive and negative predictive values were 45% and 98% respectively. These results were very similar to those of the previous, blinded research study. Compared to women with a negative FFN test, more women with a positive FFN test received corticosteroids (100% versus 71%, p=0.02) and tocolysis (35% versus 12%, p=0.04) and more remained in hospital longer than 24 hours (85% versus 56%, p=0.1).


Effects of therapeutic exercise in primary dysmenorrhea: an umbrella and mapping review.
Primary dysmenorrhea (PD) is 1 of the most prevalent gynecologic conditions. The main aim of this umbrella review was to assess the effects of therapeutic exercise (TE) on PD. A systematic search was carried out in PubMed, Embase, SPORTDiscus, CINAHL, and PEDro (December 10, 2022). The outcome measures assessed were menstrual pain intensity, menstrual pain duration, and quality of life. Methodological quality was analyzed using the AMSTAR and ROBIS scales, and the strength of evidence was established according to the advisory committee grading criteria guidelines. Nine systematic reviews were included. The results showed that TE, regardless of the exercise model and intensity, has a clinical effect in improving menstrual pain intensity in women with PD with moderate quality of evidence. In addition, the results showed that TE has a clinical effect in improving the duration of menstrual pain in women with PD with a limited quality of evidence. However, the results are controversial on the improvement of quality of life in women with PD with a limited quality of evidence. TE seems an effective option to implement in women with PD to improve the intensity and duration of menstrual pain. We cannot draw robust results for quality of life due to the low number of primary studies. More research in this field can help us establish more robust conclusions, as well as to assess whether there is one exercise model or intensity of training that is more effective than others.PROSPERO number: This review was previously registered in PROSPERO (CRD42022371428).


Substance P immunoreactivity in the post-mortem parkinsonian brain.
The amount of substance P immunoreactivity (SPI) was measured by radioimmunoassay from the cerebral cortex, caudate nucleus, putamen, pallidum, substantia nigra, hypothalamus, nucleus accumbens, amygdala and hippocampus from autopsy brains. The whole material consisted of 42 parkinsonian patients and 31 controls. The amount of SPI was significantly decreased in the substantia nigra of the parkinsonian brain. There was also a significant decrease of SPI in the putamen of those parkinsonian patients, who had not received levoDOPA treatment. The levels of SPI in the other brain regions studied did not show any difference between parkinsonian patients and controls. The results obtained suggest that substance P (SP) may have a role in the pathophysiology of Parkinson's disease.


The efficacy and safety of a novel posterior scleral reinforcement device in rabbits.
To evaluate the efficacy and safety of posterior scleral reinforcement (PSR) device for myopia suppression in rabbits' eyes. PSR surgery was performed on the normal 12 8-week-old New Zealand white rabbits' right eyes. To determine efficacy of the device, ophthalmic examination would be taken at pre-operation and post-operation (1 week, 1 month, 3 months, 6 months, and 1 year), such as A-ultrasound, diopter and B-ultrasound. Evaluation of safety were based on the following indicators: intraocular pressure (IOP), slit lamp, fundus photography, fundus fluorescein angiography and pathological examination after surgery. The efficacy and safety of PSR device were evaluated by comparison (treated eyes and contralateral eyes) of pre and post-operation. The novel PSR device could significantly shorten axial length (preoperative axial length: 16.36 ± 0.14 mm, postoperative 1 week, 1 month, 3 months, 6 months and 1 year axial lengths: 15.03 ± 0.28 mm, 15.23 ± 0.32 mm, 15.39 ± 0.31 mm, 15.45 ± 0.22 mm and 15.45 ± 0.22 mm; P=0.00037<0.001) in the treated eyes (right eyes) after surgery. At different postoperative time points, the B-ultrasound images showed that the PSR located in appropriate position and supported the posterior sclera very well. At the same time, IOP of treated eyes kept a relatively stable level (preoperative IOP: 12.56 ± 2.01 mmHg, postoperative IOP: ranging from 11.33 ± 1.23 mmHg to 13.44 ± 2.19 mmHg, P>0.05) post-operation 1 year. During observation period, there was no significant inflammatory reaction and complications such as anterior chamber flare, empyema, endophthalmitis, vitreous hemorrhage, retina detachment and retinal choroid neovascularization by slit lamp, fundus photography and fundus fluorescein angiography. In addition, there were no pathologic changes be found by comparison treated eyes group and contralateral group eyes based on pathological examinations. In vivo study, effectively and safely, the novel PSR device can inhibit rabbits' axial length elongation during postoperative 1 year. This study demonstrates that this novel PSR could be a potential treatment approach for myopia.


