31Phosphorus magnetic resonance spectroscopy in late-onset Tay-Sachs disease.
The late-onset form of GM2 gangliosidosis (Tay-Sachs disease) is an autosomal-recessive disorder with progressive neurologic disease, mainly characterized by motor neuron and spinocerebellar dysfunction. The majority of patients are of Ashkenazi Jewish origin. 31Phosphorus magnetic resonance spectroscopy of the brain was performed to study the metabolic changes of a 16-year-old patient with late-onset Tay-Sachs disease who had a heterozygous Gly269-->Ser mutation in the hexosaminidase A encoding gene in compound heterozygosity with another, yet unidentified mutation. Severe changes in phosphorus metabolism with a decreased amount of phosphodiesters and membrane-bound phosphates were demonstrated, suggesting an activation of phosphodiesterases by accumulating gangliosides. The clinical findings were well related to the changes in spectroscopically determined metabolites.


[Comprehensive computer-assisted management of a cardiology department].
We are proposing a personal computer local network system for collecting data and managing of both cardiovascular in- and outpatients. The six PCs used as work stations are located in the following areas: reception desk, ergometry, holter, echocardiography, secretarial and coronary care unit and cardiology department. Starting from a commercially available DBMS program, an "Iceberg" applied program was first made in a single personal computer and then transferred to a local network. The tree-structured data base includes the cardiopathies list, the vasculopathies list, some cardiovascular clinical data and all information regarding cardiological instrumental tests. The data are descriptive, numeric, date, text and comment. The operative program allows us to change the data base without the help of the software house staff, so the system is adaptable to cardiological departments with different instrumental equipment and sections. The report of instrumental tests and the issuing of the discharge letter are made with the local work station, with simultaneous compiling, storing and printing. It is then possible, using any work station, to restore and print quickly a summary of all data concerning each patient. This summary permits us, in nearly all cases, to identify the patient's history and present condition, as well as the diagnostical steps taken.


Hybrid-Electric Passenger Car Carbon Dioxide and Fuel Consumption Benefits Based on Real-World Driving.
Hybrid-electric vehicles (HEVs) have lower fuel consumption and carbon dioxide (CO2) emissions than conventional vehicles (CVs), on average, based on laboratory tests, but there is a paucity of real-world, on-road HEV emissions and performance data needed to assess energy use and emissions associated with real-world driving, including the effects of road grade. This need is especially great as the electrification of the passenger vehicle fleet (from HEVs to PHEVs to BEVs) increases in response to climate and energy concerns. We compared tailpipe CO2 emissions and fuel consumption of an HEV passenger car to a CV of the same make and model during real-world, on-the-road network driving to quantify the in-use benefit of one popular full HEV technology. Using vehicle specific power (VSP) assignments that account for measured road grade, the mean CV/HEV ratios of CO2 tailpipe emissions or fuel consumption defined the corresponding HEV "benefit" factor for each VSP class (1 kW/ton resolution). Averaging over all VSP classes for driving in all seasons, including temperatures from -13 to +35 °C in relatively steep (-13.2 to +11.5% grade), hilly terrain, mean (±SD) CO2 emission benefit factors were 4.5 ± 3.6, 2.5 ± 1.7, and 1.4 ± 0.5 for city, exurban/suburban arterial and highway driving, respectively. Benefit factor magnitude corresponded to the frequency of electric-drive-only (EDO) operation, which was modeled as a logarithmic function of VSP. A combined model explained 95% of the variance in HEV benefit for city, 75% for arterial and 57% for highway driving. Benefit factors consistently exceeded 2 for VSP classes with greater than 50% EDO (i.e., only city and arterial driving). The reported HEV benefits account for real-world road grade that is often neglected in regulatory emissions and fuel economy tests. Fuel use HEV benefit factors were 1.3 and 2 for the regulatory highway (HWFET) and city (FTP) cycles, respectively, 18% and 31% higher than the EPA adjusted fuel economy values. This study establishes the significant need for high-resolution vehicle activity and road grade data in transportation data sets to accurately forecast future petroleum and GHG emissions savings from hybridization of the passenger vehicle fleet.


Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.
The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared. Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms. No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS. NCT01642251.


High-dose chemotherapy and autologous peripheral blood stem cell transplantation with BCVAC regimen followed by maintenance chemotherapy for children with very high risk acute lymphoblastic leukemia.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the recommended treatment for children with very high risk acute lymphoblastic leukemia (ALL), but it requires adequate institutional infrastructure, experience, and expertise, especially for alternative donor HSCT. We review our experience with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (APBSCT), followed by post-APBSCT maintenance chemotherapy for children with very high risk ALL. Between August 1997 and November 2012, our institute was not successful with HLA-haploidentical HSCT. Thus, if patients lacked HLA-matched allogeneic donors or cord blood donors, we treated them with HDCT and APBSCT with carmustine, etoposide, cytarabine, and cyclophosphamide, followed by post-APBSCT maintenance chemotherapy with vincristine, oral prednisolone, methotrexate, and 6-mercaptopurine.Ten patients underwent HDCT and APBSCT due to relapse, biphenotype leukemia, Philadelphia translocation, MLL rearrangement, hypodiploidy, and initial white blood cell count above 20.0 × 109/L. At a median 7.4 years from HDCT to APBSCT, overall survival (OS) was 70.0% ± 14.5% and event-free survival (EFS) was 70.0% ± 14.5%. Adverse events were tolerable, without treatment-related mortality.This historical analysis may be a useful reference when allogeneic HSCT including alternative donor HSCT cannot be performed for children with very high risk ALL.


Refolding of a recombinant collagen-targeted TGF-beta2 fusion protein expressed in Escherichia coli.
In this study, a tripartite transforming growth factor-beta (TGF-beta2) fusion protein bearing an N-terminal purification tag and an auxiliary collagen binding decapeptide has been constructed and expressed at high levels in Escherichia coli. The resulting recombinant protein accumulates in an insoluble and biologically inactive inclusion-body complex. The insoluble protein was solubilized in guanidine hydrochloride and a Ni-chelating affinity column was utilized to isolate the 13.5-kDa TGF-beta2 fusion protein, which was then refolded into its native conformation under controlled redox conditions. The formation of native homodimers was monitored by nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis gradient gels and the bioactivity determined by a quantitative TGF-beta assay system using mink lung epithelial cells transfected with a plasminogen activator inhibitor-1 promoter/luciferase reporter plasmid. To optimize yields, renaturation conditions including denaturants, limiting protein concentrations, redox ratios, dialysis conditions, and refolding kinetics were studied and monitored by bioactivity. These studies demonstrate that recombinant TGF-beta2 fusion proteins can be produced in E. coli and renatured into biologically active homodimers. Furthermore, they confirm that the auxiliary collagen binding domain effectively targets the recombinant growth factor to type I collagen. Taken together, these studies advance the technology necessary to generate large quantities of targeted TGF-beta fusion proteins for specific biomedical applications.


Sexual orientation data collection and progress toward Healthy People 2010.
Without scientifically obtained data and published reports, it is difficult to raise awareness and acquire adequate resources to address the health concerns of lesbian, gay, and bisexual Americans. The Department of Health and Human Services must recognize gaps in its information systems regarding sexual orientation data and take immediate steps to monitor and eliminate health disparities as delineated in Healthy People 2010. A paper supported by funding from the Office of the Assistant Secretary for Planning and Evaluation explores these concerns and suggests that the department (1) create work groups to examine the collection of sexual orientation data; (2) create a set of guiding principles to govern the process of selecting standard definitions and measures; (3) recognize that racial/ethnic, immigrant-status, age, socioeconomic, and geographic differences must be taken into account when standard measures of sexual orientation are selected; (4) select a minimum set of standard sexual orientation measures; and (5) develop a long-range strategic plan for the collection of sexual orientation data.


Zn/InCl(3)-mediated pinacol cross-coupling reactions of aldehydes with alpha,beta-unsaturated ketones in aqueous media.
A zinc/indium chloride-mediated pinacol cross-coupling reaction between aldehyde and alpha,beta-unsaturated ketone in aqueous media was developed. The 1,2-diols were obtained in moderate to good yields with up to 93:7 diastereoselectivity.


The dynamics of spatial labor mobility in the Netherlands.
"This paper discusses several factors that may explain [the] dynamic properties of internal labor migration. [The authors] focus especially on the influence of labor market and housing conditions on the mobility of people. A two-stage, generation-allocation model is proposed to investigate the role of different factors in the explanation of aggregate interregional migration flows. This model is applied to recent data on interprovincial labor migration in the Netherlands. The results indicate that housing supply seems to be an important determinant of temporal developments of spatial mobility, and that also the conditions on national and regional labor markets are associated with specific properties of recent migration patterns."


Geographic dispersion of invasive crop pests: the role of basal, plastic climate stress tolerance and other complementary traits in the tropics.
Global pest invasions have significantly increased in recent years. These invasions together with climate warming directly impact agriculture. Tropical climates feature extreme weather events, including high temperatures and seasonal droughts. Thus, successful invasive pests in tropics have to adapt to these extreme climate features. The intrinsic factors relevant to tropical invasion of insects have been explored in many studies, but the knowledge is rather dispersed in contemporary literature. Here, we reviewed the potential biophysical characters of successful invasive pests' adaption to tropical environments including [1] inherent high basal stress tolerance and advanced life-history performances [2], phenotypic plasticity [3], rapid evolution to environmental stress, polyphagy, diverse reproductive strategies and high fecundity. We summarised how these traits and their interactive effects enhance pest invasions in the tropics. Comprehensive understanding of how these characters facilitate invasion improves models for predicting ecological consequences of climate change on invasive pest species for improved pest management.


