Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry.
The utility of immunohistochemical detection of DNA mismatch repair (MMR) protein in screening colorectal tumors for hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has been the focus of much intensive research over the last 10 years. Particular attention has been given to the relative usefulness of immunohistochemistry (IHC) versus testing of tumor microsatellite instability (MSI). Earlier work that focused on mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) has created a false impression that IHC has a lower sensitivity than MSI testing in predicting germline mutation. More recent studies that included postmeiotic segregation increased 2 (PMS2) and MSH6, on the other hand, have demonstrated an IHC predictive value that is virtually equivalent to that of MSI testing. Such added value of PMS2 and MSH6 can be explained by the biological and biochemical properties of the MMR proteins. On the premise that IHC with PMS2 and MSH6 is as sensitive as MSI testing, given that IHC is easily available and generally inexpensive and, importantly, identifies the affected gene, it is reasonable to regard IHC as a more optimal first-line screening tool than MSI testing for identifying HNPCC. MSI testing can provide a fallback position in equivocal situations, while remaining an important research tool. However, for IHC to be used as a first-line screening test requires that both pathologists and clinicians be aware that IHC results may be construed as "genetic information," and that appropriate procedures should be established to ensure patient understanding and consent.


Scientometric Review for Research Patterns on Additive Manufacturing of Lattice Structures.
Over the past 15 years, interest in additive manufacturing (AM) on lattice structures has significantly increased in producing 3D/4D objects. The purpose of this study is to gain a thorough grasp of the research pattern and the condition of the field's research today as well as identify obstacles towards future research. To accomplish the purpose, this work undertakes a scientometric analysis of the international research conducted on additive manufacturing for lattice structure materials published from 2002 to 2022. A total of 1290 journal articles from the Web of Science (WoS) database and 1766 journal articles from the Scopus database were found using a search system. This paper applied scientometric science, which is based on bibliometric analysis. The data were subjected to a scientometric study, which looked at the number of publications, authorship, regions by countries, keyword co-occurrence, literature coupling, and scientometric mapping. VOSviewer was used to establish research patterns, visualize maps, and identify transcendental issues. Thus, the quantitative determination of the primary research framework, papers, and themes of this research field was possible. In order to shed light on current developments in additive manufacturing for lattice structures, an extensive systematic study is provided. The scientometric analysis revealed a strong bias towards researching AM on lattice structures but little concentration on technologies that emerge from it. It also outlined its unmet research needs, which can benefit both the industry and academia. This review makes a prediction for the future, with contributions by educating researchers, manufacturers, and other experts on the current state of AM for lattice structures.


Telepsychotherapy. Psychotherapy by telephone, videotelephone, and computer videoconferencing.
Telepsychotherapy is defined as psychotherapy conducted by a therapist at a location different from the patient's through bidirectional communication technology supporting real-time interactivity in the audio, audiovisual, or text modalities. Various types of telecommunication equipment are considered. Vignettes of 2 cases treated by means of the AT&T Videophone 2500 are presented. Medicolegal aspects and clinical issues, including ethics, confidentiality, patient selection, and therapy technique, are addressed.


Monitoring of Benzimidazole Resistance in Botrytis cinerea Isolates from Strawberry in Korea and Development of Detection Method for Benzimidazole Resistance.
Botrytis cinerea is a major fungal plant pathogen that causes gray mold disease in strawberries, leading to a decrease in strawberry yield. While benzimidazole is widely used as a fungicide for controlling this disease, the increasing prevalence of resistant populations to this fungicide undermines its effectiveness. To investigate benzimidazole resistant B. cinerea in South Korea, 78 strains were isolated from strawberries grown in 78 different farms in 2022, and their EC50 values for benzimidazole were examined. As a result, 64 strains exhibited resistance to benzimidazole, and experimental tests using detached strawberry leaves and the plants in a greenhouse confirmed the reduced efficacy of benzimidazole to control these strains. The benzimidazole resistant strains identified in this study possessed two types of mutations, E198A or E198V, in the TUB2 gene. To detect these mutations, TaqMan probes were designed, enabling rapid identification of benzimidazole resistant B. cinerea in strawberry and tomato farms. This study utilizes TaqMan real-time polymerase chain reaction analysis to swiftly identify benzimidazole resistant B. cinerea, thereby offering the possibility of effective disease management by identifying optimum locations and time of application.


