High levels of virological failure with major genotypic resistance mutations in HIV-1-infected children after 5 years of care according to WHO-recommended 1st-line and 2nd-line antiretroviral regimens in the Central African Republic: A cross-sectional study.
A large cohort of 220 HIV-1-infected children (median [range] age: 12 [4-17] years) was cared and followed up in the Central African Republic, including 198 in 1st-line and 22 in 2nd-line antiretroviral regimens. Patients were monitored clinically and biologically for HIV-1 RNA load and drug resistance mutations (DRMs) genotyping. A total of 87 (40%) study children were virological responders and 133 (60%) nonresponders. In children with detectable viral load, the majority (129; 97%) represented a virological failure. In children receiving 1st-line regimens in virological failure for whom genotypic resistance test was available, 45% displayed viruses harboring at least 1 DRM to NNRTI or NRTI, and 26% showed at least 1 major DRM to NNRTI or NRTI; more than half of children in 1st-line regimens were resistant to 1st-generation NNRTI and 24% of the children in 1st-line regimens had a major DRMs to PI. Virological failure and selection of DRMs were both associated with poor adherence. These observations demonstrate high rate of virological failure after 3 to 5 years of 1st-line or 2nd-line antiretroviral treatment, which is generally associated with DRMs and therapeutic failure. Overall, more than half (55%) of children receiving 1st-line antiretroviral treatment for a median of 3.4 years showed virological failure and antiretroviral-resistance and thus eligible to 2nd-line treatment. Furthermore, two-third (64%) of children under 2nd-line therapy were eligible to 3rd-line regimen. Taken together, these observations point the necessity to monitor antiretroviral-treated children by plasma HIV-1 RNA load to diagnose as early as possible the therapeutic failure and operate switch to a new therapeutic line.


Brief report: leaking esophageal probe may lead to false ventilator settings when guiding positive end-expiratory pressure by transpulmonary pressure.
Esophageal pressure (Pes) is a surrogate for intrapleural pressure. Measuring Pes during mechanical ventilation allows for positive end-expiratory pressure adjustments by transpulmonary pressure (PL), which has been shown to improve oxygenation and outcome in acute respiratory distress syndrome patients. In morbidly obese patients, we saw progressively increasing PL measurements, although airway pressure (Paw), intra-abdominal pressure, and patient position did not change. On further examination, we determined that the gradual increases of PL were artifacts caused by a leak in the pressure probes, which resulted in underestimation of Pes and overestimation of PL as derived from the equation Paw - Pes = PL.


Peripheral Iron Metabolism is Associated with Leg Movements on Polysomnography but Not with the Severity of Restless Legs Syndrome or Its Impact on Patients.
This study investigated the associations of peripheral iron status with different manifestations of restless legs syndrome (RLS), including leg movements (LMs) on polysomnography (PSG), disease severity, and impact on patients. In this cross-sectional study, 108 patients with RLS were enrolled at Sir Run Run Shaw Hospital's Center for Sleep Medicine. Demographic information, disease characteristics, RLS severity, and impact on patients were assessed through a semi-structured questionnaire. Peripheral iron indicators [serum ferritin, iron, and transferrin concentrations; unsaturated iron-binding capacity (UIBC) and total iron-binding capacity (TIBC); transferrin saturation (TSAT)] were measured following PSG to assess sleep stages, respiratory events, microarousals and LM parameters. Data from patients with and without ferritin concentration < 50 µg/L were compared in crude analyses, and Spearman correlations of other iron indicators with RLS data were examined. An ordinal logistic regression model was used to adjust for age, sex, body mass index, years of education, age at the time of RLS onset, prior treatment (yes/no), C-reactive protein (CRP)/hemoglobin level, total sleep time and apnea-hypopnea index. Multivariate analysis showed that periodic LMs during sleep (PLMS) and other LM parameters were significantly associated with a ferritin concentration < 50 µg/L, UIBC, TIBC, and serum transferrin concentration, but not serum iron or TSAT. By contrast, the severity and impact of RLS were not associated with a ferritin concentration < 50 µg/L or other peripheral iron indicators in the multivariate model. In this study, peripheral iron status was associated mainly with motor components (LMs on PSG) rather than sensory components (severity and impact of RLS) after adequately controlling for potential confounders, such as CRP and hemoglobin levels. Commonly used peripheral iron metabolism indicators may therefore not be ideal biomarkers of RLS severity or impact on patients.


Efficacy of Jiedu Pingsou Decoction Combined with Azithromycin in the Treatment of Children with Mycoplasma Pneumonia and Its Effects on Inflammatory Factors and Immune Function.
The purpose of this study is to detect the clinical efficacy of Jiedu Pingsou Decoction combined with azithromycin in the treatment of children with mycoplasma pneumonia and the effect on inflammatory factors and immune function in children. A total of 68 children with mycoplasma pneumonia in our hospital from January 2021 to January 2022 were included in this study, and they were randomly divided into the control group and the observation group with 34 cases in each group. The children in the control group were treated with azithromycin, and the children in the observation group were treated with Jiedu Pingsou Decoction on this basis. The clinical manifestations, treatment effects, blood routine, serum inflammatory factor levels, and T cell subsets before and after treatment were compared between the two groups. The total effective rate in the observation group was 94.12%, which was higher than that in the control group, which was 82.35%, and the difference between the two groups was statistically significant (P < 0.05). After treatment, the levels of CD3+, CD4+, and CD4+/CD8+ in the two groups were higher than those before treatment, and the level of CD8+ was lower than before treatment. The difference between groups was statistically significant (P < 0.05). The levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interferon gamma (IFN-γ), interleukin-6 (IL-6), and interleukin-10 (IL-10) in the two groups after treatment were lower than those before treatment, and the difference between the two groups was statistically significant (P < 0.05). The difference between groups was statistically significant (P < 0.05). There were 4 cases and 2 cases of adverse reactions in the control group and the observation group, respectively, and the difference between the two groups was statistically significant (P > 0.05). Jiedu Pingsou Decoction combined with azithromycin can effectively improve the levels of T cell subsets, immune function, and inflammatory factors in children with mycoplasma pneumonia, improve clinical symptoms, and is safe and stable, and can be used in clinical practice.


Solid-state (115)In NMR study of indium coordination complexes.
The feasibility of solid-state (115)In NMR studies is demonstrated by an examination of four different coordination complexes: indium(III) acetylacetonate, indium(III) tris(tropolonato), indium(III) triiodide bis(tris(4-methoxyphenyl)phosphine oxide) and indium(III) trichloride tris(2,4,6-trimethoxyphenyl)phosphine. The results provide information about the electric field gradients and magnetic shielding at the indium nuclei through the nuclear quadrupolar and chemical shift parameters, respectively. The C(Q) values in these four complexes range between 106.0 +/- 2.0 and 200.0 +/- 4.0 MHz, while the magnetic shielding anisotropies fall in the range from 85 +/- 15 to 550 +/- 60 ppm. Finally, this research demonstrates that solid-state (115)In NMR studies are facilitated by performing experiments at the highest possible magnetic-field strengths, and that NMR offers a promising tool for the characterization of indium compounds.


The level of serum carcinoembryonic antigen is a surrogate marker for the efficacy of EGFR-TKIs but is not an indication of acquired resistance to EGFR-TKIs in NSCLC patients with EGFR mutationsm.
The aim of the present study was to define the relationship between carcinoembryonic antigen (CEA) and survival in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and to investigate whether the level of serum CEA is related to the mechanism for acquisition of resistance to EGFR-TKIs. A total of 100 patients with advanced NSCLC (stage IIIB or stage IV) and harboring EGFR mutations were included. All patients received erlotinib or gefitinib treatment. The correlation between CEA serum level and clinical benefit from erlotinib or gefitinib treatment was analyzed. Patients were appraised by a review of data from a prospective re-biopsy protocol for lung cancer patients with an EGFR-mutated phenotype with acquired resistance to EGFR-TKI therapy. Of 100 patients, 49 and 21 patients carried high and low level of CEA, respectively; 30 carried normal CEA. Median progression-free survival was 6.4 and 4.5 months in patients with high and low level of CEA, respectively (P=0.027). Median PFS of patients in low-CEA group longer than that of those with normal level of tumors (3.0 months; P=0.002). The difference between groups L and N was not significant regarding objective response rate and overall survival. No significant difference was found in three groups of acquired resistance to EGFR-TKIs. The relative CEA level could predict benefit of EGFR-TKI therapy in advanced NSCLC, but could not predict acquired resistance to EGFR-TKIs.


Extended-spectrum beta-lactamase-producing Serratia marcescens outbreak in a Bulgarian hospital.
We describe a nosocomial outbreak of extended-spectrum beta-lactamase (ESBL)-producing Serratia marcescens in a Bulgarian university hospital affecting nine patients on four wards. Phenotypic and genotypic (plasmid profile, randomly amplified polymorphic DNA analysis and amplified ribosomal DNA restriction analysis) analysis of the isolates indicated a single clone. The epidemic strain was resistant to oxyimino beta-lactams, aztreonam, aminoglycosides, tetracycline and chloramphenicol. It produced CTX-M-3 ESBL as demonstrated by isoelectric focusing, CTX-M PCR-RFLP and gene sequencing. The isolate was also found in the environment and from a nurse's hands, suggesting transmission by staff handling. The outbreak was controlled by patient isolation and intensified hand washing. This is the first report from Bulgaria describing a hospital outbreak caused by CTX-M-3 ESBL-producing S. marcescens.


Optimizations and investigations for transfer learning of iteratively pruned neural network equalizers for data center networking.
In this work, for the first time to the best of our knowledge, we introduce the iterative pruning technique into the transfer learning (TL) of neural network equalizers (NNE) deployed in optical links with different length. For the purpose of time saving during the training period of NNE, TL migrates the NNE parameters which have been already trained on the source link to the newly-routed link (the target link), which has been proved to outperform the training initialized with the random state. Based on simulations, we proved that iterative pruning technique could further enhance the convergence speed during TL between the source and target links. Moreover, we quantitatively investigate the marginal effects of pruned threshold and pruned span on the convergence performance in various transmission distance scenarios. In addition, we observed a trade-off between performance stability and complexity of NNE, which requires to be optimized compromisingly by choosing an appropriate equalizer scale.