Overexpression of Endogenous Anti-Oxidants with Selenium Supplementation Protects Trophoblast Cells from Reactive Oxygen Species-Induced Apoptosis in a Bcl-2-Dependent Manner.
The human placenta provides life support for the developing foetus, and a healthy placenta is a prerequisite to a healthy start to life. Placental tissue is subject to oxidative stress which can lead to pathological conditions of pregnancy such as preeclampsia, preterm labour and intrauterine growth restriction. Up-regulation of endogenous anti-oxidants may alleviate placental oxidative stress and provide a therapy for these complications of pregnancy. In this study, selenium supplementation, as inorganic sodium selenite (NaSel) or organic selenomethionine (SeMet), was used to increase the protein production and cellular activity of the important redox active proteins glutathione peroxidase (GPx) and thioredoxin reductase (Thx-Red). Placental trophoblast cell lines, BeWo, JEG-3 and Swan-71, were cultured in various concentrations of NaSel or SeMet for 24 h and cell extracts prepared for western blots and enzyme assays. Rotenone and antimycin were used to stimulate mitochondrial reactive oxygen species (ROS) production and induce apoptosis. Trophoblast cells supplemented with 100 nM NaSel and 500 nM SeMet exhibited significantly enhanced expression and activity of both GPx and Thx-Red. Antimycin and rotenone were found to generate ROS when measured by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, and selenium supplementation was shown to reduce ROS production in a dose-dependent manner. Rotenone, 100 μM treatment for 4 h, caused trophoblast cell apoptosis as evidenced by increased Annexin V binding and decreased expression of Bcl-2. In both assays of apoptosis, selenium supplementation was able to prevent apoptosis, preserve Bcl-2 expression and protect trophoblast cells from mitochondrial oxidative stress. This data suggests that selenoproteins such as GPx and Thx-Red have an important role in protecting trophoblast cells from mitochondrial oxidative stress and that selenium supplementation may be important in treating some placental pathologies.


A Sustainable Approach for Synthesizing (R)-4-Aminopentanoic Acid From Levulinic Acid Catalyzed by Structure-Guided Tailored Glutamate Dehydrogenase.
In this study, a novel enzymatic approach to transform levulinic acid (LA), which can be obtained from biomass, into value-added (R)-4-aminopentanoic acid using an engineered glutamate dehydrogenase from Escherichia coli (EcGDH) was developed. Through crystal structure comparison, two residues (K116 and N348), especially residue 116, were identified to affect the substrate specificity of EcGDH. After targeted saturation mutagenesis, the mutant EcGDHK116C, which was active toward LA, was identified. Screening of the two-site combinatorial saturation mutagenesis library with EcGDHK116C as positive control, the k cat/K m of the obtained EcGDHK116Q/N348M for LA and NADPH were 42.0- and 7.9-fold higher, respectively, than that of EcGDHK116C. A molecular docking investigation was conducted to explain the catalytic activity of the mutants and stereoconfiguration of the product. Coupled with formate dehydrogenase, EcGDHK116Q/N348M was found to be able to convert 0.4 M LA by more than 97% in 11 h, generating (R)-4-aminopentanoic acid with >99% enantiomeric excess (ee). This dual-enzyme system used sustainable raw materials to synthesize (R)-4-aminopentanoic acid with high atom utilization as it utilizes cheap ammonia as the amino donor, and the inorganic carbonate is the sole by-product.


Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex.
Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double-blind randomized placebo-controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long-term potentiation (LTP)-like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS-induced LTP-like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP-like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP-like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma-amino butyric acid-dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage-gated sodium channels by lamotrigine, may also depress PAS-induced LTP-like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED-related adverse effects on important LTP-dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP-like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP-associated process.


Zanthoxyli Fructus induces growth arrest and apoptosis of LNCaP human prostate cancer cells in vitro and in vivo in association with blockade of the AKT and AR signal pathways.
Zanthoxyli Fructus belongs to the family of oranges and is used as a seasoning in Asian countries including Japan. This study found that a water extract of Zanthoxyli Fructus possessed anti-tumor activity against a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC-3), breast (MCF-7, T47D, MDA-MB231), lung (NCI-H460, -H520), as well as leukemia (HL-60, NB4, Jurkat) in vitro, as measured by the trypan blue exclusion test. Importantly, Zanthoxyli Fructus slowed the proliferation of LNCaP, DU145, and MDA-MB231 cells present as xenografts in BALB/c nude mice without adverse effects. Further studies explored the molecular mechanism by which Zanthoxyli Fructus inhibited the proliferation of androgen-dependent human prostate cancer LNCaP cells because Zanthoxyli Fructus possessed the strongest anti-tumor activity against these cells. Zanthoxyli Fructus blocked androgen receptor (AR) signaling in conjunction with down-regulation of nuclear levels of AR and induced apoptosis of these cells, as measured by the reporter assay, Western blot analysis, and TUNEL assay, respectively. As expected, Zanthoxyli Fructus also decreased the level of the AR-target molecule, prostate-specific antigen in these cells. Furthermore, Zanthoxyli Fructus inhibited AKT kinase and down-regulated levels of cyclin D1 protein, as measured by the AKT kinase assay with GSK-3alpha/beta as a substrate and Western blot analysis, respectively. Taken together, Zanthoxyli Fructus might be useful as an adjunctive therapeutic agent for the treatment of individuals with a variety of cancer types.


Expression profile analysis of colon cancer cells in response to sulindac or aspirin.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have a preventive effect against colorectal cancer. Although inhibition of cyclooxygenase-2 plays a crucial role in the suppression of tumors, precise mechanisms of their action remain to be disclosed. To identify genes involved in the growth-suppressive effect of NSAIDs, we utilized cDNA microarray containing 23,040 genes and analyzed time-dependent alteration of gene expression in response to sulindac or aspirin in NSAIDs-sensitive SW480 and SW948 colon-cancer cells as well as in relatively resistant SNU-C4 cells. Consequently we identified 112 genes with commonly altered expression by sulindac and 176 with commonly altered expression by aspirin in the three lines. Addition of sulindac and that of aspirin altered expression levels of 130 and 140 genes, respectively, in SW480 and SW948 cells but not in SNU-C4 cells. These data may lead to a better understanding of growth-suppressive effects on colonic epithelium, and may provide clues for identifying novel therapeutic and/or preventive molecular targets of colon cancer.


[Distribution of the epicardiac neural ganglia in human fetuses of different age].
The epicardiac neural ganglia of the adult human heart are distributed in the seven neural ganglionated subplexuses. The aim of the present investigation was to determine the distribution of the epicardiac ganglia in human fetuses of different age, because intrinsic cardiac nervous system of the human fetus has not been enough investigated so far. In the present study seventeen human fetus hearts were investigated, in which epicardiac neural ganglionated plexus was visualized by histochemical method for acetylcholinesterase. Analysis of the total hearts preparations showed that: (1) the epicardiac neural ganglionated plexus of the fetus at fifteen weeks of gestation has already differentiated into seven ganglionated subplexuses, structure of which is typical for the adult human heart; (2) the epicardiac plexus of fetuses at 15-40 weeks of gestation contains on average 865+/-40 epicardiac ganglia, that may widely range in number from 644 to 1193; (3) the largest number of the neural ganglia is concentrated on the posterior surface of both atria, where up to 76% of all ganglia maybe located; (4) the difference between the number of epicardiac ganglia in the human fetuses at the early (15-25 weeks) and late (26-40 weeks) stages of fetogenesis is not statistically significant (p>0.05). In conclusion, both the distribution and the number of the epicardiac ganglia of fetuses ranging from 15 to 40 weeks of gestation are not age-dependent but varied substantially from heart to heart.


Some transport characteristics of mammalian renal diluting segments.
As a consequence of its ability to absorb salt in excess of water, the thick ascending limb of the mammalian kidney dilutes the urine and supplies the energy for counter current multiplication. This latter effect follows directly from the ability of the medullary thick ascending limb (mTALH) to enrich medullary osmolality. In this review, we consider certain selected aspects of mTALH function that determine its ability to dilute the urine and to contribute to overall renal concentrating power. Specifically, we shall review the mechanisms for salt absorption in the mTALH and the modulation of salt absorption in the mTALH and hence urinary concentrating power, by antidiuretic hormone (ADH), prostaglandin E2 (PGE2) and peritubular hypertonicity. Furthermore, we shall advance an explanation of how these latter three agents modulate mTALH function without affecting external salt balance.


Alcohol consumption over time and mortality in the Swedish Women's Lifestyle and Health cohort.
Alcohol consumption is steadily increasing in high-income countries but the harm and possible net benefits of light-to-moderate drinking remain controversial. We prospectively investigated the association between time-varying alcohol consumption and overall and cause-specific mortality among middle-aged women. Among 48 249 women at baseline (33 404 at follow-up) in the prospective Swedish Women's Lifestyle and Health cohort, age 30-49 years at baseline, we used repeated information on alcohol consumption and combined this method with multiple imputation in order to maximise the number of participants and deaths included in the analyses. Multivariable Cox regression models were used to calculate HRs for overall and cause-specific mortality. During >900 000 person/years, a total of 2100 deaths were recorded through Swedish registries. The median alcohol consumption increased from 2.3 g/day in 1991/1992 (baseline) to 4.7 g/day in 2004 (follow-up). Compared with light drinkers (0.1-1.5 g/day), a null association was observed for all categories of alcohol consumption with the exception of never drinkers. The HR comparing never with light drinkers was 1.46 (95% CI 1.22 to 1.74). There was a statistically significant negative trend between increasing alcohol consumption and cardiovascular and ischaemic heart diseases mortality. The results were similar when women with prevalent conditions were excluded. In conclusion, in a cohort of young women, light alcohol consumption was protective for cardiovascular and ischaemic heart disease mortality but not for cancer and overall mortality.


