Edetate sodium aerosol in Pseudomonas lung infection in cystic fibrosis.
In vitro and animal experimental data suggest the combination of edetate sodium (EDTA) by aerosol plus oral antimicrobials might be effective in the treatment of chronic Pseudomonas infection in patients with cystic fibrosis (CF). For six months we studied the effects of edetate sodium administered by ultrasonic nebulizer to ten children with CF and chronic Pseudomonas aeruginosa infection in a double-blind, placebo-controlled, crossover study. The children had evidence of mild to moderate disease at entry in the study, with a mean (+/- SD) forced expiratory volume in the first second of 85% (+/- 18%) of the predicted value and a mean (+/- SD) Shwachman-Kulczycki score of 83 (+/- 7)/100. Each child was on a three-month regimen of aerosolized edetate sodium plus oral tetracycline twice daily followed by three months of placebo aerosol plus tetracycline or vice versa. Progress was assessed by measurement of pulmonary function, physical examination, and sputum cultures at four weekly intervals, plus chest roentgenograms on entry and after each of the three-month treatment periods. Daily symptoms were assessed using a diary card system. Two patients could not complete the study, one because of severe respiratory relapse, the other because of antibiotic side effects. Of the remaining eight patients, none showed any improvement in pulmonary function, weight gain, or growth acceleration, and none was rendered free of Pseudomonas lung infection. Daily symptom scores and chest roentgenograms were unaltered by edetate sodium. We conclude that the combination of aerosol edetate sodium plus oral tetracycline over a three-month period does not modify the clinical course nor the pulmonary flora in patients with CF with chronic Pseudomonas lung infection.


Research Infrastructure Core Facilities at Research Centers in Minority Institutions: Part I-Research Resources Management, Operation, and Best Practices.
Funded by the National Institutes of Health (NIH), the Research Centers in Minority Institutions (RCMI) Program fosters the development and implementation of innovative research aimed at improving minority health and reducing or eliminating health disparities. Currently, there are 21 RCMI Specialized (U54) Centers that share the same framework, comprising four required core components, namely the Administrative, Research Infrastructure, Investigator Development, and Community Engagement Cores. The Research Infrastructure Core (RIC) is fundamentally important for biomedical and health disparities research as a critical function domain. This paper aims to assess the research resources and services provided and evaluate the best practices in research resources management and networking across the RCMI Consortium. We conducted a REDCap-based survey and collected responses from 57 RIC Directors and Co-Directors from 98 core leaders. Our findings indicated that the RIC facilities across the 21 RCMI Centers provide access to major research equipment and are managed by experienced faculty and staff who provide expert consultative and technical services. However, several impediments to RIC facilities operation and management have been identified, and these are currently being addressed through implementation of cost-effective strategies and best practices of laboratory management and operation.


Facile fabrication of single-crystal-diamond nanostructures with ultrahigh aspect ratio.
A robust and facile approach for making single-crystal-diamond MEMS and NEMS devices is presented. The approach relies entirely on commercial diamond material and standard cleanroom processes. As an example, batch fabrication of cantilever beams of thickness down to 45 nm and aspect ratios exceeding 2000:1 is demonstrated.


Telemedicine infectious diseases consultations and clinical outcomes: a systematic review and meta-analysis protocol.
Telemedicine use is increasing in many specialties, but its impact on clinical outcomes in infectious diseases has not been systematically studied and reviewed. The proposed systematic review will evaluate the current evidence regarding the effect of telemedicine infectious diseases consultation on a range of clinical outcomes, including mortality, hospital readmission, antimicrobial use, and cost. Standard systematic review methodology will be used, with searches of Ovid MEDLINE 1946-, https://embase.com/ 1947-, Scopus 1823-, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and https://clinicaltrials.gov/ 1997-. There will be no restriction on language or year of publication. The primary outcome will be 30-day all-cause mortality and secondary outcomes will include readmission within 30 days after discharge from an initial hospitalization with an infection, patient compliance/adherence, patient satisfaction, cost or cost effectiveness, length of hospital stay, antimicrobial use, and antimicrobial stewardship. Bias will be assessed using standard Cochrane methodologies. Data will be grouped by outcome and narratively synthesized. Meta-analysis will be performed for outcomes with clinical or methodological homogeneity. The systematic review and meta-analysis will be registered through PROSPERO. Pre-planned subgroup analyses will be detailed. A number of studies have documented the feasibility of telemedicine for infectious diseases, but a synthesis of clinical outcomes data with telemedicine infectious diseases consultation has not been performed. This systematic review will analyze many clinical outcomes of telemedicine infectious diseases consultation. The findings of this study will add to established literature about feasibility of telemedicine consultation by synthesizing the evidence for clinical effectiveness. PROSPERO CRD42018105225.


Differences between left and right suboccipital and intracranial vertebral artery dimensions: an influence on blood flow to the hindbrain?
Although vertebral artery (VA) blood flow is adequate in normal circumstances, reduction in the dimensions of the vessel because of atherosclerosis, or compression or stretching, may lead to hindbrain hypoxia with serious clinical manifestations. Such effects may be more pronounced in VAs that are naturally smaller than the norm. Because normative data for the suboccipital (VA3) and intracranial (VA4) vertebral artery are not readily available, it was the aim of the present study to measure the dimensions of these distal parts of the VA, to inform professional practice of the possible influence of different vessel dimensions on blood flow to the hindbrain. The study was a laboratory-based observational or descriptive study. A total of 40 and 54 left and right, suboccipital and intracranial parts of the VA (n = 188 vessels), obtained from cadavers of females and males aged 20-80 years, was processed for light microscopic study and measurement of the dimensions of the vessels. The left and right inner and outer diameters, cross-sectional areas and the tunica media thicknesses were calculated in each part of the vessel and compared by use of t-tests. The histological structure of the VA was typical of a muscular or distributing artery. Although, in the total number of specimens, no statistically significant differences were found between left and right sides in either part of the vessel, a larger left than right VA4 was demonstrated in the females. The VA3 was significantly larger than VA4 in males and females, and all dimensions in both parts of the vessel were greatest in the older age group. Reduced VA blood flow, whether because of atherosclerosis or compression or stretching of the vessel, is more likely to occur in arteries that are smaller than normal. This information is of value to clinicians in avoiding further compromising the VA and its blood flow during professional practice.


Using Linkage Maps as a Tool To Determine Patterns of Chromosome Synteny in the Genus Salvelinus.
Next generation sequencing techniques have revolutionized the collection of genome and transcriptome data from nonmodel organisms. This manuscript details the application of restriction site-associated DNA sequencing (RADseq) to generate a marker-dense genetic map for Brook Trout (Salvelinus fontinalis). The consensus map was constructed from three full-sib families totaling 176 F1 individuals. The map consisted of 42 linkage groups with a total female map size of 2502.5 cM, and a total male map size of 1863.8 cM. Synteny was confirmed with Atlantic Salmon for 38 linkage groups, with Rainbow Trout for 37 linkage groups, Arctic Char for 36 linkage groups, and with a previously published Brook Trout linkage map for 39 linkage groups. Comparative mapping confirmed the presence of 8 metacentric and 34 acrocentric chromosomes in Brook Trout. Six metacentric chromosomes seem to be conserved with Arctic Char suggesting there have been at least two species-specific fusion and fission events within the genus Salvelinus In addition, the sex marker (sdY; sexually dimorphic on the Y chromosome) was mapped to Brook Trout BC35, which is homologous with Atlantic Salmon Ssa09qa, Rainbow Trout Omy25, and Arctic Char AC04q. Ultimately, this linkage map will be a useful resource for studies on the genome organization of Salvelinus, and facilitates comparisons of the Salvelinus genome with Salmo and Oncorhynchus.


Outbreak of Klebsiella pneumoniae producing a new carbapenem-hydrolyzing class A beta-lactamase, KPC-3, in a New York Medical Center.
From April 2000 to April 2001, 24 patients in intensive care units at Tisch Hospital, New York, N.Y., were infected or colonized by carbapenem-resistant Klebsiella pneumoniae. Pulsed-field gel electrophoresis identified a predominant outbreak strain, but other resistant strains were also recovered. Three representatives of the outbreak strain from separate patients were studied in detail. All were resistant or had reduced susceptibility to imipenem, meropenem, ceftazidime, piperacillin-tazobactam, and gentamicin but remained fully susceptible to tetracycline. PCR amplified a blaKPC allele encoding a novel variant, KPC-3, with a His(272)-->Tyr substitution not found in KPC-2; other carbapenemase genes were absent. In the outbreak strain, KPC-3 was encoded by a 75-kb plasmid, which was transferred in vitro by electroporation and conjugation. The isolates lacked the OmpK35 porin but expressed OmpK36, implying reduced permeability as a cofactor in resistance. This is the third KPC carbapenem-hydrolyzing beta-lactamase variant to have been reported in members of the Enterobacteriaceae, with others reported from the East Coast of the United States. Although producers of these enzymes remain rare, the progress of this enzyme group merits monitoring.


Cold adaptation in budding yeast.
We have determined the transcriptional response of the budding yeast Saccharomyces cerevisiae to cold. Yeast cells were exposed to 10 degrees C for different lengths of time, and DNA microarrays were used to characterize the changes in transcript abundance. Two distinct groups of transcriptionally modulated genes were identified and defined as the early cold response and the late cold response. A detailed comparison of the cold response with various environmental stress responses revealed a substantial overlap between environmental stress response genes and late cold response genes. In addition, the accumulation of the carbohydrate reserves trehalose and glycogen is induced during late cold response. These observations suggest that the environmental stress response (ESR) occurs during the late cold response. The transcriptional activators Msn2p and Msn4p are involved in the induction of genes common to many stress responses, and we show that they mediate the stress response pattern observed during the late cold response. In contrast, classical markers of the ESR were absent during the early cold response, and the transcriptional response of the early cold response genes was Msn2p/Msn4p independent. This implies that the cold-specific early response is mediated by a different and as yet uncharacterized regulatory mechanism.