Yeast DNA diesterase for 3'-fragments of deoxyribose: purification and physical properties of a repair enzyme for oxidative DNA damage.
The DNA strand breaks resulting from exposure to the free radicals generated by ionizing radiation or oxidizing agents are refractory to DNA repair synthesis because of deoxyribose fragments that block their 3' termini. The restoration of normal 3'-OH nucleotide primers is the essential first step in the excision repair of these radical-induced strand breaks. We have used a synthetic DNA substrate containing 3'-phosphoglycolaldehyde esters to identify and purify to physical homogeneity the major yeast diesterase that removes such nucleotide fragments. Yeast 3'-phosphoglycolaldehyde diesterase had Mr = 40,500 upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A similar molecular weight estimate from gel filtration indicated that the active species is a nearly globular monomer. Purification of the enzyme removed a tightly bound metal, but the activity of the purified enzyme could be restored by the addition of Co2+, Mn2+, Ni2+, or Zn2+, with Co2+ the most effective cofactor. Even 3 microM Co2+ stimulated near-maximal activity, and this metal also conferred significant thermal stability on the purified protein. This is a novel enzyme, whose N-terminal amino acid sequence does not show any significant similarity to published sequences, and which is not the product of any gene in the RAD52 epistasis group.


Transient neonatal diabetes mellitus, type 4, type 1 diabetes mellitus, or MODY: which disease is it, anyway?
A 30year-old Hispanic male who presented with transient neonatal diabetes mellitus at 4 months has been intensively studied with 12 islet-cell secretagogues from 4 months to 24 years. He was both ICA- and GAD-65-negative, but at 28 years was diagnosed with hypothyroidism due to positive thyroperoxidase antibodies. The course of his disease(s) and the various presentations of hyperglycemia are documented and illustrated by the responses in islet cell hormone secretion, namely, insulin, glucagon, and C-peptide. Insulin secretion gradually fell over 24 years, glucagon secretion persisted from infancy to 24 years but was only minimal during i.v. glucose at 24 years, and C-peptide secretion remained normal, although modest, throughout the 24 years. These data suggest that, despite changing presentations of diabetes mellitus over time, the islets continued to process proinsulin, although the patient required insulin therapy.


Changes in Doppler mitral inflow patterns during parabolic flight.
Aim of the study was to evaluate by transthoracic Doppler the alterations in mitral inflow velocity pattern caused by acute changes in loading conditions occurring during parabolic flights. Each parabola included normogravity (1 Gz, 1 min), mild hypergravity (1.8 Gz, 20 sec), microgravity (0 Gz, 24 sec) and mild hypergravity (1.8 Gz, 20 sec) phases. Pulsed-Doppler images were digitally acquired in 11 unmedicated subjects (46 +/- 5 years), in standing upright position and supine resting. Doppler profiles were semi-automatically traced and inflow parameters extracted and averaged onto three consecutive beats. Only in standing position, significant alterations during microgravity (p<0.05) were noted in several parameters.


Some scanning electron microscopic studies of the surface of coronal sections cut from the rat brain.
The cut surfaces of coronal sections of the rat cerebral hemispheres have been examined with the scanning electron microscope. Under low magnification the structures of the brain are easily identified. Using the focusing power of the microscope and the ability to tilt the specimen in its column, under higher magnification the neurones, glial cells, cell processes, bundles of myelinated axons and the cerebral blood vessels can be examined in great detail. This method of study should prove of value in the future for the investigation of brains which have been subjected to experimental procedures and those affected by disease.


Novel Somatostatin Receptor Ligands Therapies for Acromegaly.
Surgery is considered the treatment of choice in acromegaly, but patients with persistent disease after surgery or in whom surgery cannot be considered require medical therapy. Somatostatin receptor ligands (SRLs) octreotide (OCT), lanreotide, and the more recently approved pasireotide, characterized by a broader receptor ligand binding profile, are considered the mainstay in the medical management of acromegaly. However, in the attempt to offer a more efficacious and better tolerated medical approach, recent research has been aimed to override some limitations related to the use of currently approved drugs and novel SRLs therapies, with potential attractive features, have been proposed. These include both new formulation of older molecules and new molecules. Novel OCT formulations are aimed in particular to improve patients' compliance and to reduce injection discomfort. They include an investigational ready-to-use subcutaneous depot OCT formulation (CAM2029), delivered via prefilled syringes and oral OCT that uses a "transient permeability enhancer" technology, which allows for OCT oral absorption. Another new delivery system is a long-lasting OCT implant (VP-003), which provide stable doses of OCT throughout a period of several months. Finally, a new SRL DG3173 (somatoprim) seems to be more selective for GH secretion, suggesting possible advantages in the presence of hyperglycemia or diabetes. How much these innovations will actually be beneficial to acromegaly patients in real clinical practice remains to be seen.


Cyanide bioremediation: the potential of engineered nitrilases.
The cyanide-degrading nitrilases are of notable interest for their potential to remediate cyanide contaminated waste streams, especially as generated in the gold mining, pharmaceutical, and electroplating industries. This review provides a brief overview of cyanide remediation in general but with a particular focus on the cyanide-degrading nitrilases. These are of special interest as the hydrolysis reaction does not require secondary substrates or cofactors, making these enzymes particularly good candidates for industrial remediation processes. The genetic approaches that have been used to date for engineering improved enzymes are described; however, recent structural insights provide a promising new approach.


Knowledge and factors associated with pain management for hospitalized children among nurses working in public hospitals in Mekelle City, North Ethiopia: cross sectional study.
American Nurses Association reflects, the role of the nurse in pain management encompasses the entire nursing process, assessment of pain, plans pharmacological and non-pharmacological pain management strategies, implements the plan, and evaluates the response of the patient to the interventions. Pediatric pain management has been left largely unaddressed due to factors like limited resources, inadequate training, as well as cultural diversity and language barriers which made sick and injured children not to receive basic pain care. The objective of this study was to assess the knowledge and factors associated with pain management for hospitalized children among nurses. Institution based cross-sectional study was employed from a total of 261 nurses in Public Hospitals of Mekelle City from March 15 to April 15, 2015. Systematic random sampling method was used to get the study subjects. Self-administered questionnaire was used to collect data. The collected data was cleared, categorized, and coded. The cleaned data was analyzed using Statistical Package for the Social Sciences, version 20 software with statistical significance p < .05 at 95% CI. Descriptive statistics was employed. Binary logistic regressions were used to see relationship between dependent and independent variables. Out of 251 participants more than half (58.6%) of nurses had adequate knowledge and had good practice 140 (55.8%). Those respondents who said yes sedation interfering with pain assessment were 2.7 more likely knowledgeable on pain management for hospitalized children than others. In addition to this those nurses who said they had a specific pain management protocol in their institution were 2.159 more likely knowledgeable than others. Majority of nurses were knowledgeable on some of pharmacological and non-pharmacological pain managements. Most of the nurses had a good practice on children pain managements. Reading guide lines, specific protocols, knowledge, charting area for pain, sedation interfering with pain assessment and working in pediatric ward were some of the factors that were significantly associated with children's pain management.


Communicating leveled clinical expectations to nursing students.
Nurse educators agree on the need for objectives in the classroom situation and frequently communicate them in a written form. Written expectations for clinical, however, are rarely given to student nurses prior to their clinical experience. Clinical expectations are understood by instructors, but communicating them to students result in mixed interpretations. The article describes the development of a written method of communicating clinical expectations to solve this problem. This method correlates clinical expectations with classroom content and course objectives and levels the expectations in increasing complexity by using the nursing process as a framework. The written leveled expectations are distributed to student nurses on a weekly basis. Clinical experiences are enhanced for students and faculty who use this method.


fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.
Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.


[The horrible end of J.K. Huysmans and the wearying genesis of the Foules de Lourdes].
The author is attempting to demonstrate the real correlation between the living of J.K. Huysman's last months and the algolagnia expressed through "Sainte Lydwine de Schiedam" and, particularly, "Les Foules de Lourdes". The author is bringing an exceptional document in the form J.K. Huysman's successive galleys ready for "Les Foules de Lourdes" printing where he delivered his ultimate and surprising corrections, chiefly to the viewpoint when he suffers grief like a "tremplin de joies" (steppingstone of delights).


Obesity Fact Sheet in Korea, 2019: Prevalence of Obesity and Abdominal Obesity from 2009 to 2018 and Social Factors.
The prevalence of obesity has rapidly increased in countries across the world in recent decades. The 2019 Obesity Fact Sheet released by the Korean Society for the Study of Obesity addressed the prevalence of obesity and abdominal obesity during the period of 2009 to 2018 and obesity-related social factors. Data from the Korean National Health Insurance Service health checkup database between 2009 and 2018 and the Korea National Health and Nutrition Examination Survey between 2010 and 2017 were analyzed. The prevalence of obesity and abdominal obesity was calculated after standardizing for age and sex based on the 2010 population and housing census. From 2009 to 2018, the prevalence of obesity and abdominal obesity increased to 35.7% and 23.8%, respectively, in 2018. Upward trends in the prevalence of obesity and abdominal obesity was observed among both sexes and nearly all age groups. The prevalence of obesity and abdominal obesity was higher among individuals with lower education and household income levels. Among occupations, managers exhibited the highest prevalence of obesity and abdominal obesity. Further, the prevalence of obesity and abdominal obesity became higher among individuals working longer hours and split and night shift workers. The 2019 Obesity Fact Sheet provides information on changes in obesity dynamics during the past decade and obesity-related social factors in the Korean adult population. This report might constitute a cornerstone by which to establish targets for future interventions for reversing the rise in the prevalence of obesity and reducing the burden of obesity in Korea.


E-Z isomerization in Suzuki cross-couplings of haloenones: ligand effects and evidence for a separate catalytic cycle.
Suzuki cross-coupling of haloalkenes is generally assumed to occur with retention of the alkene stereochemistry. While studying Suzuki cross-couplings on E-1,2-dichlorovinyl phenyl ketone, we were surprised to observe extensive isomerization. More surprisingly, the ligand employed strongly influenced the degree of isomerization: DPEphos and Xantphos led to 96% isomerized cross-coupled product whereas reactions in the absence of a phosphine ligand, or reactions employing t-BuXantphos, gave 94% retention of stereochemistry. While E-Z isomerization in Pd-catalyzed vinylic couplings has previously been attributed to events within the cross-coupling catalytic cycle, we present experimental and computational evidence for a separate Pd-catalyzed isomerization process in these reactions.