Experimental research on emission and removal of dioxins in flue gas from a co-combustion of MSW and coal incinerator.
This paper describes the experimental study of dioxins removal from flue gas from a co-combustion municipal solid waste and coal incinerator by means of a fluidized absorption tower and a fabric filter. A test rig has been set up. The flow rate of flue gas of the test rig is 150-2000 m3/h. The system was composed of a humidification and cooling system, an absorption tower, a demister, a slurry make-up tank, a desilter, a fabric filter and a measurement system. The total height of the absorption tower was 6.5m, and the diameter of the reactor pool was 1.2 m. When the absorbent was 1% limestone slurry, the recirculation ratio was 3, the jet rate was 5-15 m/s and the submerged depth of the bubbling pipe under the slurry was 0.14 m, the removal efficiency for dioxins was 99.35%. The concentration of dioxins in the treated flue gas was 0.1573 x 10(-13)kg/Nm3 and the concentration of oxygen was 11%. This concentration is comparable to the emission standards of other developed countries.


Antagonism between wild-type and mutant β-catenin controls hepatoblastoma differentiation via fascin-1.
β-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway. Using an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APCKO and β-cateninΔexon3 mice). We used transcriptomic data from mouse and human HB specimens, and used immunohistochemistry to analyse samples. We highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs. Fascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB. The FSCN1 gene, encoding fascin-1, was reported to be a metastasis-related gene in various cancers. Herein, we uncover its expression in poor-prognosis hepatoblastomas, a paediatric liver cancer. We show that fascin-1 expression is driven by the mutated beta-catenin in liver tumour cells. We provide new insights on the impact of fascin-1 expression on tumour cell differentiation. We highlight fascin-1 as a marker of immature cells in mouse and human hepatoblastomas.


Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials.
Immune checkpoint inhibitors (ICIs) and genomic biomarker-driven targeted therapies have revolutionized the modern oncologic treatment arsenal. The next step has been to combine targeted agents and ICIs. In doing so, some combination regimens may be more logical than others. Whole-exome and whole-transcriptome sequencing were performed on 2739 unselected later-stage clinical cases from 24 solid tumor subtypes in the NantHealth database, and data were also curated from 5746 similarly sequenced patients across 28 solid tumor subtypes in The Cancer Genome Atlas (TCGA). Significant differential expression of 10 immunoregulatory molecules [IRMs (genes)] was analyzed for association with mutant versus wild-type genes. Twenty-three significant associations between currently actionable variants and RNA-expressed checkpoint genes were identified in the TCGA cases; 10 were validated in the external cohort of 2739 clinical cases from NantHealth (P values were adjusted using Benjamini-Hochberg multiple hypothesis correction to reduce false-discovery rate). Within the same 5746 TCGA profiles, 2740 TCGA patients were identified as having one or more potentially oncogenic single-nucleotide variant (SNV) mutation within an established 50-gene hotspot panel. Of the 50 genes, SNVs within 15 were found to be significantly associated with differential expression of at least one IRM after adjusting for tissue enrichment; six were confirmed significant associations in an independent set of 2739 clinical cases from NantHealth. Logically combining ICIs with targeted therapies may offer unique treatment strategies for patients with cancer. The presence of specific mutations impacts the expression of IRMs, an observation of potential importance for selecting combinations of gene- and immune-targeted therapeutics.


Molecular weight determination by scanning transmission electron microscopy.
A scanning transmission electron microscope is employed to determine the mass of biological macromolecules. Elastically scattered electrons are collected by an annular detector that is capable of counting single electrons. Off-line processing of these dark field micrographs stored on a magnetic tape is accomplished by a mini-computer. It allows the number of electrons scattered by spherical or filamentous proteins to be evaluated. The calibration factor relating the number of scattered electrons to the mass of the protein is derived from scattering theory and is experimentally determined from biological macromolecules of known mass. Mass-loss kinetics of biological specimens due to the electron beam are measured for various protein structures. The application of this method is illustrated by determination of the mass of an oligometric protein (major phage T4 head protein) and the mass per unit length of a filamentous protein aggregate (F-pili). The unique possibilities of this new technique as well as its limitations are discussed.