Kidney involvement and disease in patients with diabetes.
Diabetic nephropathy is the leading cause of end-stage renal disease in western or westernised countries and the largest contributor to the total cost of diabetes care around the world. In addition to the development of diabetic nephropathy and end-stage renal failure, diabetic patients with evidence of albuminuria have a much higher risk of developing myocardial infarctions, cerebrovascular accidents, severe progressive retinopathy, and peripheral and autonomic neuropathy. A cumulative incidence of diabetic nephropathy has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients, although more recent studies have demonstrated a substantial reduction of its incidence. Before the onset of overt proteinuria, there are several renal functional changes, including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetic nephropathy. It has been postulated that diabetic nephropathy occurs as a result of the interplay of metabolic and haemodynamic factors in the renal microcirculation. Hyperglycaemia plays a pivotal role in the pathogenesis of diabetic renal disease, but genetic factors are also of crucial importance. The accumulation of advanced glycosilation end products (AGEPs), the activation of isoforms of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycaemia damages vessels. Growth factors (i.e. TGF-b, IGF-1, VEGF) may also play an important role in the pathogenesis. There is a familial clustering of diabetic kidney disease: a number of gene loci have been investigated to try to explain the genetic susceptibility to this complication. The two main treatment strategies for prevention of diabetic nephropathy are improved glycaemic control and blood pressure lowering, particularly using drugs such angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Many potential treatment modalities in preventing and treating diabetic nephropathy are presently being evaluated; some of them will possibly be available in the near future in order to try to modify the natural course of kidney involvement and disease in patients with diabetes.


Engaging stakeholders in research related to anesthesia and neurodevelopment in children.
The Fourth PANDA symposium on Anesthesia and Neurodevelopment in Children invited 4 leaders in community engagement and federal government collaboration to share their experiences with overcoming challenges in promoting public health issues. There continues to be emerging evidence from laboratory findings in animal models demonstrating neurotoxic effects and neurodevelopmental changes from early exposure to anesthetic and sedative drugs, but studies in humans have been very limited and inconclusive. Although definitive recommendations for clinical care still cannot be made given the limitations in the clinical data, the need for open communication among clinicians, parents, and other stakeholders is clear. A "top-down, bottom-up" engagement strategy including parents, children, clinicians, government agencies, and community organizations may improve communication and collaboration. To reach the goal of "improving quality, safety, efficiency, and effectiveness of health care in children," clinicians and researchers will need to adopt strategies to engage and partner with stakeholders as coinvestigators who actively participate in efforts to increase anesthetic safety in children. Collaborations with government regulatory administration can improve the efficacy and effectiveness of resource utilization to address public health needs. This session provided an opportunity for open dialog between clinicians, researchers, and community leaders to discuss strategies to engage stakeholders to partake in patient-centered outcomes research on anesthetic neurotoxicity.


Decisional Conflict in Patients With Head and Neck Cancer.
Patients who experience less decisional conflict (DC) are more engaged in treatment and less prone to decisional regret, nervousness, and fretting. To assess DC among patients with head and neck squamous cell carcinoma (HNSCC) after the treatment decision consultation and the association between DC and quality of life as well as the degree of control patients experience in the decision-making process using the control preference scale and the association with DC. This prospective cohort study with 2 separate cohorts was conducted at a tertiary cancer center and included patients who were eligible for curative treatment of a primary squamous cell carcinoma between January 2014 and August 2018. The 2 cohorts comprised 102 patients with small laryngeal squamous cell carcinoma (SLSCC) and 161 patients with other HNSCC. Decisional Conflict Scale (DCS) score, which was scored within 2 weeks after the treatment decision consultation. Other measures included patient characteristics, tumor characteristics, and Control Preference Scale , EuroQol-5D, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, Hospital Anxiety and Depression Scale (HADS), Eating Assessment Tool, and Voice Handicap Index (VHI) scores. Of 263 patients, 50 (19%) were women; the mean (SD) age was 66.1 (11.4) years in the SLSCC group and 64.9 (9.8) years in the other HNSCC group. In the SLSCC group, 51 patients (50%) experienced clinically significant DC (total score ≥25) compared with 74 patients (46%) in the other HNSCC group. In the SLSCC group, there was a large difference in the median EuroQol-5D, Global Health status, HADS anxiety, HADS depression, and VHI scores between the patients with a total DCS score of less than 25 and total DCS score of 25 or greater, whereas in the other HNSCC group, this only applied to the VHI. Forty-four patients (43.1%) in the SLSCC group felt their treatment choice was a shared decision, and 39 (38.2%) made the decision themselves. In the other HNSCC group, 62 (38.5%) felt that the physician decided, and 56 (34.8%) felt it was a shared decision. In both groups there was a weak association between control preference scale scores and DC. The results of this cohort study found that almost half of patients (48%) experienced clinically significant DC. Several quality-of-life measures associated with clinically significant DC were identified. These results suggest that there is room for improvement in aiming to reduce decision delay and decision-related distress.


An exploratory study of the relationship between diverse life events and specific personality disorders in a sample of suicide attempters.
Personality disorder (PD) increases risk for suicidal behavior. Certain life events (LE) can precipitate suicidal behaviors in patients with PD. A fundamental question is whether specific combinations of LE and PD increase suicidal risk. Four hundred forty-six suicide attempters (SA) were recruited from emergency rooms. We used a healthy control group (n = 515) to identify the best cut-off point for the instrument used to diagnose PD. We used the DSM-IV version of the International Personality Disorder Questionnaire-Screening Questionnaire, the Mini International Neuropsychiatric Interview, and the Social Adjustment Scale to assess PD, Axis I disorders, and LE, respectively. After controlling for Axis I disorders, we found that "Death of spouse" preceded suicidal acts in those with antisocial PD (FET p = 0.024) and patients with narcissistic PD attempted suicide after being Fired at work (FET p = 0.002), among others. Our data suggest the presence of particular LE-PD associations in suicide attempters. Some LE-PD relationships appear independent of Axis I disorders in suicide attempters. This may offer a basis for specific targeted therapies or prevention programs aimed at decreasing suicidal risk.


Correlation of cell apoptosis with brain edema and elevated intracranial pressure in traumatic brain injury.
To study the correlation between brain edema, elevated intracranial pressure (ICP) and cell apoptosis in traumatic brain injury (TBI). In this study, totally 42 rabbits in 7 groups were studied. Six of the animals were identified as a control group, and the remaining 36 animals were equally divided into 6 TBI groups. TBI models were produced by the modified method of Feeney. After the impact, ICP of each subject was recorded continuously by an ICP monitor until the animal was sacrificed at scheduled time. The apoptotic brain cells were detected by an terminal deoxynucleotide-transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay. Cerebral water content (CWC) was measured with a drying method and calculated according to the Elliott formula. Then, an analysis was conducted to determine the correlation between the count of apoptotic cells and the clinical pathological changes of the brain. Apoptotic cell count began to increase 2 h after the impact, and reached its maximum about 3 days after the impact. The peak value of CWC and ICP appeared 1 day and 3 days after the impact, respectively. Apoptotic cell count had a positive correlation with CWC and ICP. In TBI, occurrence of brain edema and ICP increase might lead to apoptosis of brain cells. Any therapy which can relieve brain edema and/or decrease ICP would be able to reduce neuron apoptosis, thereby to attenuate the secondary brain damage.


Astilbin from Smilax glabra Roxb. Attenuates Inflammatory Responses in Complete Freund's Adjuvant-Induced Arthritis Rats.
Astilbin, a flavonoid compound, was isolated from the rhizome of Smilax glabra Roxb. (with red cross-section) grown in Guizhou Province, China. We accessed its effect and potential mechanism on attenuation of the inflammatory response in CFA-induced AA rats. Our results showed that daily oral administration of astilbin at 5.3 mg/kg reduced joint damage in the hind paw of AA rats. Accordingly, astilbin exhibited remarkable inhibitory effects on TNF-α, IL-1β, and IL-6 mRNA expression. Significant decrease of serum cytokine levels of TNF-α, IL-1β, and IL-6 was also observed in astilbin-treated AA rats compared to the vehicle-treated AA rats. The reduced expression of these cytokines was associated with protein activity suppression of three key molecular targets in the pathogenesis of RA, including IKKβ, NF-κB p65 subunit, and TLR adaptor MyD88. Furthermore, the therapeutic effects of astilbin on the inhibition of cytokines production as well as the reduction of inflammatory response in AA rats are close to a commonly used antirheumatic drug, leflunomide. Collectively, our data suggest that the action mechanism of astilbin, as an anti-inflammatory agent for RA treatment, is associated with modulating the production of proinflammatory cytokines and inhibiting the expression of key elements in NF-κB signaling pathway mediated by TLR.


An opportunistic approach to rubella screening in general practice.
An opportunistic rubella screening programme in a general practice is described. Self-adhesive stickers placed on the medical records envelope were used to alert staff and to record information on rubella status. Out of the total target population of women aged between 10 and 40 years, three sample cohorts were audited: the 15, 20 and 30 years age groups. Between the first and second audits a practice policy on rubella immunization screening was implemented over a period of 11 months. After 11 months the proportions of 20- and 30-year-olds whose rubella status was known had risen from 50% to 88% and from 67% to 87% respectively. For the 15-year-old cohort, which would have been included in the schools immunization programme, the increase was negligible. Serological testing in the practice identified 24 women (7% of all those tested) who were seronegative and to date 19 of these women have been vaccinated. The screening method was shown to be simple and effective and to involve little extra staff time.