Role of α-copaene in the susceptibility of olive fruits to Bactrocera oleae (Rossi).
The influence of α-copaene as a fruit volatile in the susceptibility of Olea europaea L. to the olive fruit fly Bactrocera oleae (Rossi) has been investigated. By studies on the relative area of volatile components from different cultivars, a positive correlation was found between the abundance of α-copaene in the samples and the corresponding degree of fruit infestation. SPME-GC-MS analysis of volatiles from uninfested fruits of O. europaea L. cv. Serrana were performed over two years to determine the variation of α-copaene throughout the different phenological stages. The results suggested that this sesquiterpene has a significant effect on cultivar susceptibility and may act as an oviposition promoter. Further analysis by chiral GC showed that olive fruits release both α-copaene enantiomers. Bioassays on each enantiomer revealed that fruits with increased amounts of (+)-α-copaene favor oviposition of B. oleae females, whereas the increase of (-)-α-copaene affords no statistically significant differences in host preference.


Longitudinal associations between risk appraisal of base stations for mobile phones, radio or television and non-specific symptoms.
Studies found that higher risk appraisal of radiofrequency electromagnetic fields is associated with reporting more non-specific symptoms such as headache and back pain. There is limited data available on the longitudinal nature of such associations and what aspects of risk appraisal and characteristics of subjects are relevant. To examine cross-sectional and longitudinal associations between risk appraisal measures and non-specific symptoms, and assess the role of subject characteristics (sex, age, education, trait negative affect) in a general population cohort. This study was nested in the Dutch general population AMIGO cohort that was established in 2011/2012, when participants were 31-65 years old. We studied a sample of participants (n = 1720) who filled in two follow-up questionnaires in 2013 and 2014, including questions about perceived exposure, perceived risk, and health concerns as indicators of risk appraisal of base stations, and non-specific symptoms. Perceived exposure, perceived risk, and health concerns, respectively, were associated with higher symptom scores in cross-sectional and longitudinal analyses. Only health concerns (not perceived exposure and perceived risk) temporally preceded high symptom scores and vice versa. Female sex, younger age, higher education, and higher trait negative affect were associated with higher risk appraisal of mobile phone base stations. The findings in this study strengthen the evidence base for cross-sectional and longitudinal associations between higher risk appraisal and non-specific symptoms in the general population. However, the directionality of potential causal relations in non-sensitive general population samples should be examined further in future studies, providing information to the benefit of risk communication strategies.


Effects of Pathogenic Variations in the Human Rhodopsin Gene (hRHO) on the Predicted Accessibility for a Lead Candidate Ribozyme.
The mutation-independent strategy for hammerhead ribozyme (hhRz) or RNA interference (RNAi)-based gene therapeutics to treat autosomal dominant diseases is predicated on the hypothesis that a single therapeutic would equivalently suppress all/most of the diverse mutant mRNAs in patients with the disease phenotype. However, the hypothesis has not been formally tested. We address this through a comprehensive bioinformatics study of how mutations affect target mRNA structure accessibility for a single lead hhRz therapeutic (725GUC↓), designed against human rod rhodopsin mRNA (hRHO), for patients with hRHO mutations that cause autosomal dominant retinitis pigmentosa. A total of 199 in silico coding region mutations (missense, nonsense, insert, deletion, indel) were made in hRHO mRNA based on Human Gene Mutation Database and Database of Single Nucleotide Polymorphisms. Each mRNA was folded with MFold, SFold, and OligoWalk algorithms and subjected to a bioinformatics model called multiparameter prediction of RNA accessibility. Predicted accessibility of each mutant over both a broad local region and the explicit lead ribozyme annealing site were compared quantitatively to wild-type hRHO mRNA. Accessibility of the 725GUC↓ site is sensitive to some mutations. For single nucleotide missense mutations, proximity of the mutation to the hhRz annealing site increases the impact on predicted accessibility, but some distant mutations also influence accessibility. A mutation-independent strategy appears viable in this specific context but certain mutations could significantly influence ribozyme or RNAi efficacy through impact on accessibility at the target annealing site/region. This possibility must be considered in applications of this gene therapy strategy.


Long-term Follow-up of a Case of Gold Shunt Surgery for Refractory Silicone Oil-induced Glaucoma.
To report the first case of gold shunt surgery for treatment of silicone oil-induced refractory glaucoma in a tertiary care academic center, with 5-year follow-up. The study design is a case report. The participant was a patient who underwent gold shunt surgery. Institutional Research Ethics Board approval for the study was obtained. A diabetic patient was referred for refractory glaucoma with a history of proliferative diabetic retinal detachment, and surgery with silicone oil. She was uncontrolled on maximal medical therapy and following informed consent, gold shunt surgery was performed. Ocular outcomes and number of medications were reviewed over a 5-year period. Following uncomplicated surgery, intraocular pressure was reduced from 41 to 14 mm Hg, and the number of medications was reduced from 4 to 1. Glaucomatous optic neuropathy remained stable. Gold shunt surgery in this challenging case of silicone oil refractory glaucoma provided long-term intraocular pressure control and reduced need for medication over a 5-year period.


Understanding the impact of police brutality on Black sexually minoritized men.
Young Black gay, bisexual, and other sexually minoritized men (SMM) face high levels of police brutality and other negative, unwarranted encounters with the police. Such interactions have known health consequences. The purpose of this study was to understand the health, mental health, and social consequences of police brutality experienced by young Black SMM. We conducted in-depth interviews with 31 Black, cisgender men, ages of 16-30 and analyzed the data using thematic analysis. Our primary results are summarized in four themes: 1) Police brutality is built into the system and diminishes trust; 2) Videos and social media make visible violence that has long existed; 3) Police brutality contributes to anxiety and other psychosocial effects; and 4) Violence reduces feelings of safety and contributes to avoidance of police. Our results highlight the direct and vicarious police brutality participants are subjected to and sheds light on the effects of such violence on trust, perceived safety, anxiety, and trauma symptoms. Results from this study contribute to the needed public health conversation around police brutality against Black men, specifically shedding light on the experiences of Black SMM.


Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists.
Adoptive therapy with ex vivo-expanded genetically modified antigen-specific T cells can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. Lower rates of ex vivo expansion and clinical response using anti-CD19 chimeric antigen receptor (CAR) T cells have been seen in heavily pretreated lymphoma patients compared with B-cell acute lymphoblastic leukemia patients and motivate the development of novel strategies to enhance ex vivo T cell expansion and their persistence in vivo. We demonstrate that inhibition of phosphatidylinositol 3-kinase δ (PI3Kδ) and antagonism of vasoactive intestinal peptide (VIP) signaling partially inhibits the terminal differentiation of T cells during anti-CD3/CD28 bead-mediated expansion (mean, 54.4% CD27+CD28+ T cells vs 27.4% in control cultures; P < .05). This strategy results in a mean of 83.7% more T cells cultured from lymphoma patients in the presence of PI3Kδ and VIP antagonists, increased survival of human T cells from a lymphoma patient in a murine xenograft model, enhanced cytotoxic activity of antigen-specific human CAR T cells and murine T cells against lymphoma, and increased transduction and expansion of anti-CD5 human CAR T cells. PI3Kδ and VIP antagonist-expanded T cells from lymphoma patients show reduced terminal differentiation, enhanced polyfunctional cytokine expression, and preservation of costimulatory molecule expression. Taken together, synergistic blockade of these pathways is an attractive strategy to enhance the expansion and functional capacity of ex vivo-expanded cancer-specific T cells.


The effects of pulsed electromagnetism on fresh fracture healing: osteochondral repair in the rat femoral groove.
Some clinical studies have claimed significant reductions in the healing time of fresh fractures with the use of pulsed electromagnetic fields (PEMFs). Animal models, however, have produced more equivocal results. This investigation examined the effects of PEMF treatment on an osteochondral defect placed in the patellofemoral groove of the rat. The results indicated that PEMF enhances early vascular reaction and suppresses initial pannus proliferation. Early chondrogenesis and bone formation were consistently stimulated, and the restoration of normal bone trabeculae advanced. Pulsed electromagnetic field treatment therefore may be useful in advancing repair during the early proliferative stage. Later results were variable and suggest that prolonged use may have deleterious effects, enhancing chondrogenesis beyond a point observed in normal repair and thus delaying normal subsurface trabeculation.


Insights into the enhanced Ce[triple bond, length as m-dash]N triple bond in the HCe[triple bond, length as m-dash]N molecule.
Herein, an experimental study of the vibrational spectra of HCeN was carried out in solid argon, followed by theoretical investigations of molecular structures and the nature of Ce[triple bond, length as m-dash]N bond. The absorption band at 937.7 cm-1 with the 1.0311 14N/15N isotopic shift ratio is characteristic of Ce[triple bond, length as m-dash]N stretching band for HCeN, showing a 94 cm-1 higher shift relative to that of the diatomic CeN molecule. This large frequency shift indicates a much stronger Ce[triple bond, length as m-dash]N bond in HCeN, which is confirmed by DFT calculations. Qualitative orbital interaction and orbital composition analyses suggest that the addition of the H ligand to the Ce center will activate the 4f valence shell and strengthen the covalent bond between Ce and N, which may contribute to enhance the Ce[triple bond, length as m-dash]N triple bond in the HCeN molecule.


Vasopressin-2 receptor antagonist attenuates the ability of the lungs to clear edema in an experimental model.
In the last two decades, the role of the alveolar active sodium transport was extensively studied and was found to play a crucial role in regulating alveolar fluid clearance (AFC), and thus in keeping the airspaces free of edema. The recent development of highly selective nonpeptide vasopressin-receptor antagonists gives us a rare chance to explore the role of vasopressin in the pathogenesis of lung edema. Therefore, the present study examined the involvement of vasopressin in modulating the ability of the lung to clear edema. Vasopressin enhanced the rate of lung edema clearance by 30% as compared with untreated control rats (from 0.49 ± 0.02 to 0.64 ± 0.02 ml/h), whereas V(2) receptor antagonists significantly decreased the ability of the lung to clear water (from 0.64 ± 0.02 to 0.31 ± 0.06 ml/h; P < 0.0001). In contrast, V(1) receptor antagonist did not change the rate of AFC. The administration of ouabain (a Na,K-ATPase inhibitor) and amiloride (a Na(+) channel blocker) inhibited the stimulatory effects of vasopressin (from 0.64 ± 0.02 to 0.22 ± 0.02 ml/h [P < 0.0001] and from 0.64 ± 0.017 to 0.23 ± 0.02 ml/h [P < 0.0001], respectively). Vasopressin significantly increased Na,K-ATPase protein abundance in the basolateral membranes of the alveolar epithelial cells via V(2) receptor activation. We report a novel role of the vasopressin pathway in AFC. This observation indicates a beneficial role of vasopressin in AFC by up-regulating active sodium transport.


