Analysis of comparative genomic hybridization and loss of heterozygosity in 43 primary gastric carcinomas.
To investigate common chromosomal changes and the LOH frequency of microsatellite loci in primary gastric cancer samples in order to locate the deleted regions in which human gastric cancer related genes might exist. Comparative genomic hybridization (CGH) was used to define global chromosomal aberrations in 43 primary gastric tumors. Based on the results of CGH, analysis of loss of heterozygosity (LOH) was performed in chromosome 19 in which the loss was first discovered in the gastric cancers. The PCR-based approach was used to investigate 22 loci, which are spaced at 1.1 - 10.9 cM intervals throughout chromosome 19. The amplified PCR fragments were subjected to electrophoresis in PAGE gel and analyzed with Genescan trade mark and Genotyper trade mark. CGH analysis revealed gains in chromosome 3p (8/43), 8q (8/43), 20 [20 (9/43), 20p (7/43), 20q (4/43)], 12q (16/43), 13q (12/43) and losses in 19 [19 (15/43)], 7 [17 (8/43), 17p (10/43)], 16 (10/43) and 1p (11/43). Among the 43 evaluated samples, the most frequent LOH was detected at locus D19S571 (27.81%). The tumorigenesis of gastric cancer includes several chromosomal changes. The aberration of chromosome 19 was the first common change founded in gastric cancer. The region near the D19S571 might harbor potential genes related to the tumorigenesis of gastric cancer.


Could accelerated aging explain the excess mortality in patients with seropositive rheumatoid arthritis?
To determine whether the mortality pattern in patients with seropositive rheumatoid arthritis (RA) is consistent with the concept of accelerated aging, by comparing the observed mortality rates in patients with RA with the age-accelerated mortality rates from the general population. A population-based inception cohort of patients with seropositive RA (according to the American College of Rheumatology 1987 criteria) was assembled and followed up for vital status until July 1, 2008. The expected mortality rate was obtained by applying the death rates from the general population to the age, sex, and calendar year distribution of the RA population. The observed mortality was estimated using Kaplan-Meier methods. Acceleration factors for the expected mortality were estimated in accelerated failure time models. A total of 755 patients with seropositive RA (mean age 55.6 years, 69% women) were followed up for a mean of 12.5 years, during which 315 patients died. The expected median survival was age 82.4 years, whereas the median survival of the RA patients was age 76.7 years. Results of statistical modeling suggested that, in terms of mortality rates, patients with RA were effectively 2 years older than actual age at RA incidence, and thereafter the patients underwent 11.4 effective years of aging for each 10 years of calendar time. The overall observed mortality experience of patients with seropositive RA is consistent with the hypothesis of accelerated aging. The causes of accelerated aging in RA deserve further investigation.


Interleukin 2 receptor expression by activated HNK-1+ granular lymphocytes: a requirement for their proliferation.
A subpopulation of HNK-1+ cells was found to express interleukin 2 receptor (IL 2R) as monitored by the anti-Tac monoclonal antibody after lectin or allogeneic cell stimulation. When blood mononuclear cells were stimulated with phytohemagglutinin (PHA) or concanavalin A for 3 days, or with pokeweed mitogen or allogeneic mononuclear cells for 6 days, virtually all of the HNK-1+ cells remained as small resting lymphocytes. One-fourth of these HNK-1+ cells expressed IL 2R, however, usually within 18 hr after stimulation. Neither circulating HNK-1+ cells nor unstimulated HNK-1+ cells in short-term culture expressed IL 2R. Only the subset of HNK-1+ cells that expressed T cell surface markers, such as the sheep erythrocyte receptor and Leu-4 antigen, could be induced to express IL 2R. When long-term cultures of HNK-1+ cells were established with initial PHA stimulation and the continued presence of IL 2, a majority of the cells was found to express the IL 2R. When anti-Tac antibody was added to the long-term cultures, proliferation of the HNK-1+ cells was completely inhibited. These results suggest that entry into growth cycle by this subpopulation of HNK-1+ granular lymphocytes may require two signals: a relatively nonspecific ligand interaction with cell surface glycoprotein(s) to induce expression of IL 2R, and subsequent IL 2 interaction with these specific cell surface receptors.


Effects of alpha-methyl-para-tyrosine (AMPT) in drug-free depressed patients.
A variety of biologic studies have demonstrated abnormal regulation of the norepinephrine (NE) system in patients with major depression, suggesting a role for NE in the etiology of depression. Brain NE and dopamine levels can be rapidly reduced by blocking synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). In the current investigation, AMPT was administered to drug-free depressed patients to evaluate the effect on mood of diminished catecholamine levels. Seventeen drug-free patients meeting DSM-III-R criteria for major depressive episode were tested with AMPT and an active placebo control, diphenhydramine. Testing was accomplished in a double-blind, crossover fashion, with random assignment to test conditions. Each test included baseline evaluation, 2 days with administration of either AMPT or diphenhydramine, and a follow-up day. Diphenhydramine was used as an active control because of the significant sedation associated with AMPT. Behavioral ratings, including visual analogue scales for a variety of feeling states, the Hamilton Depression Rating Scale (HDRS), and plasma for 3-methoxy-4-hydroxyphenelethyleneglycol (MPHG) and homovanillic acid (HVA) levels, were obtained. AMPT significantly reduced plasma HVA by 70% and MHPG by 50%, but it had no significant effects on the HDRS. AMPT also significantly increased visual analogue ratings of "tired" and decreased ratings of "energetic." Diphenhydramine significantly decreased HDRS scores, but the change was small and was not clinically apparent. The lack of AMPT effects on depressed mood, in conjunction with a prior report that large reductions in plasma tryptophan do not systematically alter depressed mood, indicate that monoamine deficiency by itself is insufficient explanation of the cause of depression. The role of the noradrenergic system needs to be considered in relationship to the many other neurobiologic factors that could be involved in the pathophysiology of depression.


Analysis of the contribution of reverse transcriptase and integrase proteins to retroviral RNA dimer conformation.
All retroviruses contain two copies of genomic RNA that are linked noncovalently. The dimeric RNA of human immunodeficiency virus type 1 (HIV-1) undergoes rearrangement during virion maturation, whereby the dimeric RNA genome assumes a more stable conformation. Previously, we have shown that the packaging of the HIV-1 polymerase (Pol) proteins reverse transcriptase (RT) and integrase (IN) is essential for the generation of the mature RNA dimer conformation. Analysis of HIV-1 mutants that are defective in processing of Pol showed that these mutant virions contained altered dimeric RNA conformation, indicating that the mature RNA dimer conformation in HIV-1 requires the correct proteolytic processing of Pol. The HIV-1 Pol proteins are multimeric in their mature enzymatically active forms; RT forms a heterodimer, and IN appears to form a homotetramer. Using RT and IN multimerization defective mutants, we have found that dimeric RNA from these mutant virions has the same stability and conformation as wild-type RNA dimers, showing that the mature enzymatically active RT and IN proteins are dispensable for the generation of mature RNA dimer conformation. This also indicated that formation of the mature RNA dimer structure occurs prior to RT or IN maturation. We have also investigated the requirement of Pol for RNA dimerization in both Mason-Pfizer monkey virus (M-PMV) and Moloney murine leukemia virus (MoMuLV) and found that in contrast to HIV-1, Pol is dispensable for RNA dimer maturation in M-PMV and MoMuLV, demonstrating that the requirement of Pol in retroviral RNA dimer maturation is not conserved among all retroviruses.


[The carbohydrate composition of human milk].
The carbohydrate content of breast milk was investigated by capillary gas liquid chromatography. The milk samples obtained from 16 normal lactating mothers contained glucose, galactose, lactose, and 3-fucosidolactose. The content of monosaccharides in breast milk was 2-12 times higher than that in cow's milk. The lactose content amounted to 84-95%, whereas the ratio of alpha- tox beta-froms was within 0.92-0.95%. Breast milk was found to contain alpha- and beta-forms of 2- and 3-fucosidolactose which do not occur in cow's milk. The content of these forms accounted for 3%. The biological role of breast milk carbohydrates is discussed.


Improving Laboratory Efficiency in the Caribbean to Attain the World Health Organization HIV Treat All Recommendations.
Scientific evidence showing the benefits of early initiation of antiretroviral therapy (ART) prompted World Health organization (WHO) to recommend that all persons diagnosed as HIV positive should commence ART irrespective of CD4 count and disease progression. Based on this recommendation, countries should adopt and implement the HIV "Treat All" policy to achieve the UNAIDS 90-90-90 targets and ultimately reach epidemic control. Attaining this goal along the HIV treatment cascade depends on the laboratory to monitor progress and measure impact. The laboratory plays an important role in HIV diagnosis to attain the first 90 and in viral load (VL) and HIV drug resistance testing to reinforce adherence, improve viral suppression, and measure the third 90. Countries in the Caribbean region have endorsed the WHO HIV "Treat all" recommendation; however, they are faced with diminishing financial resources to support laboratory testing, seen as a rate-limiting factor to achieving this goal. To improve laboratory coverage with fewer resources in the Caribbean there is the need to optimize laboratory operations to ensure the implementation of high quality, less expensive evidence-based approaches that will result in more efficient and effective service delivery. Suggested practical and innovative approaches to achieve this include: (1) targeted testing within HIV hotspots; (2) strengthening sample referral systems for VL; (3) better laboratory data collection systems; and (4) use of treatment cascade data for programmatic decision-making. Furthermore, strengthening quality improvement and procurement systems will minimize diagnostic errors and guarantee a continuum of uninterrupted testing which is critical for routine monitoring of patients to meet the stated goal.


A catalytic mechanism for the enzyme benzylamine oxidase from pig plasma.
Initial-velocity and product-inhibition studies on the enzyme benzylamine oxidase from pig plasma indicate that the order of substrate addition and product release is benzylamine on, ammonia off, oxygen on, hydrogen peroxide off, benzaldehyde off. Ammonia, but not benzaldehyde, is released under strictly anaerobic conditions which provides independent evidence for this order. Benzyl alcohol is a substrate for the enzyme. A chemical mechanism consistent with all the data is proposed.