SARILUMAB FOR RECALCITRANT CYSTOID MACULAR EDEMA IN NON-PARANEOPLASTIC AUTOIMMUNE RETINOPATHY.
To demonstrate a rapid improvement of recalcitrant cystoid macular edema (CME) and perivascular leakage, in a patient with non-paraneoplastic autoimmune retinopathy and autoimmune optic neuropathy after treatment with sarilumab, a human anti-interleukin-6 (IL-6) receptor antibody. Observational case report. A 29-year-old woman was diagnosed with non-paraneoplastic autoimmune retinopathy and autoimmune optic neuropathy and followed over 1.5 years. She had recalcitrant CME despite local corticosteroid and immunosuppressive therapy that included azathioprine and adalimumab. Subcutaneous sarilumab was initiated at a dose of 200 mg every 2 weeks. Cystoid macular edema significantly decreased after two injections and resolved after four injections with associated improvement in visual acuity and significant improvement in perivascular leakage on fluorescein angiography. There was a sustained visual and anatomical improvement at 6 months along with mild improvement in electroretinogram responses. The patient tolerated the medication with no side effects. Management of CME in non-paraneoplastic autoimmune retinopathy is challenging, and long-term immunosuppression is often employed with varying degrees of success. The improvement in refractory CME and perivascular leakage in this case supports the potential role of an IL-6 inhibitor to treat CME associated with non-paraneoplastic autoimmune retinopathy suggesting the role.


Effects of the serotonin releasers 3,4-methylenedioxymethamphetamine (MDMA), 4-chloroamphetamine (PCA) and fenfluramine on acoustic and tactile startle reflexes in rats.
The substituted amphetamines 4-chloroamphetamine (PCA), 3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine (FEN) share the common neurochemical action of acutely releasing central serotonin (5-HT), and yet their behavioral effects are quite different. The present study evaluated the effects of these compounds on acoustic and tactile startle reflexes. PCA and MDMA were qualitatively similar in producing dose-related increases in acoustic and tactile startle reflexes that were slow in onset, but sustained throughout the 3.5-hr test session. Changes in motor activity did not account for the observed excitation of startle. In marked contrast to MDMA and PCA, FEN did not alter tactile startle and tended to depress acoustic startle. The excitatory effect of 20 mg/kg of MDMA was prevented by the 5-HT uptake blockers MDL 27,777A and fluoxetine. MDMA excitation was not affected by a dose of the dopamine antagonist haloperidol that attenuated the startle-enhancing effect of d-amphetamine. MDMA excitation was greatly attenuated by a general depletion of central 5-HT produced by prior intraventricular injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine. PCA and MDMA excitations of startle were attenuated in rats specifically depleted of spinal 5-HT or in rats with radio frequency lesions of the dorsal raphe nucleus. Thus, PCA and MDMA have similar prolonged excitatory effects on startle reflexes that are mediated by ascending (dorsal raphe) and descending (spinal) pathways, whereas FEN differs in its lack of excitation of startle. Differences in the neurochemical properties of these compounds or their patterns of 5-HT release may underlie their different behavioral profiles.


Sensorineural hearing loss in children recovered from purulent meningitis: a study in Thai children at Ramathibodi Hospital.
Hearing loss is one of the serious complications of bacterial meningitis. Conventional audiometry and auditory brainstem response (ABR) methods were used to detect this complication in eighteen children who recovered from bacterial meningitis treated at Ramathibodi Hospital from January 1983 to December 1987. Six patients (33%) were found to have persistent bilateral sensorineural hearing loss. Among them, the causes of meningitis were: Hemophilus influenzae (3 patients), Streptococcus pneumoniae (1 patient), Streptococcus agalactiae (1 patient) and Escherichia coli (1 patient). Various clinical and demographic factors were examined in relation to the hearing loss, but no significant correlation was observed. Since meningitis often affects small children and makes conventional audiometry tests difficult, ABR was found to be a more effective method for testing this group of patients.


Strategies to Improve the Potential Functionality of Fruit-Based Fermented Beverages.
It is only recently that fermentation has been facing a dynamic revival in the food industry. Fermented fruit-based beverages are among the most ancient products consumed worldwide, while in recent years special research attention has been granted to assess their functionality. This review highlights the functional potential of alcoholic and non-alcoholic fermented fruit beverages in terms of chemical and nutritional profiles that impact on human health, considering the natural occurrence and enrichment of fermented fruit-based beverages in phenolic compounds, vitamins and minerals, and pro/prebiotics. The health benefits of fruit-based beverages that resulted from lactic, acetic, alcoholic, or symbiotic fermentation and specific daily recommended doses of each claimed bioactive compound were also highlighted. The latest trends on pre-fermentative methods used to optimize the extraction of bioactive compounds (maceration, decoction, and extraction assisted by supercritical fluids, microwave, ultrasound, pulsed electric fields, high pressure homogenization, or enzymes) are critically assessed. As such, optimized fermentation processes and post-fermentative operations, reviewed in an industrial scale-up, can prolong the shelf life and the quality of fermented fruit beverages.


Isolation of sublineage I Nitrospira by a novel cultivation strategy.
Nitrification is an important process in the biogeochemical nitrogen cycle and is widely exploited in biological wastewater treatment. Recently, Nitrospira has been recognized as the numerically dominant nitrite-oxidizing bacterial genus and is primarily responsible for the second step of aerobic nitrification. Nevertheless, the physiological properties of Nitrospira remain poorly understood because the organisms are difficult to isolate and culture. Here, we report a novel cultivation strategy for obtaining members of the Nitrospira sublineage I in pure culture. The method combines: (i) selective enrichment of Nitrospira using a continuous feeding reactor and (ii) purification followed by sub-cultivation via a cell sorting system by focusing on the unique characteristics of Nitrospira forming spherical micro-colonies. This strategy is potentially applicable to other uncultured or unisolated Nitrospira and could accelerate the physiological and biochemical understandings of this important group of organisms.


Inhaled RNA Therapeutics for Obstructive Airway Diseases: Recent Advances and Future Prospects.
Obstructive airway diseases, e.g., chronic obstructive pulmonary disease (COPD) and asthma, represent leading causes of morbidity and mortality worldwide. However, the efficacy of currently available inhaled therapeutics is not sufficient for arresting disease progression and decreasing mortality, hence providing an urgent need for development of novel therapeutics. Local delivery to the airways via inhalation is promising for novel drugs, because it allows for delivery directly to the target site of action and minimizes systemic drug exposure. In addition, novel drug modalities like RNA therapeutics provide entirely new opportunities for highly specific treatment of airway diseases. Here, we review state of the art of conventional inhaled drugs used for the treatment of COPD and asthma with focus on quality attributes of inhaled medicines, and we outline the therapeutic potential and safety of novel drugs. Subsequently, we present recent advances in manufacturing of thermostable solid dosage forms for pulmonary administration, important quality attributes of inhalable dry powder formulations, and obstacles for the translation of inhalable solid dosage forms to the clinic. Delivery challenges for inhaled RNA therapeutics and delivery technologies used to overcome them are also discussed. Finally, we present future prospects of novel inhaled RNA-based therapeutics for treatment of obstructive airways diseases, and highlight major knowledge gaps, which require further investigation to advance RNA-based medicine towards the bedside.


[The coronary artery structure and early atherosclerotic lesions of 80 young adults cases in the Ningbo fishing region].
In order to study the coronary artery structure in relation to early atherosclerotic lesions of young adults residing in a fishing region, coronary arteries from 80 autopsies of people aged 15 to 39 years who died from accidents were collected and studied by pathohistological, immunohistochemical and morphometric methods. The results showed an 18.67% prevalence of Sudanophilic lesions in the right, coronary artery, the thickness of the intima of the left anterior descending branch increased with increasing age in males, but no significant difference was observed in females, the density of the coronary artery cell nuclei decreased with increasing age. The prevalence of fatty streaks and stenosis of left anterior descending branch was 25.0% and 5.0% respectively, and that of the left circumflex branch was 7.5% and 3.9% respectively. The amount of chondroinn sulfate proteoglycan in the left anterior descending branch was 23.3 +/- 8.8% in intima and 12.0 +/- 4.0% in the media. The above findings suggest that the custom of eating large amounts of sea food may have a beneficial effect on lipid deposit, smooth muscle cell proliferation, thickness of intima and percentage of proteoglycan. Thus it is one of the important factors for the low incidence of coronary heart disease in this fishing region.


CME and the role of the Journal of the Royal College of Physicians of London. Results of a survey of consultant and trainee physicians.
To assess (a) the views of Members and Fellows of the College on the role of reading general medical journals in continuing medical education (CME); (b) the place of the Journal of the Royal College of Physicians of London (JRCPL) in relation to seven other general medical journals; (c) the possible need for change in the content of the JRCPL and the demand for a systematic series of articles designed specifically for CME; (d) the extent of home ownership and use of computers and of readers' readiness for interactive teaching and electronic books and journals. Distribution of a questionnaire to all Fellows and Collegiate members of the College, mailed with the JRCPL in May 1995. Responses were received from 2,600 (26.4% home recipients and 8.4% overseas recipients). Journal reading was rated the most important form of CME. All eight journals listed play a part in CME, the three weekly journals playing the most prominent role. There was strong support for the introduction of a series of articles covering topics systematically as part of CME. Seventy-six per cent of respondents own a home computer and 40% of these have either a CD-ROM drive or full multimedia facilities. Most use their computers mainly as word-processors and few have access to the Internet or E-mail.


Development of a pronunciation teaching perception scale (PTPS) for preservice English language teachers.
The aim of this present research was to develop a valid and reliable scale to determine preservice teachers' perceptions regarding pronunciation teaching. The research sample consisted of 174 preservice teachers in their fourth year studying in English Language Teaching (ELT) departments in eight different universities in North Cyprus in 2021-2022 the academic year. The data collected within the scope of this study were analyzed through SPSS (ver.24) and SPSS Amos software (ver.24) programs to create a valid and reliable measurement tool for the ELT field. The conducted Exploratory Factor Analysis revealed that the scale consisted of 5 factors and 19 items. Moreover, the Confirmatory Factor Analysis results confirmed the five-factor structure. All the dimensions and the overall scale proved to be highly reliable and fit to be applied in the identification of ELT preservice teachers' pronunciation teaching perceptions. Finally, it is hoped that this new scale will help researchers to investigate pronunciation teaching perceptions in various contexts more reliably.


