Epigallocatechin-3-gallate inhibits STAT-1 activation and protects cardiac myocytes from ischemia/reperfusion-induced apoptosis.
We have previously demonstrated that STAT-1 plays a critical role in promoting apoptotic cell death in cardiac myocytes following ischemia/reperfusion (I/R) injury. Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has recently been reported to inhibit STAT-1 activity in noncardiac cells. In the present study, we have assessed the protective effects of EGCG and green tea extract (GTE) infusion on both cultures of cardiac myocytes and the isolated rat heart. EGCG reduced STAT-1 phosphorylation and protected cardiac myocytes against I/R-induced apoptotic cell death. Moreover, EGCG reduced the expression of a known STAT-1 pro-apoptotic target gene, Fas receptor. More interestingly, oral administration of GTE as well as EGCG infusion limited the extent of infarct size and attenuated the magnitude of myocyte apoptosis in the isolated rat heart exposed to I/R injury. This reduction cell death was associated with improved hemodynamic recovery and ventricular function in the ischemic/reperfused rat heart. This is the first report to show that consumption of green tea is able to mediate cardioprotection and enhance cardiac function during I/R injury. Because GTE-mediated cardioprotection is achieved, at least in part, through inhibition of STAT-1 activity, we may postulate that a similar action can be implemented in the clinical setting to minimize STAT-1 activation levels in patients with acute coronary artery disease (CAD).


Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.
Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.


[A new method of age determination by age-related changes in the hand bone].
An anthropological method designed for determining the age is under discussion; it is based on the point-evaluation of age-related changes observed in the hand bones by X-Ray, i.e. osteophytes, osteoporosis, osteosclerosis and joint deformations. The method was made use of to elaborate a new modified point-based assessment of the above changes in the hand bones with respect to their severity.


Intrathoracic manifestations in mixed connective tissue disease.
A high frequency of occurrence of pleuropulmonary manifestations in mixed connective tissue disease (MCTD) has been reported in the literature. A retrospective analysis of 81 adult patients with the diagnosis of MCTD who were examined at our medical center from 1973 through 1977 revealed that pleuropulmonary involvement occurred in 20 (25%). Thirteen patients (16%) had dyspnea, six (7%) had chest pain, and four (5%) had cough. Chest roentgenograms disclosed basal interstitial processes in 15 patients (19%), pleural effusion in 5 (6%), pneumonic infiltrates in 3 (4%), and pleural thickening in 2 (2%). Abnormalities of pulmonary function were noted in 9 (69%) of 13 patients tested, and esophagographic abnormalities were present in 19 (53%) of 36 patients tested. Systemic corticosteroid therapy was beneficial in two of the eight patients so treated, and nonsteroidal anti-inflammatory drugs resolved most of the clinical features in four of the seven patients so treated. Six patients died during a 5-year follow-up period.


The Impact of Adult Thoracolumbar Spinal Deformities on Standing to Sitting Regional and Segmental Reciprocal Alignment.
Regional and segmental changes of the lumbar spine have previously been described as patients transition from standing to sitting; however, alignment changes in the cervical and thoracic spine have yet to be investigated. So, the aim of this study was to assess cervical and thoracic regional and segmental changes in patients with thoracolumbar deformity versus a nondeformed thoracolumbar spine population. This study was a retrospective cohort study of a single center's database of full-body stereoradiographic imaging and clinical data. Patients were ≥ 18 years old with nondeformed spines (nondegenerative, nondeformity spinal pathologies) or thoracolumbar deformity (ASD: PI-LL > 10°). Patients were propensity-score matched for age and maximum hip osteoarthritis grade and were stratified by Scoliosis Research Society (SRS)-Schwab classification by PI-LL, SVA, and PT. Patients with lumbar transitional anatomy or fusions were excluded. Outcome measures included changes between standing and sitting in global alignment parameters: sagittal vertical axis (SVA), pelvic incidence minus lumbar lordosis (PI-LL), pelivc tilt (PT), thoracic kyphosis, cervical alignment, cervical SVA, C2-C7 lordosis (CL), T1 slop minus CL (TS-CL), and segmental alignment from C2 to T12. Another analysis was performed using patients with cervical and thoracic segmental measurements. A total of 338 patients were included (202 nondeformity, 136 ASD). After propensity-score matching, 162 patients were included (81 nondeformity, 81 ASD). When categorized by SRS-Schwab classification, all nondeformity patients were nonpathologically grouped for PI-LL, SVA, and PT, whereas ASD patients had mix of moderately and markedly deformed modifiers. There were significant differences in pelvic and global spinal alignment changes from standing to sitting between nondeformity and ASD patients, particularly for SVA (nondeformed: 49.5 mm versus ASD: 27.4 mm; P < .001) and PI-LL (20.12° versus 13.01°, P < .001). With application of the Schwab classification system upon the cohort, PI-LL (P = .040) and SVA (P = .007) for severely classified deformity patients had significantly less positional alignment change. In an additional analysis of patients with segmental measurements from C2 to T12, nondeformity patients showed significant mobility of T2-T3 (-0.99° to -0.54°, P = .023), T6-T7 (-3.39° to -2.89°, P = .032), T7-T8 (-2.68° to -2.23°, P = .048), and T10-T11 (0.31° to 0.097°, P = .006) segments from standing to sitting. ASD patients showed mobility of the C6-C7 (1.76° to 3.45°, P < .001) and T11-T12 (0.98° to 0.54°, P = 0.014) from standing to sitting. The degree of mobility between nondeformity and ASD patients was significantly different in C6-C7 (-0.18° versus 1.69°, P = .003), T2-T3 (0.45° versus -0.27°, P = .034), and T10-T11 (0.45° versus -0.30°, P = .001) segments. With application of the Schwab modifier system upon the cohort, mobility was significant in the C6-C7 (nondeformed: 0.18° versus moderately deformed: 2.12° versus markedly deformed: 0.92°, P = .039), T2-T3 (0.45° versus -0.08° versus -0.63°, P = .020), T6-T7 (0.48° versus 0.36° versus -1.85°, P = .007), and T10-T11 (0.45° versus -0.21° versus -0.23°, P = .009) segments. Nondeformity patients and ASD patients have significant differences in mobility of global spinopelvic parameters as well as segmental regions in the cervical and thoracic spine between sitting and standing. This study aids in our understanding of flexibility and compensatory mechanisms in deformity patients, as well as the possible impact on unfused segments when considering deformity corrective surgery.


Small molecule NSC1892 targets the CUL4A/4B-DDB1 interactions and causes impairment of CRL4DCAF4 E3 ligases to inhibit colorectal cancer cell growth.
Cullin 4A and 4B (CUL4A and 4B) function as oncogenes in colorectal cancer (CRC) cells. Both of them conservatively associate with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4) to form Cullin-RING E3 ligases known as CRL4DCAF4, which specifically ubiquitinate and degrade tumor suppressor ST7 (suppression of tumorigenicity 7). Knockdown either CUL4A/4B or DDB1 significantly inhibits tumor cell growth in vitro and in vivo. Thus, targeting these CRL4DCAF4 components and their interactions may be an effective strategy for the therapy of CRC. In this study, we developed an in vitro AlphaScreen assay to identify small molecules targeting the CUL4A-DDB1 interaction. We obtained a compound NSC1892, which strongly disrupted the CUL4A-DDB1 interaction (IC50 = 1.8 μM). Oncogenic phenotype analyses indicated that NSC1892 showed significant cytotoxicity to decrease cell proliferation, colony formation and invasion in CRC cells. Biochemical analyses demonstrated that NSC1892 treatment did not change CUL4A and CUL4B protein levels, but caused the degradation of DDB1, thereby leading to the impaired assembly of CRL4DCAF4 E3 ligases and resulting in the accumulation of ST7. The administration of NSC1892 in mice also significantly inhibited tumor growth through degrading DDB1 and accumulating ST7. Interestingly, NSC1892 also showed promising cytotoxicity to decrease the growth of other CUL4A- or CUL4B-overexpressing tumor cells such as SKOV3 ovarian cells and Saos2 osteosarcoma cells. Our results provide a new avenue for the development of a therapeutic compound targeting tumors through disrupting the CUL4-DDB1 interaction.


Disability Status and Secondary Prevention Among Survivors of Stroke: A Cross-Sectional Analysis of the 2011 to 2018 National Health and Nutrition Examination Survey.
Among survivors of stroke, adherence to secondary prevention care is associated with decreased risk of recurrent stroke. However, not all survivors of stroke use secondary stroke prevention treatment. We examined the association between the disability status of survivors of stroke and their treatment and control of diabetes, hyperlipidemia, and hypertension. In a cross-sectional analysis of the 2011 to 2018 National Health and Nutrition Examination Survey, we compared diabetes, hyperlipidemia, and hypertension treatment and control rates among self-reported survivors of stroke age ≥20 years with and without disability. Disability was defined as self-reporting any of 5 physical or 4 functional domains assessed using a structured questionnaire. Logistic regression models adjusted for age, sex, race and ethnicity, and history of medical conditions were used to estimate associations between disability status and risk factor treatment and control. The mean age of survivors of stroke was 65.1 years, and 55.5% were female; 76% (95% CI, 72.7%-79.3%) self-reported at least 1 disability. Age-standardized treatment rates for diabetes, hyperlipidemia, and hypertension were 33.1% (95% CI, 26.9%-39.2%), 67.5% (95% CI, 62.6%-72.3%), and 78.4% (95% CI, 74.6%-82.2%), respectively. Age-standardized control rates for diabetes, hyperlipidemia, and hypertension were 86.8% (95% CI, 83.8%-89.8%), 20.5% (95% CI, 15.0%-25.9%), and 47.1% (95% CI, 42.6%-51.7%), respectively. In adjusted models, those with and without disabilities had similar odds of risk factor treatment and control. In the United States, three-quarters of survivors of stroke self-reported a disability, and these patients had similar odds of diabetes, hyperlipidemia, and hypertension treatment and control compared with those without disability.