Efficacy of lisdexamfetamine dimesylate for promoting occupational success in adolescents and young adults with attention-deficit/hyperactivity disorder.
There has been a lack of research on the third area of impairment noted in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-"occupational functioning." It is important to understand the impact of common treatments for attention-deficit/hyperactivity disorder (ADHD) in occupational settings. Twenty individuals with ADHD between ages 16 and 25 participated in a double-blind, placebo controlled evaluation of 40 mg lisdexamfetamine dimesylate in a setting designed to approximate a restaurant workplace with associated, simulated food delivery. Outcome measures included ratings of performance, as well as behavioral productivity. Results indicated that participants completed more workplace tasks when on medication, relative to placebo. Ratings of job application quality, job interview performance, and delivery outcomes were not significantly different on medication versus placebo. These results suggest positive effects of medication in a workplace environment, but also a need for study of additional interventions to support workplace-related behavior and functioning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Endoscopy and rectal enema for fecal collection in wild sea turtles (Chelonia mydas, Eretmochelys imbricata) in a field setting.
Forty-seven free-ranging sea turtles (46- Chelonia mydas, 1- Eretmochelys imbricata) were examined via novel use of an endoscopy combined with a rectal enema to obtain large fecal sample volumes. The cloaca was insufflated using an endoscope, after which the bladder and rectum separated, allowing access to the colon. Environmental conditions and location influenced the performance of the procedure initially, but after several attempts the procedure was successfully initiated. In all cases, fecal samples were obtained, and the animals were released to their respective locations. Fecal sample collection using this approach enhances the ability to obtain diagnostic information and perform other scientific analyses of sea turtles.


[Nerve growth factor system in health and disease].
The biological effects of nerve growth factors (NGF) against the cells of the nervous, endocrine, and immune systems and the possible role of protein as an integral component of molecular communications between the above systems are studied. Based on analysis of the author's own findings, it is suggested that the impairment of regulatory mechanisms which is typical of the pathogenesis of some nervous and mental diseases is caused by diseases or at least accompanied by changes in the NGF system.


Supplementing π-systems: eumelanin and graphene-like integration towards highly conductive materials for the mammalian cell culture bio-interface.
Organic (bio)electronics appears to be the first target for competitive exploitation in the materials science of eumelanins, black insoluble photoprotective human biopolymers. Nonetheless, the low conductivity of these pigments is limiting the implementation of eumelanin-based devices. Here we present a novel organic/organic hybrid material (EUGL) by integration of conductive graphene-like (GL) layers within the EUmelanin pigment (EU). GL layers were obtained by a two-step oxidation/reduction of carbon black. The stability of GL layers over a wide pH range and the self-assembling tendency place this material in a leading position for the fabrication of hybrid materials in aqueous media. EUGL was obtained by inducing the polymerization of eumelanin precursors (5,6-dihydroxyindole, DHI and 5,6-dihydroxyindole-2 carboxylic acid, DHICA) in aqueous media containing GL layers. The new material featured promising biocompatibility and an increased conductivity with respect to eumelanin by four orders of magnitude.


Isolated tricuspid valve stenosis--probably of rheumatic etiology.
Rheumatic heart disease is still a common cardiac disease in developing countries. Triscupid valve is not usually involved in RHD and whenever it is involved, it is always associated with mitral valve disease. We report a case of isolated tricuspid stenosis, most likely of rheumatic etiology.