Effects of high fat diet-induced obesity on mammary tumorigenesis in the PyMT/MMTV murine model.
Clinical studies provide strong evidence that obesity and associated adipose tissue (AT) inflammation are risk factors for breast cancer (BrCA); however, mechanistic knowledge of the interaction of obesity, BrCA, and menopausal status has proven to be not only lacking, but contradictory. Obesity-induced inflammation and elevated biosynthesis of estrogens, through aromatase-mediated metabolism of precursors, have been linked with hormone receptor positive (HP) postmenopausal BrCA but not previously associated with premenopausal BrCA risk. Thus, further delineation of the interaction of obesity, inflammation, and aromatase is required for the development of therapeutic treatment options. The purpose of this study was to examine the effect of high fat diet (HFD)-induced inflammation on tumorigenesis in a model of pre and postmenopausal HP BrCA. Female PyMT/MMTV ovary intact and ovariectomized mice were fed low and HFD diets to examine the role of obesity-induced inflammation and hormone production in the development of HP BrCA. Tumor statistics for number, volume, weight, histopathology scoring and gene expression of macrophage and inflammatory mediators were measured in the AT and mammary gland at sacrifice. HFD feedings of ovary intact mice resulted in increased adiposity and tumorigenesis, indicated by increased primary tumor volume, multiplicity, tumor burden, and increased tumor progression represented by histopathological scoring. HFD-induced obesity significantly upregulated aromatase and macrophage marker expression in the AT (F4/80 and CD11c) and mammary gland (Mertk) in a premenopausal model of BrCA. Conversely, HFD feedings had no significant effect on tumorigenesis in a postmenopausal model of BrCA despite large increases in adiposity in ovariectomized mice; however, limitations within the model may have precluded any significant findings. This data suggests that obesity-induced increases in inflammation and hormone production, via aromatase expression, is associated with increases in tumorigenesis in a model of premenopausal HP BrCA in the PyMT/MMTV strain.


Phylogenetic structure of the Sporopachydermia cereana species complex.
A large number of isolates previously referred to as members of the 'Sporopachydermia cereana species complex' were examined by various DNA characterization methods, leading to the conclusion that the complex is in fact made up of 10 species, one of which contains three varieties. The sequences of the internal transcribed spacer (ITS) region and the D1/D2 divergent domains of the large subunit rDNA were determined for representatives of each taxon and specific primers based on differences in the ITS were designed for rapid identification of five of the taxa. Whereas the data provide additional elements for the calibration of the ITS as a criterion for species delineation, the emerging pattern is that the ITS region does not function as well as the D1/D2 domains as an evolutionary clock. Some taxa appear to be specific for the geographical regions where they were isolated, and the distribution of many taxa is mutually exclusive.


[Effect of electroacupuncture stimulation of "Guanyuan" (CV 4), bilateral "Housanli" (ST 36), etc. on anti-fatigue ability and liver mitochondrial respiratory function in ageing rats with Yang-deficiency].
To observe the effect of electroacupuncture (EA) of "Guanyuan" (CV 4) and bilateral "Housanli" (ST 36) plus acupuncture stimulation of "Baihui" (GV 20) [an acupoint recipe for "Shuanggu Yitong" (strengthening both congenital foundation and the acquired constitution and regulating the yang-qi of the body] on the anti-fatigue ability and liver mitochondrial respiratory function in yang-deficiency ageing rats. A total of 48 male SD rats were equally and randomly divided into normal control, model, EA and EA control groups. The aged yang-deficiency model was established by subcutaneous injection of D-galactose (125 mg/kg, once daily for 40 days) and sequential muscular injection of hydrocortisone (1.5 mg/100 g, once daily for 7 days). For rats of the normal control group, subcutaneous injection of same dose of normal saline was gi-ven. EA stimulation (2 Hz, 1 mA) of "Guanyuan" (CV 4) and bilateral "Housanli"(ST 36) and manual acupuncture stimulation of "Baihui" (GV 20) were given to rats of the EA group. For rats of the EA control group, EA of "Zhongji"(CV 3) and bilateral "Yinlinquan"(SP 9), and manual acupuncture stimulation of "Yintang" (EX-HN 3) were given. The treatment was conducted once daily, 6 time a week and continuously for 4 weeks. Rats of the normal control and model groups were grabbed and fixed in the same way. The anti-fatigue ability was evaluated by using the time of exhausted swimming task and liver mitochondrial respiratory function was detected by Clark oxygen electrode. In comparison with the normal control group, the exhausted swimming time was significantly shortened in the model group (P < 0.01). Compared with the model group, the exhausted swimming time was evidently prolonged in the EA group (P < 0.01) not in the EA control group (P > 0.05). As for the liver mitochondrial respi-ratory function, the oxygen consumption rate IV was obviously higher in the model group than in the normal control group (P < 0.01), and significantly lower in the EA group than in the model group (P < 0.01). Both liver mitochondrial respiratory control rate (RCR) and ratio of phosphorus/oxgen (P/O) were significantly lower in the model group than in the normal control group (P < 0.01), and considerably higher in the EA group than in the model group (P < 0.01, P < 0.05). Comparison between the EA and EA control groups showed that the effects of the former group were evidently superior to those of the latter group in prolonging the exhausted swimming time, lowering oxygen consumption rate IV and upregulating RCR and P/O (P < 0.05). Electroacupuncture of CV 4 and ST 36 plus manual acupuncture stimulation of GV 20 can improve the anti-fatigue capability in aging rats with yang-deficiency, which may be related to its effects in reducing liver mitochondrial oxygen consumption and increasing liver mitochondrial RCR and ratio of P/O.


Natural osmolyte trimethylamine N-oxide stimulates tubulin polymerization and reverses urea inhibition.
The natural osmolyte trimethylamine N-oxide (TMAO) is one of the methylamine compounds often accumulated by diverse organisms in response to osmotic stress and/or to compensate for the deleterious effects of urea. Tubulin polymerization is promoted by TMAO. At 1 M TMAO, tubulin polymers are produced with properties expected of normal steady-state microtubules (MT): polymerization is reversed by exposure to cold or the antimitotic drug podophyllotoxin, a critical concentration for polymerization at 30 degrees C of 1.5 microM is found, and the morphology of the polymers in electron micrographs is typical of MT and ribbons, or open MT. At 2 M TMAO, polymerization is very rapid and hyperstable polymers are formed. These are resistant to cold-induced depolymerization although still sensitive to podophyllotoxin inhibition. A lower critical concentration of 0.7 microM is observed, and electron micrographs reveal MT, ribbons, and other polymer forms not usually stable, such as splayed protofilaments. Inhibition of tubulin polymerization by low concentrations of urea (Sackett, D. L., B. Bhattacharyya, and J. wolff. Biochemistry 33: 12868-12878, 1994) is largely reversed by the presence of TMAO at one-half the molarity of urea, the physiological ratio observed in cartilaginous fishes. Other methylamines, including betaine, dimethylglycine, glycine, and sarcosine, failed to stimulate MT polymerization or protect against urea inhibition. Trimethylamine, taurine and glycylglycine inhibit polymerization. TMAO did not interfere with binding of MT-associated proteins (MAP) and protected both tubulin assembly and MAP binding from urea.


Effects of pharmacological preconditioning by emodin/oleanolic acid treatment and/or ischemic preconditioning on mitochondrial antioxidant components as well as the susceptibility to ischemia-reperfusion injury in rat hearts.
Using an ex vivo rat heart model of ischemia-reperfusion (I-R) injury, we examined the effect of pharmacological preconditioning by chronic treatment with emodin (EMD)/oleanolic acid (OA) at low dose (25 micromol/kg/day x 15) and/or ischemic preconditioning (IPC) (4 cycles of 5 min ischemia followed by 5 min of reperfusion) on myocardial I-R injury. The results indicated that EMD/OA pretreatment, IPC, or their combinations (EMD+IPC and OA+IPC) protected against myocardial I-R injury, as assessed by lactate dehydrogenase leakage and contractile force recovery. The cardioprotection was associated with a differential enhancement in mitochondrial antioxidant components. The combined EMD/OA and IPC pretreatment produced cardioprotective action in a semi-additive manner. This suggested that EMD/OA pretreatment and IPC protected against myocardial I-R injury via a similar but not identical biochemical mechanism.


Reduction rate constants for nitroaromatic compounds estimated from adiabatic electron affinities.
Nitroaromatic compounds (NACs) are ubiquitous environmental contaminants and predicting their environmental fate is important. Linear free energy relationships (LFERs) have been reported relating one-electron reduction potentials (E(o)(H)) of NACs in water to their reduction rate constants (k) measured under various conditions. In a recent effort to calculate E(o)(H), we found that E(o)(H) values of NACs are also linearly correlated with their adiabatic electron affinities (EA). This suggests that the reactivity of NACs--and hence their half-lives--can be predicted based on their EA values. We report here a new set of LFERs relating EA and k for NACs. Reduction of substituted nitrobenzenes mediated by quinones, natural organic matter, Fe(II) complexes, and the (CH(3))(2)COH radical was examined using EA values calculated from quantum mechanics. For monosubstituted nitrobenzenes without ortho substituents, strong linear correlations were found between EA and log k, leading to accurate estimates of k. Deviations between measured and estimated k values for most ortho-substituted and/or polysubstituted compounds were somewhat higher, but were accurate to within approximately an order of magnitude using the same LFER for all compounds. We report estimates of 169 reduction rate constants for 23 compounds in nine reducing systems for which no measured values are available.


Pierson Syndrome Associated with Hypothyroidism and Septic Shock.
Pierson syndrome is caused by mutations in the laminin β2 gene causing absent β2 laminin, which is a normal component of the basement membranes of the mature glomerulus, structures in the anterior eye and neuromuscular junctions. The mutations manifest as congenital nephrotic syndrome and microcoria which are characteristic ocular features of this disease. These mutations may also result in neurological abnormalities such as hypotonia and psychomotor retardation. We report a two-month old boy who presented to the Pediatrics Department of Dr. Ruth K. M. Pfau Civil Hospital, Karachi, Pakistan, in 2015, with the typical features of microcoria and congenital nephrotic syndrome. The hypocalcaemia, hypoproteinaemia and probable immunocompromised state consequent to nephrotic syndrome resulted in seizures, hypothyroidism and urosepsis. Despite being treated aggressively with high dose antibiotics, ionotropic support, angiotensin-converting enzyme inhibitors, thyroxine replacement and nutritional support, the infant died due to significant multiorgan disease including renal failure and septic shock.