Tarsal polishing and mucous membrane grafting for cicatricial entropion, trichiasis and epidermalization.
In a manner similar to dermabrasion, epidermalized tarsal conjunctiva is polished and then the tarsus is grafted with full-thickness buccal mucous membrane. This has been applied with rewarding results in patients afflicted with Stevens-Johnson syndrome, ocular pemphigoid and scarred eyelids with secondary epidermalization.


Progress in assessing the role of serotonin in the control of food intake.
There is evidence that serotonin inhibits food intake, particularly intake of carbohydrate and that induced by activation of catecholamine-containing neurons in different brain circuits. An agent that has contributed considerably to the hypothesis of a role of serotonin in feeding is fenfluramine, used as an anorexigenic drug in obese people. Experiments using synaptosomal preparations for studying monoamine uptake and release have shown that d-norfenfluramine preferentially releases serotonin from a reserpine-insensitive compartment. Studies on brain monoamine release and metabolism in intact animals have shown that d and l isomers of fenfluramine at relatively low doses have a specific action on brain serotonin and catecholamines, respectively. Several findings suggest that d-fenfluramine and d-norfenfluramine cause anorexia by increasing the availability of serotonin at postsynaptic receptors. Evidence has recently been provided that d-fenfluramine uses preferentially serotonin1 sites, particularly of the serotonin1B type, in the rat brain to cause anorexia in this animal species. Activation of serotonin1A sites by agents such as 8-OH-DPAT and buspirone instead has been shown to cause overeating. It is suggested that serotonin1B sites in the hypothalamus and serotonin1A sites in the serotonin neurons of the midbrain raphe nuclei mediate these effects. Evidence is provided that [3H]d-fenfluramine binding to rat brain membranes is different from serotonin uptake sites ([3H]imipramine binding) and serotonin receptors. It is, however, displaced by some drugs using serotonin to cause anorexia, raising the possibility that it is somewhat related to serotonin mechanisms involved in feeding control. These studies provide evidence that the serotoninergic system in the brain is a likely target for drugs affecting food intake and suggest new ways to develop novel and potent strategies for the treatment of clinical hyperphagia and anorexia.


Application of duplex-PCR in rapid and reliable detection of toxigenic Vibrio cholerae in water samples in Thailand.
Toxigenic Vibrio cholerae, the cause of cholera, is a native flora of the aquatic environment which is transmitted through drinking water and still remains the leading cause of morbidity and mortality in many developing countries including Thailand. The culture method (CM), which is routinely used for assessing water quality, has not proven as efficient as molecular methods because the notorious pathogen survives in water mostly in a non-culturable state. We employed duplex-polymerase chain reaction (duplex-PCR) for detection of tcpA and ctxA genes in toxigenic V. cholerae, and compared PCR detection with CM in various waters of Khon Kaen Municipality, Thailand. We also evaluated the effect of different pre-PCR conditions on the results of ctxA and tcpA detection including: 1) water filtered and enriched in alkaline peptone water (APW) for 3 h before PCR, 2) water filtered without enrichment before PCR, and 3) use of only enrichment in APW for 6 h before PCR. Of the 96 water samples (taken from waste-water, potable and waste-water from patients' houses, and from rivers) tested, 48 (50%) were positive for ctxA and tcpA by duplex-PCR, whereas only 29 (30%) were positive for V. cholerae by CM. Of the 29 V. cholerae isolated by CM, 2 (7%) were toxigenic V. cholerae belonging to serovar O1, while the rests were non-O1/ non-O139. Results revealed, therefore, that ctxA and tcpA-targeted duplex PCR is more sensitive than CM for detection of toxigenic V. cholerae from water samples because CM detected much less toxigenic V. cholerae than the non-toxigenic V. cholerae. Template DNA as low as 100 fg or 23 cells of V. cholerae in the water sample was detected in duplex PCR. Pre-PCR filtration followed by enrichment for 3 h significantly increase in the efficiency of duplex-PCR detection of toxigenic V. cholerae.


A cotton Raf-like MAP3K gene, GhMAP3K40, mediates reduced tolerance to biotic and abiotic stress in Nicotiana benthamiana by negatively regulating growth and development.
Mitogen-activated protein kinase (MAPK) cascades mediate various responses in plants. As the top component, MAP3Ks deserve more attention; however, little is known about the role of MAP3Ks, especially in cotton, a worldwide economic crop. In this study, a gene encoding a putative Raf-like MAP3K, GhMAP3K40, was isolated. GhMAP3K40 expression was induced by stress and multiple signal molecules. The plants overexpressing GhMAP3K40 had an enhanced tolerance to drought and salt stress at the germination stage. However, at the seedling stage, the transgenic plants suffered more severe damage after drought, exposure to pathogens and oxidative stress. The defence-related genes and the antioxidant system were activated in transgenic palnts, suggesting that GhMAP3K40 positively regulate the defence response. The transgenic plants were less able to prevent pathogenic invasion, which was due to defects in the cell structure of the leaves. The root system of the control plants were stronger compared with the transgenic plants. These results indicated a negative role of GhMAP3K40 in growth and development and GhMAP3K40 possibly caused the defects by down-regulating the lignin biosynthesis. Overall, these results suggest that GhMAP3K40 may positively regulate defence response but cause reduced tolerance to biotic and abiotic stress by negatively regulating growth and development.


Effect of Preoperative Stress Radiographic Findings on Radiographic and Clinical Outcomes of the Modified Broström Procedure for Chronic Ankle Instability.
The purpose of the present study is to evaluate whether findings of instability on preoperative stress radiographs of patients with chronic ankle instability affects the radiographic and clinical outcomes after a modified Broström procedure. A total of 45 consecutive patients (45 ankles) who had undergone the modified Broström procedure for unilateral ankle joint instability and were followed up for ≥2 years were selected. The patients were classified into 2 groups according to the results of the preoperative stress radiographs: 1 group with positive findings (35 [77.8%] patients; stress-positive group) and 1 group with negative findings (10 [22.2%] patients; stress-negative group). The radiographic and clinical outcomes were compared between the 2 groups. The mean preoperative talar tilt measured on the stress radiograph was 14.4° ± 4.2° and 4.8° ± 2.6° in the stress-positive and stress-negative groups, respectively, a statistically significant difference. Postoperative talar tilt improved in both groups, with a mean final talar tilt of 5.4° ± 3.4° in the stress-positive group (p < .001) and 3.0° ± 1.5° in the stress-negative group (p = .038). The average American Orthopaedic Foot and Ankle Society ankle-hindfoot score in the stress-positive and stress-negative groups improved from 65.1 ± 14.6 to 90.0 ± 6.3 (p < .001) and 72.5 ± 9.3 to 92.6 ± 7.8 (p = .007), respectively. The mean postoperative satisfaction rate was 83.9 ± 11.9 and 85.0 ± 11.8 in the 2 groups. No statistically significant differences were seen in the preoperative and postoperative American Orthopaedic Foot and Ankle Society ankle-hindfoot scores or in postoperative satisfaction rates between the 2 groups.


Determination of spin injection and transport in a ferromagnet/organic semiconductor heterojunction by two-photon photoemission.
A fundamental prerequisite for the implementation of organic semiconductors (OSCs) in spintronics devices is the still missing basic knowledge about spin injection and transport in OSCs. Here, we consider a model system consisting of a high-quality interface between the ferromagnet cobalt and the OSC copper phthalocyanine (CuPc). We focus on interfacial effects on spin injection and on the spin transport properties of CuPc. Using spin-resolved two-photon photoemission, we have measured directly and in situ the efficiency of spin injection at the cobalt-CuPc interface. We report a spin injection efficiency of 85-90% for injection into unoccupied molecular orbitals of CuPc. Moreover, we estimate an electron inelastic mean free path in CuPc in the range of 1 nm and a 10-30 times higher quasi-elastic spin-flip length. We demonstrate that quasi-elastic spin-flip processes with energy loss < or = 200 meV are the dominant microscopic mechanism limiting the spin diffusion length in CuPc.


Cell wall biology of the moss Physcomitrium patens.
The moss Physcomitrium (previously Physcomitrella) patens is a non-vascular plant belonging to the bryophytes that has been used as a model species to study the evolution of plant cell wall structure and biosynthesis. Here, we present an updated review of the cell wall biology of P. patens. Immunocytochemical and structural studies have shown that the cell walls of P. patens mainly contain cellulose, hemicelluloses (xyloglucan, xylan, glucomannan, and arabinoglucan), pectin, and glycoproteins, and their abundance varies among different cell types and at different plant developmental stages. Genetic and biochemical analyses have revealed that a number of genes involved in cell wall biosynthesis are functionally conserved between P. patens and vascular plants, indicating that the common ancestor of mosses and vascular plants had already acquired most of the biosynthetic machinery to make various cell wall polymers. Although P. patens does not synthesize lignin, homologs of the phenylpropanoid biosynthetic pathway genes exist in P. patens and they play an essential role in the production of caffeate derivatives for cuticle formation. Further genetic and biochemical dissection of cell wall biosynthetic genes in P. patens promises to provide additional insights into the evolutionary history of plant cell wall structure and biosynthesis.