Selectivity assessment of an arsenic sequential extraction procedure for evaluating mobility in mine wastes.
An optimized sequential extraction (SE) scheme for mine waste materials has been developed and tested for As partitioning over a range of pure As-bearing mineral phases, their model mixtures, and natural mine waste materials. This optimized SE procedure employs five extraction steps: (1) nitrogen-purged deionized water, 10h; (2) 0.01 M NH4H2PO4, 16 h; (3) 0.2M NH4-oxalate in the dark, pH3, 2 h; (4) 0.2 M NH4-oxalate, pH3/80°C, 4 h; (5) KClO3/HCl/HNO3 digestion. Selectivity and specificity tests on natural mine wastes and major pure As-bearing mineral phases showed that these As fractions appear to be primarily associated with: (1) readily soluble; (2) adsorbed; (3) amorphous and poorly-crystalline arsenates, oxides and hydroxosulfates of Fe; (4) well-crystalline arsenates, oxides, and hydroxosulfates of Fe; as well as (5) sulfides and arsenides. The specificity and selectivity of extractants, and the reproducibility of the optimized SE procedure were further verified by artificial model mineral mixtures and different natural mine waste materials. Partitioning data for extraction steps 3, 4, and 5 showed good agreement with those calculated in the model mineral mixtures (<15% difference), as well as that expected in different natural mine waste materials. The sum of the As recovered in the different extractant pools was not significantly different (89-112%) than the results for acid digestion. This suggests that the optimized SE scheme can reliably be employed for As partitioning in mine waste materials.


Spectrum of Joint Deformities in Children with Juvenile Idiopathic Arthritis.
To determine the frequency and types of joint deformities in children with juvenile idiopathic arthritis and their association with clinical parameters and rheumatoid factor. Cross-sectional study. Rheumatology Outpatient Clinic, the Children's Hospital and the Institute of Child Health, Lahore, from September 2014 to February 2015. All patients of both genders of less than 16 years of age, who fulfilled the International League of Association for Rheumatology (ILAR) criteria for Juvenile Idiopathic Arthritis (JIA), were enrolled in this study. Their demographic data, duration of disease at the time of presentation, types of JIA, various joint deformities and rheumatoid factor (RF) were documented. Statistical analysis of data was done on SPSS version 16. Chi-square test was applied to determine the association of clinical deformity with age of patients, disease duration at presentation, types of JIA and RF. Out of 70 patients enrolled during the study period, 51.4% were boys with mean age at presentation being 9.44 ±3.89 years (2-7 years) and median duration of disease being 24 months (interquartile range 42 months). Forty patients (57.1%) had joint deformities. Most common joints involved were hand (50%), wrist (50%), and knee (35.7%). The common types of joint deformities were boutonniere deformity (28.6%), ulnar deviation of wrist (28.6%), fixed flexion deformity of wrist (22.9%), and knee (31.4%). The most common type of JIA was polyarthritis RF negative with or without deformity. There was a strong association of deformities with older age of patients at presentation (p=0.036), longer duration of disease at presentation (p=0.028), polyarthritis (RF seronegative / seropositive) (p=0.013), and seropositivity (p=0.04). More than 50% patients with JIA have joint deformities. Joint deformities are more likely to be seen in children with long-standing disease, those with polyarthritis JIA and seropositive patients.


Contemporary Use of Oral Antithrombotic Agents: Focus on Dual and Triple Therapeutic Approaches.
Atherosclerotic cardiovascular disease (ASCVD) represents a long-standing health care burden in most industrialized countries. Management of ASCVD is multifaceted, and utilization of antithrombotic agents is a key component of care to reduce vascular events. Minimizing thrombotic risk can be accomplished via antiplatelet or anticoagulant drugs; however, combination therapy is warranted for some indications. Although reducing thrombotic complications is important, it is equally vital to consider the safety of combination regimens. Thus clinicians must effectively balance both individualized thrombotic and bleeding risks when using this strategy. Scenarios occur in practice when determining the role for combination therapy is not clear, especially for patients with ASCVD who require both dual antiplatelet therapy plus anticoagulation. The aim of this review is to discuss the role of dual or triple antithrombotic therapies across the spectrum of thrombotic disease states. In addition to critiquing relevant research studies and evaluating key recommendations from nationally published guidelines and consensus statements involving the use of these agents, we offer practical considerations that can be utilized when managing patients with ASCVD.


Comparative analysis of CD1a, S-100, CD83, and CD11c human dendritic cells in normal, premalignant, and malignant tissues.
A number of antibodies that recognize human dendritic cells (DC) have been identified. The main aim of this study was to compare and contrast different antigen retrieval techniques using both enzymatic and non-enzymatic treatments in order to determine the expression and distribution of several DC markers on formalin-fixed, paraffin-embedded tissues. Normal human lung, oral epithelial hyperplasia lesions, oral squamous cell carcinoma, and prostate adenocarcinoma tissues were evaluated using a panel of DC specific antibodies. The results of immunohistochemical staining for CD83, CD1a, CD11c, and S-100 DC markers were compared following the different antigen retrieval approaches. The overall best results for the analysis of tumor-associated DC were obtained with the enzymatic methods. Protease XXIV digestion was determined to be essential for detection of S-100 and CD11c positive DC, whereas trypsin and pepsin were required for the recognition of CD1a and CD83 expressing tumor-associated DC. These results could be easily adapted for routine practice and should be useful for characterization of the DC system in cancer patients for both diagnostic and prognostic purposes. In addition, standardized procedures for evaluating different subpopulations of tumor-associated DC should bring new insights in understanding of DC-tumor cell interaction.


Outcomes of Patients with Acute Hepatotoxicity Caused by Mushroom-Induced Poisoning.
This study aimed to investigate the characteristics of severe hepatitis (SH), acute liver injury (ALI), and acute liver failure (ALF) in patients with mushroom-induced hepatotoxicity. Data of patients between 2010 and 2019 were retrospectively reviewed. Twenty-four patients with mushroom-induced hepatotoxicity were included and divided into 3 groups: SH, ALI, and ALF. SH was defined as transaminase level ≥10 times ULN, international normalized ratio (INR) ≤1.5, and the absence of hepatic encephalopathy (HE). ALI was defined as INR > 1.5, presumed acute illness onset, and the absence of HE. ALF was diagnosed based on the presence of HE of any degree, with INR > 1.5, presumed acute illness onset, and the absence of cirrhosis. The mean age of the patients was 51.6 years; 13 (54.2%) were female. At admission, 18 patients (75%) had SH, 5 (21%) had ALI, and 1 (4.1%) had ALF. During follow-up, 6 of the 18 SH (33%) patients progressed to ALI and 2 of the 5 ALI (40%) patients progressed to ALF. No progression to ALI or ALF was observed in the 8 SH cases with a baseline MELD score of <15. One patient with grade 4 HE died (4.1%). None underwent liver transplantation. The survival was 100% in the ALI and SH groups. A MELD score of <15 at admission may be used as a predictor of no progression to ALI or ALF in patients with SH. However, since 40% of ALI cases may progress to ALF, these cases should be followed up in a tertiary care center that is equipped to perform liver transplantation and advanced therapies.


Social patterning in grip strength, chair rise, and walk speed in an aging population: the Czech HAPIEE Study.
The aim was to examine the association of objective measures of physical functioning (PF) with education and material circumstances and the decline in PF with age by socioeconomic position (SEP). In 3,205 subjects (60-75 years) from the Czech Republic, we assessed relationship between PF, SEP, and age. Linear regression was used to assess PF measures and SEP measures. Cross-sectional decline in PF by age was similar in all individuals. Differences between SEP groups were similar across age groups, except for the difference in walk speed by material circumstances in men-bigger at older ages (p = .004). Men and women with the highest education were about 2 s faster at the chair rise test than those with the lowest education. Findings suggest strong educational gradient in PF, an inconsistent role of self-assessed material circumstances, and virtually no interaction of SEP with the cross-sectional decline in PF by age.


Occupational Health and Safety in the Palm Oil Industry: A Systematic Review.
The palm oil industry is the largest contributor to global production of oils and fats. Indonesia and Malaysia are the largest producers of palm oil. More than a million workers are employed in this industry, yet there is a lack of information on their occupational health and safety. To identify and summarize occupational hazards among oil palm plantation workers. A search was carried out in June 2018 in PubMed, Web of Science, Scopus, and Ovid. Relevant publications were identified by a systematic search of four databases and relevant journals. Publications were included if they examined occupational hazards in oil palm plantation workers. 941 publications were identified; of these, 25 studies were found eligible to be included in the final review. Of the 25 studies examined, 19 were conducted in Malaysia, 2 in Costa Rica, and one each in Ghana, Indonesia, Myanmar, Papua New Guinea, and Cameroon. Oil palm plantation workers were found to be at risk of musculoskeletal conditions, injuries, psychosocial disorders, and infectious diseases such as malaria and leptospirosis. In addition, they have potential exposure to paraquat and other pesticides. In light of the potential of palm oil for use as a biofuel, this is an industry with strong growth potential. The workers are exposed to various occupational hazards. Further research and interventions are necessary to improve the working conditions of this already vast and growing workforce.


End-of-life care pathways and nursing: a literature review.
To identify and discuss the current state of knowledge about end-of-life care (EOLC) pathways in relation to nursing. Enhancing EOLC has become a central concern in governments' health policies worldwide. End-of-life care pathways have been championed as complex interventions to enhance the quality of end-of-life care. However, concerns have been expressed regarding their purpose, initiation and use. A range of published literature was used to examine EOLC pathways in relation to nursing. Three main themes emerged: nursing's contribution to the evolution of EOLC pathways, implementing EOLC pathways and the influence of EOLC pathways on nursing practice. End-of-life care pathways are to be welcomed as a means by which the quality of EOLC might be enhanced. However, the state of knowledge about EOLC pathways, their development, implementation and influence on families and professional practice is in its infancy. End-of-life care pathways are championed as a means by which the quality of EOLC, for dying people and their families might be enhanced. However, as concerns regarding the quality of EOLC persist, nursing management has a crucial role in driving forward and supporting EOLC pathway development, implementation and evaluation.