In vitro evaluation of the cytotoxicity of calcium hydroxide-based root canal sealers.
The cytotoxicity of three calcium hydroxide-containing root canal sealers (Sealapex, CRCS and Apexit) was tested by using L929 and BHK 21/C13 cells. After setting for 24 h, the sealers were covered with cell suspension. Cytotoxicity was determined by a quantitative technique at 24 h, 48 h and 72 h. All the sealers were found to be cytotoxic. Sealapex showed the highest cytotoxicity, causing a significant decrease in cell density. CRCS was less toxic than Sealapex and more toxic than Apexit. Apexit proved to be the least toxic material.


Genotype related differences in beta2 adrenergic receptor density and cardiac function.
Several common polymorphisms of the beta2 adrenergic (ADRB2) have been described including a Glycine (Gly) for arginine (Arg) substitution at amino acid 16. In vivo studies have attributed phenotypic differences in the Arg16Gly polymorphism of the ADRB2 to differences in agonist-mediated desensitization. Some studies, however, have shown differences between genotype groups under non-agonist-mediated conditions suggesting baseline differences in receptor function or in receptor density. We sought to determine whether genetic variation of the ADRB2 influenced ADRB2 density and, consequently, resting cardiovascular function. We measured ADRB2 density on isolated lymphocytes in 30 healthy subjects (15 homozygous for Arg, Arg16, and 15 homozygous for Gly, Gly16) matched for age, cardiovascular fitness, BMI, and gender. In addition, we measured cardiac output (Q), heart rate (HR), and stroke volume (SV) after 5 min of quiet rest in these same subjects. Arg16 subjects had lower receptor density (1220 +/- 78 vs 1574 +/- 110, mean +/- SE, P < 0.01) as well as lower resting cardiac output due to a reduced stroke volume, but a higher HR when compared with the Gly16 subjects (Q = 4.3 +/- 0.2 vs 5.0 +/- 0.3 L.min(-1), SV = 65 +/- 6 vs 86 +/- 7 mL.beat(-1), HR = 70 +/- 4 vs 60 +/- 3 beats.min(-1), for the Arg16 and Gly16 groups, respectively, P < 0.01). In addition, ADRB2 density for all subjects was positively associated with cardiac output (r = 0.428, P = 0.009) and stroke volume (r = 0.407, P = 0.001). These data suggest that the Arg16Gly polymorphism of the ADRB2 influences receptor density, which, in turn, contributes to resting differences in cardiac output and stroke volume.


Diacyllipid micelle-based nanocarrier for magnetically guided delivery of drugs in photodynamic therapy.
We report the design, synthesis using nanochemistry, and characterization of a novel multifunctional polymeric micelle-based nanocarrier system, which demonstrates combined function of magnetophoretically guided drug delivery together with light-activated photodynamic therapy. Specifically, the nanocarrier consists of polymeric micelles of diacylphospholipid-poly(ethylene glycol) (PE-PEG) coloaded with the photosensitizer drug 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), and magnetic Fe3O4 nanoparticles. The nanocarrier shows excellent stability and activity over several weeks. The physicochemical characterizations have been carried out by transmission electron micrography and optical spectroscopy. An efficient cellular uptake has been confirmed with confocal laser scanning microscopy. The loading efficiency of HPPH is practically unaffected upon coloading with the magnetic nanoparticles, and its phototoxicity is retained. The magnetic response of the nanocarriers was demonstrated by their magnetically directed delivery to tumor cells in vitro. The magnetophoretic control on the cellular uptake provides enhanced imaging and phototoxicity. These multifunctional nanocarriers demonstrate the exciting prospect offered by nanochemistry for targeting photodynamic therapy.


Treatment-seeking behavior among those with signs and symptoms of acute myocardial infarction.
Significant delays in seeking definitive treatment for the signs and symptoms of acute myocardial infarction increase morbidity and mortality. In most studies, delay times average more than 4 hours. The following variables are associated with increased delay: a medical history of angina, diabetes mellitus, or hypertension; older age; black race; seeking advice from a family member or a physician; symptom onset on a weekday; and attempts at self-treatment. Variables associated with reduced delay times are the following: pain recognized as cardiac in origin, hemodynamic instability, severe chest pain, younger age, and consultation with a coworker. Surprisingly, patients who have already experienced a myocardial infarction are just as likely to delay as patients who have not had this experience. These findings provide direction for developing and testing patient and family interventions, establishing community education programs, and reducing patient delay in response to the signs and symptoms of acute myocardial infarction.


Role of airway receptors in the reflex responses of human inspiratory muscles to airway occlusion.
1. This study was designed to investigate the role of airway receptors in the responses of a range of inspiratory muscles to airway occlusion. The occlusion had a rapid onset (< 10 ms), lasted 250 ms and produced only a slight impediment to inspiration. 2. Based on analysis of single trials and averaged rectified electromyographic responses (EMG) in six subjects, there was a major inhibition (IR) with an onset at 34 +/- 2 ms and a trough at 65 +/- 2 ms, and an excitation (ER) with a peak at 105 +/- 2 ms. These two responses are reflex given that voluntary reaction times to a tap on the chest wall occurred at latencies longer than the peak of ER. 3. The responses to airway occlusion did not appear in limb muscles which contracted phasically with inspiration. 4. Anaesthesia of the surface receptors of the upper airway did not attenuate the responses to occlusion. Because this procedure does not eliminate the inputs from muscle and deep laryngeal pressure receptors, two subjects were tested when intubated with a cuffed endotracheal tube so that the occlusion was delivered only to structures below the level of the trachea. Responses to airway occlusion were preserved when all upper airway receptors were 'bypassed'. 5. Responses to airway occlusion also remained after prolonged inhalation of nebulized lidocaine (lignocaine) sufficient to block the cough reflex. 6. The receptors mediating the responses to airway occlusion are therefore likely to reside in inspiratory muscles acting on the chest wall. If so, the short-latency inhibition contrasts with the excitatory stretch reflex responses observed in limb muscles.


Gastrointestinal bleeding detection in wireless capsule endoscopy images using handcrafted and CNN features.
Gastrointestinal (GI) bleeding detection plays an essential role in wireless capsule endoscopy (WCE) examination. In this paper, we present a new approach for WCE bleeding detection that combines handcrafted (HC) features and convolutional neural network (CNN) features. Compared with our previous work, a smaller-scale CNN architecture is constructed to lower the computational cost. In experiments, we show that the proposed strategy is highly capable when training data is limited, and yields comparable or better results than the latest methods.


Comparison of Roth appliance and standard edgewise appliance treatment results.
A retrospective comparison of Roth appliance and standard edgewise appliance treatment results was made using two indices. The first, the ideal tooth relationship index (ITRI), scored dental casts for the presence of ideal tooth contacts. The second judged posttreatment dental casts on the basis of criteria established by Andrews in his "Six Keys to Normal Occlusion." The sample consisted of 120 orthodontically treated cases completed by two practitioners who have used both the Roth and standard edgewise appliances. Thirty cases of each appliance type were collected from each practitioner. The overall posttreatment ITRI percentage scores showed no significant differences between the appliances. Practitioner differences existed for the anterior intraarch, anterior interarch, and posterior buccal interarch relationships. These differences were related to both treatment time and finishing arch wire size. The results of the Six Keys Analysis showed that the angulation and inclination of the maxillary posterior teeth were better with the Roth appliance. However, success in achieving some components of the six keys did not translate into an increased percentage of ideal tooth contacts as measured by the ITRI. Despite using the Roth appliance, experienced clinicians still found it difficult to achieve all six keys to normal occlusion.


Effect of regulatory mutations of sulphur metabolism on the levels of cysteine- and homocysteine-synthesizing enzymes in Neurospora crassa.
1. Regulation of four enzymes involved in cysteine and homocysteine synthesis, i.e. cysteine synthase (EC 18.104.22.168), homocysteine synthase (EC 126.96.36.199), cystathionine beta-synthase (EC 2.1.22) and gamma-cystathionase (EC 184.108.40.206) was studied in the wild type and sulphur regulatory mutants of Neurospora crassa. 2. Homocysteine synthase and cystathionine beta-synthase were found to be regulatory enzymes but only the former is under control of the cys-3 - scon system regulating several enzymes of sulphur metabolism, including gamma-cystathionase. 3. The results obtained with the mutants strongly suggest that homocysteine synthase plays a physiological role as an enzyme of the alternative pathway of methionine synthesis. Cysteine synthase activity was similar in all strains examined irrespective of growth conditions. 4. The sconc strain with derepressed enzymes of sulphur metabolism showed an increased pool of sulphur amino acids, except for methionine. Particularly characteristic for this pool is a high content of hypotaurine, a product of cysteine catabolism.


Sudden power loss in a HeartMate II left ventricular assist device due to intermittent pin contact with the battery: case report.
Left ventricular assist device technology has improved such that mechanical malfunction, particularly with newer generation continuous flow devices, is a relatively rare event. We present a case of sudden power loss in a HeartMate II caused by intermittent contact of the battery terminals after a clip was dropped with the battery inserted in it. The clip was replaced and the patient made a complete recovery. A new inspection and testing methodology, and amended approach to patient and caregiver training, designed to prevent future occurrences is described.


Rapid and simultaneous HLA class I (-A, -B and -C loci) DNA typing using the microtitre plate-reverse hybridization assay (MRHA).
We have established a precise, rapid, simple and practical HLA class I DNA typing method using the microtitre plate-reverse hybridization assay (MRHA), which enables us to perform simultaneous DNA typing of the HLA-A, -B and -C loci using the same PCR parameters and hybridization conditions. PCR-amplified products for the HLA-A, -B and -C loci were hybridized, respectively, with sequence-specific oligonucleotide (SSO) probes, which were immobilized covalently onto a microtitre plate, in hybridization buffer containing formamide at 37 degrees C. After washing at room temperature, the bound PCR products were detected by peroxidase-conjugate streptavidine followed by colour development such as enzyme immunoassay (EIA). In addition to the simple thermoregulation for hybridization and postwashing, strong positive signals, low background and high reproducibility, this DNA typing method enabled simultaneous typing of the HLA-A, -B and -C loci using a single microtitre plate as in HLA serotyping. The assignment of the HLA genotype was easily achieved by automated colorimetric reading and computer software, based on the cut-off value (threshold) established for each probe. For routine HLA class I typing, it may be possible to replace serological typing with the HLA class I DNA typing system using our MRHA method.