[Inhibitory effect of bispecific antibody targeting IL-12 p40 and TNF-α simultaneously on psoriasis in mice].
Objective To construct bispecific antibodies, which can block interleukin 12 (IL-12)/IL-23 p40 subunit and tumor necrosis factor α (TNF-α) simultaneously, and identify their biological function and inhibitory effect on psoriasis formation in mice. Methods Based on the sequences of adalimumab and ustekinumab, three kinds of bispecific antibodies were designed, named BiAU003, BiAU022 and BiAU023. The specificity and binding capacity of bispecific antibodies were determined by ELISA. After co-treated with bispecific antibodies and TNF-α, the level of endothelial leukocyte adhesion molecule-1 (ELMA-1) labeled with fluorescein isothiocyanate (FITC) in human umbilical vein endothelial cells (HUVECs) were examined by flow cytometry. Human peripheral blood mononuclear cells (PBMCs) were purified and cultured in the medium containing IL-2 and IL-12 in the absence or presence of bispecific antibodies. Commercial ELISA kit was used to detect interferon γ (IFN-γ) concentration in the supernatant. BALB/c mice were used for psoriasis model construction through injection of IL-12 and TNF-α subcutaneously. Then they were treated with the bispecific antibodies. Psoriasic skin was measured in thickness and scale under microscopy after H&E staining. Results The three kinds of bispecific antibodies could specifically recognize IL-12/23 p40 and TNF-α protein, and inhibit IFN-γ secretion and the expression of ELAM-1 protein. Data also indicated that bispecific antibodies inhibited the formation of psoriasic skin, and showed an equal or superior effect to control antibody drug. Conclusion The novel bispecific antibodies, BiAU003, BiAU022 and BiAU023, can serve as an antagonist of TNF-α and IL-12/23 p40, and have a blocking effect on mouse psoriasis formation.


Decrease in timed balance test scores with aging.
This study investigated whether 184 volunteers from 20 to 79 years of age could perform eight timed balance tests and examined the relationship between test performance and age. All subjects were able to balance with their feet together and eyes closed for 30 seconds. The ability to balance on the right and left legs did not differ significantly. Subjects over 60 years of age were unable to balance on one leg, particularly when their eyes were closed, for as long a period as younger subjects. The Pearson product-moment and Spearman correlations of age and duration of one-legged balance were -.65 and -.71 (eyes opened) and -.79 and -.75 (eyes closed). The findings suggest that when timed balance tests are performed as a part of a patient's neurologic examination, the results should be interpreted in light of the patient's age. Information is provided to assist in this interpretation.


A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans.
Physiologically based pharmacokinetic (PBPK) modeling was applied to investigate the effects of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans. Successful construction of both rat and human models was achieved by fitting model outputs to published nicotine concentration time course data in the blood and in the brain. Key parameters presumed to have the most effect on the ability of these antibodies to prevent nicotine from entering the brain were selected for investigation using the human model. These parameters, which included antibody affinity for nicotine, antibody cross-reactivity with cotinine, and antibody concentration, were broken down into different, clinically-derived in silico treatment levels and fed into the human PBPK model. Model predictions suggested that all three parameters, in addition to smoking status, have a sizable impact on anti-nicotine antibodies' ability to prevent nicotine from entering the brain and that the antibodies elicited by current human vaccines do not have sufficient binding characteristics to reduce brain nicotine concentrations. If the antibody binding characteristics achieved in animal studies can similarly be achieved in human studies, however, nicotine vaccine efficacy in terms of brain nicotine concentration reduction is predicted to meet threshold values for alleviating nicotine dependence.


Nodules in the conjunctiva, bung-eye, and bulge-eye in Africa caused by Mansonella perstans.
Eight patients from Uganda, Sudan, Nigeria, and Zaire presented with swelling of the eyelids, proptosis, or conjunctival granulomas. In 5 patients the cause was Mansonella perstans; in 1, it was a Wuchereria bancrofti-like worm; and in 2, an unidentifiable worm. The morphologic features and histopathologic changes in the conjunctiva and periorbital fat are described and illustrated.


Adult giant cerebellar cavernous malformations: case report and review of the literature.
Cavernous malformations are vascular malformations that can occur anywhere in the central nervous system (CNS). Giant cavernous malformations (GCM) are extremely rare in adults, especially in the posterior fossa. Herein, we described a 48-year-old male who presented with vertigo and postural instability for three months. Neuroimaging revealed a 131.15 cm3 heterogeneous midline upper cerebellar lesion. After a suboccipital craniotomy, a gross total resection (GTR) was accomplished. Histopathologic examination revealed a huge cavernous malformation. Only 27 GCM adult cases were reported in the English-based literature. Only two patients had cerebellar lesions and, to the best of our knowledge, this is the first case of cerebellar vermis GCM. We concluded that cerebellar GCM (CGCM) in adults are exceedingly rare and indolent lesions. These lesions can radiologically and clinically mimic neoplastic lesions that have to be considered in the differential diagnosis. GTR is the mainstay of treatment and, whenever possible, should be attempted.


Reversal of selectivity in gold-catalyzed cyclizations of 3,3-disubstituted 1,4-diynes.
A general synthetic access to 3,3-disubstituted 1,4-diynes bearing a quaternary carbon center from acetylacetone was developed. The compounds were cyclized to the corresponding enol ethers by cationic gold complexes. The reactions occur in complete exo-selectivity in contrast to compounds incorporating an alkoxy substituent in the 3-position. A mechanistic rationale for this reversal of selectivity is provided.


Outcome of surgical management of urethral stricture following hypospadias repair.
Reconstruction of urethral strictures in patients with a history of hypospadias repair is controversial. The authors policy has been that if a residual healthy urethral plate is present, single-stage urethroplasty is recommended. However, if the urethral plate is fibrotic or absent or if lichen sclerosus is present, two-stage repair is utilized. In this study, the authors report their experience in management of patients with urethral stricture and prior hypospadias surgery. Between 1993 and 2015, 62 patients with urethral stricture and a prior history of hypospadias repair underwent urethroplasty. Patients were divided into two groups; patients in group 1 (n = 39) found to have a healthy residual urethral plate and underwent single-stage urethral stricture repair using either an island skin flap or a buccal mucosa graft. Patients in group 2 (n = 23) had either a scarred urethra or evidence of lichen sclerosus and underwent staged repair using a buccal mucosa graft. Post-operatively, patients were evaluated at 3 months, 6 months, 1 year, and then annually. The median age of the patients was 10.5 years (2.5-33 years). The mean stricture length was 6.3 cm in group 1 and 7.1 cm in group 2. Overall success rate was 87.1% in group 1; a urethral fistula occurred in one patient (7.1%) who underwent skin flap onlay repair and one patient (4.5%) with a buccal mucosa graft. Recurrent urethral stricture was also diagnosed in one patient (7.1%) after repair using an island skin flap and in two patients (9%) following buccal mucosa graft. In group 2, three patients (13%) developed graft contracture and were revised before the second stage. Two patients (8.6%) had glans dehiscence following second stage urethroplasty. The final success rate in group 2 was 90.4%. Both single-stage and 2-stage repair showed successful outcome in management of urethral stricture following hypospadias repair. However, the authors continue to believe that the status of the urethral plate dictates the type of surgery to be utilized. In accordance to the previously published data, the study results also further support promising outcomes of application of buccal mucosa in surgical management of these patients. In patients with urethral stricture after hypospadias surgery who have a healthy residual urethral plate, single-stage repair using buccal mucosa graft is a viable option with high success rate. In patients with scarred urethral plate, a 2-stage repair is recommended.


Influence of plasma cortisol and other laboratory parameters on nonalcoholic Fatty liver disease.
The objective of the present study was to analyse the association between the plasma cortisol concentration and nonalcoholic fatty liver disease (NAFLD). A total of 1 326 subjects (age 18-65 years) were examined in the context of an epidemiological study of a population-based random sample. Medical history and anthropometric data of 662 women and 664 men were documented. In addition, laboratory examinations were performed and the fat concentration of the liver was estimated by ultrasound examination. Mean cortisol concentration in plasma was 260.4±156.8 nmol/l for women and 295.8±161.2 nmol/l for men. NAFLD was identified in 17.7% in women and 35.1% in men. Plasma cortisol concentration showed no association with the existence of NAFLD. NAFLD correlated positive with age, body-mass index (BMI), waist-to-hip-ratio (WHR), alanine aminotransferase (ALT), and triglycerides. The present study failed to establish any association of plasma cortisol concentrations and NAFLD.


Epidemiologic field units on narcotic-related problems.
Much more understanding is needed of the epidemiology of narcotic-related problems. This paper describes a research strategy which is responsive to the heterogeneous nature of such problems. It is suggested that it is feasible and useful to establish, for defined geographic areas, epidemiologic field units which would have continuity, be comprehensive and develop programmatically relevant information on a timely basis. The possible areas of inquiry and the components of such a unit are discussed.