Identification, solubility enhancement and in vivo testing of a cyanide antidote candidate.
Present studies focused on the in vitro testing, the solubility enhancement and the in vivo testing of methyl propyl trisulfide (MPTS), a newly identified sulfur donor to treat cyanide (CN) intoxication. To enhance the solubility of the lipophilic MPTS, various FDA approved co-solvents, surfactants and their combinations were applied. The order of MPTS solubility in the given co-solvents was found to be the following: ethanol >> PEG 200 ≈ PEG400 ≈ PEG300 > PG. The maximum solubility of MPTS was found at 90% ethanol of 177.11 ± 12.17 mg/ml. The order of MPTS solubility in different surfactants is Cremophor EL>Cremophor RH40>polysorbate 80>sodium deoxycholate>sodium cholate. The maximum solubility of 40.99 mg/ml was achieved with 20% Cremophor EL. A synergistic solubilizing effect encountered with the combination of 20% Cremophor EL+75% ethanol lead to a 2900-fold increase (compared to water solubility) in solubility. The in vivo efficacy using intramuscular administration was determined on a therapeutic mice model and expressed as a ratio of CN LD50 with and without the test antidote(s) (APR). Intramuscular administration was shown to be effective and the therapeutic antidotal protection by MPTS alone and MPTS+thiosulfate (TS) was significantly higher than the present therapy of TS.


Utility of decellularised urinary bladder extracellular matrix in full mucosalisation of a post-oncological maxillectomy defect.
This report highlights the utility of MatriStem Surgical Matrix Thick UBM™ (rebranded as Gentrix® ACell, Inc), a decellularised urinary bladder extracellular matrix in the reconstruction of a post-oncological maxillectomy defect. In utilising this biological construct to serve as a biological dressing, our patient underwent complete mucosalisation of his surgical site without the development of an oroantral fistula and with adequate maxillary vestibule to allow for definitive oral rehabilitation with a removable partial denture.


Mechanical Bond Approach to Introducing Self-Adaptive Active Sites in Covalent Organic Frameworks for Zinc-Catalyzed Organophosphorus Degradation.
Mechanically interlocked molecules (MIMs) with discrete molecular components linked through a mechanical bond in space can be harnessed for the operation of molecular switches and machines, which shows huge potential to imitate the dynamic response of natural enzymes. In this work, rotaxane compounds were adopted as building monomers for the synthesis of a crown-ether ring mechanically intercalated covalence organic framework (COF). This incorporation of MIMs into open architecture implemented large amplitude motions, whose wheel slid along the axle in response to external stimulation. After impregnation with Zn2+ ions, the relative locations of two zinc active sites (crown-ether coordinated Zn(II) and bipyridine coordinated Zn(II)) are endowed with great flexibility to fit the conformational transformation of an organophosphorus agent during the hydrolytic process. Notably, the resulting self-adaptive binuclear zinc center in a crown-ether-threaded COF network is endowed with a record catalytic ability, with a rate over 85.5 μM min-1 for organophosphorus degradation. The strategy of synthesis for porous artificial enzymes through the introduction of mechanically bound crown ether will enable significant breakthroughs and new synthetic concepts for the development of advanced biomimetic catalysts.