Predominant dendriform pulmonary ossification in a usual interstitial pneumonia-like distribution: to be distinguished from idiopathic pulmonary fibrosis.
Idiopathic dendriform diffuse pulmonary ossification (DPO) is a rare disorder. High resolution CT (HRCT) with appropriate osteoporosis window setting reveals the diagnosis. We report the features of eight patients, of whom two brothers, with HRCT findings compatible with predominant DPO in a bibasal subpleural distribution (usual interstitial pneumonia (UIP)-like distribution) and review the literature for DPO in this UIP-like distribution. DPO in a UIP-like distribution seems to be a disorder of the very old (age 75-87 (mean 83.6) male (8 out of 8), with familial occurrence, with associated cardiovascular disease and frequent use of anticoagulants as common findings, and with a slowly progressive nature and the absence of radiological honeycombing despite long lasting disease contrasting with idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) should be differentiated from predominant DPO in a UIP-like distibution. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 251-256).


PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS.
HIV infection in humans and simian immunodeficiency virus (SIV) infection in macaques result in encephalitis in approximately one-quarter of infected individuals and is characterized by infiltration of the brain with infected and activated macrophages. 1-(2-chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (PK11195) is a ligand specific for the peripheral benzodiazepine receptor abundant on macrophages and is expressed in low levels in the noninfected brain. We hypothesized that positron-emission tomography (PET) with the carbon-11-labeled, R-enantiomer form of PK11195 ([(11)C](R)-PK11195) could image brain macrophages and hence the development of encephalitis in vivo. [(11)C](R)-PK11195 binding was assessed in the brain using PET in 11 SIV infected macaques, six of which showed increased binding in vivo. Postmortem examination of the brain in these six macaques demonstrated encephalitis, while macaques that did not show an increase in [(11)C](R)-PK11195 binding did not develop SIV encephalitis. Brain tissue from SIV encephalitic macaques also showed increased [(3)H](R)-PK11195 binding compared with binding in nonencephalitic macaques. Increased PK11195 binding in vivo and in postmortem brain tissue correlated with abundance of macrophages but not astrocytes. Our results suggest that PET [(11)C](R)-PK11195 imaging can detect the presence of macrophages in SIV encephalitis in vivo and may be useful to predict the development of HIV encephalitis and in studies of the pathogenesis and treatment of HIV dementia.


Identification by gene coregulation mapping of novel genes involved in embryonic stem cell differentiation.
A combined analysis of data from a series of literature studies can lead to more reliable results than that based on a single study. A common problem in performing combined analyses of literature microarray gene expression data is that the original raw data are not always available and not always easy to combine in one analysis. We propose an approach that does not require analyzing original raw data, but instead takes literature gene sets derived from (supplementary) tables as input and uses gene co-occurrence in these sets for mapping a co-regulation network. An algorithm for this method was applied to a collection of literature-derived gene sets related to embryonic stem cell (ESC) differentiation. In the resulting network, genes involved in similar biological processes or expressed at similar time points during differentiation were found to cluster together. Using this information, we identified 43 genes not previously associated with cardiac ESC differentiation for which we were able to assign a putative novel biological function. For 6 of these genes (Apobec2, Cth, Ptges, Rrad, Zfp57, and 2410146L05Rik), literature data on mouse knockout phenotypes support their putative function. Three other genes (Rcor2, Zfp503, and Hspb3) are part of major pathways within the network and therefore likely mechanistically relevant candidate genes. We anticipate that these 43 genes can help to improve the understanding of the molecular events underlying ESC differentiation. Moreover, the approach introduced here can be more widely applied to identify possible novel gene functions in biological processes.


TNF is a critical cytokine in age-related dry eye disease.
Aging is a complex biological process that is characterized by low-grade inflammation, called inflammaging. Aging affects multiple organs including eye and lacrimal gland. Tumor necrosis factor (TNF) is a pleiotropic cytokine that participates in inflammation, activation of proteases such as cathepsin S, and formation of ectopic lymphoid organs. Using genetic and pharmacological approaches, we investigated the role of TNF in age-related dry eye disease, emphasizing the ocular surface and lacrimal gland inflammation. Our results show the increased protein and mRNA levels of TNF in aged lacrimal glands, accompanied by increased TNF, IL1β, IL-18, CCL5, CXCL1, IL-2, IL-2 receptor alpha (CD25), IFN-γ, IL-12p40, IL-17, and IL-10 proteins in tears of aged mice. Moreover, genetic loss of the Tnf-/- in mice decreased goblet cell loss and the development of ectopic lymphoid structures in the lacrimal gland compared to wild-type mice. This was accompanied by a decrease in cytokine production. Treatment of mice at an early stage of aging (12-14-month-old) with TNF inhibitor tanfanercept eye drops for eight consecutive weeks decreased cytokine levels in tears, improved goblet cell density, and decreased the marginal zone B cell frequency in the lacrimal gland compared to vehicle-treated animals. Our studies indicate that modulation of TNF during aging could be a novel strategy for age-related dry eye disease.


Integrating CAR-T cell therapy into the management of DLBCL: what we are learning.
Chimeric Antigen Receptor ;(CAR) T cells therapies have become part of the standard of care for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The weakness of CAR-T therapies is that there are no comparative clinical trials, although many publications based on real-life data have confirmed the results obtained in pivotal studies. After several years of the commercialization of CAR-T, some points still need to be fully clarified. Healthcare professionals have questions about identifying patients who may benefit from therapy. There are aspects inherent in the accessibility of care related to improved relationships between CAR-T-delivering and referral centers. Open questions are inherent in the salvage and bridge therapy, predictive criteria for response and persistence of CAR-T after infusion. Managing toxicities remain a top priority and one of the points on which further knowledge is needed. This review aims to describe the current landscape of CAR-T cells in DLBCL, outline their outcomes and toxicities, and explain the outstanding questions that remain to be addressed.


Modeling biodegradation and kinetics of glyphosate by artificial neural network.
An artificial neural network (ANN) model was developed to simulate the biodegradation of herbicide glyphosate [2-(Phosphonomethylamino) acetic acid] in a solution with varying parameters pH, inoculum size and initial glyphosate concentration. The predictive ability of ANN model was also compared with Monod model. The result showed that ANN model was able to accurately predict the experimental results. A low ratio of self-inhibition and half saturation constants of Haldane equations (< 8) exhibited the inhibitory effect of glyphosate on bacteria growth. The value of K(i)/K(s) increased when the mixed inoculum size was increased from 10(4) to 10(6) bacteria/mL. It was found that the percentage of glyphosate degradation reached a maximum value of 99% at an optimum pH 6-7 while for pH values higher than 9 or lower than 4, no degradation was observed.


Resveratrol loaded polymeric micelles for theranostic targeting of breast cancer cells.
Treatment of breast cancer underwent extensive progress in recent years with molecularly targeted therapies. However, non-specific pharmaceutical approaches (chemotherapy) persist, inducing severe side-effects. Phytochemicals provide a promising alternative for breast cancer prevention and treatment. Specifically, resveratrol (res) is a plant-derived polyphenolic phytoalexin with potent biological activity but displays poor water solubility, limiting its clinical use. Here we have developed a strategy for delivering res using a newly synthesized nano-carrier with the potential for both diagnosis and treatment. Methods: Res-loaded nanoparticles were synthesized by the emulsion method using Pluronic F127 block copolymer and Vitamin E-TPGS. Nanoparticle characterization was performed by SEM and tunable resistive pulse sensing. Encapsulation Efficiency (EE%) and Drug Loading (DL%) content were determined by analysis of the supernatant during synthesis. Nanoparticle uptake kinetics in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in MCF-10A breast epithelial cells were evaluated by flow cytometry and the effects of res on cell viability via MTT assay. Results: Res-loaded nanoparticles with spherical shape and a dominant size of 179±22 nm were produced. Res was loaded with high EE of 73±0.9% and DL content of 6.2±0.1%. Flow cytometry revealed higher uptake efficiency in breast cancer cells compared to the control. An MTT assay showed that res-loaded nanoparticles reduced the viability of breast cancer cells with no effect on the control cells. Conclusions: These results demonstrate that the newly synthesized nanoparticle is a good model for the encapsulation of hydrophobic drugs. Additionally, the nanoparticle delivers a natural compound and is highly effective and selective against breast cancer cells rendering this type of nanoparticle an excellent candidate for diagnosis and therapy of difficult to treat mammary malignancies.


Adaptive changes in degree of eye reduction in eyeless mutants of Drosophila melanogaster after thermal shock during the critical periods of faceted eye development.
Brief heating of the oocytes and larvae of eyeless mutants during the critical periods of faceted-eye development caused an increase in the thermal sensitivity of the eye rudiments, which led to an increase in the number of one-eyed individuals among the flies that hatched. These changes eye development were transmitted through a number of successive generations without exposure to additional thermal shock, by maternal inheritance. It was established that repeated heating of oocytes and larvae of eyeless mutants whose ancestors had been subjected to similar heating during the same stages of development caused a decrease rather than the expected increase in thermal sensitivity, i.e., there was an adaptive increase in the thermostability of the eye rudiments. Thus, the effect of reheating was the opposite of that of the original heating.


Risk and safety of pediatric sedation/anesthesia for procedures outside the operating room.
Sedation and anesthesia outside the operating room represents a rapidly growing field of practice that involves a number of different specialty providers including anesthesiology. The literature surrounding this work is found in a variety of journals - many outside anesthesiology. This review is intended to inform readers about the current status of risk and safety involving sedation/anesthesia for tests and minor procedures utilizing a wide range of sources. Two large database studies have helped to define the frequency and nature of adverse events in pediatric sedation/anesthesia practice from a multispecialty perspective. A number of papers describing respiratory and hemodynamic aspects of dexmedetomidine sedation have also been published. Finally, a number of studies relating to training sedation providers, reporting of sedation adverse events, sedation for vulnerable populations, and (in particular) ketamine sedation adverse respiratory events have also come to light. The latest publications continue to document a relatively low risk to pediatric sedation yet also warn us about the potential adverse events in this field. The results help to define competencies required to deliver pediatric sedation and make this practice even safer. Particularly interesting are new jargon and methodologies for defining adverse events and the use of new methods for training sedation providers.