Efficacy of 2% metronidazole gel in moderate acne vulgaris.
Acne vulgaris is an inflammatory disease of the pilosebaceous units. Various systemic and topical options are available for its treatment. This study aimed to evaluate the efficacy of 2% metronidazole gel in acne vulgaris. Double-blind, randomized, placebo-controlled, split-face clinical trial. Seventy young adults with moderate acne vulgaris received 2% metronidazole gel on the right side of their face and placebo on the left side of their face twice daily for 8 weeks. The number of inflamed and noninflamed facial lesions and side effects of treatment were documented on weeks 1, 2, 4, and 8. The patients' overall satisfaction was recorded at the end of the study. For statistical analysis we used the repeated-measures analysis, the chi-square test, Fisher's exact test, and the independent-samples t-test as appropriate. Counts of inflamed and noninflamed facial lesions were comparable between the two sides at baseline. The number of the lesions was significantly lower on the metronidazole-treated side at all follow-up visits. Erythema and oily face decreased by 85.7% and 87.1%, respectively, on the metronidazole-treated side. Mild burning sensation and dryness on the metronidazole-treated side was reported by 3.4% and 22.9% of the patients, respectively. Eighty-eight percent of the patients were satisfied with the results of treatment on the metronidazole-treated side. Metronidazole gel (2%) is an effective, safe, and well-tolerated topical medication for moderate acne vulgaris.


Chitosan hydrogel for localized gene silencing.
To achieve effective delivery of siRNA into target cells in vivo, we have developed a novel approach of siRNA delivery by using local drug delivery systems. The chitosan hydrogel (CH-HG) displayed a liquid-solid phase transition in a temperature-dependent manner and formed an endothermic hydrogel in tumor tissue after intra-tumoral injection. Additionally, we tested the extent of in vivo delivery following a single intra-tumoral injection of Alexa555 siRNA/CH-HG into A375SM-bearing mice. The Alexa555 siRNA demonstrated higher localization into tumor cells compared to control. The Alexa555 siRNA delivery extends to tumor cells outside of CH-HG and some tumor cells also infiltrated into CH-HG. For therapeutic proof-of-concept studies, CH-HG including TG2-targeted siRNA significantly inhibited tumor growth in melanoma (A375SM) and breast (MDA-MB231) tumor models compared to control (A375SM: 72% reduction and MDA-MB231: 92% reduction, p < 0.001). we prepared a CH-HG system loaded with siRNA to enhance localized therapeutic efficacy without risk for systemic side effects. Delivery of siRNA into CH-HG was confirmed by fluorescence microscopy. Antitumor efficacy was examined in mouse models of melanoma (A375SM) and breast (MDA-MD231) cancer. This study developed a novel local delivery method for siRNA therapy using the CH-HG system. This approach could have broad applications for multiple localized diseases.


Purely Behavioral: A Scoping Review of Nonpharmacological Behavioral and Lifestyle Interventions to Prevent Cardiovascular Disease in Persons Living With HIV.
Cardiovascular disease (CVD) is the leading cause of death in the United States, accounting for 900,000 deaths annually. People living with HIV are at a higher risk of developing CVD. We conducted a scoping review guided by the Joanna Briggs Institute Manual for Evidence Synthesis. In July 2020, six databases were searched: PubMed, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Web of Science, Embase, and The Cochrane Central Register of Controlled Trials, as well as reference lists of relevant studies and key journals. Our review identified 18 studies that addressed nonpharmacological behavioral interventions into the following: physical activity (n = 6), weight loss (n = 2), dietary interventions (n = 1), and multicomponent interventions (n = 9). In the past 10 years, there has been an increased emphasis on nonpharmacological behavioral approaches, including the incorporation of multicomponent interventions, to reduce cardiovascular risk in people living with HIV. The extant literature is limited by underrepresentation of geographic regions and populations that disproportionately experience CVD.


Beyond the obvious: Environmental health implications of polar polycyclic aromatic hydrocarbons.
The genotoxic, mutagenic and carcinogenic effects of polar polycyclic aromatic hydrocarbons (polar PAHs) are believed to surpass those of their parent PAHs; however, their environmental and human health implications have been largely unexplored. Oxygenated PAHs (oxy-PAHs) is a critical class of polar PAHs associated with carcinogenic effects without enzymatic activation. They also cause an upsurge in reactive oxygen species (ROS) in living cells. This results in oxidative stress and other consequences, such as abnormal gene expressions, altered protein activities, mutagenesis, and carcinogenesis. Similarly, some nitrated PAHs (N-PAHs) are probable human carcinogens as classified by the International Agency for Research on Cancer (IARC). Heterocyclic PAHs (polar PAHs containing nitrogen, sulphur and oxygen atoms within the aromatic rings) have been shown to be potent endocrine disruptors, primarily through their estrogenic activities. Despite the high toxicity and enhanced environmental mobility of many polar PAHs, they have attracted only a little attention in risk assessment of contaminated sites. This may lead to underestimation of potential risks, and remediation end points. In this review, the toxicity of polar PAHs and their associated mechanisms of action, including their role in mutagenic, carcinogenic, developmental and teratogenic effects are critically discussed. This review suggests that polar PAHs could have serious toxicological effects on human health and should be considered during risk assessment of PAH-contaminated sites. The implications of not doing so were argued and critical knowledge gaps and future research requirements discussed.


Expression of ERCC1, RRM1, TUBB3 in correlation with apoptosis repressor ARC, DNA mismatch repair proteins and p53 in liver metastasis of colorectal cancer.
Liver metastasis in colorectal cancer is common and the primary treatment is chemotherapy. To date, there is no routinely used test in clinical practice to predict the effectiveness of conventional chemotherapy. Therefore, biomarkers with predictive value for conventional chemotherapy would be of considerable benefit in treatment planning. We analysed three proteins [excision repair cross-complementing 1 (ERCC1), ribonucleoside-diphosphate reductase 1 (RRM1) and class III β-tubulin (TUBB3)] in colorectal cancer liver metastasis. We used tissue microarray slides with 101 liver metastasis samples, stained for ERCC1, RRM1 and TUBB3 and established scoring systems (fitted for tissue microarray) for each protein. In statistical analysis, we compared the expression of ERCC1, RRM1 and TUBB3 to mismatch proteins (MLH1, MSH2, MSH6 and PMS2), p53 and to apoptosis repressor protein (ARC). Statistically significant correlations were found between ERCC1, TUBB3 and MLH1, MSH2 and RRM1 and MSH2, MSH6. Noteworthy, our analysis revealed a strong significant correlation between cytoplasmic ARC expression and RRM1, TUBB3 (p=0.000 and p=0.001, respectively), implying an additional role of TUBB3 and RRM1 not only in therapy resistance, but also in the apoptotic machinery. Our data strengthens the importance of ERCC1, TUBB3 and RRM1 in the prediction of chemotherapy effectiveness and suggest new functional connections in DNA repair, microtubule network and apoptotic signaling (i.e. ARC protein). In conclusion, we showed the importance and need of predictive biomarkers in metastasized colorectal cancer and pointed out the relevance not only of single predictive markers but also of their interactions with other known and newly explored relations between different signaling pathways.


Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia.
Previous studies have yielded conflicting results and substantial uncertainty about any independent association of Helicobacter pylori infection with dyspepsia, and about any benefits of antibiotic treatments for nonulcer or uninvestigated dyspepsia. To perform a systematic review of the literature to determine whether chronic infection with H pylori is relevant to nonulcer or uninvestigated dyspepsia. Observational studies of associations between H pylori and dyspepsia published before April 1999 and randomized trials of the effects of H pylori eradication on dyspepsia published before January 2000 were identified by computer-assisted literature searches of relevant journals, reference lists, and discussions with authors. Relevant data were abstracted from the published reports by 2 investigators according to a fixed protocol. Thirty relevant observational studies were identified involving approximately 3392 patients with nonulcer dyspepsia, and 11 separate observational studies were identified, involving 6426 patients with uninvestigated dyspepsia. Reports of strong associations in small observational studies without appropriate adjustment for potential confounding factors were not generally confirmed by larger and better-designed studies. No studies have been reported, however, that can reliably confirm or exclude the existence of any weak associations. Twenty-two randomized trials of treatments against H pylori were found involving a total of 2340 patients with nonulcer dyspepsia, almost all with positive H pylori test results. Only a few of these trials involved effective antibacterial regimens with prolonged follow-up, and even these studies were too small to assess the possibility of moderate benefits. The available evidence indicates that there is no strong association between H pylori and dyspepsia, but there is insufficient evidence to confirm or refute the existence of a modest association.


Geniposide improves CLP-induced sepsis model prognosis by upregulating PPARγ to modulate monocyte phenotype and cytokine network.
We explored the efficacy and main biological mechanism of geniposide intervention in sepsis. A sepsis model was established in male BALB/c mice through cecal ligation and puncture (CLP). Different doses of geniposide (20 or 40 mg/kg) were administered intravenously at 0 and/or 24 h after CLP surgery. The survival rate of different groups was observed. Additionally, the expression levels of CD16 and MHC-II in monocytes were assessed using flow cytometry. The concentration of TNF-α, IL-1β, IL-6, and IL-10 in the serum were measured by ELISA. We also observed the biological effects of geniposide on CD16 and MHC-II expression levels in RAW264.7 cells, as well as the secretion of TNF-α, IL-1β, IL-6, and IL-10, in the LPS-induced RAW264.7 cell model. The PPARγ levels were determined using western blot analysis. Intravenous administration of 40 mg/kg of geniposide at 0 h after CLP significantly improved the survival outcomes in the septic mouse model, with no significant benefits from low dosing (20 mg/kg) or delayed administration (24 h). The effective dose of geniposide significantly decreased the serum cytokine TNF-α, IL-1β, IL-6, and IL-10 concentrations in septic mice (P < 0.05). Notably, in vitro assays showed that geniposide specifically increased the IL-10 level. Geniposide significantly reduced the CD16 expression (P < 0.05) and increased MHC-II expression in monocytes (P < 0.05). Additionally, geniposide elevated the PPARγ level in monocytes (P < 0.05). High-dose early-stage geniposide administration significantly improved the survival rate in a CLP mouse sepsis model by modulating the monocyte phenotype and regulating the cytokine network (IL-6/IL-10 levels). The pharmacological mechanism of geniposide action might be exerted primarily through PPARγ upregulation.