Loss of laminin and of the laminin receptor integrin subunit alpha 6 in situ correlates with cytokine induced down regulation of alpha 6 on fibroblast-like synoviocytes from rheumatoid arthritis.
To investigate in situ the expression of the integrin receptor subunits alpha 6 and beta 1 and the distribution of the ligand laminin in the synovia from osteoarthritis (OA) and rheumatoid arthritis (RA) patients and to study the effect of cytokines and antirheumatic drugs on the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of fibroblast-like synoviocytes (FBS) derived from OA and RA. The expression of the alpha 6 and beta 1 integrin subunits and the distribution of laminin were examined immunohistochemically in normal synovia and in synovia from patients with OA and RA. The effect of proinflammatory cytokines (IL1 beta and TNF alpha), and of antirheumatic drugs (salicylic acid, dexamethasone, and methotrexate) on the alpha 6 and beta 1 expression of cultured normal FBS and FBS from patients with OA and RA was determined by flow cytometry. In normal synovia and in OA synovia samples with a low grade of inflammation, synovial lining cells (SLC) showed a parallel expression and distribution of alpha 6 and laminin. In synovia samples of OA with a higher grade of inflammation and in the majority of RA synovia samples laminin was pericellularly distributed in a low number of SLC, whereas alpha 6 was expressed on the surface of a high number of SLC. In RA synovia samples with severe inflammatory changes the gradual loss of laminin generally corresponded to a decrease of the alpha 6 integrin subunit. beta 1 was always strongly expressed in all synovia samples detected. Proinflammatory cytokines up regulated the expression of alpha 6 and beta 1 on OA-FBS, whereas these effectors decreases alpha 6 and beta 1 on RA-FBS. In contrast, antirheumatic drugs, in particular methotrexate and dexamethasone, reduced the expression of alpha 6 and beta 1 on OA-FBS, whereas the same treatment on RA-FBS stimulated the expression of these integrin subunits. The gradual loss of laminin in chronic synovitis may contribute to the altered expression of alpha 6 in SLC. IL1 beta and TNF alpha down regulated the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of FBS derived from RA. Therefore, these cytokines may be among the effectors regulating the expression of the alpha 6 integrin subunit in SLC in vivo. As antirheumatic drugs increase the expression of alpha 6 on RA-FBS, the presence of the laminin receptor may confer a protective effect on the synovia in vivo.


Bumetanide and furosemide.
We assessed the response to and handling of furosemide and bumetanide in 30 experiments with the former and 46 with the latter in normal subjects. Oral doses of furosemide (20, 40, and 80 mg) were used, and subjects received oral doses of 0.5, 1, and 2 mg bumetanide and intravenous doses of 0.5 and 1 mg bumetanide. both drugs were quickly absorbed and peak urinary amounts were reached at 75 min (median). Approximately 30% of an oral dose of each drug was excreted unchanged in the urine with no evidence of dose-dependent elimination. After intravenous injection, 36% of the bumetanide was excreted unchanged. Consequently, bumetanide has an estimated bioavailability of 80% (approximately 40% for furosemide). The relationship between the logarithm of the urinary bumetanide excretion rate and the logarithm of the sodium excretion rate was described by a sigmoid-shaped dose-response curve, with a dose inducing half-maximal response of 1 +/- 0.04 micrograms/min; it was 69.8 micrograms/min for furosemide. Overall, the distinguishing features between the two drugs are the 200% greater bioavailability and the much greater potency of bumetanide.


Idiopathic retroperitoneal fibrosis with bilateral lower ureteric obstruction--a case report with literature review.
Whilst prostatic enlargement remains the commonest cause of bilateral hydronephrosis in males greater than 50 years of age, other rarer conditions such as retroperitoneal fibrosis should be borne in mind. We report a case of bilateral hydronephrosis which was eventually diagnosed as idiopathic retroperitoneal fibrosis and treated with open surgical ureterolysis with omental wrapping.


The effect of progressive muscle relaxation exercise on the intensity of symptoms and quality of sleep and quality of life in pregnant women with restless leg syndrome.
This study, accordingly, was conducted with the purpose of investigating the effect of progressive muscle relaxation exercise on the intensity of restless leg syndrome (RLS) and RLS-related quality of life and sleep in pregnant women with RLS. This one-centered, parallel randomized controlled study was conducted with 52 pregnant women. 27-28th of pregnancy, progressive muscle relaxation exercises training was shown and they were asked to practice them 3 times a week for 8 weeks. It was found that the RLS Intensity Scale and PSQI posttest mean scores of the women in experiment group are lower on a statically significant level than the mean scores of the women in control group (p = 0.000 and p = 0.001). It was detected that the RLS-Qol posttest mean scores of the women in the experiment group are higher than the mean scores in the control group on a statistically significant level (p = 0.000). It was seen that progressive muscle relaxation exercises alleviate RLS intensity and symptoms and improve RLS-related quality of life and sleep in pregnant women. Progressive muscle relaxation exercises are beneficial for pregnant women and can be easily integrated into practice.