Timing of renal replacement therapy initiation for acute kidney injury.
Acute kidney injury (AKI) is a common condition among patients in intensive care units (ICUs), and is associated with high death. Renal replacement therapy (RRT) is a blood purification technique used to treat the most severe forms of AKI. The optimal time to initiate RRT so as to improve clinical outcomes remains uncertain.This review complements another Cochrane review by the same authors: Intensity of continuous renal replacement therapy for acute kidney injury. To assess the effects of different timing (early and standard) of RRT initiation on death and recovery of kidney function in critically ill patients with AKI. We searched the Cochrane Kidney and Transplant's Specialised Register to 23 August 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We also searched LILACS to 11 September 2017. We included all randomised controlled trials (RCTs). We included all patients with AKI in ICU regardless of age, comparing early versus standard RRT initiation. For safety and cost outcomes we planned to include cohort studies and non-RCTs. Data were extracted independently by two authors. The random-effects model was used and results were reported as risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI). We included five studies enrolling 1084 participants. Overall, most domains were assessed as being at low or unclear risk of bias. Compared to standard treatment, early initiation may reduce the risk of death at day 30, although the 95% CI does not rule out an increased risk (5 studies, 1084 participants: RR 0.83, 95% CI 0.61 to 1.13; I2 = 52%; low certainty evidence); and probably reduces the death after 30 days post randomisation (4 studies, 1056 participants: RR 0.92, 95% CI 0.76 to 1.10; I2= 29%; moderate certainty evidence); however in both results the CIs included a reduction and an increase of death. Earlier start may reduce the risk of death or non-recovery kidney function (5 studies, 1076 participants: RR 0.83, 95% CI 0.66 to 1.05; I2= 54%; low certainty evidence). Early strategy may increase the number of patients who were free of RRT after RRT discontinuation (5 studies, 1084 participants: RR 1.13, 95% CI 0.91 to 1.40; I2= 58%; low certainty evidence) and probably slightly increases the recovery of kidney function among survivors who discontinued RRT after day 30 (5 studies, 572 participants: RR 1.03, 95% CI 1.00 to 1.06; I2= 0%; moderate certainty evidence) compared to standard; however the lower limit of CI includes the null effect. Early RRT initiation increased the number of patients who experienced adverse events (4 studies, 899 participants: RR 1.10, 95% CI 1.03 to 1.16; I2 = 0%; high certainty evidence). Compared to standard, earlier RRT start may reduce the number of days in ICU (4 studies, 1056 participants: MD -1.78 days, 95% CI -3.70 to 0.13; I2 = 90%; low certainty evidence), but the CI included benefit and harm. Based mainly on low quality of evidence identified, early RRT may reduce the risk of death and may improve the recovery of kidney function in critically patients with AKI, however the 95% CI indicates that early RRT might worsen these outcomes. There was an increased risk of adverse events with early RRT. Further adequate-powered RCTs using appropriate criteria to define the optimal time of RRT are needed to reduce the imprecision of the results.


The pathophysiology of amenorrhea in the adolescent.
Menstrual irregularity is a common occurrence during adolescence, especially within the first 2-3 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. Estrogen-deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen-replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities.