[Human endostatin antiangiogenic gene therapy mediated by recombinant adeno-associated virus vector in nude mouse with endometriosis].
To study the therapeutic effect of recombinant adeno-associated virus carrying human endostatin gene therapy on endometriosis in mice model. Recombinant adeno-associated virus vector carrying human endostatin gene and enhanced green fluorescent proteins gene (rAAV2-endostatin-EGFP) was constructed. Endometrium was from 12 patients with leiomyoma undergoing hysterectomy in Second Hospital, Tianjin Medical University between November and December 2008. Endometriosis models of nude mice were established by transplanting human endometrial fragments intooperitoneal surface. After 1 week, those 60 mice were divided into 3 groups: treatment group including 20 mice injected with rAAV2-endostatin-EGFP to ectopic lesion, control group including 20 mice injected with rAAV2-EGFP to ectopic lesion and blank control group including 20 mice injected with phosphate buffered saline (PBS) to the ectopic lesion. At 1, 2 and 3 weeks after treatment, those mice underwent laparotomy to observe the location and size of ectopic lesion in abdominal cavity. The expression of endostain protein, number of gland, microvessel density (MVD) and vascular endothelial growth factor (VEGF) were measured in ectopic lesions. The serum level of estradiol and progesterone were detected in nude mice among every groups. (1) All endometriosis of nude mice models were established successfully through peritoneum transplanting. After 1 week's treatment, flat lesion nodes, decreased gland number and narrow and atrophy glandular cavity were observed by light microscope. (2) The endostatin gene was transferred into nude mice successfully and expressed effectively. It was observed that endostatin protein expression was shown with enhanced green fluorescent proteins in ectopic lesion. (3) Glands number of ectopic lesion in rAAV2-endostatin-EGFP group (7.8 ± 1.9, 7.0 ± 1.5 and 5.5 ± 1.7) were significantly less than 10.1 ± 1.7, 10.2 ± 2.0 and 9.8 ± 2.4 in rAAV2-EGFP control group and 10.2 ± 2.2, 10.0 ± 2.0 and 9.7 ± 2.2 in PBS control group at 1, 2 and 3 weeks after treatment (all P < 0.05). Glands number of ectopic lesion in rAAV2-endostatin-EGFP group at 3 weeks was significantly less than those at 1 and 2 weeks after treatment (P < 0.05). (4) MVD of ectopic lesion in rAAV2-endostatin-EGFP group (12.2 ± 1.5, 11.4 ± 2.1 and 9.0 ± 1.4) was significantly less than those at rAAV2-EGFP control group (16.5 ± 1.7, 16.5 ± 1.9 and 16.9 ± 1.9) and PBS control group (16.2 ± 1.6, 16.0 ± 1.6 and 16.3 ± 1.7) at 1, 2 and 3 weeks after treatment (all P < 0.05). MVD of ectopic lesion in rAAV2-endostatin-EGFP group at 3 weeks was significantly less than those at 1 and 2 weeks after treatment (P < 0.05). (5) The rate and density of VEGF expression at ectopic lesion in rAAV2-endostatin-EGFP group (35%, 30%, 25% and 1.60 ± 0.43, 1.33 ± 0.30, 1.03 ± 0.36) were significantly less than those at rAAV2-EGFP control group (80%, 75%, 85% and 2.43 ± 0.53, 2.43 ± 0.29, 2.66 ± 0.45) and PBS control group (85%, 90%, 90% and 2.36 ± 0.53, 2.64 ± 0.57, 2.53 ± 0.52) at one 1, 2 and 3 weeks after treatment (all P < 0.05). The expression of VEGF at ectopic lesion in rAAV2-endostatin-EGFP group at 3 weeks was significantly less than those at 1 and 2 weeks after treatment (P < 0.05). (6) The level of estradial and progesterone in serum of nude mice of rAAV2-endostatin-EGFP group [E(2): (48 ± 7) pmol/L, P: (61 ± 8) nmol/L] did not reach statistical difference when compared with those at rAAV2-EGFP control group [E(2): (50 ± 9) pmol/L, P: (60 ± 10) nmol/L] and PBS control group [E(2): (48 ± 7) pmol/L, P: (58 ± 10) nmol/L, P > 0.05]. The recombinant adeno-associated virus carrying human endostatin gene therapy could inhibit angiogenesis at endometriotic lesions and not influence steroid level. The antiangiogenic gene therapy might become a novel option for endometriosis.


Reproductive and repeated dose toxicity of cyclododecatriene (CDDT) in rats following oral (gavage) treatment.
Cyclododecatriene (CDDT, CAS No. 4904-61-4) was administered daily by oral gavage to groups of Crl:CD (SD)IGS BR rats at dose levels of 0 (control), 30, 100, or 300 mg/kg/day. Female rats were dosed for four weeks premating, through mating, gestation, and lactation (a total of 55 to 63 days of treatment). Male rats were treated for 55 days (four weeks premating and through mating). Premating, body weights, food consumption, and clinical signs were recorded. Hematology, clinical chemistry, and urine analyses were conducted at the end of the premating period. A neurobehavioral test battery was conducted prior to and after four weeks of treatment. After the premating period, females were paired with males from the same groups for 1-2 weeks. Litters were delivered, pups were evaluated for structural integrity, and pup body weights were recorded on days 0 and 4 postpartum. Lactating females and their offspring were sacrificed on postpartum day 4. Selected organs were weighed and the tissues were examined microscopically from the lactating females. Offspring were examined for clinical abnormalities. A test substance-related reduction in body weight gain occurred in male rats administered 300 mg/kg/day. Decreased body weight gain in the 300 mg/kg/day males was accompanied by increased food consumption and decreased food efficiency. Females administered 100 or 300 mg/kg/day had test substance-related, significantly decreased body weight and body weight gain during gestation, that was accompanied by a significant increase in food consumption (300 mg/kg/day group only), and significantly decreased food efficiency. There were no test-substance related effects on clinical observations in males or females during the premating phase, or in females during gestation or lactation. Neurobehavioral parameters and motor activity were unaffected by CDDT-treatment. During this study, statistically significant treatment-related changes were observed in several clinical pathology parameters. The decreases in red cell mass (RBC, HGB, HCT) were minimal and, due to the magnitude, were not expected to result in biological effects. Similarly, minimally increased potassium and mildly decreased triglycerides were not of a magnitude to be biologically significant. Finally, changes in serum enzymes (AST, ALT, ALP), urea nitrogen, and serum protein occurred in directions that are not associated with toxicity. The changes in urine volume, urine concentration, and urea nitrogen may be the result of elevated glomerular filtration rate and altered tubular fluid flow, in the absence of any histopathological change. No effects on reproduction in parental males or females were produced by CDDT. Body weights of pups in the 300 mg/kg group were significantly decreased on postpartum days 0 and 4. There were no test-substance related effects on clinical observations, number of pups born, and the number of pups born alive, or the number of pups surviving through lactation day 4. The no-observed-adverse-effect level (NOAEL) for CDDT was 30 mg/kg/day based on decreased body weight and body weight gain, increased food consumption, and decreased food efficiency in females administered 100 or 300 mg/kg/day. The NOEL in pups was 100 mg/kg/day, based on decreased body weights of pups in the 300 mg/kg/day group during lactation.


Morphology and scaling of impact craters in granular media.
We present the results of experiments on impact craters formed by dropping a steel ball vertically into a container of small glass beads. As the energy of impact increases, we observe a progression of crater morphologies analogous to that seen in craters on the moon. We find that both the diameter and the depth of the craters are proportional to the 1/4 power of the energy. The ratio of crater diameter to rim-to-floor depth is constant for low-energy impacts, but increases at higher energy, similar to what is observed for lunar craters.


Tandem-multimeric F3-gelonin fusion toxins for enhanced anti-cancer activity for prostate cancer treatment.
Despite significant progress in prostate cancer treatment, yet, it remains the leading diagnosed cancer and is responsible for high incidence of cancer related deaths in the U.S. Because of the insufficient efficacy of small molecule anti-cancer drugs, significant interest has been drawn to more potent macromolecular agents such as gelonin, a plant-derived ribosome inactivating protein (RIP) that efficiently inhibits protein translation. However, in spite of the great potency to kill tumor cells, gelonin lacks ability to internalize tumor cells and furthermore, cannot distinguish between tumor and normal cells. To address this challenge, we genetically engineered gelonin fusion proteins with varied numbers of F3 peptide possessing homing ability to various cancer cells and angiogenic blood vessels. The E. coli produced F3-gelonin fusion proteins possessed equipotent activity to inhibit protein translation in cell-free protein translation systems to unmodified gelonin; however, they displayed higher cell uptake that led to significantly augmented cytotoxicity. Compared with gelonin fusion with one F3 peptide (F3-Gel), tandem-multimeric F3-gelonins showed even greater cell internalization and tumor cell killing ability. Moreover, when tested against LNCaP s.c. xenograft tumor bearing mice, more significant tumor growth inhibition was observed from the mice treated with tandem-multimeric F3-gelonins. Overall, this research demonstrated the potential of utilizing tandem multimeric F3-modified gelonin as highly effective anticancer agents to overcome the limitations of current chemotherapeutic drugs.


Direct Intermolecular C-H Functionalization Triggered by 1,5-Hydride Shift: Access to N-Arylprolinamides via Ugi-Type Reaction.
A novel Ugi-type reaction triggered by 1,5-hydride shift has been established, giving access to N-arylprolinamides and related compounds in high atom economy and good yields. This is an example of a two starting material-three component reaction. The benzyl alcohol substrate 1 acts as a dual synthon, which upon treatment with a Brønsted acid affords iminium ion and water. Nucleophilic attack at the iminium ion by the third component isocyanide, followed by hydrolysis with the endogenic water, gives the Ugi-type reaction products. The reaction proceeds under mild conditions and is tolerable to a broad scope of substrates.


Secondary stroke prevention among stroke survivors in Riyadh city, Saudi Arabia. Risk Knowledge, adherence to stroke discharge medications and preventive strategies.
To assess knowledge about secondary stroke and adherence to stroke discharge medication and prevention strategies among stroke survivors, and to identify possible causes of poor adherence. A cross-sectional study that involved 82 stroke survivors who were treated at Prince Mohammed Bin Abdulaziz Hospital (PMAH) in Riyadh, Saudi Arabia, from July 2015 to August 2018. Patient adherence level (PAL) was assessed using a tool developed by Sidorkiewicz et al (2016). Of the 82 participants, 63.4% believed that the risk of secondary stroke is higher and 70.7% believed it would results in worse outcome, compared to primary stroke. Out of a list of 7 preventive strategies, treating risk factors (80.5%), keeping a healthy diet (65.9%) and regular exercise (63.4%) were the most frequently identified. Forgetful-ness (51.2%), polypharmacy (18.3%) and patient-perceived improvement (17.1%) were the most frequently reported causes for nonadherence. At the patients` level, PAL was adequate among 46.8%, and was higher among females (60.0% versus 35.7%, p=0.033) and married (52.2% versus 0.0%, p=0.006) ones, and lower among smokers (22.2% versus 54.2%, p=0.029), compared to their counterparts. No correlation of adherence level with knowledge was observed. Regression showed approximation to statistical significance for smoking (OR=4.28 [0.99, 18.41], p=0.051) as a predictor for inadequate adherence. Stroke survivors have suboptimal adherence to discharge prescriptions and preventive strategies, despite a relatively sound knowledge, which exposes them to high risk of secondary stroke. It is part of the healthcare providers` role to identify eventual barriers to adherence and to implement efficacious strategies to alleviate such barriers and improve patients` adherence.