Genome-wide DNA methylation sequencing identifies epigenetic perturbations in the upper airways under long-term exposure to moderate levels of ambient air pollution.
While the link between exposure to high levels of ambient particulate matter (PM) and increased incidences of respiratory and cardiovascular diseases is widely recognized, recent epidemiological studies have shown that low PM concentrations are equally associated with adverse health effects. As DNA methylation is one of the main mechanisms by which cells regulate and stabilize gene expression, changes in the methylome could constitute early indicators of dysregulated signaling pathways. So far, little is known about PM-associated DNA methylation changes in the upper airways, the first point of contact between airborne pollutants and the human body. Here, we focused on cells of the upper respiratory tract and assessed their genome-wide DNA methylation pattern to explore exposure-associated early regulatory changes. Using a mobile epidemiological laboratory, nasal lavage samples were collected from a cohort of 60 adults that lived in districts with records of low (Simmerath) or moderate (Stuttgart) PM10 levels in Germany. PM10 concentrations were verified by particle measurements on the days of the sample collection and genome-wide DNA methylation was determined by enzymatic methyl sequencing at single-base resolution. We identified 231 differentially methylated regions (DMRs) between moderately and lowly PM10 exposed individuals. A high proportion of DMRs overlapped with regulatory elements, and DMR target genes were involved in pathways regulating cellular redox homeostasis and immune response. In addition, we found distinct changes in DNA methylation of the HOXA gene cluster whose methylation levels have previously been linked to air pollution exposure but also to carcinogenesis in several instances. The findings of this study suggest that regulatory changes in upper airway cells occur at PM10 levels below current European thresholds, some of which may be involved in the development of air pollution-related diseases.


Proton MR study of different types of experimental acute renal failure in rats.
Kidney cortical and medullary spin-lattice (T1) and spin-spin (T2) relaxation times were measured in several types of experimental acute renal failure in rats with a Bruker PC "Multispec." Gentamicin ARF was obtained after one i.p. injection of 100mg Gentamicin/kg BW/day for 8 days. Glycerol ARF: 24 hours after one i.m. injection of 10 ml 50% Glycerol/kg BW. Obstruction ARF: 3 days after complete ureteral ligation. Renal tissue total water content, hydration fraction, fraction bound, blood urea and creatinine were measured at the end of the experiments. Shortened T1 and prolonged T2 were found in both cortex and medulla in the Glycerol ARF group. Gentamicin renal toxicity and the non-functioning kidney with ureteral obstruction are characterized by significant prolongation of T1 and T2 in cortex, while the medullary T1 and T2 were prolonged only in obstruction ARF. The highest T1 and T2 were found in the obstructed non-functioning kidney. The total water content decreased in the Glycerol ARF, increased in the obstruction and remain unchanged in Gentamicin ARF. The hydration fraction and the fraction bound changed significantly in the opposite direction with the total water content. Different profiles of renal cortical and medullary magnetic resonance properties found in several models of experimental ARF in rats indicate that MR properties may provide etiopathogenetic diagnostic possibilities.


Introduction to Multiparametric Flow Cytometry and Analysis of High-Dimensional Data.
Multiparametric flow cytometry is a technique utilized in translational experiments that utilizes fluorescently tagged antibodies and functional fluorescent dyes to measure proteins on the surface or in the cytoplasm of cells and to measure processes occurring within cells themselves. These fluorescent molecules, or fluorophores, can be tagged to antibodies to measure specific biological molecules such as proteins inside or on the surface of cells. Small organic compounds such as the nucleic acid binding dye propidium iodide (PI) can permeate compromised cell membranes when cells are no longer viable or used to measure DNA content of cycling cells. Successful completion of flow cytometry experiments requires expertise in both the preparation of the samples, acquisition of the samples on instruments, and analyses of the results. This chapter describes the principles needed to conduct a successful multiparameter flow cytometry experiment needed for drug development with references to well established internet resources that are useful to those less experienced in the field. In addition, we provide a brief introduction to data analysis including complex analysis of 10+ parameters simultaneously. These high-dimensional datasets require novel methods for analysis due to the volume of data collected, which are also introduced in this chapter.