Probing molecular motion by double-quantum (13C,13C) solid-state NMR spectroscopy: application to ubiquitin.
We demonstrate the use of two-dimensional ((13)C,(13)C) double-quantum spectroscopy to detect molecular dynamics by solid-state NMR. Data collected on tyrosine-ethylester (TEE) are in line with previously determined ((1)H,(13)C) order parameters. Application of these experiments to microcrystalline ubiquitin reveals the presence of dynamics on millisecond or faster time scales and differences in local mobility depending on microcrystal preparation. In addition, solid-state NMR-based structure calculation indicates conformational variability of loop regions between different solid-phase ubiquitin preparations. Our data relate preparation-dependent changes observed in NMR spectral parameters such as chemical shifts and through-space correlations to differences in ubiquitin dynamics and conformation and suggest a prominent role of molecular mobility in microcrystalline ubiquitin.


Hepatoprotective effect of Anacyclus pyrethrum Linn. against antitubercular drug-induced hepatotoxicity in SD rats.
Traditional remedies employ herbal drugs for the treatment of liver ailments and hepatoprotection. Thus, the present study was designed to evaluate the hepatoprotective effect of "extract of Anacyclus pyrethrum Linn" (APE) against antitubercular drug-induced hepatotoxicity in rats. Group I rats (normal control) received vehicle (1 % CMC), while group II rats (hepatotoxic control) isoniazid (INH) plus rifampicin (RIF) each 50 mg/kg/day po, for 28 days. Group III, IV and V rats were administered with APE 200, APE 400 and silymarin 100 mg/kg/day po, respectively, for 28 days. Concurrently, hepatotoxicity was tried to induce by coadministration of INH and RIF each 50 mg/kg/day po for 28 days in group III, IV and V rats. After 24 h of the last dosing, blood was obtained under light anesthesia and the rats were killed. Hepatoprotective effect was assessed by liver weight, relative liver weight and biochemical parameters such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), serum bilirubin, cholesterol, total protein and albumin levels. Group IV rats showed significant (p<0.01) decrease in SGPT, SGOT, ALP, LDH, cholesterol, serum bilirubin, liver weight and relative liver weight Levels, while significant (p<0.01) increase in final body weight (b. wt.), total protein and albumin levels as compared to group II rats. Hepatoprotective effect of APE 400 mg/kg/day was comparable to that of silymarin 100 mg/kg/day and the hepatic marker levels were also restored. Hepatoprotective effect of APE was well supported by the histopathological results. Hydroalcoholic APE root possesses hepatoprotective activity as it exhibited the protective effect against INH plus RIF-induced hepatotoxicity in rats.


Successful treatment of endobronchial amyloidosis using Nd:YAG laser therapy as an alternative to lobectomy.
Endobronchial amyloidosis may cause local obstruction associated with a variety of clinical presentations including recurrent respiratory infection. Although some patients may require surgical intervention, encouraging experience with endobronchial Neodymium (Nd):YAG laser therapy in the management of this condition is reported. Two patients with localized endobronchial amyloidosis were treated with endobronchial Nd:YAG laser therapy. One patient received two treatments for right upper lobe amyloid and another patient received three treatments for right lower lobe amyloid. Excellent clearance of amyloid was achieved in each patient. The first patient remains well, 16 months post-treatment with full patency of the apical and posterior segments. Ten months post-treatment, the second patient has full patency of the right lower lobe. No complications occurred in association with Nd:YAG laser therapy. Endobronchial Neodymium:YAG laser treatment should be considered for selected patients with localized endobronchial obstruction due to amyloidosis.


A bivalent typhoid live vector vaccine expressing both chromosome- and plasmid-encoded Yersinia pestis antigens fully protects against murine lethal pulmonary plague infection.
Live attenuated bacteria hold great promise as multivalent mucosal vaccines against a variety of pathogens. A major challenge of this approach has been the successful delivery of sufficient amounts of vaccine antigens to adequately prime the immune system without overattenuating the live vaccine. Here we used a live attenuated Salmonella enterica serovar Typhi strain to create a bivalent mucosal plague vaccine that produces both the protective F1 capsular antigen of Yersinia pestis and the LcrV protein required for secretion of virulence effector proteins. To reduce the metabolic burden associated with the coexpression of F1 and LcrV within the live vector, we balanced expression of both antigens by combining plasmid-based expression of F1 with chromosomal expression of LcrV from three independent loci. The immunogenicity and protective efficacy of this novel vaccine were assessed in mice by using a heterologous prime-boost immunization strategy and compared to those of a conventional strain in which F1 and LcrV were expressed from a single low-copy-number plasmid. The serum antibody responses to lipopolysaccharide (LPS) induced by the optimized bivalent vaccine were indistinguishable from those elicited by the parent strain, suggesting an adequate immunogenic capacity maintained through preservation of bacterial fitness; in contrast, LPS titers were 10-fold lower in mice immunized with the conventional vaccine strain. Importantly, mice receiving the optimized bivalent vaccine were fully protected against lethal pulmonary challenge. These results demonstrate the feasibility of distributing foreign antigen expression across both chromosomal and plasmid locations within a single vaccine organism for induction of protective immunity.


Influence of Carbon Substrates on Lactic Acid, Cell Mass and Diacetyl-Acetoin Production in Lactobacillus plantarum.
Production of diacetyl-acetoin, lactic acid and cell mass by L. plantarum strains ATCC 8014, ATCC 14431, ATCC 4008 and ATCC 8041 were examined in the growth medium of Craig and Snell (J. Bacteriol. 61:283,1951) containing glucose, lactose, citrate or pyruvate as substrates. The yield coefficient, μM lactate produced per mg cell dry weight, averaged 73.4 for glucose-grown cells and 64.9 for lactose-grown cells with no significant inter-strain difference. Strains that produced higher lactic acid concentrations did so because they produced more cell mass. Glucose and lactose reduced diacetyl-acetoin synthesis in all strains except 8041. Diacetyl-acetoin synthesis doubled when strains 14431 and 8014 were grown in medium containing 20 mM citrate, but was not markedly affected in strains 4008 and 8041. Pyruvate stimulated diacetyl-acetoin synthesis in all four strains 10- to 20-fold. Conversion of pyruvate to diacetyl and acetoin was ⩾30% of the theoretical molar yield for strains 8014, 8041 and 14431 grown in the presence of 20 mM pyruvate.


Pneumopericardium associated with face-mask continuous positive airway pressure.
This is an uncommon case of a patient who developed pneumopericardium while being treated with face-mask continuous positive airway pressure (CPAP) for hypoxic respiratory failure following a coronary artery bypass graft surgery. A pneumopericardium detected by chest radiograph resolved completely after discontinuation of face-mask CPAP. Possible mechanisms that may have been involved in this unusual complication are reviewed.


Recent advances in the management of nut allergy.
Peanut/tree nut allergy is common and has been associated with particularly severe reactions. Epidemiological data have shown that the prevalence ranges between 0.05% and 4.9% for tree nut and between 0.5% and 3% for peanut. These large variations can be explained by differences in the age of included patients and the geographical region. In addition, the food consumption modality (ie, raw versus roasted) plays a major role, as heat treatment has the capacity to modify the allergenicity of nuts and legumes. Nut allergies tend to persist into adulthood and consequently have a high impact on quality of life. Recently, it has been demonstrated that a significant proportion of nut allergic patients are able to tolerate other nuts. As opposed to the avoidance of all nuts, this approach is currently proposed in several tertiary allergy centers. However, diagnosis of nut allergy is particularly difficult due to co-sensitization leading to high rate of false positive skin prick tests and/or specific IgE to whole allergen extracts. The use of component resolved diagnosis leads to major improvement of diagnosis, particularly to distinguish between primary and secondary nut allergies. The basophil activation test has been suggested to be useful but is still used mainly as a research tool. Thus, diagnosis remains mainly based on the oral food challenge, which is considered as the gold standard. Regarding treatment, avoidance remains the cornerstone of management of nut allergy. Oral immunotherapy is increasingly proposed as an alternative management strategy.


Analysis of endogenous glutathione-adducts and their metabolites.
The ability to conduct validated analyses of glutathione (GSH)-adducts and their metabolites is critically important in order to establish whether they play a role in cellular biochemical or pathophysiological processes. The use of stable isotope dilution (SID) methodology in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides the highest bioanalytical specificity possible for such analyses. Quantitative studies normally require the high sensitivity that can be obtained by the use of multiple reaction monitoring (MRM)/MS rather than the much less sensitive but more specific full scanning methodology. The method employs a parent ion corresponding to the intact molecule together with a prominent product ion that obtained by collision induced dissociation. Using SID LC-MRM/MS, analytes must have the same relative LC retention time to the heavy isotope internal standard established during the validation procedure, the correct parent ion and the correct product ion. This level of specificity cannot be attained with any other bioanalytical technique employed for biomarker analysis. This review will describe the application of SID LC-MR/MS methodology for the analysis of GSH-adducts and their metabolites. It will also discuss potential future directions for the use of this methodology for rigorous determination of their utility as disease and exposure biomarkers.


Crystallization of a core fragment of the flagellar hook protein FlgE.
A core fragment of the bacterial flagellar hook protein FlgE was overexpressed, purified and crystallized. The crystal diffracted to 1.6 A resolution using synchrotron X-radiation. The crystal belongs to the orthorhombic crystal system, with space group P2(1)2(1)2 and unit-cell parameters a = 128.4, b = 48.8, c = 96.7 A. SeMet protein was also overexpressed, purified, crystallized and a set of 2.3 A MAD data was collected.