DNA polymerase alpha associated primase from rat liver: physiological variations.
A primase activity associated to DNA polymerase alpha from rat liver is described. Both activities were absent in normal adult rat liver but were concomitantly induced after partial hepatectomy. As previously shown for polymerase alpha and DNA topoisomerase II, primase activity reached a maximum value 40-43 h after the partial removal of the liver. Primase activity was shown to catalyze dNMP incorporation on unprimed single-stranded DNA template (M13 DNA) in the presence of rNTP. The activity was not detectable on poly(dA) or poly(dG) but was efficient on poly(dT) or poly(dC). However, the reliability of the primase assay in the presence of poly(dC) was dependent upon the degree of purification of the enzyme. The ribo primers were about 10 nucleotides long, and the reaction was completely independent of alpha-amanitin, a strong inhibitor of RNA polymerases II and III. Primase and polymerase were found tightly associated. A cosedimentation on a 5-20% sucrose gradient was always obtained, independent of the ionic strength. There was also a close coincidence between alpha-polymerase and primase activities during phosphocellulose, hydroxylapatite, and single-stranded DNA Ultrogel chromatography. It has been previously demonstrated by us and others that primase and alpha-polymerase are on separated polypeptides. The association of two activities in the replication complex and the conditions allowing their separation are discussed.


Identification and electrophysiological studies of (4S,5S)-5-hydroxy-4-methyl-3-heptanone and 4-methyl-3,5-heptanedione in male lucerne weevils.
An investigation to identify a sex or aggregation pheromone of Sitona discoideus Gyllenhål (Coleoptera: Curculionidae) is presented. Antenna flicking and attraction behaviors evoked by conspecifics of both sexes were recorded in arena bioassays, where attraction of females to males was observed. Air entrainment of both males and females was conducted in separate chambers. Gas chromatographic-mass spectrometric analysis of headspace volatiles revealed that two male-specific compounds, 4-methyl-3,5-heptanedione (major) and (4S,5S)-5-hydroxy-4-methyl-3-heptanone (minor), were emitted during the autumnal post-aestivatory flight period. The stereoisomers of the minor component were separated by enantioselective gas chromatography and their absolute configurations assigned by NMR (diastereomers) and the known preference of enantioselective transesterification reactions catalyzed by Candida antarctica lipase B. Electroantennogram and single sensillum recording studies indicate that 4-methyl-3,5-heptanedione as well as all individual stereoisomers of 5-hydroxy-4-methyl-3-heptanone are detected by the antennae of male and female S. discoideus. Further, single sensillum recordings suggest that both sexes of S. discoideus have specialized olfactory receptor neurons (ORNs) for detecting 4-methyl-3,5-heptanedione and different populations of stereoselective ORNs for detecting the stereoisomers of 5-hydroxy-4-methyl-3-heptanone. Some of these stereoselective ORNs appear to be sex-specific in S. discoideus.


Patient engagement in fertility research: bench research, ethics, and social justice.
Patient and Public Involvement (PPI) in research is increasingly being utilized to better connect patients and researchers. The Patient Engagement Studio (PES) supports PPI in research by working directly with researchers throughout various stages of their projects. Recently, two researchers presented to the PES for assistance with their project, Embryo+™. The purpose of Embryo+™ is to decrease miscarriage rates using RNA sequencing technology that screens for the most viable embryos. To date, no examples of PPI directly in the planning or implementation of bench research concerning in vitro fertilization and embryo transfer have been identified. Embryo+™ researchers met in-person with the PES two times (fall 2019; each meeting had 9 PES members in attendance) for initial feedback and protocol development. After these meetings, PES leadership and Embryo+™ researchers decided that the unique nature of the project merited a PPI evaluation. Subsequent evaluation of engagement efforts occurred by reviewing the PES reports for the Embryo+™ researchers, conducting two recorded web-based discussion meetings with the PES (summer 2020; meeting 1 n = 7; meeting 2 n = 6), and a brief survey (n = 13). The discussion meetings provided an opportunity for the PES members to define engagement themes through consensus via verbal agreement to the studio director's periodic summaries during the discussions. Combining survey results and PES themes allowed for a broad discussion for meaningful engagement. The Embryo+™ researchers established trust with the patients by changing some of their language in response to patient suggestions, allowing for unintended ethical conversations, and implementing the patient developed protocols. Overall, the patient experts thought this project was very meaningful and valuable, quantified by a mean loyalty score 89.43 (s.d. 10.29). Bench science researchers may need additional PPI training prior to engaging with patient groups. PPI in this project was successful in large part due to this training, where the director emphasized the importance of gaining trust with the patients. The researchers applied what they learned and several examples of how to develop trust with patients are discussed. If trust is established, PPI in an ethically charged, basic science research study can be both valuable and successful.


Cultured retinal pigment epithelium cells from donors with type I diabetes show an altered insulin response.
Retinal pigment epithelium (RPE) isolated from 13 of 49 eyes of donors with insulin-dependent diabetes produced viable, proliferating cultures. No difference was found in baseline glucose uptake and lactate production, as measured by 13C and 1H nuclear magnetic resonance, between the RPE cells from diabetic donors and those cultured from normal donors. Insulin-mediated stimulation of glucose uptake and lactate production was decreased significantly in the RPE cells from diabetic donors compared with those from normal controls. Oxygen consumption and the percentage of endogenous oxygen consumption from fatty-acid oxidation, determined by using a specific inhibitor, were similar in both groups. Cellular proliferation and endocytosis, measured by liposome uptake, also were stimulated by insulin similarly in both types of cells. These results show that at least one or more mechanisms of insulin action in the RPE, thought to be a noninsulin-dependent tissue, may be altered permanently by chronic insulin-dependent diabetes. This finding may have implications for the pathogenesis of disease in noninsulin-dependent tissues even in patients with tight glycemic control.


Metaanalysis of filler materials in periapical surgery.
To evaluate the success and failure, apical sealing and biocompatibility of silver amalgam, IRM, SuperEBA and MTA as retrograde filler materials. A metaanalysis is made of filler materials in periapical surgery, evaluating a total of 30 articles published in recent years. Percentage success with silver amalgam was 76.5% and slightly inferior to that afforded by IRM. Performance in turn increased considerably when the materials used were SuperEBA or MTA. As regards marginal leakage, MTA with a mean leakage time of 65.5 days afforded the best results, followed by SuperEBA, IRM and silver amalgam. MTA was the most biocompatible of the materials studied, with practically no inflammatory response, while inflammation proved mild or moderate with SuperEBA, mild with IRM, and moderate to severe in the case of silver amalgam. Tissue regeneration was only observed with MTA, in the same way as cement appositioning. Bone neoformation was observed with all four filler materials. MTA appears to be an ideal material, though the results obtained require confirmation by in vivo studies.


Minimal distributed charges: Multipolar quality at the cost of point charge electrostatics.
Most empirical force fields use atom-centered point charges (PCs) to represent the electrostatic potential (ESP) around molecules. While such PC models are computationally efficient, they are unable to capture anisotropic electronic features, such as σ holes or lone pairs. These features are better described using atomic multipole (MTP) moments, which significantly improve the quality of the resulting ESP. However, the improvement comes at the expense of a considerably increased computational complexity and cost for calculating the interaction energies and forces. In the present work, a novel minimal distributed charge model (MDCM) based on off-centered point charges is presented and the quality of the resulting ESP is compared to the performance of MTPs and atom-centered PC models for several test molecules. All three models are fitted using the same algorithm based on differential evolution, which is available as a Fortran90 program from the authors upon request. We show that the MDCM is capable of approximating the reference ab initio ESP with an accuracy as good as, or better than, MTPs without the need for computationally expensive higher order multipoles. Further it is demonstrated that the MDCM is numerically stable in molecular dynamics simulations and is able to reproduce electrostatic interaction energies and thermodynamic quantities with the same accuracy as MTPs at reduced computational cost.


Stoichiometric design of metabolic networks: multifunctionality, clusters, optimization, weak and strong robustness.
Starting from a limited set of reactions describing changes in the carbon skeleton of biochemical compounds complete sets of metabolic networks are constructed. The networks are characterized by the number and types of participating reactions. Elementary networks are defined by the condition that a specific chemical conversion can be performed by a set of given reactions and that this ability will be lost by elimination of any of these reactions. Groups of networks are identified with respect to their ability to perform a certain number of metabolic conversions in an elementary way which are called the network's functions. The number of the network functions defines the degree of multifunctionality. Transitions between networks and mutations of networks are defined by exchanges of single reactions. Different mutations exist such as gain or loss of function mutations and neutral mutations. Based on these mutations neighbourhood relations between networks are established which are described in a graph theoretical way. Basic properties of these graphs are determined such as diameter, connectedness, distance distribution of pairs of vertices. A concept is developed to quantify the robustness of networks against changes in their stoichiometry where we distinguish between strong and weak robustness. Evolutionary algorithms are applied to study the development of network populations under constant and time dependent environmental conditions. It is shown that the populations evolve toward clusters of networks performing a common function and which are closely neighboured. Under changing environmental conditions multifunctional networks prove to be optimal and will be selected.


Mcl-1 Interacts with Akt to Promote Lung Cancer Progression.
Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth. Depletion of endogenous Mcl-1 from human lung cancer cells using CRISPR/Cas9 or Mcl-1 shRNA significantly decreased Akt activity, leading to suppression of lung cancer cell growth in vitro and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in tumor tissues from patients with non-small cell lung cancer. Using the Mcl-1-binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer in vitro and in vivo. By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of lung cancer. SIGNIFICANCE: These findings indicate that targeting Mcl-1/Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for cancer treatment.