The role of fascial slings in the treatment of stress urinary incontinence in women: a 2013 update.
During the last decade, a variety of commercial innovations in synthetic sling materials have emerged as a result of an evolution in the understanding of the pathophysiology of stress urinary incontinence (SUI), and a push to less invasive surgical approaches. The advent of midurethral slings (MUS), with their relative ease of placement, has modernized and become the most commonly used technique for treatment of SUI. Nevertheless, this innovative technology has been associated with complications not previously associated with anti-incontinence procedures. In this article, we review the current literature regarding the use, indications, and efficacy of pubovaginal fascial slings (PVS) in the era of expanding synthetic sling use.


Efficacy and adherence of auto-CPAP therapy in patients with obstructive sleep apnea: a prospective study.
The use of auto-continuous positive airway pressure (auto-CPAP) therapy has been recommended for subjects with moderate-to-severe obstructive sleep apnea (OSA) without significant comorbidities. This study is aimed at evaluating the efficacy and adherence of auto-CPAP therapy in subjects with OSA. It was a perspective and descriptive study. All study subjects who had apnea-hypopnea index (AHI) > 30/h, measured by polysomnography, were included. They were treated with auto-CPAP and followed-up for 6 months for evaluating the effect of CPAP-therapy on clinical and biological features and treatment adherence. One hundred and thirty-nine subjects with severe OSA were accepted for auto-CPAP therapy at inclusion. BMI was 28.4±3.8 kg/m2; neck and abdomen circumferences were 38.2±6.4 and 85.7±11.6. Epworth and Pichot scores were 18.4±6.3 and 28.3±4.5, respectively; AHI was 39±7/h and arousal index was 39±13/h. At 6th month, 96.4% of study subjects continued to use auto-CPAP-therapy within 6.5±2.4 h/night. There was a significant correlation between the modification (Δ) of Epworth scores and (Δ) AHI after 3 and 6 months of auto-CPAP-therapy (R=0.568 and p=0.003; R=0.745 and p=0.002; respectively). At 6th month follow up, the main side effects of auto-CPAP were difficult sleeping, dry mouth or nose, skin marks or rashes, discomfort when breathing, and nasal congestion (36.1%, 32.0%, 20.8%, 16.0%, and 11.9%, respectively). Auto-CPAP is effective in treatment of Vietnamese patients with severe OSA in short term follow up.


[Interrelation between hemodynamic parameters and the functional state of components of the endocrine system in patients with pheochromocytoma].
Ten patients with pheochromocytoma were examined before operation, 8 were examined 2-4 weeks after surgical treatment, and 30 in the long-term periods after elimination of hypercatecholaminemia. The patients with pheochromocytoma manifested activation of the renin-aldosterone system and inhibition of PGE2 secretion. In the long-term postoperative period, the level of aldosterone in the blood plasma was increased and that of PGE2 was reduced. In the patients with pheochromocytoma, the interrelation was discovered between the magnitude of arterial blood pressure and secretion of catecholamines, deoxycorticosterone, depressor prostaglandins. At different times after surgical treatment the central hemodynamics was found to be related to the level of mineralocorticoid hormones.


Passion Fruit Green Spot Virus Genome Harbors a New Orphan ORF and Highlights the Flexibility of the 5'-End of the RNA2 Segment Across Cileviruses.
Passion fruit green spot and passion fruit sudden death are two reportedly distinct viral diseases that recurrently affect passion fruit (Passiflora spp.) groves in Brazil. Here we used a systematic approach that interconnects symptoms, transmission electron microscopy, RT-PCR detection assays followed by Sanger sequencing, and high-throughput sequencing of the RNA of affected passion fruit plants to gain insights about these diseases. Our data confirmed not only the involvement of cileviruses in these two pathologies, as previously suggested, but also that these viruses belong to the same tentative species: passion fruit green spot virus (PfGSV). Results revealed that PfGSV has a positive-sense RNA genome split into two molecules of approximately 9 kb (RNA1) and 5 kb (RNA2), which share about 50-70% nucleotide sequence identity with other viruses in the genus Cilevirus. Genome sequences of five PfGSV isolates suggest that they have more conserved RNA1 (<5% of nucleotide sequence variability) compared to RNA2 (up to 7% of variability) molecules. The highest nucleotide sequence divergence among PfGSV isolates and other cileviruses is in the genomic segment covering from the 5'-end of the RNA2 until the 5'-end of the open reading frame (ORF) p61, which includes the ORF p15 and the intergenic region. This genomic stretch also harbors a novel orphan ORF encoding a 13 kDa protein presenting a cysteine-rich domain. High variability of 5'-end of the RNA2 in cileviruses is discussed in an evolutionary context assuming that they share putative common ancestors with unclassified arthropod-infecting single-strand positive RNA viruses, including mosquito-specific viruses of the group Negevirus (clades Nelorpivirus and Sandwavirus), and other viruses in the family Kitaviridae.


Making the weight: a case study from professional boxing.
Professional boxing is a combat sport categorized into a series of weight classes. Given the sport's underpinning culture, boxers' typical approach to "making weight" is usually via severe acute and/or chronic energy restriction and dehydration. Such practices have implications for physical performance and also carry health risks. This article provides a case-study account outlining a more structured and gradual approach to helping a professional male boxer make weight for the 59-kg superfeatherweight division. Over a 12-week period, the client athlete adhered to a daily diet approximately equivalent to his resting metabolic rate (6-7 MJ; 40% carbohydrate, 38% protein, 22% fat). Average body-mass loss was 0.9 + or - 0.4 kg/wk, equating to a total loss of 9.4 kg. This weight loss resulted in a decrease in percent body fat from 12.1% to 7.0%. In the 30 hr between weigh-in and competition, the client consumed a high-carbohydrate diet (12 g/kg body mass) supported by appropriate hydration strategies and subsequently entered the ring at a fighting weight of 63.2 kg. This nutritional strategy represented a major change in the client's habitual weight-making practices and did not rely on any form of intended dehydration during the training period or before weighing in. The intervention demonstrates that a more gradual approach to making weight in professional boxing can be successfully achieved via a combination of restricted energy intake and increased energy expenditure, providing there is willingness on the part of the athlete and coaches involved to adopt novel practices.


Children of home dialysis patients.
Fifteen children of six families in which one parent was undergoing home dialysis were examined by the Minnesota Multiphasic Personality Inventory, human figure drawings, and family interviews. All the children were found to be clinically depressed, and two thirds had a history of being referred by teachers to school counselors and psychiatrists for behavioral problems in school. Of these referred children, all showed disorders of psychomotor activity and reduced academic achievement. There was no clear-cut evidence that these children were depressed because of exposure to home dialysis per se. The most disturbed children seemed to be responding to depressed parents or to partial object loss. A controlled, prospective study is planned to clarify this question.


ZnO nanoparticles applied to bioimaging and drug delivery.
The last decade has seen significant achievements in biomedical diagnosis and therapy at the levels of cells and molecules. Nanoparticles with luminescent or magnetic properties are used as detection probes and drug carriers, both in vitro and in vivo. ZnO nanoparticles, due to their good biocompatibility and low cost, have shown promising potential in bioimaging and drug delivery. The recent exciting progress on the biomedical applications of ZnO-based nanomaterials is reviewed here, along with discussions on the advantages and limitations of these advanced materials and suggestions for improving methods.


Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the United States.
Two recent randomized controlled trials (RCTs) reported that inhaled nitric oxide (iNO) decreased the incidence of extracorporeal membrane oxygenation (ECMO) or death in term and near-term newborns with hypoxic respiratory failure. Our objective was to estimate the cost-effectiveness ratio of iNO in this population. We studied 1000 simulation cohorts (n = 483 for each cohort) of term/near-term newborns with hypoxemic respiratory failure. We conducted our study following US Public Health Service Panel on Cost-Effectiveness in Health and Medicine guidelines, adopting the US societal perspective. We constructed a decision tree reflecting iNO use, subsequent ECMO use, death, and long-term neurologic and respiratory morbidity in survivors, as determined from the combined outcomes of the 2 RCTs (n = 483). We estimated costs on the basis of length-of-stay data for the initial episode of care from 1 of the RCTs, unit costs from administrative data sets, and current pricing for iNO. We ran a Monte Carlo simulation to generate estimates of differences in costs and effects at 1 year, along with the stochastic uncertainty around these estimates. We expressed effects as quality-adjusted survival, assuming quality of life = 1 with no comorbidity, 0.7 with 1 comorbidity, and 0.49 (0.7 x 0.7) with 2 comorbidities. We constructed a base case, in which iNO was initiated at tertiary care ECMO centers (mimicking the RCTs) and a Public Health Service Panel on Cost-effectiveness in Health and Medicine reference case, in which iNO was initiated at the local hospital before transfer (mimicking real-world practice). We exposed our assumptions to a sensitivity analysis. Direct application of the trial results (base case) suggested that iNO was both more effective and cheaper (cost savings of 1880 dollars per case despite acquisition costs of 5150 dollars, predominantly as a result of decreased need for ECMO), with 84.6% probability that the cost-effectiveness ratio was better than 100,000 dollars per quality-adjusted life-year. Under the reference case, iNO was also more effective (though slightly less so) and was even cheaper (cost savings of 4400 dollars per case), with 71.6% probability that iNO was cheaper and more effective and 91.6% probability that the cost effectiveness ratio was better than 100,000 dollars per quality-adjusted life-year. Sensitivity analyses showed these estimates to be sensitive to patient selection and the price of iNO but insensitive to assumptions regarding quality of life. From a US societal perspective, iNO has a favorable cost-effectiveness profile when initiated either at ECMO centers or at local hospitals in term/near-term neonates with hypoxemic respiratory failure.