Distributional change of fodrin in the wound healing process of the corneal epithelium.
Distribution of fodrin, F-actin, and E-cadherin in the wound healing process of the mouse corneal epithelium was examined by immunolabeling techniques. In the normal epithelium, fodrin, F-actin, and E-cadherin were observed only in the cell periphery. After wounding, however, fodrin was observed diffusely in the basal cell cytoplasm. Distribution of the other two proteins was not changed. Fodrin in the upper cell layers did not show cytoplasmic labeling. The distributional change of fodrin in the basal cell was seen not less than 1 mm apart from the wound edge and as early as 5 min after the wounding, lasted for about 12 hr, and then gradually disappeared. The change in fodrin localization is one of the earliest phenomena which occur in the corneal epithelium after wounding. Because fodrin is an actin-binding protein and is believed to interact with E-cadherin, this change may be important in modulating the cytoskeleton and the intercellular junction before cell migration occurs.


A review of the treatment of psoriasis with infliximab.
Patients afflicted with moderate to severe psoriasis experience a reduction in the quality of life. They not only suffer the aggravation associated with the pain, itchiness, and bleeding of the psoriatic lesions, but also experience a negative impact on their daily functions and social well-being. Unfortunately, traditional therapeutic measures have not been effective enough in treating individuals suffering from moderate to severe forms of psoriasis. Most of the conventional medications have produced at best only partial responses. However, the recent chimeric monoclonal TNF-alpha inhibiting antibody, infliximab, has been proven effective for the treatment of patients with moderate to severe psoriasis. Most patients treated with infliximab have shown rapid and remarkable improvement in the clinical manifestations of the disease. This article will closely examine the efficacy and safety of infliximab through the analysis of past case reports and clinical trials.


MEKK4 regulates developmental EMT in the embryonic heart.
Congenital heart malformations occur at a rate of one per one hundred births and are considered the most frequent birth defects. This high incidence of cardiac defects underscores the complex developmental processes required to form the first functioning organ in mammals. The molecular cues which govern heart development are poorly defined and require an improved understanding in order to advance repair strategies for heart defects. The cytoplasmic MAP kinase kinase kinase, MEKK4, is a critical effector in cellular stress responses; however, the function of MEKK4 during embryonic development and cardiogenesis is not well understood. We have identified MEKK4 as a critical signaling molecule during cardiovascular development. We report the detection of MEKK4 transcripts to early myocardium, endocardium and to cardiac cushion cells that have executed epithelial to mesenchymal transformation (EMT). These observations suggest that MEKK4 may function during production of the cushion mesenchyme as required to create valves and the septated heart. We used a kinase inactive form of MEKK4(MEKK4(KI)) in an in vitro assay that recapitulates in vivo EMT, and show that MEKK4(KI) attenuates mesenchyme production. However, addition of a constitutively active MEKK4 into ventricular explants, a system that does not normally undergo EMT, is not able to cause mesenchymal cell outgrowth. Thus, the kinase activity of MEKK4 is essential, but not sufficient, to support developmental EMT. This knowledge provides a basis to understand how MEKK4 may integrate signaling cascades controlling heart development.


Path to Clonal Theranostics in Luminal Breast Cancers.
Integrating tumor heterogeneity in the drug discovery process is a key challenge to tackle breast cancer resistance. Identifying protein targets for functionally distinct tumor clones is particularly important to tailor therapy to the heterogeneous tumor subpopulations and achieve clonal theranostics. For this purpose, we performed an unsupervised, label-free, spatially resolved shotgun proteomics guided by MALDI mass spectrometry imaging (MSI) on 124 selected tumor clonal areas from early luminal breast cancers, tumor stroma, and breast cancer metastases. 2868 proteins were identified. The main protein classes found in the clonal proteome dataset were enzymes, cytoskeletal proteins, membrane-traffic, translational or scaffold proteins, or transporters. As a comparison, gene-specific transcriptional regulators, chromatin related proteins or transmembrane signal receptor were more abundant in the TCGA dataset. Moreover, 26 mutated proteins have been identified. Similarly, expanding the search to alternative proteins databases retrieved 126 alternative proteins in the clonal proteome dataset. Most of these alternative proteins were coded mainly from non-coding RNA. To fully understand the molecular information brought by our approach and its relevance to drug target discovery, the clonal proteomic dataset was further compared to the TCGA breast cancer database and two transcriptomic panels, BC360 (nanoString®) and CDx (Foundation One®). We retrieved 139 pathways in the clonal proteome dataset. Only 55% of these pathways were also present in the TCGA dataset, 68% in BC360 and 50% in CDx. Seven of these pathways have been suggested as candidate for drug targeting, 22 have been associated with breast cancer in experimental or clinical reports, the remaining 19 pathways have been understudied in breast cancer. Among the anticancer drugs, 35 drugs matched uniquely with the clonal proteome dataset, with only 7 of them already approved in breast cancer. The number of target and drug interactions with non-anticancer drugs (such as agents targeting the cardiovascular system, metabolism, the musculoskeletal or the nervous systems) was higher in the clonal proteome dataset (540 interactions) compared to TCGA (83 interactions), BC360 (419 interactions), or CDx (172 interactions). Many of the protein targets identified and drugs screened were clinically relevant to breast cancer and are in clinical trials. Thus, we described the non-redundant knowledge brought by this clone-tailored approach compared to TCGA or transcriptomic panels, the targetable proteins identified in the clonal proteome dataset, and the potential of this approach for drug discovery and repurposing through drug interactions with antineoplastic agents and non-anticancer drugs.


Instillation of bradykinin into femoral artery elicits cardiorespiratory reflexes involving perivascular afferents in anesthetized rats.
The physiology of baroreceptors and chemoreceptors present in large blood vessels of the heart is well known in the regulation of cardiorespiratory functions. Since large blood vessels and peripheral blood vessels are of the same mesodermal origin, therefore, involvement of the latter in the regulation of cardiorespiratory system is expected. The role of perivascular nerves in mediating cardiorespiratory alterations produced after intra-arterial injection of a nociceptive agent (bradykinin) was examined in urethane-anesthetized male rats. Respiratory frequency, blood pressure, and heart rate were recorded for 30 min after the retrograde injection of bradykinin/saline into the femoral artery. In addition, paw edema was determined and water content was expressed as percentage of wet weight. Injection of bradykinin produced immediate tachypneic, hypotensive and bradycardiac responses of shorter latency (5-8 s) favoring the neural mechanisms involved in it. Injection of equi-volume of saline did not produce any responses and served as time-matched control. Paw edema was observed in the ipsilateral hind limb. Pretreatment with diclofenac sodium significantly attenuated the bradykinin-induced responses and also blocked the paw edema. Ipsilateral femoral and sciatic nerve sectioning attenuated bradykinin-induced responses significantly, indicating the origin of responses from the local vascular bed. Administration of bradykinin in the segment of an artery produced reflex cardiorespiratory changes by stimulating the perivascular nociceptors involving prostaglandins. This is a novel study exhibiting the role of peripheral blood vessels in the regulation of the cardiorespiratory system.


CD4+ CD45RB low-density cells from untreated mice prevent acute allograft rejection.
In the absence of therapy that suppresses the action of the immune system, the immune response to transplantation Ags results in rapid rejection of the transplant. The most successful mechanism so far described that achieves organ-specific immunological tolerance is that which controls peripheral tolerance to self-tissue. Until now, no similarities have been documented between the peripheral response to self-Ags and the response to transplantation Ags. CD4+ cells that express a high density of CD45RB (in the mouse) and CD45RC (in the rat) on their surface have been shown to cause a number of autoimmune disorders. In contrast, autoimmunity caused by the CD45RB high-density cells is inhibited by CD4+ CD45RB cells that express a low density of CD45RB (CD45RC in the rat). In this paper we show that CD4+ CD45RB high-density cells are sufficient to cause rejection of a MHC-mismatched pancreas allograft, whereas CD4+ CD45RB low-density cells are not. Unexpectedly, the CD45RB low-density cells prevent the CD45RBhigh expressing cells from causing rejection. These data suggest that the response to foreign tissue can be controlled in the same way as the response to self-tissue.


The Effectiveness of Reform in the Dental Health Systems of Transitional Countries: The Case of Montenegro Health Reform (pilot study).
The main objective of this research is to evaluate the influence of reform in the dental health care system in Montenegro on the oral hygiene awareness and health practices among children aged 11 to 14. The research was performed among public schoolchildren in Montenegro. Data was obtained by evaluating a structured questionnaire fulfilled by 300 children, aged between 11 and 14 years, at the beginning of reform in the dental health care system in 2009 (n = 150) and in 2018 (n = 150). Participants were selected from three different geographical regions (North, Central and Southern). Most participants reported brushing their teeth twice daily (2009: 46% in Rozaje, 48% in Podgorica and 36% in Budva; 2018: 50% in Rozaje, 48% in Podgorica and 40% in Budva). There was no difference by region in either 2009 or 2018 in the rate of self-reported gum bleeding when brushing teeth (p values 0.387 and 0.825, respectively). Most respondents went to the dentist only when they needed treatment. There is no significant change in the awareness and practices of oral hygiene maintenance among children aged 11 to 14 years in Montenegro at the beginning of the reform of dental health care compared to nine years later. It is necessary to introduce more continuous education programs to promote oral health.