Guideline-Based Clinical Assessment Versus Procalcitonin-Guided Antibiotic Use in Pneumonia: A Pragmatic Randomized Trial.
Efforts to reduce unnecessary and unnecessarily long antibiotic treatment for community-acquired pneumonia have been attempted through use of procalcitonin and through guidelines based on serial clinical assessment. Our aim is to compare guideline-based clinical assessment- and procalcitonin algorithm-guided antibiotic use among patients with community-acquired pneumonia. We performed a pragmatic, randomized, multicenter trial from November 2012 to April 2015 at 12 French hospitals. We included emergency department (ED) patients older than 18 years with community-acquired pneumonia. Patients were randomly assigned to either the procalcitonin-guided or clinical assessment group. In accordance with past studies, we hypothesized that serial clinical assessment would be superior to procalcitonin-guided care. The primary outcome was antibiotic duration, and secondary outcomes included rates of antibiotic duration less than or equal to 5 days, and clinical success and combined serious adverse outcomes at 30 days in the intention-to-treat population. Of 370 eligible patients, 285 (77%) were randomly assigned to either clinical assessment- (n=143) or procalcitonin-guided care (n=142). Median age was 67 years (range 18 to 93 years) and 40% of patients were deemed to have Pneumonia Severity Index class IV or V. Procalcitonin algorithm adherence was 76%. Antibiotic duration was not significantly different between clinical assessment- and procalcitonin-guided groups (median 9 versus 10 days, respectively). Clinical success rate was 92% in each group and serious adverse outcome rates were similar (15% versus 20%, respectively). Guideline-based serial clinical assessment did not reduce antibiotic exposure compared with procalcitonin-guided care among ED patients with community-acquired pneumonia. The strategies were similar in terms of duration of antibiotic use and clinical outcomes.


Prognostic value of renin and prorenin in heart failure patients with decreased kidney function.
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of heart failure (HF) and concomitant kidney dysfunction. Despite the use of RAAS blockade, sustained activation of RAAS has been suggested to link with adverse outcome. We aimed to investigate the prognostic value of active plasma renin concentration (APRC) and prorenin in patients with HF treated with RAAS-blocking agents and its relationship with kidney function parameters. One hundred clinically stable patients with HF, treated with RAAS-blocking agents, were studied. Renal function parameters including effective renal plasma flow and glomerular filtration rate were measured invasively. The combined end point consisted of all-cause mortality, heart transplantation, and admission to hospital for HF. Mean age was 58 ± 12 years, and 76% were men. Mean left ventricular ejection fraction was 28 ± 9, and median APRC levels were 24.3 ng/mL per hour. Active plasma renin concentration was most strongly associated with mean arterial pressure (r = 0.60, P < .001). In multivariate linear regression analysis, age, mean arterial pressure, angiotensin II concentration, and use of aldosterone antagonists were significantly related with APRC (adjusted R(2) = 0.53). Patients in the highest quartile of APRC had a worse prognosis. In multivariate analysis, APRC remained associated with worse prognosis: HR 2.87 (95% CI 1.14-7.20), P = .025. Prorenin did not show prognostic value. The prognostic value of APRC was strongest in patients with decreased kidney function. Our data indicate that APRC is a strong prognostic factor in patients with HF in the presence of RAAS inhibition, especially in patients with kidney dysfunction.


Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: a randomized, controlled pilot trial with long-term follow-up.
It is proposed that Fusobacterium varium might be one of the elusive pathogenic factors in ulcerative colitis (UC). Our goal was to assess whether an antibiotic combination therapy against F. varium is effective for induction and maintenance of remission of UC. Twenty chronic, active UC patients with F. varium infection were enrolled consecutively and were randomly assigned to receive amoxicillin, tetracycline or metronidazole per os for 2 weeks (treatment group; n=10), or no antibiotics (control group; n=10). F. varium was sensitive to the antibiotics. Symptom assessment, endoscopic and histological evaluations were performed blind before enrollment at 3-5 months and 12-14 months after the treatment. Serum immunoglobulins to F. varium were measured using an enzyme-linked immunosorbent assay (ELISA). Immunohistochemical detection of F. varium in biopsy specimens was carried out using the avidin-biotin complex method. The clinical activity, endoscopic and histological scores in the treatment group decreased significantly at 3-5 and 12-14 months after the end of treatment compared with those in the control group (p=0.001-0.036). The remission rate in the treatment group was higher than that in the control group (p=0.037). In addition, the titers of antibody to F. varium and the F. varium density in the mucosa decreased at both the short- and long-term follow-ups in the treatment group (p=0.0002-0.049). No serious drug-related toxicity was observed during the trial. The 2-week antibiotic combination therapy against F. varium was effective and safe in patients with chronic, active ulcerative colitis in this long-term follow-up study.


Morphine versus oxycodone in pancreatic cancer pain: a randomized controlled study.
According to experimental findings, oxycodone (OX) could have some advantages over morphine (MO) in clinical models of visceral pain. It was hypothesized that OX could have some advantages over MO in terms of efficacy and dose escalation in pancreatic cancer pain. Sixty patients with pancreatic cancer with a pain intensity rating of 4/10 who required opioids were included in the study. Patients were randomized to receive 30 mg/d of sustained release oral MO or sustained release oral OX (20 mg/d). Opioid doses were increased according to the clinical needs. Daily doses of opioids, pain and symptom intensity were recorded at admission (T0) and at weekly intervals for the subsequent 4 weeks (T1, T2, T3, and T4), with an extension at 8 weeks (T8). Opioid escalation index (OEI) as percentage (OEI %) and in mg (OEI mg) was calculated. Nineteen and 20 patients in groups OX and MO, respectively, were followed for the entire period of study (T4). No differences between groups were found in age (P=0.400), Karnofsky (P=0.667), or escalation indexes at T4 and T8 (OEImg, P=0.945 and OEI %, P=0.295). No statistical differences in pain and symptoms intensity between the groups were observed. OX and MO provided similar analgesia and adverse effects with similar escalating doses in patients with pancreatic cancer pain, resembling observations reported in the general cancer pain population. The experimental hypothesis that OX would be superior to MO in the clinical model of pancreatic cancer pain was not confirmed.


Jejunal/kidney glucose transporter isoform (Glut-5) is expressed in the human blood-brain barrier.
The recently cloned Glut-5, glucose transporter isoform, is expressed in human jejunum and kidney. Employing previously characterized polyclonal antibodies directed towards the C-terminus region of the derived human Glut-5 peptide and Western blot analysis, a 50-55 kilodalton Glut-5 protein was detected in adult human brain homogenates. The amount of Glut-5 protein in brain was 4-fold lower when compared to the levels in adult kidney. Immunohistochemical analysis using cerebral and cerebellar sections demonstrated Glut-5 immunoreactivity in only some of the Glut-1 and factor VIII-positive brain microvascular endothelial cells, the intravascular red and white blood cells being negative. This selective localization pattern was confirmed by the 5-fold enrichment of Glut-5 vs. a 20-fold enrichment of Glut-1 in an isolated human cerebral cortical microvascular preparation, when compared to whole cerebral homogenates. We conclude that Glut-5 is localized in the endothelial cells of human brain microvasculature. Unlike other fructose using tissues, where Glut-5 may subserve the role of a fructose carrier, in brain where fructose is not used as a substrate, Glut-5 may transport glucose alone. This role of Glut-5 in conjunction with the previously characterized brain endothelial Glut-1 and Glut-3 needs further elucidation.


Differential use of signal peptides and membrane domains is a common occurrence in the protein output of transcriptional units.
Membrane organization describes the orientation of a protein with respect to the membrane and can be determined by the presence, or absence, and organization within the protein sequence of two features: endoplasmic reticulum signal peptides and alpha-helical transmembrane domains. These features allow protein sequences to be classified into one of five membrane organization categories: soluble intracellular proteins, soluble secreted proteins, type I membrane proteins, type II membrane proteins, and multi-spanning membrane proteins. Generation of protein isoforms with variable membrane organizations can change a protein's subcellular localization or association with the membrane. Application of MemO, a membrane organization annotation pipeline, to the FANTOM3 Isoform Protein Sequence mouse protein set revealed that within the 8,032 transcriptional units (TUs) with multiple protein isoforms, 573 had variation in their use of signal peptides, 1,527 had variation in their use of transmembrane domains, and 615 generated protein isoforms from distinct membrane organization classes. The mechanisms underlying these transcript variations were analyzed. While TUs were identified encoding all pairwise combinations of membrane organization categories, the most common was conversion of membrane proteins to soluble proteins. Observed within our high-confidence set were 156 TUs predicted to generate both extracellular soluble and membrane proteins, and 217 TUs generating both intracellular soluble and membrane proteins. The differential use of endoplasmic reticulum signal peptides and transmembrane domains is a common occurrence within the variable protein output of TUs. The generation of protein isoforms that are targeted to multiple subcellular locations represents a major functional consequence of transcript variation within the mouse transcriptome.


Kinetic modeling of the polymer-derived ceramics route: investigation of the thermal decomposition kinetics of poly[B-(methylamino)borazine] precursors into boron nitride.
A complete kinetic modeling of the polymer-derived ceramics (PDCs) route is achieved for the first time through the investigation of the solid-state decomposition of a typical melt-spinnable poly[B-(methylamino)borazine] into boron nitride fibers at various heating rates. Through the use of the Lorentz fitting approach, it is shown that the two-step weight loss associated with the polymer-to-ceramic conversion is governed by a complex interplay of five diffusion-type transport mechanisms that are independent of the applied heating schedule. The application of the Friedman method to dynamic thermogravimetry data yields Ea and ln A values that are seen to increase with the extent of the ceramic conversion from region one (Ea = 38.73 kJ mol(-1)) to region five (Ea = 146.64 kJ mol(-1)). This fact indicates that both the mechanisms within those regions are parallel routes to the formation of the final solid-state material and their complexity increases with the conversion progress. The cross-linking process (first weight loss) of the polymer is governed by three dependent poorly energetic mechanisms. The first weight loss is activated by ammonolysis reactions that provide a modified polymer capable of undergoing condensation reactions in regions two and three to yield a highly cross-linked polymer. A large evolution of methylamine is identified during this process. Mineralization (region four) and ceramization (region five) steps are represented by two highly energetic multistep mechanisms. The mineralization step is associated with a large evolution of methylamine and occurs during the transition between the cross-linking and ceramization processes through the cleavage of the inter-ring B-N bonds. Ceramization represents the end of the polymer-to-ceramic conversion in which the planar consolidation of BN hexagons occurs through complex structural rearrangements of the borazine units (cleavage of the intraring B-N bonds) accompanied with an ammonia evolution. Finally, the simulation of the polymer-to-ceramic conversion was demonstrated through a simplified model that appropriately predicted experimental data.