Real-time closed-loop control in a rodent model of medically induced coma using burst suppression.
A medically induced coma is an anesthetic state of profound brain inactivation created to treat status epilepticus and to provide cerebral protection after traumatic brain injuries. The authors hypothesized that a closed-loop anesthetic delivery system could automatically and precisely control the electroencephalogram state of burst suppression and efficiently maintain a medically induced coma. In six rats, the authors implemented a closed-loop anesthetic delivery system for propofol consisting of: a computer-controlled pump infusion, a two-compartment pharmacokinetics model defining propofol's electroencephalogram effects, the burst-suppression probability algorithm to compute in real time from the electroencephalogram the brain's burst-suppression state, an online parameter-estimation procedure and a proportional-integral controller. In the control experiment each rat was randomly assigned to one of the six burst-suppression probability target trajectories constructed by permuting the burst-suppression probability levels of 0.4, 0.65, and 0.9 with linear transitions between levels. In each animal the controller maintained approximately 60 min of tight, real-time control of burst suppression by tracking each burst-suppression probability target level for 15 min and two between-level transitions for 5-10 min. The posterior probability that the closed-loop anesthetic delivery system was reliable across all levels was 0.94 (95% CI, 0.77-1.00; n = 18) and that the system was accurate across all levels was 1.00 (95% CI, 0.84-1.00; n = 18). The findings of this study establish the feasibility of using a closed-loop anesthetic delivery systems to achieve in real time reliable and accurate control of burst suppression in rodents and suggest a paradigm to precisely control medically induced coma in patients.


A genome-wide association study of periodontitis in a Japanese population.
Periodontitis is a multifactorial disease in which bacterial, lifestyle, and genetic factors are involved. Although previous genetic association studies identified several susceptibility genes for periodontitis in European populations, there is little information for Asian populations. Here, we conducted a genome-wide association study and a replication study consisting of 2,760 Japanese periodontitis patients and 15,158 Japanese controls. Although single-nucleotide polymorphisms that surpassed a stringent genome-wide significance threshold (P < 5 × 10(-8)) were not identified, we found 2 suggestive loci for periodontitis: KCNQ5 on chromosome 6q13 (rs9446777, P = 4.83 × 10(-6), odds ratio = 0.82) and GPR141-NME8 at chromosome 7p14.1 (rs2392510, P = 4.17 × 10(-6), odds ratio = 0.87). A stratified analysis indicated that the GPR141-NME8 locus had a strong genetic effect on the susceptibility to generalized periodontitis in Japanese individuals with a history of smoking. In conclusion, this study identified 2 suggestive loci for periodontitis in a Japanese population. This study should contribute to a further understanding of genetic factors for enhanced susceptibility to periodontitis.


Learning from Monocyte-Macrophage Fusion and Multinucleation: Potential Therapeutic Targets for Osteoporosis and Rheumatoid Arthritis.
Excessive bone resorption by osteoclasts (OCs) covers an essential role in developing bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA). Monocytes or macrophages fusion and multinucleation (M-FM) are key processes for generating multinucleated mature cells with essential roles in bone remodelling. Depending on the phenotypic heterogeneity of monocyte/macrophage precursors and the extracellular milieu, two distinct morphological and functional cell types can arise mature OCs and giant cells (GCs). Despite their biological relevance in several physiological and pathological responses, many gaps exist in our understanding of their formation and role in bone, including the molecular determinants of cell fusion and multinucleation. Here, we outline fusogenic molecules during M-FM involved in OCs and GCs formation in healthy conditions and during OP and RA. Moreover, we discuss the impact of the inflammatory milieu on modulating macrophages phenotype and their differentiation towards mature cells. Methodological approach envisaged searches on Scopus, Web of Science Core Collection, and EMBASE databases to select relevant studies on M-FM, osteoclastogenesis, inflammation, OP, and RA. This review intends to give a state-of-the-art description of mechanisms beyond osteoclastogenesis and M-FM, with a focus on OP and RA, and to highlight potential biological therapeutic targets to prevent extreme bone loss.


Immunoglobulin G Subclass-Specific Glycosylation Changes in Primary Epithelial Ovarian Cancer.
Epithelial ovarian cancer (EOC) was previously shown to be associated with glycosylation changes of total serum and total IgG proteins. However, as a majority of previous studies analyzed released glycan profiles, still little is known about IgG subclass-specific alterations in ovarian cancer. Hence, in this study, we investigated EOC-related glycosylation changes of the three most abundant IgG subclasses, namely, IgG1, IgG2 and IgG3 isolated from sera of 87 EOC patients and 74 age-matched healthy controls. In order to separate IgG2 and IgG3, we performed a two-step affinity purification employing Protein A and Protein G Sepharose. After tryptic digestion, IgG glycopeptides were enriched and measured by MALDI-TOF-MS. Finally, EOC-related glycosylation changes were monitored at the level of total agalactosylation, monogalactosylation, digalactosylation, sialylation, bisection and fucosylation, which were calculated separately for each IgG subclass. Interestingly, aside from an EOC-related increase in agalactosylation/decrease in monogalactosylation and digalactosylation observed in all IgG subclasses, some subclass-specific trends were detected. Glycosylation of IgG1 was found to be most strongly affected in EOC, as it exhibited the highest number of significant differences between healthy controls and EOC patients. Specifically, IgG1 was the only subclass that showed a significant decrease in sialylation and a significant increase in fucosylation in EOC patients. Interestingly, IgG2 and IgG3 that were often investigated collectively in previous studies, were found to have distinct glycosylation patterns. IgG3 displayed stronger EOC-related increase in agalactosylation/decrease in digalactosylation and was characterized by notably higher sialylation, which consequently decreased in EOC patients. In conclusion, our study indicates that IgG subclasses exhibit subtly distinct glycosylation patterns of EOC-related alterations and that IgG1 and IgG3 agalactosylation show the strongest association with CA125, the routine diagnostic marker. Additionally, our results show that simultaneous analyses of IgG2 and IgG3 might lead to wrong conclusions as these two subclasses exhibit noticeably different glycosylation phenotypes.


Loss of Smell and Taste After General Anesthesia: A Case Report.
This case report describes a patient, who lost the ability to smell and taste after receiving a propofol-based general anesthesia for a laparoscopic inguinal hernia repair. Immediately after the procedure, the patient had anosmia (loss of smell), ageusia (loss of taste), and light dysphagia. Assessment by an otorhinolaryngologist and the results of a magnetic resonance imaging could not clarify the pathology behind these symptoms. Although there are several plausible explanations for the patient's anosmia and ageusia (eg, cerebral infarcts, nerve damage, chronic sinusitis), the most likely explanation is an uncommon adverse drug reaction to the anesthetic agents used during the procedure.


[Introduction and Reflection on Novel Medical Device Regulatory Science Tool MDDT].
In recent years, emerging technology medical devices have developed rapidly. How to more scientifically and more efficiently regulate these novel medical devices so as to improve access to advanced medical technology while ensuring safety and effectiveness is a new challenge faced by regulatory authorities, and is also the core topic of regulatory science. New tools, new standards and new methods are important means to achieve regulatory science. "Medical Device Development Tool" proposed by the U.S. FDA is a novel medical device regulatory science tool, which can help medical device developers to predict and evaluate product performance more efficiently. It is also helpful for regulatory authorities to make regulatory decisions more efficiently. This study introduces the concept, qualification process, role of MDDT in medical device regulation and MDDT examples, and makes some discussion on the device evaluation from the perspective of reliability and validity. MDDT can facilitate the developing of novel medical device.


Endoscopic Excision of Supracondylar Humeral Spur for Decompression of the Median Nerve and Brachial Artery.
The humeral supracondylar process and Struthers ligament comprise a relatively rare but well-known anatomic variant. They are usually asymptomatic but may produce clinical symptoms related to compression of the median nerve or brachial artery below the ligament. Previously, surgery has been performed with an open ligament release and supracondylar process excision. This article reports on the use of endoscopic findings and the method of ligament release and process excision. Endoscopy is a minimally invasive technique that provides excellent visualization and enables the surgeon to perform dissection with magnification and precision. It allows the surgeon to introduce open surgical techniques into the depths of the wound in a controlled manner. Because of the dead space created, there is a risk of hematoma formation. Many of the concepts used in open surgery are now being used for endoscopic surgery, and vice versa. The barriers and differences among endoscopic, arthroscopic, and open procedures are being broken down. We report another endoscopic technique, which is part of the ongoing evolution of musculoskeletal surgery.


[The gastroepiploic artery graft in coronary artery bypass surgery].
From March 1986 to October 1989, 91 patients underwent CABG using the right gastroepiploic artery (GEA) at Osaka Medical College and Mitsui Memorial Hospital. Including 14 females, the mean age was 57.9 years old ranged from 34 to 73 years old. Triple vessel disease and left main disease occupied over 90% of the patients. There were 5 emergency operations and 6 reoperations. Associated serious diseases were; renal failure with hemodialysis in 2 pts., familial hyperlipidemia in 5 pts., severe atherosclerotic ascending aorta in 8 pts., arteriosclerosis obliterance in 3 pts., and each one of abdominal aortic aneurysm and idiopathic thrombocytopenic purpura. The internal thoracic artery (ITA) graft was concomitantly utilized in 96% of the patients. Single ITA in 60 pts., double ITA in 23 pts. and sequential ITA in 5 patients. Saphenous vein graft was used in 58 patients and remaining 33 patients were operated without leg wound. The mean number of distal anastomoses was 3.3 ranged from 1 to 5, and the mean number of arterial grafts was 2.5 ranged from 1 to 4. The mean aortic cross clamp time and cardiopulmonary bypass time was 62.8 minutes and 113.6 minutes, respectively. Sites of GEA anastomosis were; 4 anterior descending, 3 diagonal, 11 circumflex and 73 right coronary arteries. There were 86 in situ grafts mostly for the right coronary arteries, and remaining 5 GEAs were used as a free graft to bypass the left coronary arteries. On the contrary, ITA was used to bypass the left coronary artery system preferentially. There was 3 combined procedures; splenectomy, abdominal aorta replacement, and ascending aorta to bifemoral artery bypass in each one patients. Three patients including one emergency case died within 30 days after surgery. Two were cardiac and one was renal failure. Other 2 patients died of stroke at late period. New Q wave infarction was noted in 2 patients. Relief of angina was obtained in 98% of survivors. The patency rate of the GEA graft was 97% in 61 grafts restudied within 6 postoperative months, which was identical with that of the ITA graft, that is 97% of 76 grafts. In conclusion, the GEA has several advantages as a coronary artery bypass graft such as similarity in size to the coronary artery, rare arteriosclerosis, feasibility of in situ graft, and no gastric complication. Its flow capacity is studying now and favourable results are being obtained. The final problem, its long term patency, will be resolved in future. GEA is a promising conduit for the coronary bypass surgery.


Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions.
Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.


Dietary Protein and Changes in Biomarkers of Inflammation and Oxidative Stress in the Framingham Heart Study Offspring Cohort.
Chronic inflammation is thought to be a major characteristic of aging, which may increase need for substrates, specifically protein, to support anti-inflammatory processes. The aim of this study was to assess associations between dietary protein and changes in biomarkers of inflammation and oxidative stress over the long term in a community-dwelling population. In 2061 participants of the Framingham Heart Study Offspring cohort who attended exams 7 (1998-2001; mean ± SD age 60.0 ± 8.8 y, 56% female) and 8 (2005-2008), total, animal, and plant protein intakes were assessed by food-frequency questionnaire at each exam, energy adjusted, and averaged. We defined an inflammation and oxidative stress score as the sum of rank-normalized values of 9 circulating biomarkers (C-reactive protein, osteoprotegerin, P-selectin, tumor necrosis factor receptor II, soluble intercellular adhesion molecule-1, interleukin 6, monocyte chemoattractant protein 1, and lipoprotein phospholipase A2 mass and activity), and urinary isoprostanes, along with 2 subscores. Adjusted least-square means of changes in the scores and log individual biomarkers in quartile categories of intake were estimated with the use of linear regression models, across mean ± SD 6.6 ± 0.7 y of follow-up. Protein intake was inversely associated with changes in the inflammation and oxidative stress score (mean ± SE in Q1 compared with Q4: 0.77 ± 0.17 compared with 0.31 ± 0.19; P-trend = 0.02), indicating overall inflammation/oxidative stress increased less in those with the highest intake than in those with the lowest. Favorable associations were observed for plant protein (Q1 compared with Q4: 0.89 ± 0.25 compared with 0.14 ± 0.25; P-trend = 0.001), but only trended toward significance for animal protein (Q1 compared with Q4: 0.70 ± 0.26 compared with 0.31 ± 0.26; P-trend = 0.05). Total protein and plant protein intakes were also inversely associated with changes in monocyte chemoattractant protein 1 (total: Q1 compared with Q4: 0.19 ± 0.01 compared with 0.15 ± 0.01 log-pg/mL; P-trend = 0.03; plant: Q1 compared with Q4: 0.21 ± 0.01 compared with 0.16 ± 0.01 log-pg/mL; P-trend = 0.003). Dietary protein, particularly from plant sources, may be associated with beneficial changes in the inflammatory burden in aging populations.


A qualitative study exploring experiences of discrimination associated with mental-health problems in Ireland.
Stigma and discrimination related to mental-health problems impacts negatively on people's quality of life, help seeking behaviour and recovery trajectories. To date, the experience of discrimination by people with mental-health problems has not been systematically explored in the Republic of Ireland. This study aimed to explore the experience impact of discrimination as a consequence of being identified with a mental-health problem. Transcripts of semi-structured interviews with 30 people about their experience of discrimination were subject to thematic analysis and presented in summary form. People volunteered accounts of discrimination which clustered around employment, personal relationships, business and finance, and health care. Common experiences included being discounted or discredited, being mocked or shunned and being inhibited or constrained by oneself and others. Qualitative research of this type may serve to illustrate the complexity of discrimination and the processes whereby stigma is internalised and may shape behaviour. Such an understanding may assist health practitioners reduce stigma, and identify and remediate the impact of discrimination.


[The influences of exercise fulfillment on mental and physical functions of targeted older adults and the effect of a physical exercise intervention].
To investigate the influence of the differences in exercise fulfillment on mental and physical functions and the effects of exercise intervention on community-dwelling older adults. Participants in this study included 260 community-dwelling older adults (mean age +/- SD, 70.4 +/- 6.0 years) who participated in the exercise intervention study (intervention and control groups). Exercise fulfillment levels (low or high), physical activity levels (low or high), mental health (WHO-5 scores), health-related QOL (SF-8 score), and physical abilities of these adults were measured during a baseline health checkup. Based on the status of the 3 exercise fulfillment groups, multivariate analysis of variance (MANOVA), which was adjusted for age, sex, and physical activity levels, was performed to compare the results of the outcome measures among the 3 groups. The intervention group (n = 88, aged 70.3 +/- 6.2 years) was divided into 2 subgroups: the deterioration subgroup (participants with low-exercise fulfillment after the intervention) and the improvement subgroup (participants with high-exercise fulfillment after the intervention). Subsequently, the intervention effects were assessed by repeated measurements of the analysis of variance (ANOVA) between the 2 subgroups. MANOVA analysis revealed that body mass index, grip strength, maximum walking speed, the WHO-5 score, and the SF-8 subscale (8 items) score differed significantly amongst the groups. The high-exercise fulfillment group demonstrated better results for these variables than the low-exercise fulfillment group. Similar results were obtained for each group with respect to the physical activity levels. The repeated-measures ANOVA revealed that time had an important effect on lower physical functions and the SF-8 subscale (1 item) score; it also revealed the important effects of body mass index, the WHO-5 score, the SF-8 subscale (6 items) score, and psychological independence on the group. Older adults with higher exercise fulfillment demonstrated better mental and psychological health, regardless of their physical activity levels. Older adults with low-exercise fulfillment could potentially improve their physical abilities; however, their mental and psychological health significantly differed from that of older adults with medium- or high-exercise fulfillment after exercise intervention. These findings provide preliminary evidence, which indicates that exercise can provide sufficient fulfillment and contribute to the promotion and improvement of health in older adults. Moreover, performing adequate tests on exercise fulfillment may aid in assessing the effects of intervention programs in regional healthcare systems.


Agonist photoaffinity labeling of A1 adenosine receptors: persistent activation reveals spare receptors.
This study describes experiments investigating the mechanism of activation of A1 adenosine receptors. Isolated rat fat cells were used as a cellular model. The A1 receptors of these cells were covalently labeled with the agonist photoaffinity label R-2-azido-N6-p-hydroxyphenylisopropyladenosine. The covalent incorporation of the label into the binding subunit of the receptor was verified by demonstration of specific labeling of a peptide with Mr = 35,000 by the radioiodinated label. Such covalent labeling followed by removal of label not covalently bound led to a concentration-dependent reduction of cellular cAMP levels. This persistent effect of covalent labeling occurred with an IC50 value of 9 nM compared to an IC50 value of 0.9 nM for the direct reduction of cAMP levels by the label. The affinity of the label was determined in binding experiments. The Ki value of 19 nM was about 20 times higher than the corresponding IC50 value of cAMP reduction. Finally, the comparison between covalent binding and its effects suggests that covalently labeled receptors were fully activated. The data are interpreted as evidence for a receptor activation according to the occupancy theory. The analysis of the various concentration-response curves reveals the presence of spare receptors, which can be demonstrated by the method of agonist photoaffinity labeling.


Selection ratios on community aggregated traits estimate ecological filters imposed on species by sites.
Variation in community structure is mediated by interactions between species traits and a site's environmental characteristics. Previously, data on community composition at sites has been employed to correlate trait and environmental variables (e.g., RLQ analysis) and to predict community-level expression of quantitative traits (i.e., community aggregated traits). Here, we demonstrate that the selection ratio, a method originating in animal resource selection studies, can estimate the ecological filters that site conditions impose on species traits by combining observed community aggregated traits with null models of species availability. This flexible, nonparametric approach expresses the filter at each site as a probability density function for the selection of individuals possessing a given trait value. By doing so, it generalizes the community aggregated trait concept to include categorical as well as continuous traits and allows for both intraspecific variation in trait expression and differences in species availability among sites. The resulting site-level filter functions can be related to environmental covariates by standard statistical approaches (e.g., regression). The method complements existing techniques for analyzing trait-environment interactions in community ecology.


Growth Promoting Effect of Vacuum Sealing Drainage in the Healing Processes of Diabetic Foot Ulcers.
To explore the growth-promoting effect of vacuum sealing drainage (VSD) during the healing processes of diabetic foot ulcers (DFUs). From November 2018 to December 2019, 38 patients with unilateral DFUs were enrolled in this retrospective study. All patients were divided into two groups according to the use of VSD or not: the VSD group (n=20) and the control group (n=18). The following parameters were used to evaluate the healing process: changes in the mean areas of the ulcers; healing rate (HR); epithelial hyperplasia and angiogenesis as determined by hematoxylin-eosin staining (HE staining); and expression of CD34, CD68 and VEGF as assessed through immunohistochemistry. Perioperative side effects and complications were also recorded. All patients received follow-up and eventually healed. The mean area of wounds was reduced in the VSD group compared to the control group (1.75±0.64 cm2 vs 0.88±0.54 cm2, P=0.031). The mean HR of the ulcers in the VSD group was significantly higher than that in the control group (35.23±2.87% vs 28.78±1.09%, P=0.017). HE staining showed that the amount of epithelial hyperplasia and angiogenesis increased significantly after VSD, and the immunohistochemistry results showed that the expression of CD34, CD68 and VEGF increased significantly in the VSD group. VSD could significantly accelerate the wound healing process, probably by enhancing the inflammatory response and promoting granulation and angiogenesis in DFUs.


Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson's disease.
Psychotic symptoms are the main and the most disabling "nonmotor" complications of Parkinson's disease (PD), the pathophysiology of which is poorly recognized. Polysomnographic studies have shown a relationship between visual hallucinations and rapid eye movement (REM) sleep. The objective of this study is to clarify the relationship between psychotic symptoms and REM sleep behavior disorder (RBD) in PD. In a Parkinson's disease outpatient unit, 289 consecutive subjects with idiopathic PD were administered (in the period from January to December 2002) a multiple-choice questionnaire and structured interview on sleep and mental disorders. RBD was diagnosed in accordance with the minimal diagnostic criteria of the International Classification of Sleep Disorders. Hallucinations and delusional disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. The presence or absence of psychotic symptoms, of RBD, and of daytime sleepiness, as well as motor status, cognitive status, and mood were assessed. Approximately 32% (n = 92) of the subjects presented with psychotic disorders; 30% (n = 86) had experienced hallucinations; 2% (n = 6) had delusions without hallucinations. Sixty-two (72%) hallucinators reported nocturnal hallucinations. A total of 6.6% (n = 19) of the subjects complained of a delusional disorder. There were 26.6% (n = 77) of subjects who presented with RBD: 28 (36%) with onset before and 49 (63%) with onset after PD diagnosis. The presence of RBD was associated with an increased risk of manifesting hallucinations and delusions (odds ratio [OR], 2.73). Other independent clinical factors found to have an effect on psychotic disorders were cognitive impairment (OR, 3.92), disease duration (OR, 2.46), advanced age (OR, 2.34), and severity of motor symptoms (OR, 2.06). These results suggest that RBD is widely associated with psychosis in PD.


Automatisms: bridging clinical neurology with criminal law.
The law, like neurology, grapples with the relationship between disease states and behavior. Sometimes, the two disciplines share the same terminology, such as automatism. In law, the "automatism defense" is a claim that action was involuntary or performed while unconscious. Someone charged with a serious crime can acknowledge committing the act and yet may go free if, relying on the expert testimony of clinicians, the court determines that the act of crime was committed in a state of automatism. In this review, we explore the relationship between the use of automatism in the legal and clinical literature. We close by addressing several issues raised by the automatism defense: semantic ambiguity surrounding the term automatism, the presence or absence of consciousness during automatisms, and the methodological obstacles that have hindered the study of cognition during automatisms.


Isolation of Borrelia burgdorferi from arthropods collected in Texas.
The Texas Department of Health Laboratory cultured arthropods from November 1988 through December 1989 in an attempt to isolate Borrelia burgdorferi, the etiologic agent of Lyme disease. Spirochetes were isolated from eight of 1,093 pools of arthropods cultured. The spirochetal isolates were from several tick and one flea species, including Amblyomma americanum, A. maculatum, Ixodes scapularis, and Ctenocephalides felis. These 8 isolates reacted specifically when treated with monoclonal antibodies to B. burgdorferi. Polyacrylamide gel electrophoresis of six lysates showed them to be virtually identical with strain B31 of B. burgdorferi.


Zoledronic acid and geranylgeraniol regulate cellular behaviour and angiogenic gene expression in human gingival fibroblasts.
The mevalonate pathway (MVP) and the anti-angiogenic effect of bisphosphonates have been shown to play a role in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study determined the effect of the bisphosphonate, zoledronic acid and the replenishment of the MVP by geranylgeraniol on human gingival fibroblasts. Cell viability, apoptosis, morphological analysis using transmission electron microscopy, and gene expression for vascular endothelial growth factor A, bone morphogenic protein 2, ras homologue gene family member B, epiregulin and interferon-alpha were conducted. Results showed cellular viability was decreased in the presence of zoledronic acid and the co-addition of zoledronic acid with geranylgeraniol restored cell viability to control levels. Caspase 3/7 was detected in zoledronic-acid-treated cells indicating apoptosis. Transmission electron microscopy revealed dilation of the rough endoplasmic reticulum with zoledronic acid and the appearance of multiple lipid-like vesicles following the addition of geranylgeraniol. Zoledronic acid significantly (P < 0.05, FR > ± 2) up-regulated vascular endothelial growth factor A, bone morphogenic protein 2, ras homologue gene family member B and epiregulin at one or more time points but not interferon-alpha. Addition of geranylgeraniol resulted in a reduction in the expression of all five genes compared with zoledronic-acid-treated human gingival fibroblasts. The study concluded geranylgeraniol partially reversed the effects of zoledronic acid in human gingival fibroblasts both at the cellular and genetic levels, suggesting the regulation of these genes is mediated via the mevalonate pathway.


A Deep Learning Approach for Psychosis Spectrum Label Noise Detection from Multimodal Neuroimaging Data.
Understanding the structural and functional mechanisms of the brain is challenging for mood and mental disorders. Many neuroimaging techniques are widely used to reveal hidden patterns from different brain imaging modalities. However, these findings are bounded by the limitation of each modality. In addition, the lack of validity of current psychosis nosology created more complications in understanding biomarkers. In this study, we introduced a deep convolutional framework to classify and identify label noises using structural and functional magnetic resonance imaging data. We applied our method to functional and structural MRI data from a schizophrenia dataset and evaluated the model's performance in a cross-validated form. In addition, we introduced a noise criterion to distinguish a potentially noisy subject for each modality. Our results show the learned model using resting-state functional MRI data is more informative and has higher performance in comparison with structural MRI data. Lastly, based on the noise level, we investigated potential borderline subjects as possible subtypes and made a statistical analysis to distinguish differences between resting-state static functional connectivity features.Clinical Relevance- Results show schizophrenia patients are separable from the healthy control group based on their neuroimaging data and resting-state functional MRI data is more informative than structural MRI data and hence contains less label noise.


Roundtable discussion at the UICC World Cancer Congress: looking toward the realization of universal health coverage for cancer in Asia.
The Japan National Committee for the Union for International Cancer Control (UICC) and UICC-Asia Regional Office (ARO) organized a Roundtable Discussion as part of the official program of the UICC World Cancer Congress 2014 in Melbourne, Australia. The theme for the Roundtable Discussion was - Looking Toward the Realization of Universal Health Care (UHC) for Cancer in Asia - and it was held on December 5, 2014. The meeting was held based on the recognition that although each country may take a different path towards the realization of UHC, one point that is common to all is that cancer is projected to be the most difficult disease to address under the goals of UHC and that there is, therefore, an urgent and pressing need to come to a common understanding and awareness with regard to UHC concepts that are a priority component of a post-MDG development agenda. The presenters and participants addressed the issue of UHC for cancer in Asia from their various perspectives in academia and international organizations. Discussions covered the challenges to UHC in Asia, collaborative approaches by international organizations, the need for uniform and relevant data, ways to create an Asia Cancer Barometer that could be applied to all countries in Asia. The session concluded with the recognition that research on UHC in Asia should continue to be used as a tool for cancer cooperation in Asia and that the achievement of UHC would require research and input not only from the medical community, but from a broad sector of society in a multidisciplinary approach. Discussions on this issue will continue towards the Asia-Pacific Cancer Conference in Indonesia in August 2015.


Cardiac resynchronization therapy in patients with intrinsic and right ventricular pacing-induced left bundle branch block pattern.
We studied 95 consecutive patients, mean age 70 years, who received cardiac resynchronization therapy (CRT) for class III or IV heart failure with a left ventricular (LV) ejection fraction < or =35% and a QRS duration > or =120 ms. Sixty-seven patients had intrinsic left bundle branch block (LBBB) (group 1), and 28 patients had right ventricular pacing-induced LBBB (group 2). The time difference (TPW-TDI) between onset of QRS to the end of LV ejection by pulsed wave Doppler and onset of QRS to the end of systolic wave in the basal segment with greatest delay by tissue Doppler imaging was measured before CRT and at the last follow-up after CRT. TPW-TDI >50 ms was defined as left ventricular mechanical dyssynchrony. A positive response to CRT was defined as LV volume at end-systole decreasing > or =15% after CRT. The percentage of CRT responders in group 2 was significantly greater than that in group 1 (68% versus 42%, P = 0.04) during follow-up of 16 months. After adjusting for age, gender, and clinical features, this pattern of CRT response persisted (P = 0.008). Similarly, there was a greater reduction in QRS duration in group 2 (178 ms) after CRT versus 154 ms for group 1, P = 0.01. There was no significant difference in TPW-TDI between the 2 groups at baseline or at follow-up. There was no significant difference in mortality (15% versus 14%) and Kaplan-Meier survival plot during follow-up. Patients with heart failure and right ventricular pacing-induced LBBB have a better response rate to CRT than patients with intrinsic LBBB. The change in left ventricular mechanical dyssynchrony after CRT was similar in these 2 groups of patients.


Semantic development of African-American children prenatally exposed to cocaine.
Semantic content categories were described for the single word, multiple word, and verb relation utterances of 22 African-American 2-year-olds during a 90-min laboratory session. Half of the toddlers had been exposed prenatally to cocaine and half were unexposed, as documented by biological assay in the newborn period. The exposed and unexposed groups were carefully matched on demographic, medical, and proximal caregiving variables. Children's spontaneous utterances were transcribed from audio- and videotapes during the laboratory session and scored for semantic features by a team of reliable coders who were masked to child exposure status. General productive language features (utterance length, verbosity, and intelligibility) were also assessed. To evaluate general language and cognitive skills, the toddlers were evaluated with the Sequenced Inventory of Communicative Development-Revised (SICD-R) and the Bayley Scales of Infant Development (BSID). Although exposed and nonexposed toddlers exhibited similar sequences of semantic development, the exposed toddlers were more restricted and delayed in their semantic representations. No significant group differences were observed, however, for structural features of language (e.g., utterance length, distribution of utterance types) or for children's general language and cognitive functioning as assessed by standardized assessments (i.e., SICD-R, BSID). Thus, a history of prenatal cocaine exposure and associated risk factors (e.g., prenatal exposure to alcohol, diminished birth weight) are related to delays in early semantic development. Proposed diagnostic and treatment strategies are discussed.