"Tandem" duplication of 4p16.1p16.3 chromosome region associated with 4p16.3pter molecular deletion resulting in Wolf-Hirschhorn syndrome phenotype.
Chromosome imbalance affecting the short arm of chromosome 4 results in a variety of distinct clinical conditions. Most of them share a number of manifestations, such as mental retardation, microcephaly, pre- and post-natal growth retardation, anteverted and low-set ears, that can be considered as nonspecific signs, generally attributable to gene dosage impairment. On the other hand, more distinctive phenotypic traits correlate with the segmental aneuploidy. Duplications of the distal half of 4p give rise to the partial trisomy 4 syndrome, characterized by a "boxer" nose configuration and deep-set eyes. These signs are usually observed even in cases of small terminal duplications. Haploinsufficiency of 4p16.3 results in the so-called Wolf-Hirschhorn (WH) syndrome, a contiguous gene syndrome characterized by maxillary hypoplasia, large and protruding eyes, high nasal bridge, skeletal abnormalities, and midline defects. The smallest overlapping deletion described so far as a cause of this condition is only 165 kb long, suggesting that one or a few genes in this region act as "master" regulators of different developmental pathways. A "tandem" duplication of 4p16.1p16.3 was detected in association with a subtle deletion of 4p16.3pter on the same chromosome in a patient with the WH phenotype. The 3.2 Mb deletion, spanning the genomic region from the vicinity of D4S43 to the telomere, encompasses the recently delimited "WHS critical region" [Wright et al., 1997: Hum. Mol. Genet. 6:317-324]. This unusual chromosome rearrangement resulted in WH phenotype, clinical manifestations of partial 4p trisomy being mild or absent. This observation led us to speculate that the regulatory gene/genes in the critical WH region affect the expression of other genes in a dose-dependent manner. Haploinsufficiency of this region could be more deleterious than various partial trisomies.


Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.
Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small-animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra-myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.


On the use of spleen mass as a measure of avian immune system strength.
The avian spleen has been frequently used in studies of avian ecology, parasitology, and evolution to infer immune system strength in birds. Traditionally, it has been assumed that a large spleen is representative of a strong immune system and conclusions based on this assumption have led to interesting interpretations of the role of disease and parasitism, for example in predator-prey interactions. This assumption of a positive relationship between spleen size and immune system strength has been made despite an incomplete understanding of the physiology of the avian spleen and little evidence of the validity of such an assumption. In this response, we demonstrate that the assumption of a predictable, positive relationship between spleen size and immunocompetence may be unjustified based on what is known of avian splenology. We also review recent research that may indicate that the inverse of the above assumption is true and we discuss general limitations of the use of the spleen as an indicator of immune system strength in birds. Finally, we make recommendations for future research topics in this field of study.


Investigating genetic links between grapheme-colour synaesthesia and neuropsychiatric traits.
Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme-colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.


Naturopathy as a Model of Prevention-Oriented, Patient-Centered Primary Care: A Disruptive Innovation in Health Care.
Background and Objective: The concept of a "disruptive innovation," recently extended to health care, refers to an emerging technology that represents a new market force combined with a new value system, that eventually displaces some, or all, of the current leading "stakeholders, products and strategic alliances." Naturopathy is a distinct system of traditional and complementary medicine recognized by the World Health Organization (WHO), emerging as a model of primary care. The objective here is to describe Naturopathy in the context of the criteria for a disruptive innovation. Methods: An evidence synthesis was conducted to evaluate Naturopathy as a potentially disruptive technology according to the defining criteria established by leading economists and health technology experts: (1) The innovation must cure disease; (2) must transform the way medicine is practiced; or (3) have an impact that could be disruptive or sustaining, depending on how it is integrated into the current healthcare marketplace. Results: The fact that Naturopathy de-emphasizes prescription drug and surgical interventions in favor of nonpharmacological health promotion and self-care could disrupt the present economic model that fuels health care costs. The patient-centered orientation of Naturopathy, combined with an emphasis on preventive behaviors and popular complementary and integrative health services like natural products, mind and body therapies, and other therapies not widely represented in current primary care models increase the likelihood for disruption. Conclusions: Because of its patient-centered approach and emphasis on prevention, naturopathy may disrupt or remain a durable presence in healthcare delivery depending on policymaker decisions.