Regulation of B cell functions by C3a and C3a(desArg): suppression of TNF-alpha, IL-6, and the polyclonal immune response.
Regulation of the humoral immune response by fragments of complement component C3 has been shown to play an important role in host defense. In this study, we investigated expression of the C3a receptor (C3aR) by human B cells and the effects of C3a and C3a(desArg) on IgG, TNF-alpha, and IL-6 production in Staphylococcus aureus Cowan strain I (SAC)/IL-2-activated B cells. Here we report that tonsil-derived human B cells express a C3aR that is indistinguishable at both the protein (by flow cytometry) and mRNA (by reverse transcription-PCR) levels from that on human neutrophils or on C3aR-transfected mouse L cells. Incubation of SAC/IL-2-activated B cells with C3a or C3a(desArg) resulted in a dose-dependent suppression of the polyclonal immune response. Under these same experimental conditions, IL-6 and TNF-alpha release was suppressed in a dose-dependent manner. Kinetic studies with SAC/IL-2-activated B cells revealed that C3a must be present at initiation of the culture to exert its suppressive effect on IgG and IL-6 production. These results demonstrate that tonsil-derived B cells express the C3aR and that C3a as well as C3a(desArg) have a direct immunomodulatory effect on these cells.


Stacking interactions of borazine: important stacking at large horizontal displacements and dihydrogen bonding governed by electrostatic potentials of borazine.
Potential energy surfaces of borazine-benzene and borazine-borazine stacking interactions were studied by performing DFT, CCSD(T)/CBS and SAPT calculations. The strongest borazine-benzene stacking was found in a parallel-displaced geometry, with a CCSD(T)/CBS interaction energy of -3.46 kcal mol-1. The strongest borazine-borazine stacking has a sandwich geometry, with a CCSD(T)/CBS interaction energy of -3.57 kcal mol-1. The study showed that borazine forms significant stacking interactions at large horizontal displacements (over 4.5 Å), with energies of -2.20 kcal mol-1 for the borazine-benzene and -1.96 kcal mol-1 for the borazine-borazine system. The strength of interactions and their geometrical preferences can be rationalized by observing the electrostatic potentials of borazine and benzene, which is in agreement with SAPT analysis showing that electrostatics is the most important energy component for borazine stacking. All the interactions found in crystal structures of borazine and related compounds were identified either as potential curve minima or the geometries obtained from their optimizations. We also report a new dihydrogen bonding dimer with a CCSD(T)/CBS interaction energy of -2.37 kcal mol-1, which is encountered in the borazine crystal structures and enables the formation of additional simultaneous interactions that contribute to the overall stability of the crystals.


Impact of jail sanctions during drug court participation upon substance abuse treatment completion.
This study of participants in a US drug treatment court describes the relationship between the imposition of short-term jail sanctions and substance abuse treatment dropout, and examines offender characteristics moderating or modifying the impact of jail sanctions on treatment dropout. Data were derived from administrative information collected by the Dane County Wisconsin Drug Treatment Court from 1996-2004 on all 573 participants achieving a final disposition of treatment completion or failure during those program years. Iterative Cox proportional hazards models of time to treatment failure were created; jail sanctions during drug court participation were framed as time-dependent covariates. A theoretical framework and specific statistical criteria guided construction of a final parsimonious model of time to treatment drop-out. Treatment failure was associated with unemployment [hazard ratio (HR) in unemployed versus employed = 1.41, P-value 0.0079], lower educational attainment (HR in high school non-graduate versus graduate = 1.41, P = 0.02) and application of the first jail sanction (HR 2.71, P < 0.001). The association between treatment failure and a first sanction was considerably stronger for sanctions administered earlier in participation (HR for sanction 1 at <30 days 11.34, P-value 0.0002). Conclusions An initial jail sanction for non-adherence may be more likely to foster treatment compliance in less refractory individuals (i.e. those not already acclimated or socialized to incarceration or other corrections interventions). More stringent supervisory conditions and individualized services may be required to reintegrate such offenders and promote longer-term public safety.


Development of natural and synthetic DNA probes for OXA-2 and TEM-1 beta-lactamases.
Cloning of a 6.3-kilobase BglII DNA fragment from plasmid R46 permitted the isolation of the OXA-2 beta-lactamase gene. Selected DNA fragments internal and adjacent to the OXA-2 beta-lactamase structural gene were used as probes in homology studies with other plasmid-mediated beta-lactamases. Under conditions of high stringency, no cross hybridization could be detected with DNA probes from within the open reading frame of the OXA-2 structural gene. At a lower stringency, one of two DNA fragments used as probes cross hybridized weakly with the OXA-3 bla gene. Other DNA fragments tested and known to contain sequences flanking the OXA-2 determinant cross hybridized with OXA-3 and PSE-4 plasmid DNA. From the known nucleotide sequence of OXA-2 and TEM-1, we synthesized a series of oligonucleotides corresponding to sequences internal to their respective structural genes. A 12-mer oligonucleotide containing the OXA-2-active-site nucleotide sequences cross hybridized only with OXA-3. All other oligonucleotides tested were found to be specific for their respective OXA-2 or TEM-1 gene. Such beta-lactamase gene probes should facilitate studies of beta-lactamase molecular epidemiology and beta-lactamase gene polymorphism.


Estimating SpO2 with Deep Oxygen Desaturations from Facial Video Under Various Lighting Conditions: A Feasibility Study.
This paper presents a feasibility study to collect data, process signals, and validate accuracy of peripheral oxygen saturation (SpO2) estimation from facial video in various lighting conditions. We collected facial videos using RGB camera, without auto-tuning, from subjects when they were breathing through a mouth tube with their nose clipped. The videos were record under four lighting conditions: warm color temperature and normal brightness, neutral color temperature and normal brightness, cool color temperature and normal brightness, neutral color temperature and dim brightness. The air inhaled by the subjects was manually controlled to gradually induce hypoxemia and lower subjects' SpO2 to as low as 81%. We first extracted the remote photoplethysmogram (rPPG) signals from the videos. We applied the principle of pulse oximetry and extracted the ratio of ratios (RoR) for two color combinations: Red/Blue and Red/Green. Next, we assessed SpO2 estimation accuracy against the ground truth, a Transfer Standard Pulse Oximeter. We have achieved an RMSE of 1.93% and a PCC of 0.97 under the warm color temperature and normal brightness lighting condition using leave-one-subject-out cross validation between two subjects. The results have demonstrated the feasibility to estimate SpO2 remotely and accurately using consumer level RGB camera with suitable camera configuration and lighting condition.Clinical Relevance- This work demonstrates that SpO2 can be estimated accurately using an RGB camera without auto-tuning and under warm color temperature, enabling continuous SpO2 monitoring applications that require noncontact sensing.


Introduction: the EUROCARE II Study.
This introduction provides a general overview of the aims, methods and procedures used in the EUROCARE II study and the types of analyses presented in each article of this Special Issue of the European Journal of Cancer. The main aims of the EUROCARE II project are the updating of the survival database of the European Cancer Registries, the study of recent trends in relative survival rates and the interpretation of the survival differences observed both in time and across populations. Once having completed the preliminary stage of data checking, a total of 3,473,659 individual records from patients of all cancer sites, diagnosed between 1978 and 1989 and provided by 45 cancer registries in 17 European countries were accepted to build up the EUROCARE database. The quality of these data, in terms of the accuracy of the diagnosis and the validity of vital status assessment, was checked by indirect indicators, based on cross-validation analysis of consistency of the relevant variables. Statistical analysis was based on age-specific relative survival rates, computed for each cancer sites as the ratio of observed survival to the expected survival of the general population of the same area, gender and age, according to the Hakulinen method. An estimate of the European survival was computed as a weighted mean of the corresponding survival of the different countries, using as weights the expected yearly number of incident cases in each country. For comparison purposes, age-standardised survival was also calculated for Europe and for each country involved in the study.


Bidirectional Attention for Text-Dependent Speaker Verification.
Automatic speaker verification provides a flexible and effective way for biometric authentication. Previous deep learning-based methods have demonstrated promising results, whereas a few problems still require better solutions. In prior works examining speaker discriminative neural networks, the speaker representation of the target speaker is regarded as a fixed one when comparing with utterances from different speakers, and the joint information between enrollment and evaluation utterances is ignored. In this paper, we propose to combine CNN-based feature learning with a bidirectional attention mechanism to achieve better performance with only one enrollment utterance. The evaluation-enrollment joint information is exploited to provide interactive features through bidirectional attention. In addition, we introduce one individual cost function to identify the phonetic contents, which contributes to calculating the attention score more specifically. These interactive features are complementary to the constant ones, which are extracted from individual speakers separately and do not vary with the evaluation utterances. The proposed method archived a competitive equal error rate of 6.26% on the internal "DAN DAN NI HAO" benchmark dataset with 1250 utterances and outperformed various baseline methods, including the traditional i-vector/PLDA, d-vector, self-attention, and sequence-to-sequence attention models.


Volatile components of cigarette smoke: effect of acrolein and acetaldehyde on human gingival fibroblasts in vitro.
Tobacco and some of its volatile and non-volatile components have been found to affect many types of cells including gingival fibroblasts. Since normal gingival fibroblast functioning is fundamental to the maintenance of the periodontal connective tissue, as well as to wound healing, we examined the effect of acrolein and acetaldehyde, volatile components of cigarette smoke, on proliferation, attachment, and ultrastructure of human gingival fibroblasts (HGFs) in culture. Human gingival fibroblast (HGF) strains derived from healthy individuals with non-inflamed gingiva were used in this study. The cells were incubated in the presence of different concentrations of acrolein and acetaldehyde. Cell attachment and proliferation were evaluated after incubation for 3 hours and 5 days, respectively. In addition, the cells were examined with a transmission electron microscope in order to evaluate their morphology. The results show that acrolein and acetaldehyde produced dose-dependent inhibition of HGF attachment and proliferation. The cytotoxic effect was, however, reversible when both substances were removed, after 3 days, from the medium. The main ultrastructural finding for the HGF cytoplasm was the presence of vacuoles and lysosomal structures that became prominent with increasing concentration of acrolein and acetaldehyde. Our experimental data suggest that acrolein and acetaldehyde, volatile components of tobacco smoke, are detrimental to HGF survival and consequently to the oral connective tissue. According to our morpho-functional evidence, these findings corroborate clinical and epidemiological investigations demonstrating smoke as a risk factor in the development of periodontal disease.