Lifetime family violence exposure is associated with current symptoms of eating disorders among both young men and women.
This study examines (a) whether different forms of lifetime family violence exposure are associated with current eating disorder symptoms among young adults, (b) whether current symptoms of depression and anxiety both mediate these links, and (c) whether findings differ by gender. Participants were 319 university students aged 18-20 years (56% male). Independent of gender, both direct victimization by family violence and witnessing family violence were associated with eating disorder symptoms. Symptoms of depression and anxiety partially mediated these associations, and results did not vary by gender. Findings suggest that depression and anxiety may play a role in the development and maintenance of eating disorder symptoms subsequent to repeated incidents of family violence exposure.


Shallow sink in an antenna pigment system of photosystem I of a marine centric diatom, Chaetoceros gracilis, revealed by ultrafast fluorescence spectroscopy at 17 K.
The ultrafast fluorescence dynamics of photosystem I (PS I) purified from a marine centric diatom, Chaetoceros gracilis, at 17 K was studied using fluorescence up-conversion and streak-camera setups. The experiments were done for two kinds of sample preparations containing different amounts of the peripheral antenna proteins, the fucoxanthin-chlorophyll (Chl) binding proteins associated with PS I (FCPI). Upon excitation at 430 nm, which selectively excites Chl a mainly contained in the core complex, the fluorescence dynamics of both samples was roughly expressed by four decay-associated spectra (DASs) with time constants of ca. 5, ca. 22, ca. 100, and ca. 400 ps. These DAS components have corresponding counterparts in the results of a previous study of Thermosynechococcus elongatus PS I (Shibata et al. J. Phys. Chem. B 2010, 114, 2954) except for that with a time constant of ca. 22 ps. The similar distribution of the time constants suggests a shared light-harvesting pathway by PS I of these two organisms. The DAS with a ca. 400 ps time constant has its peak wavelength at around 710 nm, suggesting the presence of antenna pigment states with slightly lower excitation energy than that of P700. This antenna state acts as a shallow sink in the core complex of the diatom PS I and causes a specific temperature dependence of its fluorescence spectrum below 77 K. Excitation energy funneling into the shallow-sink state seems to take place within 0.2 ps, suggesting an extremely efficient energy transfer. Upon the selective excitation of Chl c in FCPI by a 460 nm laser, three DAS components suggesting excitation energy transfers were obtained. The 0.2 ps DAS shows the energy transfer from Chl c to Chl a within FCPI, while the 0.7 and 40 ps DASs suggest the energy transfer from FCPI to the core complex. The excitation energy seems to be effectively transferred from FCPI to the core complex in diatom PS I because the selective excitation of Chl c in FCPI does not induce a severe retardation of the overall light-harvesting kinetics.


A review of the recent progress in biotrickling filters: packing materials, gases, micro-organisms, and CFD.
Organic pollutants in the air have serious consequences on both human health and the environment. Among the various methods for removing organic pollution gas, biotrickling filters (BTFs) are becoming more and more popular due to their cost-effective advantages. BTF can effectively degrade organic pollutants without producing secondary pollutants. In the current research on the removal of organic pollutants by BTF, improving the performance of BTF has always been a research hotspot. Researchers have conducted studies from different aspects to improve the removal performance of BTF for organic pollutants. Including research on the performance of BTF using different packing materials, research on the removal of various mixed pollutant gases by BTF, research on microbial communities in BTF, and other studies that can improve the performance of BTF. Moreover, computational fluid dynamics (CFD) was introduced to study the microscopic process of BTF removal of organic pollutants. CFD is a simulation tool widely used in aerospace, automotive, and industrial production. In the study of BTF removal of organic pollutants, CFD can simulate the fluid movement, mass transfer process, and biodegradation process in BTF in a visual way. This review will summarize the development of BTFs from four aspects: packing materials, mixed gases, micro-organisms, and CFD, in order to provide a reference and direction for the future optimization of BTFs.


DWT-CNNTRN: a Convolutional Transformer for ECG Classification with Discrete Wavelet Transform.
Cardiovascular diseases are the leading cause of death worldwide. The diagnoses of cardiovascular diseases are usually carried out by cardiologists utilizing Electrocardiograms (ECGs). To assist these physicians in making an accurate diagnosis, there is a growing need for reliable and automatic ECG classifiers.In this study, a new method is proposed to classify 12-lead ECG recordings. The proposed model is composed of four components: the CNN(Convolutional Neural Network) module, the transformer module, the global hybrid pooling layer, and a classification layer. To improve the classification performance, the model takes the discrete wavelet transform of ECG signals as the model inputs and utilizes a hybrid pooling layer to condense the most important features over each period.The proposed model is evaluated using the test set of the China Physiological Signal Challenge 2018 dataset with 12-lead ECGs. It performs with an average accuracy of 0.86 and an average F1-scores of 0.83. The scores are particularly good for the block conditions (LBBB, RBBB, I-AVB). The main advantage of the proposed model is that, it obtains good results with a significantly smaller number of parameters compared to other individual and ensemble models.Clinical relevance- This work establishes a new ECG classifier model with high performance and low model size. It can make automatic ECG analysis more accessible, efficient, and accurate, especially in remote or underserved areas.


An unusual etiology of epigastric mass.
Bezoar is described as presence of indigested or poorly digested material forming a mass in the gastrointestinal lumen. Patients may present with abdominal pain, dyspeptic complaints, gastrointestinal obstruction, perforation or bleeding, as well as, incidental abdominal mass in asymptomatic patients. We report a 30-year-old female patient with no history of previous illness who was presented to the emergency ward with complaints of epigastric pain and abdominal bloating. The diagnostic features and treatment of bezoar are presented.


The Caenorhabditis elegans vitellogenin gene family includes a gene encoding a distantly related protein.
While the nematode Caenorhabditis elegans is more primitive than most egg-laying organisms, it's vitellogenins, or yolk protein precursors, appear to be more complex. C. elegans oocytes accumulate two major classes of yolk proteins. The first consists of two polypeptides with an Mr of about 170,000 (yp170A and yp170B) encoded by a family of five closely related genes called vit-1 through vit-5. The second class consists of two smaller proteins with Mr values of 115,000 (yp115) and 88,000 (yp88) which are cut from a single precursor. Here we report the cloning and analysis of a single-copy gene (vit-6) that encodes this precursor. The lengths of the gene and its mRNA are about 5 X 10(3) base pairs. Like vit-1 through vit-5, vit-6 is expressed exclusively in adult hermaphrodites. Comparison of portions of the coding sequence indicates that vit-6 is distantly related to the vit-1 through vit-5 gene family. Thus, even though the two classes of yolk proteins are antigenically and physically distinct, they are encoded by a single highly diverged gene family.


Ultrasound-Guided Placement of a Hemodialysis Catheter into the Distal Femoral Vein in a Patient with Multiple Catheters: A Case Report.
Cardiac surgery-associated acute kidney injury may require postoperative renal replacement therapy. Although the right internal jugular vein and femoral veins are generally the preferred insertion sites for the hemodialysis catheter for continuous renal replacement therapy, the presence of other indwelling catheters or prior thrombotic events from previous catheters may preclude use of these sites. We present a case in which the hemodialysis catheter was inserted into the distal femoral vein using point-of-care ultrasound in a patient with multiple catheter insertions after coronary artery bypass grafting. Although the tip of the dialysis catheter was more distal than the classic femoral approach, renal replacement therapy was performed without problems. Moreover, it was easier for the nurses to keep the insertion site clean and to change the patient's position.


Genotoxicity of environmentally relevant concentrations of water-soluble oil components in cod (Gadus morhua).
Large discharges from oil and gas production platforms (produced water) have led to concerns for adverse biological effects in marine areas. The aim of this study was to investigate the development of DNA adductformation and related biomarkers in fish after chronic exposure to water-soluble components of oil. Atlantic cod (Gadus morhua) were exposed for up to 44 weeks to three treatments (low, pulsed, high) containing environmentally relevant concentrations of low-molecular-weight polycyclic aromatic hydrocarbons (PAHs) and short-chained alkylphenols (APs). A time- and dose-related pattern of DNA adduct formation (measured using 32P-postlabeling) was observed. The results suggested that an extended exposure period (more than 16 weeks) would be required for the formation of DNA adduct levels above background. Interestingly, fish receiving pulsed high exposure did not develop elevated concentrations of DNA adducts, possibly due to DNA repair processes. No obvious relationship between DNA adduct concentration and cytochrome P4501A activity (EROD) was observed. This study has demonstrated the genotoxic potential of water-soluble oil components, relevant for operational discharges (produced water) and chronic oil spills. The quantification of PAH metabolites in bile and hepatic DNA adduct formation appear to be suitable for environmental monitoring of chronic oil pollution.


Compressibility of High-Density EEG Signals in Stroke Patients.
Stroke is a critical event that causes the disruption of neural connections. There is increasing evidence that the brain tries to reorganize itself and to replace the damaged circuits, by establishing compensatory pathways. Intra- and extra-cellular currents are involved in the communication between neurons and the macroscopic effects of such currents can be detected at the scalp through electroencephalographic (EEG) sensors. EEG can be used to study the lesions in the brain indirectly, by studying their effects on the brain electrical activity. The primary goal of the present work was to investigate possible asymmetries in the activity of the two hemispheres, in the case one of them is affected by a lesion due to stroke. In particular, the compressibility of High-Density-EEG (HD-EEG) recorded at the two hemispheres was investigated since the presence of the lesion is expected to impact on the regularity of EEG signals. The secondary objective was to evaluate if standard low density EEG is able to provide such information. Eighteen patients with unilateral stroke were recruited and underwent HD-EEG recording. Each EEG signal was compressively sensed, using Block Sparse Bayesian Learning, at increasing compression rate. The two hemispheres showed significant differences in the compressibility of EEG. Signals acquired at the electrode locations of the affected hemisphere showed a better reconstruction quality, quantified by the Structural SIMilarity index (SSIM), than the EEG signals recorded at the healthy hemisphere (p < 0.05), for each compression rate value. The presence of the lesion seems to induce an increased regularity in the electrical activity of the brain, thus an increased compressibility.