Label-Free Assay of Protein Tyrosine Phosphatase Activity in Single Cells.
Populations of cells exhibit variations in biochemical activity, resulting from many factors including random stochastic variability in protein production, metabolic and cell-cycle states, regulatory mechanisms, and external signaling. The development of methods for the analysis of single cells has allowed for the measurement and understanding of this inherent heterogeneity, yet methods for measuring protein activities on the single-cell scale lag behind their genetic analysis counterparts and typically report on expression rather than activity. This paper presents an approach to measure protein tyrosine phosphatase (PTP) activity in individual cells using self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry. Using flow cytometry, individual cells are first sorted into a well plate containing lysis buffer and a phosphopeptide substrate. After lysis and incubation-during which the PTP enzymes act on the peptide substrate-the reaction substrate and product are immobilized onto arrays of self-assembled monolayers, which are then analyzed using mass spectrometry. PTP activities from thousands of individual cells were measured and their distributions analyzed. This work demonstrates a general method for measuring enzyme activities in lysates derived from individual cells and will contribute to the understanding of cellular heterogeneity in a variety of contexts.


Flow-induced dilation of rat soleus feed arteries.
Flow-induced dilation is thought to contribute to dilation of skeletal muscle arteries and arterioles during exercise hyperemia. We sought to determine whether rat soleus feed arteries (SFA) exhibit flow-induced dilation and to evaluate the potential contribution of flow-induced dilation of SFA to exercise hyperemia. Rat SFA were isolated and cannulated to allow pressure and intraluminal flow to be independently controlled. Intraluminal pressure was maintained at 90 cmH2O throughout the experiment. All SFA (n = 13) developed spontaneous tone and dilated in response to flow. Flow of 10 and 14 microliters/min produced a 34 +/- 14 and 56 +/- 17 microns increase above basal diameter (135 +/- 12 microns), respectively. Flows > 14 microliters/min produced little further dilation. Maximum flow-induced dilation was 86 +/- 3% of passive diameter determined in calcium-free physiological saline solution. Calculated shear stress was maintained at 4-6 dyn/cm2 at flows of 10-20 microliters/min but increased at greater flows because SFA did not dilate further. To determine whether dilation in response to flows in this range may contribute to exercise hyperemia, we estimated in vivo SFA blood flows from previously published soleus blood flow data. Anesthetized rats are estimated to have flows of 10 microliters/min per SFA, and conscious rats are estimated to have flows of 95 (nonexercising), 153 (walking), and 225 (running) microliters/min per SFA. Corresponding shear stresses were estimated to be 26 (anesthetized), 47 (conscious, nonexercising), 75 (walking), and 111 (running) dyn/cm2. Because estimated in vivo values for both flow and wall shear stress are far greater than the flow and/or shear stresses at which maximal flow-induced dilation occurs in vitro, we conclude that flow-induced dilation contributes little to dilation of SFA during locomotory exercise.


Regulation and role of the ER stress transcription factor CHOP in alveolar epithelial type-II cells.
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp1) in MLE12 cells did not result in a substantial Chop induction, as compared to the ER stress inducer thapsigargin. Employing reporter gene assays of distinct CHOP promoter fragments, we could identify that, next to the conventional amino acid (AARE) and ER stress response elements (ERSE) within the CHOP promoter, activator protein-1 (AP-1) and c-Ets-1 TF binding sites are necessary for CHOP induction. Serial deletion and mutation analyses revealed that both AP-1 and c-Ets-1 motifs act in concert to induce CHOP expression. In agreement, CHOP promoter activity was greatly enhanced upon combined versus single overexpression of AP-1 and c-Ets-1. Moreover, combined overexpression of AP-1 and c-Ets-1 in MLE12 cells alone in the absence of any other ER stress inducer was sufficient to induce Chop protein expression. Further, AP-1 and c-Ets-1 were upregulated in AECII under ER stress conditions and in human IPF. Finally, Chop overexpression in vitro resulted in AECII apoptosis, lung fibroblast proliferation, and collagen-I production. We propose that CHOP activation by AP-1 and c-Ets-1 plays a key role in AECII maladaptive ER stress responses and consecutive fibrosis, offering new therapeutic prospects in IPF. KEY MESSAGES: Overexpression of active ER stress sensors Atf4, Atf6, and Xbp1 does not induce Chop. AP-1 and c-Ets-1 TFs are necessary for induction of the ER stress factor Chop. AP-1 and c-Ets-1 alone induce Chop expression in the absence of any ER stress inducers. AP-1 and c-Ets-1 are induced in AECII under ER stress conditions and in human IPF. Chop expression alone triggers AECII apoptosis and consecutive profibrotic responses.