[The gastrin-producing function of the stomach in patients with chronic alcoholism].
Basal and maximum gastrin levels were measured in 81 patients with various stages of chronic alcoholism and different periods of alcohol intake, in 23 patients with chronic gastritis of nonalcohol etiology, and in 12 normal subjects. The findings permit a conclusion on the depressive effect of alcohol on the function of gastrin-producing G-cells, this resulting in lowered levels of both basal and maximal gastrin. A direct correlation between the degree of alcohol depression of gastric gastrin production and the length of alcohol consumption was revealed.


[The relationship between respiratory system reactivity and neutrophil metabolism in hypoxia in persons subjected to ionizing radiation exposure].
The group of 18 men exposed to radiation during amelioration work in the Chernobyl NPP was examined in the course of adaptation to intermittent hypoxia (rebreathing technique during 10 days of three daily 5-7 min sessions with 15 min break). The starting level of ventilatory response to hypoxic stimulus (HVR) did not differ from the one in persons living in non-contaminated areas. This hypoxic training (HT) caused the increase of HVR, activity of NADPH-oxidase and cationic protein content in neutrophils as well as various changes in myeloperoxidase activity. The correlation between respiration reactivity and deviations in neutrophil metabolism under HT was found.


Emerging 'A' therapies in hemoglobinopathies: agonists, antagonists, antioxidants, and arginine.
Sickle cell disease and thalassemia have distinctly different mutations, but both share common complications from a chronic vasculopathy. In the past, fetal hemoglobin-modulating drugs have been the main focus of new therapy, but the increased understanding of the complex pathophysiology of these diseases has led to the development of novel agents targeting multiple pathways that cause vascular injury. This review explores the pathophysiology of hemoglobinopathies and novel drugs that have reached phase 1 and 2 clinical trials. Therapies that alter cellular adhesion to endothelium, inflammation, nitric oxide dysregulation, oxidative injury, altered iron metabolism, and hematopoiesis will be highlighted. To evaluate these therapies optimally, recommendations for improving clinical trial design in hemoglobinopathies are discussed.


Field flow fractionation techniques to explore the "nano-world".
Field flow fractionation (FFF) techniques are used to successfully characterize several nanomaterials by sizing nano-entities and producing information about the aggregation/agglomeration state of nanoparticles. By coupling FFF techniques to specific detectors, researchers can determine particle-size distributions (PSDs), expressed as mass-based or number-based PSDs. This review considers FFF applications in the food, biomedical, and environmental sectors, mostly drawn from the past 4 y. It thus underlines the prominent role of asymmetrical flow FFF within the FFF family. By concisely comparing FFF techniques with other techniques suitable for sizing nano-objects, the advantages and the disadvantages of these instruments become clear. A consideration of select recent publications illustrates the state of the art of some lesser-known FFF techniques and innovative instrumental set-ups.


High Sulfur Content Material with Stable Cycling in Lithium-Sulfur Batteries.
We demonstrate a novel crosslinked disulfide system as a cathode material for Li-S cells that is designed with the two criteria of having only a single point of S-S scission and maximizing the ratio of S-S to the electrochemically inactive framework. The material therefore maximizes theoretical capacity while inhibiting the formation of polysulfide intermediates that lead to parasitic shuttle. The material we report contains a 1:1 ratio of S:C with a theoretical capacity of 609 mAh g-1 . The cell gains capacity through 100 cycles and has 98 % capacity retention thereafter through 200 cycles, demonstrating stable, long-term cycling. Raman spectroscopy confirms the proposed mechanism of disulfide bonds breaking to form a S-Li thiolate species upon discharge and reforming upon charge. Coulombic efficiencies near 100 % for every cycle, suggesting the suppression of polysulfide shuttle through the molecular design.


A bayesian approach to joint mixed-effects models with a skew-normal distribution and measurement errors in covariates.
In recent years, nonlinear mixed-effects (NLME) models have been proposed for modeling complex longitudinal data. Covariates are usually introduced in the models to partially explain intersubject variations. However, one often assumes that both model random error and random effects are normally distributed, which may not always give reliable results if the data exhibit skewness. Moreover, some covariates such as CD4 cell count may be often measured with substantial errors. In this article, we address these issues simultaneously by jointly modeling the response and covariate processes using a Bayesian approach to NLME models with covariate measurement errors and a skew-normal distribution. A real data example is offered to illustrate the methodologies by comparing various potential models with different distribution specifications. It is showed that the models with skew-normality assumption may provide more reasonable results if the data exhibit skewness and the results may be important for HIV/AIDS studies in providing quantitative guidance to better understand the virologic responses to antiretroviral treatment.


Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing.
Epidemiologic evidence suggests that air pollution is a risk factor for childhood obesity. Limited experimental data have shown that early-life exposure to ambient particles either increases susceptibility to diet-induced weight gain in adulthood or increases insulin resistance, adiposity, and inflammation. However, no data have directly supported a link between air pollution and non-diet-induced weight increases. In a rodent model, we found that breathing Beijing's highly polluted air resulted in weight gain and cardiorespiratory and metabolic dysfunction. Compared to those exposed to filtered air, pregnant rats exposed to unfiltered Beijing air were significantly heavier at the end of pregnancy. At 8 wk old, the offspring prenatally and postnatally exposed to unfiltered air were significantly heavier than those exposed to filtered air. In both rat dams and their offspring, after continuous exposure to unfiltered air we observed pronounced histologic evidence for both perivascular and peribronchial inflammation in the lungs, increased tissue and systemic oxidative stress, dyslipidemia, and an enhanced proinflammatory status of epididymal fat. Results suggest that TLR2/4-dependent inflammatory activation and lipid oxidation in the lung can spill over systemically, leading to metabolic dysfunction and weight gain.-Wei, Y., Zhang, J., Li, Z., Gow, A., Chung, K. F., Hu, M., Sun, Z., Zeng, L., Zhu, T., Jia, G., Li, X., Duarte, M., Tang, X. Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing.


Long-term care hospitals in Turkey: a review.
A long-term care hospital (LTCH) is a specialized facility for patients with serious health problems who require continuous and intensive care but not comprehensive diagnostic methods. LTCHs provide prolonged complex care and wound care in the period following the acute stage of disease. When intensive care unit (ICU) stay is prolonged in the United States of America, the patients may be transferred to an LTCH. Medicare suggests hospitalization > 25 days in LTCHs. The LTC system in Europe differs from that in other non-European countries and differences are also seen among European countries. In practice, patients who need LTC in Turkey are hospitalized in ICUs. Long term care is a new concept for the Turkish health system and there are no studies on LTCHs in Turkey. A significant proportion of intensive care beds in Turkey are used for long-term hospitalized patients with complex problems. This is a clear waste of resources. The establishment of LTCHs in Turkey would prevent from this waste and provide the opportunity to increase experience of complex treatments.


Enzymic synthesis of sym-homospermidine in Lathyrus sativus (grass pea) seedlings.
An enzyme catalysing the synthesis of sym-homospermidine from putrescine and NAD+ with concomitant liberation of NH3 was purified 100-fold from Lathyrus sativus (grass pea) seedlings by affinity chromatography on Blue Sepharose. This thiol enzyme had an apparent mol.wt. of 75000 and exhibited Michelis-Menten kinetics with Km 3.0mM for putrescine. The same enzyme activity could also be demonstrated in the crude extracts of sandal (Santalum album) leaves, but with a specific activity 15-fold greater than that in L. sativus seedlings.


Super-extended (D3) lymphadenectomy in advanced gastric cancer.
To analyze our experience with D3 lymphadenectomy in the treatment of advanced GC with specific reference to post-operative morbidity and mortality, incidence of para-aortic node (PAN) metastases, and long-term prognosis. Short- and long-term results of D3 lymphadenectomy were analyzed in 286 patients with advanced GC. PAN metastases were demonstrated in 37 patients. PAN involvement was significantly higher in upper third tumours (29%) compared to middle and lower third (7%; P < 0.001). Eighty patients developed post-operative complications, being pulmonary disorders (6%), abdominal abscesses (4.5%) and pancreatic fistulas (3%) the most frequently observed. In-hospital mortality was 2%. Overall 5-year survival rate for R0 pT2-4 patients was 52%. When considering survival in relation to nodal involvement, both pN3 and non-regional lymph node metastases (M1a) patients showed a chance of long-term survival: 5-year survival was 31% for pN3 and 17% for M1a cases. Furthermore, the 5-year survival rate was remarkably high (about 60%) even in pN2 and pN3 subsets when no serosal invasion (pT2) was demonstrated. D3 lymphadenectomy could be further explored in specialized centers for curative surgery of advanced GC, especially for upper third tumours, providing that an acceptable morbidity and no increase in mortality can be offered.


Topical provocation in 27 cases of cotrimoxazole-induced fixed drug eruption.
The purpose of this study was to investigate the usefulness of topical provocation in the diagnosis of cotrimoxazole-induced fixed-drug eruption (FDE). 27 patients with established cotrimoxazole-induced FDE by oral provocation and 20 healthy controls were tested with drugs at increasing concentrations in white petrolatum and dimethyl sulfoxide (DMSO) both on previously involved and uninvolved skin sites. Tape-stripping occlusive patch testing in petrolatum remained negative in 19 tested patients. Open testing with drug preparations in DMSO revealed positive results in 25 of 27 tested patients. 1 patient showed an additional positive reaction on previously uninvolved skin. Lesions on male genitalia and on face reacted to testing once with 10% or 20% of the suspected drug, whereas repeated testing with concentrations up to 50% was necessary in lesions on trunk & extremities. Open testing with drug preparations in DMSO at concentrations of 10%, 20% and 50% and pure DMSO remained negative in 20 healthy controls. The present study shows that repeated open testing with graded concentrations of the drugs up to 50% in DMSO is a reliable test method in sulfamethoxazole/trimethoprim-induced FDE. Patients and physicians should be aware of the transient irritant reaction to DMSO that is not infrequent, so as to avoid false-positive interpretations.


Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.
To assess the comparative clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis (AS). Major electronic databases were searched up to November 2005. Unpublished evidence such as conference abstracts, reviews of published economic evaluations, and company submissions to the National Institute for Health and Clinical Excellence (NICE) were also reviewed. The assessment was conducted according to accepted procedures for conducting and reporting systematic reviews and economic evaluations. Full economic evaluations that compared two or more options for treatment and considered both costs and consequences were eligible for inclusion in the economic literature review. Nine placebo controlled randomised controlled trials (RCTs) were included in the review of clinical effects. These included two studies of adalimumab, five of etanercept and two of infliximab in comparison with placebo (along with conventional management). No RCTs directly comparing anti-tumour necrosis factor-alpha (TNF-alpha) agents were identified. Meta-analyses were conducted for data on Assessment in Ankylosing Spondylitis (ASAS) (20, 50 and 70% improvement), mean change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and mean change in Bath Ankylosing Spondylitis Functional Index (BASFI) at 12 weeks following initiation of anti-TNF-alpha therapy or placebo for all three drugs. Meta-analyses were also conducted at 24 weeks for etanercept and infliximab. Each meta-analysis of anti-TNF-alpha therapy demonstrated statistically significant advantages over placebo, although there was no significant difference between individual anti-TNF-alpha agents. At 12 weeks, ASAS 50% responses were 3.6-fold more likely with anti-TNF-alpha treatment than placebo. Compared with baseline, BASDAI scores were reduced by close to 2 points at 12 weeks. Functional scores (BASFI) were reduced at 12 weeks. Six full economic evaluations (two peer-reviewed published papers, four abstracts) were included in the review. The conclusions among economic evaluations were mixed, although the balance of evidence indicates that over short time-frames anti-TNF-alpha therapies are unlikely to be considered cost-effective. The limitations of the clinical outcome data impose restrictions on the economic assessment of cost-effectiveness. Direct unbiased RCT evidence is only available in the short term. Current assessment tools are limited and at present BASDAI and BASFI are the best available, although not designed for, or ideal for, use in economic evaluations. The review of the three models submitted to NICE identified a number of inherent flaws and errors. The incremental cost-effectiveness ratios (ICERs) of etanercept and adalimumab were roughly similar, falling below an assumed willingness-to-pay threshold of 30,000 pounds. The ICER for infliximab was in the range of 40,000-50,000 pounds per quality-adjusted life-year (QALY). The short-term (12-month) model developed by this report's authors confirmed the large front-loading of costs with a result that none of the three anti-TNF-alpha agents appears cost-effective at the current acceptable threshold, with infliximab yielding much poorer economic results (57,000-120,000 pounds per QALY). The assumptions of the short-term model were used to explore the cost-effectiveness of the use of anti-TNF-alpha agents in the long term. This model is far more speculative than the first since trends and parameter values must be projected far beyond the available evidence. Sensitivity analyses reveal wide variations in estimates of cost over the long term although it is considered unlikely that costs will decrease over time. The review of clinical data related to the three drugs (including conventional treatment) compared with conventional treatment plus placebo indicates that in the short term (12-24 weeks), the three treatments are clinically effective in relation to assessment of ASAS, BASDAI and BASFI. Indirect comparisons of treatments were limited and did not show a significant difference in effectiveness between the three agents. The short-term economic assessment indicates that none of the three anti-TNF-alpha agents is likely to be considered cost-effective at current acceptability thresholds, with infliximab consistently the least favourable option. There is an absence of evidence concerning a number of limiting factors related to patients suffering from AS, the disease itself and its treatment. In order to obtain robust estimates of the longer term clinical effectiveness and cost-effectiveness of anti-TNF-alpha agents for AS, clinical trials that aim to address these limiting factors need to be conducted.


Attractiveness of working in home care: An online focus group study among nurses.
Many western countries are experiencing a substantial shortage of home-care nurses due to the increasing numbers of care-dependent people living at home. In-depth knowledge is needed about what home-care nurses find attractive about their work in order to make recommendations for the recruitment and retention of home-care nursing staff. The aims of this explorative, qualitative study were to gain in-depth knowledge about which aspects home-care nurses find attractive about their work and to explore whether these aspects vary for home-care nurses with different levels of education. Discussions were conducted with six online focus groups in 2016 with a total of 38 Dutch home-care nurses. The transcripts were analysed using the principles of thematic analysis. The findings showed that home-care nurses find it attractive that they are a "linchpin", in the sense of being the leading professional and with the patient as the centre of care. Home-care nurses also find having autonomy attractive: autonomy over decision-making about care, freedom in work scheduling and working in a self-directed team. Variety in patient situations and activities also makes their work attractive. Home-care nurses with a bachelor's degree did not differ much in what they found attractive aspects from those with an associate degree (a nursing qualification after completing senior secondary vocational education). It is concluded that autonomy, variety and being a "linchpin" are the attractive aspects of working in home care. To help recruit and retain home-care nursing staff, these attractive aspects should be emphasised in nursing education and practice, in recruitment programmes and in publicity material.


Effect of intercropping period management on runoff and erosion in a maize cropping system.
The management of winter cover crops is likely to influence their performance in reducing runoff and erosion during the intercropping period that precedes spring crops but also during the subsequent spring crop. This study investigated the impact of two dates of destruction and burial of a rye (Secale cereale L.) and ryegrass (Lolium multiflorum Lam.) cover crop on runoff and erosion, focusing on a continuous silage maize (Zea mays L.) cropping system. Thirty erosion plots with various intercrop management options were monitored for 3 yr at two sites. During the intercropping period, cover crops reduced runoff and erosion by more than 94% compared with untilled, post-maize harvest plots. Rough tillage after maize harvest proved equally effective as a late sown cover crop. There was no effect of cover crop destruction and burial dates on runoff and erosion during the intercropping period, probably because rough tillage for cover crop burial compensates for the lack of soil cover. During two of the monitored maize seasons, it was observed that plots that had been covered during the previous intercropping period lost 40 to 90% less soil compared with maize plots that had been left bare during the intercropping period. The burial of an aboveground cover crop biomass in excess of 1.5 t ha(-1) was a necessary, yet not always sufficient, condition to induce a residual effect. Because of the possible beneficial residual effect of cover crop burial on erosion reduction, the sowing of a cover crop should be preferred over rough tillage after maize harvest.


Identification of protein signatures for lung cancer subtypes based on BPSO method.
The objective of this study was to identify protein biomarkers that can distinguish between LUAD and LUSC, critical for personalized treatment plans. The proteomic profiling data of LUAD and LUSC samples from TCPA database, along with phenotype and survival information from TCGA database were downloaded and preprocessed for analysis. We used BPSO feature selection method and identified 10 candidate protein biomarkers that have better classifying performance, as analyzed by t-SNE and PCA algorithms. To explore the causalities among these proteins and their associations with tumor subtypes, we conducted the PCStable algorithm to construct a regulatory network. Results indicated that 4 proteins, MIG6, CD26, NF2, and INPP4B, were directly linked to the lung cancer subtypes and may be useful in guiding therapeutic decision-making. Besides, spearman correlation, Cox proportional hazard model and Kaplan-Meier curve was employed to validate the biological significance of the candidate proteins. In summary, our study highlights the importance of protein biomarkers in the classification of lung cancer subtypes and the potential of computational methods for identifying key biomarkers and understanding their underlying biological mechanisms.


The cystic fibrosis transmembrane regulator (CFTR) in the kidney.
The cystic fibrosis transmembrane regulator (CFTR) is a Cl - channel. Mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the Cystic Fibrosis disease (CF). In spite of the high expression of CFTR in the kidney, patients with CF do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. CFTR mRNA is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (CCD) and medullary (IMCD) collecting ducts. Several studies have demonstrated that CFTR does not only transport Cl - but also secretes ATP and, thus, controls other conductances such as Na+ (ENaC) and K+ (ROMK2) channels, especially in CCD. In the polycystic kidney the secretion of chloride through CFTR contributes to the cyst enlargement. This review is focused on the role of CFTR in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.


LOXL2 catalytically inactive mutants mediate epithelial-to-mesenchymal transition.
Lysyl-oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family that catalyzes the cross-linking of collagens or elastins in the extracellular matrix, thus regulating the tensile strength of tissues. However, many reports have suggested different intracellular roles for LOXL2, including the ability to regulate gene transcription and tumor progression. We previously reported that LOXL2 mediates epithelial-to-mesenchymal transition (EMT) by Snail1-dependent and independent mechanisms, related to E-cadherin silencing and downregulation of epidermal differentiation and cell polarity components, respectively. Whether or not the catalytic activity of LOXL2 is required to induce/sustain EMT is actually unknown. Here we show that LOXL2 catalytic inactive mutants collaborate with Snail1 in E-cadherin gene repression to trigger EMT and, in addition, promote FAK/Src pathway activation to support EMT. These findings reveal a non-conventional role of LOXL2 on regulating epithelial cell plasticity.