CC16 drives VLA-2-dependent SPLUNC1 expression.
CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated. We sought to determine if CC16 deficiency impairs epithelial-driven host responses and identify novel receptors expressed within the pulmonary epithelium through which CC16 imparts activity. We utilized mass spectrometry and quantitative proteomics to investigate how CC16 deficiency impacts apically secreted pulmonary epithelial proteins. Mouse tracheal epithelial cells (MTECS), human nasal epithelial cells (HNECs) and mice were studied in naïve conditions and after Mp challenge. We identified 8 antimicrobial proteins significantly decreased by CC16-/- MTECS, 6 of which were validated by mRNA expression in Severe Asthma Research Program (SARP) cohorts. Short Palate Lung and Nasal Epithelial Clone 1 (SPLUNC1) was the most differentially expressed protein (66-fold) and was the focus of this study. Using a combination of MTECs and HNECs, we found that CC16 enhances pulmonary epithelial-driven SPLUNC1 expression via signaling through the receptor complex Very Late Antigen-2 (VLA-2) and that rCC16 given to mice enhances pulmonary SPLUNC1 production and decreases Mycoplasma pneumoniae (Mp) burden. Likewise, rSPLUNC1 results in decreased Mp burden in mice lacking CC16 mice. The VLA-2 integrin binding site within rCC16 is necessary for induction of SPLUNC1 and the reduction in Mp burden. Our findings demonstrate a novel role for CC16 in epithelial-driven host defense by up-regulating antimicrobials and define a novel epithelial receptor for CC16, VLA-2, through which signaling is necessary for enhanced SPLUNC1 production.


[Dysontogenesis of the brain of the progeny born to mothers drinking alcohol during pregnancy].
A study was made of the development of the brain from 44 embryos (5-12 weeks) and 1 fetus (14 weeks) obtained from mothers who used alcohol during pregnancy. 16 cases made up the control group. In 34 cases out of 45 (75.5%), deviations in the development of the brain were established and distributed into the three degrees of gravity: mild, moderate and severe. 11 variants of brain pathology are described. Deviations in the formation of brain walls and disorders of the development of the cortical lamina occurred most frequently (70.6 and 57.9%, respectively). In alcoholic mothers, brain pathology in their progeny was revealed in 100% of cases. Provided they used alcohol systematically and frequently, brain pathology was identified in 83.3% of cases, in systematic rare use of alcohol in 77.3%, and in episodic use of alcohol in 28.5% of cases.


Estimating genetic variation in sugar beets and wild beets using pools of individuals.
The study describes the genetic structure in sugar beets and in wild beets (Beta vulgaris) using 30 RFLP markers. Samples consisting of pooled plant material of 100 individuals from each line and population were used to analyse 120 sugar beet breeding lines and 91 wild beet populations. Greater variation was found among the wild populations than among the breeding lines. Although the two major groups of breeding lines, monogerm and multigerm, had approximately equal amounts of genetic variation, in the monogerm group more of this variation was partitioned among the lines than within the lines. Furthermore, despite most of the variation being shared by the two groups, the two groups were found to be separated along the first two components in a principal component analysis. Computer simulations were carried out to evaluate the usefulness of the pooled-sample strategy employed in the investigation. These simulations showed the use of pooled samples to be a better alternative than that of analysing a few plants individually.


Gene expression in IFN-gamma-activated murine macrophages.
Macrophages are critical for natural immunity and play a central role in specific acquired immunity. The IFN-gamma activation of macrophages derived from A/J or BALB/c mice yielded two different patterns of antiviral state in murine hepatitis virus 3 infection, which were related to a down-regulation of the main virus receptor. Using cDNA hybridization to evaluate mRNA accumulation in the cells, we were able to identify several genes that are differently up- or down-regulated by IFN-gamma in A/J (267 and 266 genes, respectively, up- and down-regulated) or BALB/c (297 and 58 genes, respectively, up- and down-regulated) mouse macrophages. Macrophages from mice with different genetic backgrounds behave differently at the molecular level and comparison of the patterns of non-activated and IFN-gamma-activated A/J or BALB/c mouse macrophages revealed, for instance, an up-regulation and a down-regulation of genes coding for biological functions such as enzymatic reactions, nucleic acid synthesis and transport, protein synthesis, transport and metabolism, cytoskeleton arrangement and extracellular matrix, phagocytosis, resistance and susceptibility to infection and tumors, inflammation, and cell differentiation or activation. The present data are reported in order to facilitate future correlation of proteomic/transcriptomic findings as well as of results obtained from a classical approach for the understanding of biological phenomena. The possible implication of the role of some of the gene products relevant to macrophage biology can now be further scrutinized. In this respect, a down-regulation of the main murine hepatitis virus 3 receptor gene was detected only in IFN-gamma-activated macrophages of resistant mice.


A comparison of the binge eating scale, questionnaire for eating and weight patterns-revised, and eating disorder examination questionnaire with instructions with the eating disorder examination in the assessment of binge eating disorder and its symptoms.
The current study assesses concordance between self-administered measures and a diagnostic standard for assessment of binge frequency and diagnosis of binge eating disorder (BED) in a sample of binge eaters. The Questionnaire for Eating and Weight Patterns-Revised (QEWP-R), Binge Eating Scale (BES), two items from the Eating Disorder Examination Questionnaire with Instructions (EDE-Q-I), and the Eating Disorder Examination (EDE) were administered. Participants were 157 adults volunteering for a clinical study, of whom 129 (79%) were diagnosed with BED using the EDE as the diagnostic standard. In the identification of BED, the QEWP-R yielded a sensitivity value of .74 and a specificity value of .35. The BES yielded a sensitivity value of .85 and a specificity value of .20. Frequency of binge eating days and episodes on the EDE-Q-I correlated highly with the EDE (.65 and .48, respectively; p < .001). The accuracy of diagnosis and symptomatology among self-administered questionnaires is variable. The BES and the QEWP-R performed satisfactorily as initial screens for the diagnosis of BED, but were less accurate in identifying non-BED individuals and the frequency of binge eating. The EDE-Q-I most accurately assessed the frequency of binge eating.


Her-2/neu expression and amplification in early stage ovarian surface epithelial neoplasms.
The aim of this study is to examine Her-2/neu gene amplification and protein overexpression in a spectrum of ovarian neoplasms using both immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) techniques that are FDA approved. This study is focused on early stage tumors including both carcinomas and borderline tumors. FDA-approved IHC and FISH for Her-2/neu were performed on formalin-fixed, paraffin-embedded tissue from 79 ovarian neoplasms representing a broad spectrum of tumor types as well as four normal ovaries. All tumors were either stage I or stage II. Tumor and normal tissue were studied collectively using a tissue microarray (TMA). HercepTest (DAKO) and PathVysion Her-2/neu probe kit (Vysis Inc.) were used for IHC and FISH analysis. FISH analysis of serous carcinomas demonstrated Her-2/neu gene amplification in 3 (18%) of 17 cases. Two of three cases showing Her-2/neu gene amplification were scored 1+ using IHC, while the remaining case was scored as 0. Analysis of endometrioid carcinomas demonstrated Her-2/neu amplification using FISH in 1 of 10 (10%) cases. IHC in this case was scored 2+ (positive). None of the remaining 44 tumors, including clear cell carcinoma (n = 12), transitional cell carcinoma (n = 1), mixed epithelial carcinoma (n = 7), carcinoma not otherwise specified (n = 1), and 31 borderline tumors (mucinous, n = 17; endometrioid, n = 7; serous, n = 7), showed Her-2/neu gene amplification or protein overexpression. Normal ovaries were negative as well. Amplification of Her-2/neu in early stage ovarian neoplasms is infrequent, 6.7% overall. Due to the limited number of informative cases, we were unable to determine the clinical significance of Her-2/neu amplification in this study. Her-2/neu amplification was restricted to carcinomas and was not encountered in ovarian borderline tumors.


Biphasic Feline Mammary Carcinomas Including Carcinoma and Malignant Myoepithelioma.
Feline mammary tumors are usually malignant and aggressive carcinomas. Most cases are simple monophasic carcinomas (1 epithelial population), and additional phenotyping is usually not needed. In this study, we describe 10 malignant mammary tumors from 9 female cats that had unusual histomorphology: they appeared biphasic, with 2 distinct cell populations. Initially, they were morphologically diagnosed as either carcinosarcoma (1/10) or malignant pleomorphic tumor (9/10) of the mammary gland, as the latter did not match any previously described histological subtype. Immunohistochemistry (IHC) was performed for pancytokeratin, cytokeratins 8 and 18, cytokeratin 14, cytokeratins 5 and 6, vimentin, p63, calponin, alpha-smooth muscle actin, Ki-67, ERBB2, estrogen receptor alpha, and progesterone receptor. In 7 of 10 cases, the biphasic nature was confirmed and, on the basis of the IHC results, they were classified as carcinoma and malignant myoepithelioma (4/10), ductal carcinoma (1/10), and carcinosarcoma (2/10). The other 3 of 10 cases were monophasic based on IHC. In the cases of carcinoma and malignant myoepithelioma, the malignant myoepithelial cells were 100% positive for vimentin (4/4) and variably positive for p63, calponin, and cytokeratins (4/4). These findings show that, although rare, biphasic mammary carcinomas do occur in cats. In dogs and humans, tumors composed of malignant epithelial and myoepithelial cells have a less aggressive behavior than certain simple carcinomas, and therefore, their identification might also be clinically significant in the cat.


Switching of the direction of reflectionless light propagation at exceptional points in non-PT-symmetric structures using phase-change materials.
We introduce a non-parity-time-symmetric three-layer structure, consisting of a gain medium layer sandwiched between two phase-change medium layers for switching of the direction of reflectionless light propagation. We show that for this structure unidirectional reflectionlessness in the forward direction can be switched to unidirectional reflectionlessness in the backward direction at the optical communication wavelength by switching the phase-change material Ge2Sb2Te5 (GST) from its amorphous to its crystalline phase. We also show that it is the existence of exceptional points for this structure with GST in both its amorphous and crystalline phases which leads to unidirectional reflectionless propagation in the forward direction for GST in its amorphous phase, and in the backward direction for GST in its crystalline phase. Our results could be potentially important for developing a new generation of compact active free-space optical devices.