Heterologous Expression of ethA and katG in Mycobacterium marinum Enables the Rapid Identification of New Prodrugs Active against Mycobacterium tuberculosis.
Screening strategies for antituberculosis compounds using Mycobacterium tuberculosis are time consuming and require biosafety level 3 (BSL3) facilities, which makes the development of high-throughput assays difficult and expensive. Mycobacterium marinum, a close genetic relative of M. tuberculosis, possesses several advantages as a suitable model for tuberculosis drug screening. However, despite the high genetic similarity, there are some obvious differences in susceptibility to some tuberculosis drugs between these two species, especially for the prodrugs ethionamide and isoniazid. In this study, we aimed to improve M. marinum as a model for antituberculosis drug identification by heterologous expression of two common drug activators, EthA and KatG. These two activators were overexpressed in M. marinum, and the strains were tested against ethionamide, isoniazid, and a library of established antimycobacterial compounds from TB Alliance to compare drug susceptibility. Both in vitro and in vivo using zebrafish larvae, these genetically modified M. marinum strains showed significantly higher susceptibility against ethionamide and isoniazid, which require activation by EthA and KatG. More importantly, a strain overexpressing both ethA and katG was potentially more susceptible to approximately 20% of the antituberculosis hit compounds from the TB Alliance library. Most of these compounds were activated by EthA in M. marinum Four of these compounds were selected for further analysis, and three of them showed obvious EthA-dependent activity against M. tuberculosis Overall, our developed M. marinum strains are valuable tools for high-throughput discovery of potential novel antituberculosis prodrugs.


Susceptibility of domestic cats to chronic wasting disease.
Domestic and nondomestic cats have been shown to be susceptible to feline spongiform encephalopathy (FSE), almost certainly caused by consumption of bovine spongiform encephalopathy (BSE)-contaminated meat. Because domestic and free-ranging nondomestic felids scavenge cervid carcasses, including those in areas affected by chronic wasting disease (CWD), we evaluated the susceptibility of the domestic cat (Felis catus) to CWD infection experimentally. Cohorts of 5 cats each were inoculated intracerebrally (i.c.) or orally (p.o.) with CWD-infected deer brain. At 40 and 42 months postinoculation, two i.c.-inoculated cats developed signs consistent with prion disease, including a stilted gait, weight loss, anorexia, polydipsia, patterned motor behaviors, head and tail tremors, and ataxia, and the cats progressed to terminal disease within 5 months. Brains from these two cats were pooled and inoculated into cohorts of cats by the i.c., p.o., and intraperitoneal and subcutaneous (i.p./s.c.) routes. Upon subpassage, feline CWD was transmitted to all i.c.-inoculated cats with a decreased incubation period of 23 to 27 months. Feline-adapted CWD (Fel(CWD)) was demonstrated in the brains of all of the affected cats by Western blotting and immunohistochemical analysis. Magnetic resonance imaging revealed abnormalities in clinically ill cats, which included multifocal T2 fluid attenuated inversion recovery (FLAIR) signal hyperintensities, ventricular size increases, prominent sulci, and white matter tract cavitation. Currently, 3 of 4 i.p./s.c.- and 2 of 4 p.o. secondary passage-inoculated cats have developed abnormal behavior patterns consistent with the early stage of feline CWD. These results demonstrate that CWD can be transmitted and adapted to the domestic cat, thus raising the issue of potential cervid-to-feline transmission in nature.


Tracheal occlusion modulates the gene expression profile of the medial thalamus in anesthetized rats.
Conscious awareness of breathing requires the activation of higher brain centers and is believed to be a neural gated process. The thalamus could be responsible for the gating of respiratory sensory information to the cortex. It was reasoned that if the thalamus is the neural gate, then tracheal obstructions will modulate the gene expression profile of the thalamus. Anesthetized rats were instrumented with an inflatable cuff sutured around the trachea. The cuff was inflated to obstruct 2-4 breaths, then deflated for a minimum of 15 breaths. Obstructions were repeated for 10 min followed by immediate dissection of the medial thalamus. Following the occlusion protocol, 588 genes were found to be altered (P < 0.05; log(2) fold change ≥ 0.4), with 327 genes downregulated and 261 genes upregulated. A significant upregulation of the serotonin HTR2A receptor and significant downregulation of the dopamine DRD1 receptor genes were found. A pathway analysis was performed that targeted serotonin and dopamine receptor pathways. The mitogen-activated protein kinase 1 (MAPK1) gene was significantly downregulated. MAPK1 is an inhibitory regulator of HTR2A and facilitatory regulator for DRD1. Downregulation of MAPK1 may be related to the significant upregulation of HTR2A and downregulation of DRD1, suggesting an interaction in the medial thalamus serotonin-dopamine pathway elicited by airway obstruction. These results demonstrate an immediate change in gene expression in thalamic arousal, fear, anxiety motivation-related serotonin and dopamine receptors in response to airway obstruction. The results support the hypothesis that the thalamus is a component in the respiratory mechanosensory neural pathway.


Childhood adversity, adult stress, and the risk of major depression or generalized anxiety disorder in US soldiers: a test of the stress sensitization hypothesis.
The stress sensitization theory hypothesizes that individuals exposed to childhood adversity will be more vulnerable to mental disorders from proximal stressors. We aimed to test this theory with respect to risk of 30-day major depressive episode (MDE) and generalized anxiety disorder (GAD) among new US Army soldiers. The sample consisted of 30 436 new soldier recruits in the Army Study to Assess Risk and Resilience (Army STARRS). Generalized linear models were constructed, and additive interactions between childhood maltreatment profiles and level of 12-month stressful experiences on the risk of 30-day MDE and GAD were analyzed. Stress sensitization was observed in models of past 30-day MDE (χ2 8 = 17.6, p = 0.025) and GAD (χ2 8 = 26.8, p = 0.001). This sensitization only occurred at high (3+) levels of reported 12-month stressful experiences. In pairwise comparisons for the risk of 30-day MDE, the risk difference between 3+ stressful experiences and no stressful experiences was significantly greater for all maltreatment profiles relative to No Maltreatment. Similar results were found with the risk for 30-day GAD with the exception of the risk difference for Episodic Emotional and Sexual Abuse, which did not differ statistically from No Maltreatment. New soldiers are at an increased risk of 30-day MDE or GAD following recent stressful experiences if they were exposed to childhood maltreatment. Particularly in the military with an abundance of unique stressors, attempts to identify this population and improve stress management may be useful in the effort to reduce the risk of mental disorders.


[Quantitative evaluation of the anxiolytic and nootropic effects of potassium orotate in a wide range of doses].
Chronic administration of potassium orotate to rats per os in doses of 5, 10, 20, 50 and 100 mg/kg was followed by different correlations of the training under stress with anxiolytic activity. The doses of the drug were defined, at which the maximally pronounced effects under consideration were in optimal correlations, as were doses which entailed inhibition of the training in the presence of a relatively low tranquilizing activity, low emotional responsiveness and aggressiveness. It is suggested that natural analogs of pyrimidine, whose precursor is orotic acid, are universal endogenous regulators of mnemonic and antianxiety functions.


Targeting SHP-1-STAT3 signaling: A promising therapeutic approach for the treatment of cholangiocarcinoma.
Sorafenib is a multiple kinase inhibitor which targets Raf kinases, VEGFR, and PDGFR and is approved for the treatment of hepatocellular carcinoma (HCC). Previously, we found that p-STAT3 is a major target of SC-43, a sorafenib derivative. In this study, we report that SC-43-induced apoptosis in cholangiocarcinoma (CCA) via a novel mechanism. Three CCA cell lines (HuCCT-1, KKU-100 and CGCCA) were treated with SC-43 to determine their sensitivity to SC-43-induced cell death and apoptosis. We found that SC-43 activated SH2 domain-containing phosphatase 1 (SHP-1) activity, leading to p-STAT3 and downstream cyclin B1 and Cdc2 downregulation, which induced G2-M arrest and apoptotic cell death. Importantly, SC-43 augmented SHP-1 activity by direct binding to N-SH2 and relief of its autoinhibition. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 counteracted the effect of SC-43-induced SHP-1 phosphatase activation and antiproliferation ability in CCA cells. In vivo assay revealed that SC-43 exhibited xenograft tumor growth inhibition, p-STAT3 reduction and SHP-1 activity elevation. In conclusion, SC-43 induced apoptosis in CCA cells through the SHP-1/STAT3 signaling pathway.


Hemostatic agents and their safety.
The pharmacologic management of hemostasis in patients undergoing cardiopulmonary bypass may be accompanied by adverse responses. Evaluating the safety profile of hemostatic agents (eg, lysine analogs, aprotinin, protamine, or even donor blood) should be done objectively. Subsequent to early anecdotal reports, the safety profile of aprotinin, a broad-spectrum serine protease inhibitor, has been thoroughly evaluated in multiple double-blind, placebo-controlled, multicenter studies. Although associated with decreased fibrinolysis, aprotinin has not been associated with an increased risk of post-cardiopulmonary bypass myocardial infarction, graft closure, stroke, or increased risk of renal dysfunction from US studies. As with any polypeptide, there is a risk of anaphylaxis, which is influenced not only by prior exposure but also by time since prior exposure. In a similar fashion, after early anecdotal reports, evaluations involving large numbers of patients have helped define adverse reactions to protamine. Adverse reactions to blood products also must be considered in any safety comparisons involving hemostatic agents.


Early prediction of skin viability using visible diffuse reflectance spectroscopy and autofluorescence spectroscopy.
Accurate and early prediction of skin flap viability is vitally important in reconstructive surgery. To the best of the authors' knowledge, this is the first pilot study to evaluate the simultaneous use of both visible diffuse reflectance and autofluorescence spectroscopy on a reverse MacFarlane rat dorsal skin flap model in the early prediction of skin viability. A total of 62 flap measurement sites from 11 Sprague-Dawley rats were monitored for 72 hours. Both statistical analysis using measured spectra and quantification of physiologically relevant tissue parameters using empirical methods were performed. The statistical analysis results suggest that either visible diffuse reflectance spectroscopy or autofluorescence spectroscopy alone can predict the skin viability accurately; however, autofluorescence spectroscopy is more sensitive to tissue changes in the first 2 hours after induction of ischemia. The pilot study shows that it is feasible to predict flap failures in the first 2 hours when using autofluorescence spectroscopy alone; moreover, it is possible to predict flap failures even in the first 15 minutes with high accuracy when using diffuse reflectance and autofluorescence spectroscopy simultaneously. Meanwhile, several physiologically relevant parameters including hemoglobin oxygenation, total hemoglobin concentration, and redox ratio indicators estimated from diffuse reflectance and autofluorescence spectra show distinctively different trends over time for nonviable and viable skin. These findings will be helpful to clinicians for making a precise judgment on flap viability. Furthermore, the authors' results highlight the advantage of using autofluorescence spectroscopy in the early prediction of skin flap viability relative to diffuse reflectance spectroscopy.


Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Echocardiography is the key tool for the diagnosis and evaluation of aortic stenosis. Because clinical decision-making is based on the echocardiographic assessment of its severity, it is essential that standards are adopted to maintain accuracy and consistency across echocardiographic laboratories. Detailed recommendations for the echocardiographic assessment of valve stenosis were published by the European Association of Echocardiography and the American Society of Echocardiography in 2009. In the meantime, numerous new studies on aortic stenosis have been published with particular new insights into the difficult subgroup of low gradient aortic stenosis making an update of recommendations necessary. The document focuses in particular on the optimization of left ventricular outflow tract assessment, low flow, low gradient aortic stenosis with preserved ejection fraction, a new classification of aortic stenosis by gradient, flow and ejection fraction, and a grading algorithm for an integrated and stepwise approach of artic stenosis assessment in clinical practice.


Systematic kinome shRNA screening identifies CDK11 (PITSLRE) kinase expression is critical for osteosarcoma cell growth and proliferation.
Identification of new targeted therapies is critical to improving the survival rate of patients with osteosarcoma. The goal of this study is to identify kinase based potential therapeutic target in osteosarcomas. We used a lentiviral-based shRNA kinase library to screen for kinases which play a role in osteosarcoma cell survival. The cell proliferation assay was used to evaluate cell growth and survival. siRNA assays were applied to confirm the observed phenotypic changes resulting from the loss of kinase gene expression. CDK11 (PITSLRE) was identified as essential for the survival of osteosarcoma cells, and its expression was confirmed by Western blot analysis and immunohistochemistry. Overall patient survival was correlated with the CDK11 expression and its prognosis. The role of CDK11 expression in sustaining osteosarcoma growth was further evaluated in an osteosarcoma xenograft model in vivo. Osteosarcoma cells display high levels of CDK11 expression. CDK11 expression knocked down by either lentiviral shRNA or siRNA inhibit cell growth and induce apoptosis in osteosarcoma cells. Immunohistochemical analysis showed that patients with osteosarcoma with high CDK11 tumor expression levels were associated with significantly shorter survival than patients with osteosarcoma with low level of tumor CDK11 expression. Systemic in vivo administration of in vivo ready siRNA of CDK11 reduced the tumor growth in an osteosarcoma subcutaneous xenograft model. We show that CDK11 signaling is essential in osteosarcoma cell growth and survival, further elucidating the regulatory mechanisms controlling the expression of CDK11 and ultimately develop a CDK11 inhibitor that may provide therapeutic benefit against osteosarcoma.


Perception and application of flywheel training by professional soccer practitioners.
Growing evidence supports use of eccentric methods for strength development and injury prevention within elite soccer, yet uncertainty remains regarding practitioners' application of flywheel (isoinertial) methods. The aims of this study were to investigate how the flywheel training literature is perceived and applied by elite soccer practitioners, highlight gaps in knowledge and develop industry-relevant research questions. Fifty-one practitioners completed an electronic questionnaire. Fourteen Likert scale statements were grouped into topics: strength and performance; post-activation performance enhancement and methodological considerations; chronic strength; chronic performance; injury prevention. Three general questions followed, allowing more detail about flywheel training application. A Majority of the participants reported ≥ 2 years' experience of programming flywheel training. Nearly all participants agreed that familiarisation is needed. Practitioners agree that flywheel training can improve sport performance, strength and likelihood of non-contact injury outcomes. Most practitioners prescribe 2 weekly sessions during pre- and in-season periods. Flywheel sessions mostly consist of squats but a variety of exercises (lunge, hip hinge, and open kinetic chain) are also frequently included. Practitioners are mostly unsure about differences between flywheel and traditional resistance training equipment and outcomes, practicality of flywheel equipment, and evidence-based guidelines. The investigation provides valuable insight into the perspectives and application of flywheel training within elite soccer, highlighting its perceived efficacy for strength and injury prevention.


Safety, Tolerability, and Pharmacodynamics of Intrathecal Injection of Recombinant Human HGF (KP-100) in Subjects With Amyotrophic Lateral Sclerosis: A Phase I Trial.
Hepatocyte growth factor is an endogenous pleiotropic factor shown to act as a potent neuroprotectant against disease progression in animal models of amyotrophic lateral sclerosis, which is a devastating, adult-onset motor neuron disease. To evaluate the safety, tolerability, and pharmacokinetics of recombinant 5-residue-deleted human hepatocyte growth factor (KP-100) injected intrathecally through an implantable catheter connected to a subcutaneous port, we conducted a first-in-human phase I trial of intrathecal KP-100 in 15 Japanese patients with amyotrophic lateral sclerosis. The regimen was a single injection of 3 escalating doses (0.2, 0.6, and 2.0 mg/body) in 9 subjects followed by 2 doses (0.6 and 2.0 mg/body) repeated 5 times at 1-week intervals in 6 subjects (3 subjects/group). With single-dose administration, the mean half-life of KP-100 in the cerebrospinal fluid was 1.2 to 1.4 days, with its maximum concentration increasing in a dose-dependent manner. With multiple-dose administration, the trough KP-100 concentrations in the cerebrospinal fluid generally remained constant for any dose, despite multiple dosing. There were no deaths, serious adverse events, or device malfunctions leading to discontinuation. In all subjects, plasma KP-100 concentrations were <1 ng/mL, or below the lower limit of detection at all time points of measurement. Anti-KP-100 antibody was not detected in the cerebrospinal fluid or plasma specimens from any of the subjects throughout the KP-100 dosing period. These results suggest that KP-100, as well as the device used to administer it, is safe and tolerable. A phase II trial is warranted in patients with various central nervous system diseases such as amyotrophic lateral sclerosis.


A Large Scale Test of the Effect of Social Class on Prosocial Behavior.
Does being from a higher social class lead a person to engage in more or less prosocial behavior? Psychological research has recently provided support for a negative effect of social class on prosocial behavior. However, research outside the field of psychology has mainly found evidence for positive or u-shaped relations. In the present research, we therefore thoroughly examined the effect of social class on prosocial behavior. Moreover, we analyzed whether this effect was moderated by the kind of observed prosocial behavior, the observed country, and the measure of social class. Across eight studies with large and representative international samples, we predominantly found positive effects of social class on prosociality: Higher class individuals were more likely to make a charitable donation and contribute a higher percentage of their family income to charity (32,090 ≥ N ≥ 3,957; Studies 1-3), were more likely to volunteer (37,136 ≥N ≥ 3,964; Studies 4-6), were more helpful (N = 3,902; Study 7), and were more trusting and trustworthy in an economic game when interacting with a stranger (N = 1,421; Study 8) than lower social class individuals. Although the effects of social class varied somewhat across the kinds of prosocial behavior, countries, and measures of social class, under no condition did we find the negative effect that would have been expected on the basis of previous results reported in the psychological literature. Possible explanations for this divergence and implications are discussed.


Associations Between Age-Related Hearing Loss, Cognitive Impairment, and Multiple Chronic Conditions in a Group Care Setting.
The purpose of this study was to explore the relationships between hearing loss, cognitive status, and a range of health outcomes over a period of 2 years in a sample of older adults who are enrolled in Program of All-Inclusive Care for the Elderly, which is a Medicare/Medicaid beneficiary program for individuals who are nursing home eligible but living in the community at time of enrollment. The sample (N = 144) includes a diverse (47% White/non-Hispanic, 35% Black/African American, and 16% Latin/Hispanic) group of adults ranging from 55 to 93 years old. We used medical chart data to measure respondents' cognitive and health status, including chronic conditions and hospital use. Hearing status was measured once at the beginning of the 2-year review period. We used logistic regression and negative binomial hurdle models for analyses. We used latent class analysis (LCA) to explore the extent to which respondents cluster into a set of "health profiles" characterized by their hearing, cognitive status, and health conditions. We found that hearing loss is weakly associated with heart disease and diabetes and associated with cerebrovascular disease and falls; cognitive impairment is also associated with cerebrovascular disease and the number of falls. LCA indicates that respondents cluster into a variety of health profiles with a consistent pairing of hearing loss and depression. The results are largely consistent with associations reported in epidemiological studies that include age-related hearing loss. Of particular interest in this study is the LCA that suggested that all of the profiles associated with a high likelihood of hearing loss included a high risk of depression. The co-occurrence of these two factors highlights the need to identify and treat hearing loss in older adults, especially as part of the treatment plan for individuals with depressive symptoms.


Computer vision syndrome and associated factors in university students and teachers in Nampula, Mozambique.
Computer Vision Syndrome (CVS) is a complex of eye and visual problems that arise while using a computer or other Video Display Terminal (DVT). With the advent of the COVID-19 pandemic, the use of these DVTs has become indispensable in the lives of students and teachers. This study aims to identify the prevalence of CVS and associated factors in students and teachers at Lúrio University, in Nampula, during the pandemic period. This is a cross-sectional study, carried out between November 2020 and March 2021. The validated CVS questionnaire (CVS-Q) and another semi-structured questionnaire on ergonomic risk factors were applied. Odds ratios (OR) and adjusted odds ratios (aOR) were calculated to measure the association between CVS and computer use conditions. The prevalence of CVS was 76.6%, and the female gender, age ≤ 20 years, levels I, II, III of course, lack of knowledge about ergonomics, use the computer to study, use more than 6 hours daily, absence of anti-reflex treatment, use of other devices and sitting in an inappropriate chair were risk factors for the occurrence of CVS, while being a teacher was a protective factor. The prevalence of CVS found in this study was high, due to several factors, especially not using ergonomic principles when using computers and other DVTs. There is a need to adopt intervention strategies focused on the most vulnerable groups such as women, age group ≤20 years and students, especially at the first year level, right after entering the University.