Progesterone and modulation of endothelium-dependent responses in canine coronary arteries.
Chronic treatment with estrogens enhances some endothelium-dependent relaxations. Whether or not progesterone would exert a similar effect is unknown. Experiments were designed to determine the effect of chronic treatment with progesterone on endothelium-dependent responses. Adult female dogs were ovariectomized and pellets containing carrier substance, estrogen, progesterone, or estrogen plus progesterone were implanted subcutaneously. After 14-21 days coronary arteries were removed, cut into rings, and suspended for the measurement of isometric force in organ chambers in the presence of indomethacin. Endothelium-dependent relaxations to ADP, bradykinin, or the calcium ionophore did not differ among groups. However, relaxations to acetylcholine and to the alpha 2-adrenergic agonist BHT-920 were greater in the estrogen-treated group than in the estrogen plus progesterone-treated group. In rings without endothelium, relaxations to nitric oxide and isoproterenol did not differ among groups. However, relaxations of the smooth muscle to ADP were greater in the progesterone-treated group than in the progesterone plus estrogen group. These results suggest that progesterone alone minimally affects endothelium-dependent responses. However, progesterone seems to antagonize the stimulatory effects of estrogen on two endothelium-dependent responses that are associated with pertussis toxin-sensitive guanine nucleotide regulatory proteins and the production of nitric oxide. These studies suggest that a specific receptor/second messenger system can be modulated by female reproductive steroid hormones.


Bioactive proteins in bovine colostrum and effects of heating, drying and irradiation.
Bovine colostrum (BC) contains bioactive proteins, such as immunoglobulin G (IgG), lactoferrin (LF) and lactoperoxidase (LP). BC was subjected to low-temperature, long-time pasteurization (LTLT, 63 °C, 30 min) or high-temperature, short-time pasteurization (HTST, 72 °C, 15 s) and spray-drying (SD), with or without γ-irradiation (GI, ∼14 kGy) to remove microbial contamination. Relative to unpasteurized liquid BC, SD plus GI increased protein denaturation by 6 and 11%, respectively, increasing to 19 and 27% after LTLT and to 48% after HTST, with no further effects after GI (all P < 0.05). LTLT, without or with GI, resulted in 15 or 29% denaturation of IgG, compared with non-pasteurized BC, and 34 or 58% for HTST treatment (all P < 0.05, except LTLT without GI). For IgG, only GI, not SD or LTLT, increased denaturation (30-38%, P < 0.05) but HTST increased denaturation to 40%, with further increases after GI (60%, P < 0.05). LTLT and HTST reduced LP levels (56 and 81% respectively) and LTLT reduced LF levels (21%), especially together with GI (47%, P < 0.05). Denaturation of BSA, β-LgA, β-LgB and α-La were similar to IgG. Methionine, a protective amino acid against free oxygen radicals, was oxidised by LTLT + GI (P < 0.05) while LTLT and HTST had no effect. Many anti-inflammatory proteins, including serpin anti-proteinases were highly sensitive to HTST and GI but preserved after LTLT pasteurization. LTLT, followed by SD is an optimal processing technique preserving bioactive proteins when powdered BC is used as a diet supplement for sensitive patients.


Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base.
Ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.


Microbial and volatile profiling of soils suppressive to Fusarium culmorum of wheat.
In disease-suppressive soils, microbiota protect plants from root infections. Bacterial members of this microbiota have been shown to produce specific molecules that mediate this phenotype. To date, however, studies have focused on individual suppressive soils and the degree of natural variability of soil suppressiveness remains unclear. Here, we screened a large collection of field soils for suppressiveness to Fusarium culmorum using wheat (Triticum aestivum) as a model host plant. A high variation of disease suppressiveness was observed, with 14% showing a clear suppressive phenotype. The microbiological basis of suppressiveness to F. culmorum was confirmed by gamma sterilization and soil transplantation. Amplicon sequencing revealed diverse bacterial taxonomic compositions and no specific taxa were found exclusively enriched in all suppressive soils. Nonetheless, co-occurrence network analysis revealed that two suppressive soils shared an overrepresented bacterial guild dominated by various Acidobacteria. In addition, our study revealed that volatile emission may contribute to suppression, but not for all suppressive soils. Our study raises new questions regarding the possible mechanistic variability of disease-suppressive phenotypes across physico-chemically different soils. Accordingly, we anticipate that larger-scale soil profiling, along with functional studies, will enable a deeper understanding of disease-suppressive microbiomes.


[mTOR inhibitor].
Mammalian target of rapamycin(mTOR)exists downstream in the PI3K/AKT signal transmission pathway that is constantly activated in many cancers. It regulates translation of mRNA that codes for proteins involved in survival signals, such as for the cell cycle and apoptosis, by phosphorylation of p70S6K and 4E-BP1 that are further downstream. Thus, mTOR promotes cell proliferation and translation. It is also related to the growth and proliferation of cancer vascular endothelial cells. Inhibition of mTOR has been shown to lead to the inhibition of cancer cell proliferation and cancer angiogenesis, which are activated by mTOR, and to have an antitumor effect. In recent years, advances have been made in the development of drugs that target mTOR; that is, mTOR inhibitors. These drugs are being incorporated into the first and second-line therapies as standard treatment for renal cell cancer. The usefulness of mTOR has also been shown in pancreatic neuroendocrine tumor. The next task is to discover a clinically effective biomarker that predicts effect and toxicity of mTOR.


Applications of TALENs and CRISPR/Cas9 in human cells and their potentials for gene therapy.
The newly developed TALENs and emerging CRISPR/Cas9 have spurred interests in the field of genome engineering because of their ease of customization and high-efficient site-specific cleavages. Although these novel technologies have been successfully used in many types of cells, it is of great importance to apply them in human-derived cells to further observe and evaluate their clinical potentials in gene therapy. Here, we review the working mechanism of TALEN and CRISPR/Cas9, their effectiveness and specificity in human cells, and current methods to enhance efficiency and reduce off-target effects. Besides, CCR5 gene was chosen as a target example to illustrate their clinical potentials. Finally, some questions are raised for future research and for researchers to consider when making a proper choice bases on different purposes.


Effects of passive music therapy on anxiety and vital signs in lung cancer patients undergoing peripherally inserted central catheter placement procedure.
To evaluate the effects of passive music therapy on anxiety and vital signs among lung cancer patients at their first peripherally inserted central catheter placement procedure in China. A randomized controlled clinical trial was conducted in the cancer center of a hospital in Chengdu from May to December 2017. A total of 304 lung cancer patients who met the inclusion and exclusion criteria were recruited and randomly assigned to experimental (n = 152) and control (n = 152) group, respectively. The control group only received standard care, while the experimental group received standard care and passive music therapy during peripherally inserted central catheter placement (30-45 min) and after catheterization, until discharged from the hospital (twice a day, 30 min once). Measures include anxiety and vital signs (blood pressure, heart rate, and respiratory rate). Repetitive measurement and analysis of variance showed that the patients in experimental group had a statistically significant decrease in anxiety, diastolic blood pressure, and heart rate over time compared to the control group, but no significant difference was identified in systolic blood pressure and respiratory rate. Passive music therapy can efficiently relieve the anxiety of lung cancer patients during peripherally inserted central catheter placement. It also can lower the patient's diastolic blood pressure and slow down the heart rate. So, music therapy benefits patients with peripherally inserted central catheter.


Lysogeny in Leuconostoc oenos.
Thirty strains of Leuconostoc oenos were exposed to mitomycin C to induce lysogenic bacteriophages. Lysis curves typical for lysogenic strains were obtained with 19 strains. Indicator strans were found for 17 of these phages. Five were characterized by electron microscopy, lytic spectrum, molecular masses of the proteins, sequencing of five N-terminal amino acids of the two major proteins and DNA analysis (restriction patterns, cross hybridization). The results revealed a very close relationship between the phages. Hybridization experiments between the DNAs of the temperate phages and the appropriate lysogenic strains revealed phage-related sequences in the DNA of the lysogenic strain.


PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability.
Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy.Significance: PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatin-level functions are critical to understanding its oncogenic activity. We find that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8); 884-99. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.


Mechanism and dynamics of cadherin adhesion.
Cadherins are essential cell adhesion molecules involved in tissue morphogenesis and the maintenance of tissue architecture in adults. The adhesion and selectivity functions of cadherins are located in their extracellular regions. Biophysical studies show that the adhesive activity is not confined to a single interface. Instead, multiple cadherin domains contribute to binding. By contrast, the specificity-determining site maps to the N-terminal domains, which adhere by the reciprocal binding of Trp2 residues from opposing proteins. Structural cooperativity can transmit the effects of subtle structural changes or ligand binding over large distances in the protein. Increasingly, studies show that differential cadherin-mediated adhesion, rather than exclusive homophilic binding between identical cadherins, direct cell segregation and the organization of tissue interfaces during morphogenesis. Force measurements quantified both kinetic and strength differences between different classical cadherins that may underlie cell sorting behavior. Despite the complex adhesion mechanisms and differences in binding properties, cadherin-mediated cell adhesion is also regulated by many other biochemical processes. Elucidating the mechanisms by which cadherins organize cell junctions and tissue architecture requires not only quantitative, mechanistic investigations of cadherin function but also investigations of the biochemical and cellular processes that can modulate those functions.


An Aspergillus awamori acetylesterase: purification of the enzyme, and cloning and sequencing of the gene.
An inducible acetylesterase was purified from the culture medium of Aspergillus awamori strain IFO4033 growing on wheat-bran culture by ion-exchange, gel-filtration and hydrophobic-interaction chromatographies. The purified enzyme had an Mr of 31000 and contained Asn-linked oligosaccharides. The enzyme liberated acetic acid from wheat bran, hydrolysed only alpha-naphthyl acetate and propionate when aromatic esters were used for the substrate, and was tentatively classified as a carboxylic esterase (EC 18.104.22.168). The gene encoding acetylesterase was cloned and sequenced. The deduced amino acid sequence showed that acetylesterase was produced as a 304-amino-acid-residue precursor, which was converted post-translationally into a 275-amino-acid-residue mature protein. Part of the sequence of acetylesterase was similar to the region near the active-site serine of lipases of Geotrichum candidum and Candida cylindracea. A unique site of putative Asn-linked oligosaccharides was presented.