Call to Action: Urgent Challenges in Cardiovascular Disease: A Presidential Advisory From the American Heart Association.
Although advances in care have spurred improvements in cardiovascular outcomes, cardiovascular disease remains the leading cause of death in the United States and around the world. Previous declines in cardiovascular disease mortality have slowed and even reversed for certain demographics. Further concerns exist with regard to cardiovascular drug innovation, quality of care, and healthcare costs. The Value in Healthcare Initiative-Transforming Cardiovascular Care, a collaboration of the American Heart Association and Duke University, Robert J. Margolis, MD, Center for Health Policy, aims to increase access to and affordability of cardiovascular treatment and to decrease barriers to care. The following Call to Action describes trends in cardiovascular care, identifies gaps in areas of cardiovascular disease prevention and treatment, highlights challenges with medical product innovation, and finally, outlines a series of learning collaboratives that will aid in the development of road maps for transforming cardiovascular care.


Effects of Anma massage therapy (Japanese massage) for gynecological cancer survivors: study protocol for a randomized controlled trial.
Cancer patients and survivors regularly feel anxious about cancer recurrence or death, even after the conclusion of medical treatment, and they are often highly physiologically and psychologically stressed. Massage therapy is one of the most widely used complementary and alternative therapies used in the hope of alleviating such stress and physical and psychological complaints and to improve health-related quality of life. This randomized phase III, two-armed, parallel group, clinical trial was designed after obtaining positive findings in a preliminary study. The primary objective is to verify the effects of continuous Japanese massage therapy, referred to as Anma therapy, for cancer survivors. The secondary objective is to confirm the immediate effects of a single Anma massage session for cancer survivors. Sixty cancer survivors older than 20 years of age who have had histologically confirmed uterine cervical, endometrial, ovarian, fallopian tube or peritoneal cancer in the past, but with no recurrence for more than 3 years since receiving standard medical treatment, are being recruited by gynecologists in medical facilities. In the coordinating office, they are randomly allocated to two groups (n = 30 each): an Anma massage group receiving a 40-min Anma massage session once weekly over a 2-month intervention period (total of eight Anma massage sessions) and a control group being followed by medical doctors and receiving no Anma massage sessions. The primary end point is the severity of physical subjective symptoms that cancer survivors report in daily life, assessed using a Visual Analogue Scale. Secondary end points are urine and saliva analyses, psychological condition and health-related quality-of-life scores as determined on the basis of a self-report questionnaire. Using the evidence-based findings of this trial, medical professionals should be able to explain the benefits conferred by Anma massage to cancer survivors and provide higher-quality information to better inform patients regarding their decisions about whether to receive such therapy. This trial is registered with the UMIN Clinical Trials Registry as UMIN000009097.


Prediction of cumulative incidence function under the proportional hazards model.
In the presence of dependent competing risks in survival analysis, the Cox model can be utilized to examine the covariate effects on the cause-specific hazard function for the failure type of interest. For this situation, the cumulative incidence function provides an intuitively appealing summary curve for marginal probabilities of this particular event. In this paper, we show how to construct confidence intervals and bands for such a function under the Cox model for future patients with certain covariates. Our proposals are illustrated with data from a prostate cancer trial.


Does Interpersonal Psychotherapy improve clinical care for adolescents with depression attending a rural child and adolescent mental health service? Study protocol for a cluster randomised feasibility trial.
Depression amongst adolescents is a costly societal problem. Little research documents the effectiveness of public mental health services in mapping this problem. Further, it is not clear whether usual care in such services can be improved via clinician training in a relevant evidence based intervention. One such intervention, found to be effective and easily learned amongst novice clinicians, is Interpersonal Psychotherapy (IPT). The study described in the current paper has two main objectives. First, it aims to investigate the impact on clinical care of implementing Interpersonal Psychotherapy for Adolescents for the treatment of adolescent depression within a rural mental health service compared with Treatment as Usual (TAU). The second objective is to record the process and challenges (i.e. feasibility, acceptability, sustainability) associated with implementing and evaluating an evidence-based intervention within a community service. This paper outlines the study rationale and design for this community based research trial. The study involves a cluster randomisation trial to be conducted within a Child and Adolescent Mental Health Service in rural Australia. All clinicians in the service will be invited to participate. Participating clinicians will be randomised via block design at each of four sites to (a) training and delivery of IPT, or (b) TAU. The primary measure of impact on care will be a clinically significant change in depressive symptomatology, with secondary outcomes involving treatment satisfaction and changes in other symptomatology. Participating adolescents with significant depressive symptomatology, aged 12 to 18 years, will complete assessment measures at Weeks 0, 12 and 24 of treatment. They will also complete a depression inventory once a month during that period. This study aims to recruit 60 adolescent participants and their parent/guardian/s. A power analysis is not indicated as an intra-class correlation coefficient will be calculated and used to inform sample size calculations for subsequent large-scale trials. Qualitative data regarding process implementation will be collected quarterly from focus groups with participating clinicians over 18 months, plus phone interviews with participating adolescents and parent/guardians at 12 weeks and 24 weeks of treatment. The focus group qualitative data will be analysed using a Fourth Generation Evaluation methodology that includes a constant comparative cyclic analysis method. This study protocol will be informative for researchers and clinicians interested in considering, designing and/or conducting cluster randomised trials within community practice such as mental health services. Australian Clinical Trials Registry ACTRNO12607000324415.


Prostanoids in the pathophysiology of human coronary artery.
Coronary artery disease is one of the leading causes of death in wordwide. There is growing evidence that prostanoids are involved in the physiology and pathophysiology of the human coronary artery by controlling vascular tone, remodelling of the vascular wall or angiogenesis. In this review, the production of prostanoids and the expression of prostanoid receptors in human coronary artery in health or disease are described. In addition, the interactions between sex hormones and prostanoids, their participations in the development of coronary artery diseases have been addressed. Globally, most of the studies performed in human coronary artery preparations have shown that prostacyclin (PGI2) has beneficial effects by inducing vasodilatation and promoting angiogenesis while reverse effects are confirmed by thromboxane A2 (TxA2). More studies are needed to determine the roles of the other prostanoids (PGE2, PGD2 and PGF2α) in vascular functions of the human coronary artery. Finally, in addition to the in vitro data about the human coronary artery, myocardial infarction induced by cyclooxygenase-2 (COX-2) inhibitor and the protective effects of aspirin after coronary artery bypass surgery suggest that prostanoids are key mediators in coronary homeostasis.


Physiologic effects of seatback angles 45degrees (from the vertical) relative to G.
Eight experimental subjects from the USAF Sschool of Aerospace Medicine (SAM) and four YF-16/17 test pilots were exposed to a simulated aerial combat maneuver (SACM) which included a maximum G exposure of 6 s at 8 G. The following physiologic parameters were examined relative to seatback angles of 23degrees, 28degrees, and 40degrees; heart rate and rhythm; arterial oxygen saturation; performance; intrathoracic (esophageal) pressure; arterial pressure; and subject comfort, effort, and fatigue. Relaxed and straining high sustained G (HSG) tolerances (6 G for 60 s) were also determined using only SAM subjects. The advantages of the 40 degree setback angle during the SACM included increased subject comfort, less fatigue and effort, greater pilot acceptance and a statisically significant reduction in the increased mean heart rate associated with G exposure. On the other hand, a statistically significant reduction in arterial oxygen saturation was obtained during the SACM at 40 degrees compared with the 23 degree back angle. An increase in relaxed G tolerance was found with the 40degree seatback angle--statistically significant only compared with the 28 degree seatback angle.


Incorporation of leucine into human skeletal muscle proteins.
The in vitro incorporation of labelled leucine into human skeletal muscle proteins was studied with the aim to elucidate the relationship between the amino acid tissue pools and protein biosynthesis. The distribution volumes of leucine and cycloleucine in skeletal muscle tissue were similar but the equilibration time was shorter for leucine than for cycloleucine. The cellular uptake of leucine and cycloleucine was competitively inhibited by increased concentration of amino acids in the medium indicating an active transport. Optimal stimulation for incorporation of leucine into proteins was obtained at an amino acid concentration in the medium corresponding to 10 times that of normal human plasma. The incorporation of 14C-leucine into skeletal muscle proteins was linear before the total pool of free intracellular 14C-leucine and the incorporation rate of leucine calculated from the specific activity in the medium versus the amino acid concentration in the medium were different in the same experiment indicating a re-utilization of amino acids released at protein degradation. The results are compatible with the hypothesis that the proteolytically released amino acids have a competitive advantage for incorporation as compared with extra- and intracellular free amino acids. It is concluded that the amino acid pool which is in the immediate continuity with the protein biosynthesis sites equilibrates rapidly with the extracellular amino acid pool.


Efficient hybrid density functional calculations in solids: assessment of the Heyd-Scuseria-Ernzerhof screened Coulomb hybrid functional.
The present work introduces an efficient screening technique to take advantage of the fast spatial decay of the short range Hartree-Fock (HF) exchange used in the Heyd-Scuseria-Ernzerhof (HSE) screened Coulomb hybrid density functional. The screened HF exchange decay properties and screening efficiency are compared with traditional hybrid functional calculations on solids. The HSE functional is then assessed using 21 metallic, semiconducting, and insulating solids. The examined properties include lattice constants, bulk moduli, and band gaps. The results obtained with HSE exhibit significantly smaller errors than pure density functional theory (DFT) calculations. For structural properties, the errors produced by HSE are up to 50% smaller than the errors of the local density approximation, PBE, and TPSS functionals used for comparison. When predicting band gaps of semiconductors, we found smaller errors with HSE, resulting in a mean absolute error of 0.2 eV (1.3 eV error for all pure DFT functionals). In addition, we present timing results which show the computational time requirements of HSE to be only a factor of 2-4 higher than pure DFT functionals. These results make HSE an attractive choice for calculations of all types of solids.


Contribution of human melanopsin retinal ganglion cells to steady-state pupil responses.
The recent discovery of melanopsin-containing retinal ganglion cells (mRGCs) has led to a fundamental reassessment of non-image forming processing, such as circadian photoentrainment and the pupillary light reflex. In the conventional view of retinal physiology, rods and cones were assumed to be the only photoreceptors in the eye and were, therefore, considered responsible for non-image processing. However, signals from mRGCs contribute to this non-image forming processing along with cone-mediated luminance signals; although both signals contribute, it is unclear how these signals are summed. We designed and built a novel multi-primary stimulation system to stimulate mRGCs independently of other photoreceptors using a silent-substitution technique within a bright steady background. The system allows direct measurements of pupillary functions for mRGCs and cones. We observed a significant change in steady-state pupil diameter when we varied the excitation of mRGC alone, with no change in luminance and colour. Furthermore, the change in pupil diameter induced by mRGCs was larger than that induced by a variation in luminance alone: that is, for a bright steady background, the mRGC signals contribute to the pupillary pathway by a factor of three times more than the L- and M-cone signals.