Short and long term results after intracoronary stenting in human coronary arteries: monocentre experience with the balloon-expandable Palmaz-Schatz stent.
Intracoronary stenting was designed to overcome acute complications after percutaneous transluminal coronary angioplasty and to achieve a reduced rate of restenosis, both of which are major limitations of this well accepted method for treating coronary heart disease. This report describes the experience at one centre with the implantation of balloon-expandable Palmaz-Schatz stents and focuses on device related complications and the short and long term angiographic outcome. A retrospective data analysis. Stenting was attempted in 50 patients. Restenosis after an initially successful angioplasty procedure, inadequate postangioplasty results, saphenous coronary bypass stenoses, and bail-out situations were regarded as indications. In 49 of 50 attempted patients 61 stents (1-4 per patient) were implanted. Delivery problems occurred in three patients and were successfully overcome in two patients. Bail-out situations were successfully managed in 16 patients. Complications included acute thrombus formation within the stent immediately after implantation in one patient, which was successfully treated by thrombolysis. One patient was sent for bypass surgery the day after implantation; another died 10 days after implantation for unknown reasons. Subacute stent thrombosis occurred in seven patients 5-9 days after implantation and was successfully treated by thrombolysis or balloon angioplasty in five patients. Bleeding complications occurred in nine patients, five of whom required blood transfusions. Angiography showed long term vessel patency after 4-6 months in 31 (76%) of the 41 patients who were followed up, restenosis in six (14%), and reocclusion in four (10%). Late restenosis or reocclusion was found in five (15%) of 33 patients with a single stent in contrast to five (63%) of eight patients with multiple stents. Balloon-expandable intracoronary stenting is a feasible method for treating the acute complications of balloon angioplasty. It reduced the rate of restenosis for single stent implantation. Subacute thrombotic events must be regarded as previously unknown and serious complications.


Residues on Adeno-associated Virus Capsid Lumen Dictate Interactions and Compatibility with the Assembly-Activating Protein.
The adeno-associated virus (AAV) serves as a broadly used vector system for in vivo gene delivery. The process of AAV capsid assembly remains poorly understood. The viral cofactor assembly-activating protein (AAP) is required for maximum AAV production and has multiple roles in capsid assembly, namely, trafficking of the structural proteins (VP) to the nuclear site of assembly, promoting the stability of VP against multiple degradation pathways, and facilitating stable interactions between VP monomers. The N-terminal 60 amino acids of AAP (AAPN) are essential for these functions. Presumably, AAP must physically interact with VP to execute its multiple functions, but the molecular nature of the AAP-VP interaction is not well understood. Here, we query how structurally related AAVs functionally engage AAP from AAV serotype 2 (AAP2) toward virion assembly. These studies led to the identification of key residues on the lumenal capsid surface that are important for AAP-VP and for VP-VP interactions. Replacing a cluster of glutamic acid residues with a glutamine-rich motif on the conserved VP beta-barrel structure of variants incompatible with AAP2 creates a gain-of-function mutant compatible with AAP2. Conversely, mutating positively charged residues within the hydrophobic region of AAP2 and conserved core domains within AAPN creates a gain-of-function AAP2 mutant that rescues assembly of the incompatible variant. Our results suggest a model for capsid assembly where surface charge/neutrality dictates an interaction between AAPN and the lumenal VP surface to nucleate capsid assembly.IMPORTANCE Efforts to engineer the AAV capsid to gain desirable properties for gene therapy (e.g., tropism, reduced immunogenicity, and higher potency) require that capsid modifications do not affect particle assembly. The relationship between VP and the cofactor that facilitates its assembly, AAP, is central to both assembly preservation and vector production. Understanding the requirements for this compatibility can inform manufacturing strategies to maximize production and reduce costs. Additionally, library-based approaches that simultaneously examine a large number of capsid variants would benefit from a universally functional AAP, which could hedge against overlooking variants with potentially valuable phenotypes that were lost during vector library production due to incompatibility with the cognate AAP. Studying interactions between the structural and nonstructural components of AAV enhances our fundamental knowledge of capsid assembly mechanisms and the protein-protein interactions required for productive assembly of the icosahedral capsid.


Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans.
Serotonin 5-HT(4) receptors are located on enteric cholinergic neurones and may regulate peristalsis. 5-HT(4) receptors on primary afferent neurones have been postulated to modulate visceral sensation. While 5-HT(4) agonists are used as prokinetic agents, the physiological role of 5-HT(4) receptors in the human gut is unknown. Our aim was to characterise the role of 5-HT(4) receptors in regulating gastrointestinal motor and sensory function in healthy subjects under baseline and stimulated conditions with a 5-HT(4) receptor antagonist. Part A compared the effects of placebo to four doses of a 5-HT(4) receptor antagonist (SB-207266) on the cisapride mediated increase in plasma aldosterone (a 5-HT(4) mediated response) and orocaecal transit in 18 subjects. In part B, 52 healthy subjects received placebo, or 0.05, 0.5, or 5 mg of SB-207266 for 10-12 days; gastric, small bowel, and colonic transit were measured by scintigraphy on days 7-9, and fasting and postprandial colonic motor function, compliance, and sensation during distensions were assessed on day 12. Part A: 0.5, 5, and 20 mg doses of SB-207266 had significant and quantitatively similar effects, antagonising the cisapride mediated increase in plasma aldosterone and acceleration of orocaecal transit. Part B: SB-207266 tended to delay colonic transit (geometric centre of isotope at 24 (p=0.06) and 48 hours (p=0.08)), but did not have dose related effects on transit, fasting or postprandial colonic motor activity, compliance, or sensation. 5-HT(4) receptors are involved in the regulation of cisapride stimulated orocaecal transit; SB 207266 tends to modulate colonic transit but not sensory functions or compliance in healthy human subjects.


Drink driving as a social problem: comparing the attitudes and knowledge of drink driving offenders and the general community.
Using data from a community survey together with data from a survey of drink-driving offenders, this paper compares the attitudes and knowledge of two matched samples on a number of drink driving issues. The total sample (149 offenders and 149 community sample respondents) were interviewed using a survey instrument containing a number of comparable questions. The offender sample were interviewed by trained interviewers in a face-to-face format, while the general community sample were interviewed using a computer aided telephone interview system. The specific issues dealt with include: a) knowledge of safe drinking and blood alcohol consumption (BAC) levels; b) attitudes towards strategies for avoiding drink driving; and c) general attitudes regarding drink driving. The analysis uses logistic regression to investigate the differences between the responses given by the two samples. The findings illustrate a number of significant differences in knowledge and attitudes between offenders and the general community.


A comparison of electronic and manual fracture risk assessment tools in screening elderly male US veterans at risk for osteoporosis.
This study compares four screening tools in their ability to predict osteoporosis. We found that there was no significant difference between the tools. These results provide support for the use of automated screening tools which work in conjunction with the electronic medical record and help improve screening rates for osteoporosis. The purpose of this study is to compare the performance of four fracture risk assessment tools (FRATs) in identifying osteoporosis by bone mineral density (BMD) T-score: Veterans Affairs Fracture Absolute Risk Assessment Tool (VA-FARA), World Health Organization's Fracture Risk Assessment Tool (FRAX), electronic FRAX (e-FRAX), and Osteoporosis Self-Assessment Screening Tool (OST). We performed a cross-sectional analysis of all patients enrolled in the VA Salt Lake City bone health team (BHT) who had completed a DXA scan between February 1, 2012, and February 1, 2013. DXA scan results were obtained by chart abstraction. For calculation of FRAX, osteoporosis risk factors were obtained from a screening questionnaire completed prior to DXA. For VA-FARA and e-FRAX, risk factors were derived from the electronic medical record (EMR). Clinical risk scores were calculated and compared against the gold standard of DXA-based osteoporosis. Sensitivity, specificity, and predictive values were calculated. Receiver operator characteristic (ROC) curves were plotted, and areas under the curve (AUC) were compared. A cohort of 463 patients met eligibility criteria (mean age 80.4 years). One hundred twelve patients (24%) had osteoporosis as defined by DXA T-score ≤-2.5. Sensitivity, specificity, and predictive values were calculated. ROC statistics were compared and did not reach statistical significance difference between FRATs in identifying DXA-based osteoporosis. Our study suggests that all FRATs tested perform similarly in identifying osteoporosis among elderly, primarily Caucasian, male veterans. If these electronic screening methods perform similarly for fracture outcomes, they could replace manual FRAX and thus improve efficiency in identifying individuals who should be sent for DXA scan.


Communication: Broad manifold of excitonic states in light-harvesting complex 1 promotes efficient unidirectional energy transfer in vivo.
In photosynthetic organisms, the pigment-protein complexes that comprise the light-harvesting antenna exhibit complex electronic structures and ultrafast dynamics due to the coupling among the chromophores. Here, we present absorptive two-dimensional (2D) electronic spectra from living cultures of the purple bacterium, Rhodobacter sphaeroides, acquired using gradient assisted photon echo spectroscopy. Diagonal slices through the 2D lineshape of the LH1 stimulated emission/ground state bleach feature reveal a resolvable higher energy population within the B875 manifold. The waiting time evolution of diagonal, horizontal, and vertical slices through the 2D lineshape shows a sub-100 fs intra-complex relaxation as this higher energy population red shifts. The absorption (855 nm) of this higher lying sub-population of B875 before it has red shifted optimizes spectral overlap between the LH1 B875 band and the B850 band of LH2. Access to an energetically broad distribution of excitonic states within B875 offers a mechanism for efficient energy transfer from LH2 to LH1 during photosynthesis while limiting back transfer. Two-dimensional lineshapes reveal a rapid decay in the ground-state bleach/stimulated emission of B875. This signal, identified as a decrease in the dipole strength of a strong transition in LH1 on the red side of the B875 band, is assigned to the rapid localization of an initially delocalized exciton state, a dephasing process that frustrates back transfer from LH1 to LH2.