Identification of flurazepam (Dalmane) and a primary metabolite in urine by thin-layer chromatography.
A relatively simple, routine method has been described for the qualitative identification of flurazepam and its primary metabolite 7-chloro-1-(2-hydroxyethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in urine. We have described two extractions and several identification procedures by which flurazepam and its primary urinary metabolite can be identified by TLC.


Hyaloid vasculature and mmp2 activity play a role during optic fissure fusion in zebrafish.
Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Failure of this event leads to congenital vision impairment in the form of coloboma. Recent studies have suggested hyaloid vasculature to be involved in OF fusion. In order to examine this link, we analyzed OF fusion and hyaloid vasculogenesis in the zebrafish pax2a noi mutant line. We first determined that pax2a-/- embryos fail to accumulate F-actin in the OF prior to basement membrane (BM) degradation. Furthermore, using 3D and live imaging we observed reduced OF hyaloid vascularization in pax2a-/- embryos. When examining the connection between pax2a loss of function and hyaloid vasculature, we observed significant reduction of talin1 expression, a regulator of hyaloid vasculature. In addition, cranial VEGF expression was found to be reduced in pax2a-/- embryos. Pharmacological inhibition of VEGF signaling phenocopied the pax2a-/- vasculature, F-actin and BM degradation phenotypes. Lastly, we determined that OF associated hyaloid vasculature is a source of mmp2, mmp14a and mmp14b expression and showed that mmp2 is functionally necessary for degradation of OF BM. Taken together we propose a pax2a driven mechanism that ensures proper and timely hyaloid vasculature invasion of the OF in order to facilitate availability of the BM remodeler mmp2.


Epstein-Barr virus-dependent lymphoproliferative disease: critical role of IL-6.
Epstein-Barr virus (EBV)-induced lymphoproliferative disease (lpd) is a B cell neoplasm that affects patients who are immunosuppressed in the context of organ transplantation or HIV infection. A model for the aggressive form of this entity was generated by xenotransplantation of SCID mice with human peripheral blood leukocytes from individuals with prior contact with EBV. This model, where large B cell lymphoma occurs, was used to test the hypothesis that IL-6 has a major role in EBV-induced B cell tumorigenesis. IL-6 is known to differentiate B cells into immunoglobulin-secreting plasma cells and induce EBV replication, and xenochimeric animals have detectable serum levels of human IL-6. Human IL-6 inhibition with a neutralizing monoclonal antibody decreased tumor incidence from 62 % to 27 %. In addition, anti-IL-6 treatment significantly improved xenotransplanted animal survival, with median survival at > 245 days when compared to that of controls at 132 days. In conclusion, IL-6 plays a critical role in the pathogenesis of EBV-induced human lpd, and IL-6 inhibition may represent a new and promising preventive or therapeutic approach against this malignancy.


Methods for estimating insulin resistance from untargeted metabolomics data.
Insulin resistance is associated with multiple complex diseases; however, precise measures of insulin resistance are invasive, expensive, and time-consuming. Develop estimation models for measures of insulin resistance, including insulin sensitivity index (SI) and homeostatic model assessment of insulin resistance (HOMA-IR) from metabolomics data. Insulin Resistance Atherosclerosis Family Study (IRASFS). Community based. Mexican Americans (MA) and African Americans (AA). Estimation models for measures of insulin resistance, i.e. SI and HOMA-IR. Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net regression were used to build insulin resistance estimation models from 1274 metabolites combined with clinical data, e.g. age, sex, body mass index (BMI). Metabolite data were transformed using three approaches, i.e. inverse normal transformation, standardization, and Box Cox transformation. The analysis was performed in one MA recruitment site (San Luis Valley, Colorado (SLV); N = 450) and tested in another MA recruitment site (San Antonio, Texas (SA); N = 473). In addition, the two MA recruitment sites were combined and estimation models tested in the AA recruitment sample (Los Angeles, California; N = 495). Estimated and empiric SI were correlated in the SA (r2 = 0.77) and AA (r2 = 0.74) testing datasets. Further, estimated and empiric SI were consistently associated with BMI, low-density lipoprotein cholesterol (LDL), and triglycerides. We applied similar approaches to estimate HOMA-IR with similar results. We have developed a method for estimating insulin resistance with metabolomics data that has the potential for application to a wide range of biomedical studies and conditions.