Regulation of retinal vascular endothelial growth factor and receptors in rabbits exposed to hyperoxia.
To evaluate the molecular responses of vascular endothelial growth factor (VEGF) and its receptors to dexamethasone (Dex) and celecoxib (Cel) during hyperoxia and during hyperoxia followed by recovery in room air, in newborn rabbit retinas. Newborn rabbits at 3 days postnatal age (n = 96) received room air or oxygen (80%-100%) for 4 days, during which they were administered saline (Sal), Dex, vehicle (Veh), or Cel (n = 12/treatment group). Six animals from each group were killed immediately after hyperoxia (or room air) and the remainder exposed to room air for 5 days. Retinal mRNA expression of VEGF(121), VEGF(165), VEGF receptor-1 (VEGFR-1, or Flt-1), and VEGFR-2 (or KDR/Flk-1) was determined. Hyperoxia resulted in increased retinal expression of mRNA of the VEGF splice variants in the groups treated with Sal, Dex, and Veh, whereas a decrease in VEGF(121) was noted in the Cel-treated group. In contrast, retinal Flt-1 receptor mRNA was markedly increased in the Cel-treated group only, whereas retinal VEGFR-2 (KDR/Flk-1) receptor mRNA was suppressed in all the treatment groups. Hyperoxia followed by recovery in room air resulted in a minimal decrease in expression of retinal Flt-1 mRNA in the Sal and Dex groups. Cel treatment abolished its expression. The findings of increased retinal expression of VEGF mRNA in the newborn rabbit in response to hyperoxia are most likely due to species differences. Selective targeting of VEGF(121) and Flt-1 mRNA by Cel may represent one regulatory pathway for their anti-inflammatory effects. Further studies are needed to evaluate the therapeutic benefits of cyclooxygenase (COX)-2 inhibitors for the treatment and/or prevention of diseases associated with neovascularization.


Evaluation of three screening tests and a risk assessment model for diagnosing peripheral neuropathy in the diabetes clinic.
with the aim of evaluating predictive power, three simple screening tests as alternates to nerve conduction tests for diagnosing diabetic peripheral neuropathy (DPN) were investigated. Results of the screening tests, along with the subjects' demographic and clinical characteristics, were planned as the variables for the development of a risk assessment tool for predicting DPN. this is a cross-sectional multi-group comparison study. The study utilized a predictive model derived from one subset of the study population, and prospectively tested in the other subset to predict the presence of neuropathy. Diabetic Neuropathy Research Clinic of the Toronto General Hospital and University Health Network in Toronto, Ontario, Canada from June 1998 to August 1999. data come from 478 subjects consisting of non-diabetic reference subjects, and patients with type 1 and type 2 diabetes mellitus. nerve conduction studies (NCS) comprised the primary defined outcome. The three screening sensory tests examined in the study were the Semmes-Weinstein 10 g monofilament examination (SWME), superficial pain sensation, and vibration by the on-off method. the three screening tests are significantly and positively correlated with NCS. An increase in the number of insensate responses in the screening test is associated with an increase in the abnormal NCS score. The strength of the association between NCS and each sensory test was greater when the neuropathy severity stage of the subject was added to the model. Both the SWME and vibration by the on-off method tests demonstrated sufficient statistical power to differentiate non-diabetic control subjects from subjects with diabetes, as well as to differentiate subjects with diabetes with and without neuropathy. These two tests, when compared with NCS, also demonstrated acceptable diagnostic performance characteristics in terms of high sensitivity and specificity, total number of correctly predicted cases, and receiver-operating characteristic curves. this data, through the development of a model involving training and validation sets, demonstrates that the knowledge of clinical risk factors alters the interpretation of sensory tests for DPN. This finding lends further support to the validity of simple sensory testing maneuvers in the conditional diagnosis of DPN. We recommend annual screening with either the SWME or vibration by the on-off method in the primary care and diabetes clinics.


Macrophages kill T9 glioma tumor cells bearing the membrane isoform of macrophage colony stimulating factor through a phagocytosis-dependent pathway.
Rat T9 glioma cells transfected with the gene for the membrane isoform of macrophage-CSF (mM-CSF) but not for the secreted isoform of M-CSF were directly killed by bone marrow-derived macrophages. Macrophage-mediated cytolysis of the mM-CSF-transfected clone was blocked by using chemical inhibitors of phagocytosis such as iodoacetate, 2-deoxyglucose, gadolinium chloride, and cytochalasin B. In contrast, macrophage-mediated killing of mM-CSF-expressing tumor cells was augmented by the microtubule inhibitor, colchicine. Use of nitric oxide and reactive oxygen intermediate inhibitors failed to alter the macrophage-mediated killing of the mM-CSF-transfected tumor cells. Photomicroscopy, using immunohistochemical staining with the anti-Hck Ab to distinguish macrophages from tumor cells, revealed that phagocytosis began within 2 h after addition of the mM-CSF-bearing tumor cells. Photocinematography confirmed that macrophages first phagocytosized and then lysed the internalized mM-CSF transfectant cells. Using annexin V and acridine orange staining techniques, macrophages phagocytosized living mM-CSF-transfected tumor cells.


The adult rat hippocampus contains primordial neural stem cells.
Adult-derived hippocampal progenitors generate neurons, astrocytes, and oligodendrocytes in vitro and following grafting into the adult brain. Although these progenitors have a considerable capacity for in vitro self renewal, it is not known if each lineage is generated by separate committed precursors or by multipotent stem cells. By genetic marking, we have followed individual cells through the process of proliferative expansion, commitment, and differentiation. All three lineages are generated by single marked cells and the relative proportions of each lineage can be strongly influenced by environmental cues. Differentiation is accompanied by a characteristic progression of lineage-specific markers and can be potentiated by retinoic acid, elevated cyclic AMP, or neurotrophic factors. The ability to genetically mark and clone normal diploid hippocampal progenitors provides the first definitive evidence that multipotent neural stem cells exist outside of the adult striatal subventricular zone and supports the hypothesis that FGF-2-responsive neural stem cells may be broadly distributed in the adult brain.


Bendamustine and its role in the treatment of unfit patients with chronic lymphocytic leukaemia: a perspective review.
With a median age of 72 years at first diagnosis, chronic lymphocytic leukaemia (CLL) is a disease of the elderly. At this age, many patients cannot bear an intensive chemoimmunotherapy like fludarabine, cyclophosphamide and rituximab (FCR), and therapeutic decisions are commonly complicated by a high burden of accompanying comorbidities. Clinical trials, on the other hand, are mostly designed to include a far healthier and younger trial population, with a median age in most studies well below 70 years, leading to an insufficient reflection of clinical reality. With the introduction of new targeted therapies, treatment of CLL is currently undergoing a profound change. New compounds like ibrutinib or idelalisib have enlarged the therapeutic options in treating CLL. However, so far, these oral medications imply continuous intake by the patient, which will at some point lead to the issue of adherence in most patients. In addition, long-term experiences are largely missing. In this setting, one of the oldest chemoactive substances remains a viable option for many CLL patients and their treating physicians: bendamustine, a nitrogen-mustard derivative, has proven to be a safe and efficient agent for treatment of CLL in the first- and second-line setting. In particular, there is some evidence that the substance is relatively well tolerated in elderly and unfit patients. In this review, we summarize the current data on bendamustine in the treatment of elderly and unfit patients with CLL and aim to provide a concise analysis and outlook on the current and future role of this substance in the era of new targeted agents.


Amino Catalytic Oxidative Thioesterification Approach to α-Ketothioesters.
An efficient metal-free method for the synthesis of α-ketothioesters is described for the first time. This reaction features the ability of pyrrolidine to fine-tune the reaction between 2-oxoaldehyde and thiols through iminium to the desired product in moderate to good yields. As an advantage, no external oxidants or metal catalysts are required in our method. Reactions performed under modified conditions lead to an apparent balance in reactivity of secondary amine and thiols toward 2-oxoaldehydes.


[Prognostic significance of lactate concentration and indicators of acid-base balance in air embolism of cerebral vessels].
Acid-base balance and lactate concentration in the arterial blood and spinal liquor have been studied in 32 patients after air embolism of the brain vessels developed during cardiopulmonary bypass surgery. It has been shown that an increase of lactate concentration in the spinal liquor over 3.5 mmol/l after air embolism of the brain vessels is indicative of severe hypoxic brain damage, in which the prospect of stable consciousness recovery is doubtful. In lactate concentration 4.5-5 mmol/l and higher as well as in metabolic acidosis of liquor (sodium hydrocarbonate concentration less than 20 mmol/l) the intensive care procedures used were not effective. It is believed that these parameters are of prognostic value in the condition under study.


Spontaneous combined lung and bowel hernia following an episode of acute bronchitis.
Spontaneous lung hernias are unusual conditions which usually follow attacks of excessive straining. Spontaneous bowel hernias are even rarer. Here, we present the first reported case of a combined spontaneous herniation of both the lung and bowel following an attack of acute bronchitis and coughing together with a description of surgical approach and repair.


Simultaneous intracochlear stimulation based on channel interaction compensation: analysis and first results.
A simultaneous paradigm for electric stimulation of the acoustic nerve based on a monopolar electrode configuration and sign-correlated pulses is presented. Simultaneous pulse amplitudes are determined by taking into account parameters of spatial channel interaction. The computation of simultaneous amplitudes requires the solution of linear systems of equations in an iterative procedure. The computation amount can be reduced significantly, if the spatial impulse responses in individual electrodes can be approximated by two exponentially decaying branches with decay constants alpha toward apex and beta toward base. Generally, the associated inverse of the channel interaction matrix is tridiagonal. Preliminary vowel and consonant identification tests with four cochlear implant patients have been conducted for sequential and simultaneous processor settings. For equal overall pulse repetition rates, comparable speech perception scores were obtained, when the decay constants alpha and beta were set accordingly. Theoretically, the pulse rate of an N-channel system can be increased up to a factor of N as compared to the standard sequential paradigm, and pulses with technically reasonable phase durations can be utilized.