[Progress of immune system indices in the treatment of chronic inflammatory diseases of the biliary duct].
In 105 patients with chronic inflammatory illness of gallbladder and biliary ducts the generally-accepted therapy have influenced the IgM and IgG contents in serum, the lymphocytes sensibilization to the tissue antigens of gallbladder, liver, pancreas, the titre of antibodies to this antigens only. The authors insist on necessity of supplementary application of immunomodulating agents in the complex of patients treatment, especially if reactive hepatitis or pancreatitis is present.


Microlens fabrication using an excimer laser and the diaphragm method.
A new microlens fabrication method using an excimer laser is described in this paper. This method is based on the light vignetting effect. An excimer laser beam was propagated through two groups of fly's-eye lens arrays and separated by the groups, after which divergent beams were formed. When the beams were sectioned by a mask and passed through a circular diaphragm, a vignetting effect was produced relative to an excimer laser mask projection image lens. Then the irradiating intensity at the processing plane varied from the beam center to its margin. This intensity difference in the transverse distribution would result in microlens curvature forming. This diaphragm method has the extinct advantage of short production time, few steps and easy setup construction.


Spermine inhibits the phosphorylation of the 11,000- and 10,000-dalton nuclear proteins catalyzed by nuclear protein kinase NI in NB-15 mouse neuroblastoma cells.
The nuclear protein kinase NI (NI kinase) was purified from NB-15 mouse neuroblastoma cells by phosphocellulose column and casein affinity column chromatography. The purified NI kinase exhibited (i) an apparent subunit molecular weight of about 37,000, (ii) autophosphorylation, and (iii) insensitivity to inhibition by heparin. When NI kinase was added to heat-treated neuroblastoma nuclei in the presence of [gamma-32P] ATP, two proteins with apparent subunit molecular weights of 11,000 and 10,000 were prominently phosphorylated. Other protein kinases tested including the nuclear protein kinase NII, Type I cAMP-dependent protein kinase, and protein kinase C did not catalyze the phosphorylation of these two proteins. The NI kinase-catalyzed phosphorylation of these two proteins was completely inhibited by 1 mM spermine. In contrast, 10 mM putrescine, 2 mM spermidine, 5 mM arginine, and 10 mM NH4Cl, had no inhibitory effect on this phosphorylation reaction. Our study also indicated that the phosphorylation of the 11,000- and 10,000-dalton proteins occurred in the nuclear matrix fraction but not in heterogeneous nuclear ribonucleoproteins, high mobility group proteins, or histone fractions. We have previously reported that spermine specifically inhibits the endogenous phosphorylation of an 11,000-dalton nuclear protein in various mammalian cell lines (Chen, K. Y., and Verma, R. (1984) Biochem. Biophys. Res. Commun. 118, 710-716). The present study suggests that the 11,000- and 10,000-dalton nuclear proteins may be native substrates of nuclear protein kinase NI and that their phosphorylation can be affected by physiological concentrations of spermine.


Iliac Vein Compression Syndrome (IVCS): An Under-Recognized Risk Factor for Left-Sided Deep Venous Thrombosis (DVT) in Old Hip Fracture Patients.
BACKGROUND The aim of this study was to identify whether iliac vein compression syndrome (IVCS) is a risk factor for left-sided deep venous thrombosis (DVT) in hip fracture patients and the influence IVCS may have on the treatment of DVT. MATERIAL AND METHODS A retrospective study was carried out among 424 hip fracture patients admitted to our hospital from 2011 to 2016. Clinical data were analyzed, and all patients were classified into the DVT group and the non-DVT group based on plasmin D-Dimer concentration and results of Doppler ultrasound of the left lower limb. Also, a 50% intraluminal constriction of the left iliac vein in the venography image was considered as IVCS. Comparison of IVCS prevalence was made between the DVT group and the non-DVT group. Patients in the DVT group were further divided into the DVT+/IVCS+ group and the DVT+/IVCS- group to evaluate the influence IVCS may have on the treatment of DVT. RESULTS There were 204 patients in the DVT group and 220 patients in the non-DVT group. No statistically significant differences were found regarding the mean age, sex distribution, fracture type, and accompanying risk factors between the two groups. A total of 70 patients (34.3%) were diagnosed with IVCS in the DVT group, while confirmed IVCS was found in 52 patients (23.6%) in the non-DVT group (P=0.02). Postoperatively, the incidence of symptomatic DVT in the DVT+/IVCS+ group and the DVT+/IVCS- group was 30.0% and 11.9%, respectively (P=0.002). CONCLUSIONS IVCS is an under-recognized risk factor for left-sided DVT in hip fracture patients. What's more, anticoagulation alone is insufficient for the treatment of DVT when it is complicated with IVCS. More aggressive measures have to be taken to achieve a favorable outcome.


Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ Tumor Lymphocyte Density, Safety, and Efficacy in Patients with Oropharynx Cancer: CIAO Trial Results.
In oropharyngeal squamous cell carcinoma (OPC), high CD8+ tumor-infiltrating lymphocyte (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab + tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in patients with OPC. Patients with newly diagnosed stage II-IVA OPC or locoregionally recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab + tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes. Of 28 eligible patients (14/arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P = 0.97; 95% CI: -1.07-2.28). In each group, 6 patients (43%, 95% CI: 17.66-71.14) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P = 0.059; 95% CI: -0.33-3.46). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence. Durvalumab + tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC.


Replication and meta-analysis of 13,000 cases defines the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease.
Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohn's disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed. British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants in IL23R and ATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations between IL23R and ATG16L1 variants and CD, respectively. In the present cohort, both susceptibility variants showed highly significant associations, including IL23R (rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) and ATG16L1 (rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and the IL23R or ATG16L1 polymorphisms (P=0.44 and P=0.24, respectively). The present cohort and meta-analysis provides strong evidence that, in addition to CARD15, polymorphisms in both IL23R and ATG16L1 alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, only ATG16L1 is relevant to inflammatory bowel disease in the Asian population.


Morell Mackenzie's The Hygiene of the Vocal Organs: a study in longevity or durability.
Morell Mackenzie's The Hygiene of the Vocal Organs: A Practical Handbook for Singers and Speakers (1886), is his only work that has been continually published into the 20th century. Why is this? The bibliographic history and details of all the editions from the first in 1886 until the ninth and last in 1928 were examined. Reviews and all other commentary about the book were ascertained though literature and library document searches. The book is still in use as the first edition is available online from the Cornell University library, and that hard copy was last taken out from that library on December 19, 1986, and returned with the fine paid on January 8, 1987. It was translated and published in Swedish, French, German, and Spanish. All of the editions are small, inexpensively bound, and printed on inexpensive paper so the cost was minimal in contradistinction to other works on the voice which are larger and expensive. To make it accessible for performers and practitioners, the contents of the earlier editions were modified by placing the technical, anatomical, and physiological information as an appendix. The book was in part criticized by Manuel Garcia in Felix Semon's German journal, Internationales Centralblatt fur Laryngologie, Rhinologie und verwandte Wissenchaften, McKenzie answered these critiques in the seventh edition and noted that Garcia did not know German and that the translator, Semon, was an antagonist. Mackenzie is emphatic in his advice to avoid singing when there's any sign of vocal difficulty. The medical advice was, on the whole, good common sense and provided substantial authority for a person to decline a performance-how grateful the singers must have been for that! The Hygiene of the Vocal Organs: A Practical Handbook for Singers and Speakers was, for the professional voice users-singers, actors, speakers, and for their teachers and physicians, a useful, concise, small, inexpensive, and authoritative book. With these virtues noted, we can well understand why it remained in circulation and use for a century. In terms of the dissemination of ideas, this heretofore neglected work may be Mackenzie's most long-lasting contribution to laryngology.


Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design.
The aurora kinases are a novel oncogenic family of mitotic serine/threonine kinases (S/T kinases) that are overexpressed in a number of solid tumors, including pancreas and colorectal cancer. A PSI-BLAST search [National Center for Biotechnology Information (NCBI)] with the sequence of the S/T kinase domain of human aurora1 kinase [also known as AUR1, ARK2, AIk2, AIM-1, and STK12] and human aurora2 kinase (also known as AUR2, ARK1, AIK, BTAK, and STK15) showed a high sequence similarity to the three-dimensional structures of bovine cAMP-dependent kinase [Brookhaven Protein Data Bank code 1CDK], murine cAMP-dependent kinase (1APM), and Caenorhabditis elegans twitchin kinase (1KOA). When the aurora1 or aurora2 sequence was input into the tertiary structure prediction programs THREADER and 3D-PSSM (three-dimensional position-sensitive scoring matrix), the top structural matches were 1CDK, 1APM, and 1KOA, confirming that these domains are structurally conserved. The structural models of aurora1 and aurora2 were built using 1CDK as the template structure. Molecular dynamics and docking simulations, targeting the ATP binding site of aurora2 with adenylyl imidodiphosphate (AMP-PNP), staurosporine, and six small molecular S/T kinase inhibitors, identified active-site residues that interact with these inhibitors differentially. The docked structures of the aurora2-AMP-PNP and aurora2-staurosporine complexes indicated that the adenine ring of AMP-PNP and the indolocarbazole moiety of staurosporine have similar positions and orientations and provided the basis for the docking of the other S/T kinase inhibitors. Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2 in which H-89 and 6,7-dimethoxyquinazoline compounds exhibited high binding energies compared with that of staurosporine. The calculated binding energies for the docked small-molecule inhibitors were qualitatively consistent with the IC(50) values generated using an in vitro kinase assay. The aurora2 structural model provides a rational basis for site-directed mutagenesis of the active site; design of novel H-89, staurosporine, and quinazoline analogues; and the screening of the available chemical database for the identification of other novel, small-molecular entities.