Preterm birth: associated neuroendocrine, medical, and behavioral risk factors.
Increased CRH secretion by the placenta of pregnant women has been associated with preterm birth. Certain indices of risk, both medical and psychosocial in nature, have been linked to preterm delivery. Levels of total, bound, and free CRH, CRH-binding protein (CRH-BP), and cortisol were measured prospectively in a large sample of pregnant Danish women who delivered preterm and term infants. Measures of maternal serum hormones were taken at 7--23 and 27--37 weeks gestation and, for those who delivered at term, at 37--43 weeks gestation. At 7--23 weeks gestation, maternal levels of total CRH (P = 0.01), bound CRH (P = 0.03), and CRH-BP (P = 0.01) were higher in the preterm than in the term group. At 27--37 weeks gestation, levels of total CRH (P < 0.0001), bound CRH (P < 0.0001), free CRH (P < 0.0001), and cortisol (P < 0.0001) were all higher in the preterm than the term group, whereas levels of CRH-BP (P < 0.0001) were lower in the preterm than in the term group. The best medical and behavioral factors associated with preterm delivery were, respectively, previous preterm delivery (P < 0.0001) and engagement in certain risk-taking behaviors (P = 0.008). The positive relations between preterm delivery and various adverse medical and socioeconomic variables with increases in placental secretion of CRH suggest that the latter may participate in the pathophysiology of preterm delivery.


Alteration of phosphotyrosine phosphatase activity in tissues from diabetic and pregnant rats.
Membrane-associated tyrosine phosphatase activities were studied in two distinct states of insulin resistance: diabetes and pregnancy. Using a novel immunoenzymatic assay with intact insulin-like growth factor-I (IGF-I) and insulin receptors as substrates, we show that phosphotyrosine-protein phosphatases (PTP-ases) from normal rat tissues induce a decrease in tyrosine phosphorylation of both receptors. Membrane fractions from kidney, brain, and liver contain the highest PTP-ase activity toward the insulin receptor. After 20-day streptozotocin-induced diabetes, PTP-ase activities are increased by 70% in the placenta, reduced by 40-50% in liver and skeletal muscle, and remained unchanged in the nonclassical insulin target tissues, kidney and brain. In general, the dephosphorylation of IGF-I receptor follows a pattern similar to that of insulin receptor except in red skeletal muscle in which it is not modified. Pregnancy also induces alterations of liver PTP-ases similar to those elicited by diabetes with a 50% reduction of insulin and IGF-I receptor dephosphorylation. This effect of pregnancy is further potentiated by diabetes. The alterations in the activity of hepatic PTP-ases from diabetic and pregnant rats are associated with a decreased autophosphorylation of the insulin receptor, suggesting that the diminution of phosphatase activity might be associated to the state of receptor phosphorylation and activation. Our data demonstrate that alterations of PTP-ases in insulin target tissues are found in two insulin-resistant states, one characterized by hyperinsulinemia, pregnancy and one by insulinopenia, streptozotocin-diabetes. These observations suggest a possible relationship between the defective activity of receptor tyrosine kinases and membrane-associated phosphatases from insulin responsive tissues.


Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats.
The present study was aimed to evaluate the antihypertensive effect of diosmin in deoxycorticosterone acetate (DOCA)-salt induced hypertension in male Wistar rats. Hypertension was induced in uninephrectomized rats by weekly twice subcutaneous injection of DOCA (25 mg/kg body weight) and 1% NaCl in the drinking water for six consecutive weeks. The important pathological events that occurred in DOCA-salt treated rats were significant increase in systolic, diastolic blood pressure, sodium and chloride in serum and lipid peroxidation products (thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes) in plasma and tissues (liver, kidney, heart and aorta) and significant decrease in serum potassium, total nitrite and nitrate levels in plasma. The activities of hepatic aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase and the levels of renal urea, uric acid, creatinine in serum, water intake, and organ weight (kidney and heart) were significantly increased in DOCA-salt hypertensive rats. DOCA-salt treated rats also showed a significant decrease in body weight, activities of superoxide dismutase, catalase and glutathione peroxidase in erythrocyte and tissues and the levels of reduced glutathione, vitamin C and vitamin E in plasma and tissues. Treatment with diosmin (25, 50 and 100 mg/kg body weight) brings back all the above parameters to near normal level, in which 50 mg/kg body weight showed the highest effect than that of other two doses. Histopathology of heart and kidney also confirmed the protective effect of diosmin. Thus the experiment clearly showed that diosmin acts as an antihypertensive agent against DOCA-salt induced hypertension.


Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors.
Enzastaurin is an oral serine/threonine kinase inhibitor that targets the protein kinase C (PKC) and phosphoinositide 3-kinase/AKT pathways to induce apoptosis and suppress proliferation of various cancer cell lines. This phase I study evaluated the tolerability and pharmacokinetics of enzastaurin in Japanese patients with advanced solid tumors and determined the recommended dose for phase II. Eligible patients had advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received enzastaurin orally once daily until disease progression (PD) or unacceptable toxicity occurred. Enzastaurin was started at 250 mg/day followed by stepwise dose increases based on the incidence of dose-limiting toxicities (DLT). Twenty-three patients (seven patients: 250 mg; six patients: 375 mg; six patients: 500 mg; four patients: 750 mg) were enrolled and received enzastaurin. The major tumor types were non-small-cell lung cancer (n = 5) and breast cancer (n = 3). No DLT was reported at doses of 500 mg or less. Because two DLT (grade 2 QTc prolongation lasting for a week) were observed at 750 mg enzastaurin, this was determined as the maximum tolerated dose. Multiple daily doses at 500 mg achieved the target plasma concentration to inhibit PKC activity (1400 nmol/L). Enzastaurin was well tolerated up to 500 mg in Japanese patients with advanced solid tumors. The recommended dose for phase II was determined to be 500 mg daily for a 28-day cycle on the basis of safety and plasma exposures.


Stress changes in intervertebral discs of the cervical spine due to partial discectomies and fusion.
Spine discectomy and fusion is a widely used surgical procedure to correct irreversible degenerative diseases and injuries to the intervertebral disk. The surgical procedure involves the removal of the damage disk material, the decortication of the fusion site, and the placement of the bone graft. Fusion is believed to generate additional stresses in the neighboring disks, which can subsequently lead to new disk degeneration and re-operation. The autologous bone has proven to be the best material for the fusion. However, the autologous bone has three major disadvantages: the high rate of donor site morbidity, the limited and sometimes poor quality of the amounts of bone available, and the extra operative time needed for harvest. For these reasons this study is undertaken to estimate the optimum amount of bone graft needed for a discectomy and correlate it to the change in stress in adjacent levels. A detailed and validated 3D finite element model of the complete human cervical spine (C1-T1) was altered to simulate segmental full and partial discectomies. One full fusion (bone graft occupies about 90% of the vertebral body) and seven partial fusions (bone graft occupies about 10%, 20%, 30%, 40%, 50%, 65%, and 75% of the vertebral body) were simulated at each of the four mid- and lower single levels of the cervical spine and the relationship between the change in stresses in the adjacent levels and the bone graft size (area) was studied. The changes in stress were compared with the previously obtained results of the unfused models. The fused and unfused models were preloaded with a 73.6 N compressive force representing the weight of the head and with a 1.5 Nm physiological moment in flexion, extension, lateral bending, and axial rotation. More than 132 cases were analyzed. The results showed that the necessary amount of bone graft needed for discectomy depends on the cervical disk level to be fused and varies between 30% and 75% of the disk area. The results also suggested that there is a threshold size of the bone graft area, before and/or after which, the long-term effects of the change in stresses in adjacent disks are biomechanically consequential.


Ethylene-Mediated Regulation of Gibberellin Content and Growth in Helianthus annuus L.
Elongation of hypocotyls of sunflower can be promoted by gibberellins (GAs) and inhibited by ethylene. The role of these hormones in regulating elongation was investigated by measuring changes in both endogenous GAs and in the metabolism of exogenous [(3)H]- and [(2)H(2)]GA(20) in the hypocotyis of sunflower (Helianthus annuus L. cv Delgren 131) seedlings exposed to ethylene. The major biologically active GAs identified by gas chromatography-mass spectrometry were GA(1), GA(19), GA(20), and GA(44). In hypocotyls of seedlings exposed to ethylene, the concentration of GA(1), known to be directly active in regulating shoot elongation in a number of species, was reduced. Ethylene treatment reduced the metabolism of [(3)H]GA(20) and less [(2)H(2)]GA(1) was found in the hypocotyls of those seedlings exposed to the higher ethylene concentrations. However, it is not known if the effect of ethylene on GA(20) metabolism was direct or indirect. In seedlings treated with exogenous GA(1) or GA(3), the hypocotyls elongated faster than those of controls, but the GA treatment only partially overcame the inhibitory effect of ethylene on elongation. We conclude that GA content is a factor which may limit elongation in hypocotyls of sunflower, and that while exposure to ethylene results in reduced concentration of GA(1) this is not sufficient per se to account for the inhibition of elongation caused by ethylene.


Altered expression of SIRPγ on the T-cells of relapsing remitting multiple sclerosis and type 1 diabetes patients could potentiate effector responses from T-cells.
Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.


Beta-amyloid fragment 25-35 selectively damages platelets from patients with Alzheimer's disease.
In order to analyze the metabolic response of AD patient platelets to beta-amyloid, we have carried out fluorimetric measurements of intracellular calcium and an ultrastructural survey of platelets exposed to the beta-amyloid active fragment 25-35 (betaA(25-35)). Since it is not possible to analyze directly the damaged neurons in AD, the study of peripheral blood cells, especially platelets, may be of great value for the investigation of the toxic effects of beta-amyloid on AD neuronal cells.


[The protective effect of SOD on injury of bone marrow hematopoietic progenitor cells of mice under 4 degrees C storage].
The protective effect of Cu, Zn, SOD on bone marrow hematopoietic progenitor cells of mice, under 4 degrees C storage was studied. The results showed, if 1.65 U or 0.165 U/ml SOD was added to the cell suspension for 3 days at 4 degrees C, the production rate of CFU-GM, CFU-E, BFU-E, CFU-Meg and CFU-Mix were 6.2, 2.6, 2.9, 4.0 and 5.1 times that of control group (without SOD) respectively. The survival rate of hematopoietic progenitor cells increased obviously. The mechanism of SOD effect is supposed to prevent hematopoietic progenitor cells from death, instead of the regulating proliferation. It may be closely related to the antioxidation of SOD which scavenges the superoxide free radicals.


Comparison of acute coronary syndromes among elderly African Americans, elderly whites, and elderly patients of other races.
The purpose of this study was to investigate acute coronary syndromes (ACS) in elderly persons of different races. A prospective study was performed in which 177 consecutive unselected patients aged > or = 70 years hospitalized for ACS had coronary angiography. The patients included 11 blacks, 140 whites, and 26 patients of other races. Obstructive coronary artery disease (CAD) was present in 8 of 11 blacks (73%), 121 of 140 whites (86%), and 25 of 26 patients of other races (96%) (P < 0.05 comparing black patients with those of other races). Left main CAD was present in 0 of 11 blacks (0%), 9 of 140 whites (6%), and in 1 of 26 patients of other races (4%) (P not significant). Left anterior descending or diagonal CAD was present in 4 of 11 blacks (36%), 96 of 140 whites (67%), and 18 of 26 patients of other races (69%) (P < 0.05 comparing blacks with whites). Left circumflex or obtuse marginal disease was present in 5 of 11 blacks (45%), 72 of 140 whites (51%), and in 17 of 26 patients of other races (65%) (P not significant). Right CAD was present in 5 of 11 blacks (45%), 81 of 140 whites (58%), and 18 of 26 patients of other races (69%) (P not significant). Coronary revascularization was performed in 7 of 11 blacks (64%), 72 of 140 whites (52%), and 17 of 26 patients of other races (66%) (P not significant).


A pilot study of a primary prevention curriculum to address preschool behavior problems.
Behavior problems among preschool children are common. They are important targets for intervention because early externalizing problems and self-regulation issues tend to persist without appropriate attention, and can affect later mental health and school achievement outcomes. However, few preschool curricula addressing social and emotional development exist, and evidence for effects are mixed. In this study, the Second Step Pre/Kindergarten Social and Emotional Learning curriculum was adapted and tested in a small cluster randomized pilot study of community preschool classrooms to determine if it could improve outcomes in: (1) individual children's teacher-rated behavior problems and prosocial skills; (2) classroom climate (classroom interactions and two measures of disruptive behavior); and (3) teacher interaction skills. Year 1 outcomes were modest and were accounted for by baseline differences. In Year 2, classroom climate, measured by independent observers, differed significantly in intervention classrooms, largely because of declines in control classrooms, and there was some evidence for better teacher interaction skills in intervention classrooms. The pattern of effects suggests important impacts on classroom quality worth investigating in a larger study. Both fidelity and implementation rates, as well as positive teacher responses to the curriculum, indicate potential for widespread adoption.


A role for tumor necrosis factor-alpha in the increased mortality associated with Vibrio vulnificus infection in the presence of hepatic dysfunction.
The present study was designed to evaluate whether pre-existing hepatic dysfunction (cirrhosis) leads to increased morbidity and mortality, in part through an inappropriate in vivo tumor necrosis factor-alpha response. Vibrio vulnificus is the most commonly isolated member of the noncholera Vibrio sp., responsible for fulminant and frequently fatal septicemia. A strong clinical association exists between hepatic dysfunction and increased morbidity and mortality from Vibrio sp. infection. However, the underlying mechanism behind this association has not been fully delineated. Cirrhosis was induced in C57BL/6 (15 to 20 g) mice using thrice-weekly injections of carbon tetrachloride (CCl4) for 7 weeks. Either a 7.0 to 9.5 X 10(7) (low dose) or a 0.8 to 1.2 X 10(9) colony-forming unit (high dose) of V. vulnificus was administered through a mini-laparotomy incision via transgastric puncture into both cirrhotic and control animals. Mortality in cirrhotic mice to low- and high-dose Vibrio infection was 88% (7/8) and 100% (8/8), respectively, whereas mortality in control animals was 0% (0/8) and 12% (1/8), respectively (p<0.01). Tumor necrosis factor-alpha mRNA could be detected by reverse transcriptase polymerase chain reaction in livers and lungs from infected animals 2 and 4 hours after Vibrio administration in both control and cirrhotic animals. Lung and liver tumor necrosis factor-alpha bioactivity, however, was significantly lower in cirrhotic animals infected with Vibrio when compared with controls. Serum tumor necrosis factor-alpha was only sporadically detected in both groups of Vibrio-infected animals. When cirrhotic mice challenged with a low dose of Vibrio sp. were pretreated with 1.0 mg/kg body weight of a novel tumor necrosis factor-alpha receptor immunoadhesin, the increased mortality was completely prevented. Cirrhotic mice show increased mortality to Vibrio infection, and this increased mortality is dependent on an in vivo tumor necrosis factor-alpha response.


Time-optimized analysis of slit-scan chromosome profiles on a general-purpose personal computer.
Slit-scan flow cytometry provides a method to analyze large numbers of metaphase chromosomes in a relatively short time due to morphological features. The high detection rate requires fast computing for on-line analysis. Up to now, this has been achieved using special-purpose computers, parallel systems or other complex hardware. Here, we describe an algorithm that can be implemented on a general-purpose personal computer. Digitized chromosome profiles can be classified by several criteria especially for the detection of chromosome abnormalities in biological dosimetry. A data set of approximately 4600 profiles was used. Programming in assembler results in an average computing time of about 600 microseconds per profile. Thus on-line evaluation of slit-scanning data appears to become feasible for many flow cytometers running nowadays.


Elevated high sensitivity C-reactive protein levels in aging men with low testosterone.
We examined baseline data from a lipid treatment study to assess the relationship between testosterone (T) and the cardiovascular inflammatory marker, high sensitivity C-reactive protein (hsCRP). The baseline T, hsCRP, lipid, glycemic, and anthropometric data were obtained from 467 men (mean age: 52 years). Inclusion criteria included low-density lipoprotein cholesterol > or = 3.4 to 4.9 mmol/l and triglycerides < or = 4.0 mmol/l. The baseline hsCRP levels were examined across the following T subgroups: <6.9 nmol/l (moderate to severe hypogonadism), 6.9 to <10.4 nmol/l (mild to moderate hypogonadism), 10.4 to <15 nmol/l (low-normal T), and > or = 15 nmol/l (normal T). The median hsCRP levels were significantly (p = 0.041) different across the four T subgroups; patients in the lower T subgroups had higher median hsCRP levels than patients in the higher T subgroups. The percentage of men with elevated hsCRP (>2 mg/l) was also significantly (p = 0.038) different across the four T subgroups; 83% of men with T < 6.9 nmol/l had elevated hsCRP compared with 40% with T > or = 15 nmol/l. This analysis demonstrated an inverse relationship between serum T and hsCRP in aging men. Urologists need to be aware that low T levels may not only adversely affect sexual function but also may worsen cardiovascular risk in aging, hypogonadal men.


Can Evoked Potential Changes during the Superficial Temporal Artery-Middle Cerebral Artery Bypass Surgery Predict Postoperative Improvement of Cerebral Perfusion and Functional Status?
We investigated evoked potential (EP) changes during superficial temporal artery to middle cerebral artery (STA-MCA) bypass surgery and their correlations with imaging and clinical findings postoperatively. This retrospective study included patients who underwent STA-MCA bypass surgery due to ischemic stroke with large artery occlusion (MB group). Patients who underwent unruptured MCA aneurysm clipping were enrolled in the control group (MC group). Median and tibial somatosensory evoked potentials (SSEP), and motor evoked potentials recorded from the abductor pollicis brevis (APB-MEP) and abductor hallucis (AH-MEP) were measured intraoperatively. Modified Rankin scale (mRS) and perfusion-weighted imaging (PWI) related variables, i.e., mean transit time (MTT) and time to peak (TTP), were assessed. Δmedian SSEP, ΔAPB-MEP, and ΔAH-MEP were significantly higher in the MB group than in the MC group (p = 0.027, p = 0.006, and p = 0.015, respectively). APB-MEP and AH-MEP amplitudes were significantly increased at the final measurement (p = 0.010 and p < 0.001, respectively). The ΔTTP asymmetry index was moderately correlated with ΔAPB-MEP (r = 0.573, p = 0.005) and ΔAH-MEP (r = 0.617, p = 0.002). ΔAPB-MEP was moderately correlated with ΔMTT (r = 0.429, p = 0.047) and ΔmRS at 1 month (r = 0.514, p = 0.015). MEP improvement during STA-MCA bypass surgery was partially correlated with PWI and mRS and could reflect the recovery in cerebral perfusion.


[Effect of 10-15% carbamide peroxide on enamel fluoride concentration in vital bleached teeth].
The objective of the study was to evaluate the concentration of fluoride in human enamel before and after bleaching using 10-15% carbamide peroxide and after application of the fluoride varnish. Microsamples of enamel were collected using acid biopsy and the concentration of fluoride in the superficial and underlying layer was assayed. No significant differences were observed in the concentration of fluoride in both layers of enamel before and after bleaching as well as after varnish application. Bleaching with 10-15% carbamide peroxide has no influence on the concentration of fluoride in enamel.