Discovery of the 'porosome'; the universal secretory machinery in cells.
The release of neurotransmitters at the nerve terminal for neurotransmission, release of insulin from beta-cells of the endocrine pancreas for regulating blood glucose levels, the release of growth hormone from GH cells of the pituitary gland to regulate body growth, or the expulsion of zymogen from exocrine pancreas to digest food, are only a few examples of key physiological processes made possible by cell secretion. It comes as no surprise that defects in cell secretion are the cause for numerous diseases, and have been under intense investigation for over half century. Only in the last decade, the molecular machinery and mechanism of cell secretion has become clear. Cell secretion involves the docking and transient fusion of membrane-bound secretory vesicles at the base of plasma membrane structures called porosomes, and the regulated expulsion of intravesicular contents to the outside, by vesicle swelling. The discovery of the porosome in live cells, its morphology and dynamics at nanometer resolution and in real time, its isolation, its composition, and its structural and functional reconstitution in lipid membrane, are complete. The molecular mechanism of secretory vesicle fusion at the base of porosomes, and the regulated expulsion of intravesicular contents during cell secretion, are also resolved. In this minireview, the monumental discovery of the porosome, a new cellular structure at the cell plasma membrane, is briefly discussed.


Metal ions in enzymes using ammonia or amides.
In an attempt to understand the role of nickel in jack bean urease (1), we turned to a variety of other enzymes important in the utilization, production, or transfer of ammonia. We found several, including the L-histidine and L-phenylalanine ammonialyases and some enzymes that utilize glutamine or ammonia in amidotransferase reactions, all of which show evidence for the involvement of as yet unreported transition metal ions in their mechanism of action. We support the view that catalysis by metalloenzymes may be a reflection of the chemistry of the metal ion itself as a Lewis acid, and that perhaps too much emphasis has been placed on supposed special characteristics (such as strains, "entasis") of the enzyme-metal ion association. In this context, we have discussed the mechanism of catalysis of hydrolysis of specific substrates by carboxypeptidase A, and have returned to urease to examine the role of nickel in its mechanism of action.


Subthreshold micropulse laser reduces anti-VEGF injection burden in patients with diabetic macular edema.
To evaluate the efficacy of micropulse laser in the early treatment of diabetic macular edema (DME) and its associated burden of anti-vascular endothelial growth factor (VEGF) injections. This retrospective comparative study compared a group of 19 eyes with DME treated with micropulse laser to a matched control group of 19 eyes with DME treated with ranibizumab injections without micropulse laser. Recorded parameters included previous medical and ocular history, previous and subsequent ranibizumab injections administered for DME, visual acuity (VA), central macular thickness throughout the follow-up period, and the occurrence of any complications. The improvement in VA was comparable in both groups, at 12 months and at the final follow-up. Patients treated with micropulse laser required significantly fewer ranibizumab injections than their controls, both at 12 months (1.7 ± 2.3 vs 5.6 ± 2.1) and by the end of the follow-up (2.6 ± 3.3 vs 9.3 ± 5.1) (p<0.001 for both). No complications related to the micropulse laser were encountered. Micropulse laser is a safe and effective treatment for DME, which may achieve comparable improvement in VA along with a significant reduction in the burden of anti-VEGF injections. We suggest a treatment approach for its inclusion in the early stages of DME.


Retinal breaks in vitrectomy for retained lens fragments.
To describe the incidence and outcome of retinal breaks in vitrectomy for retained lens fragments. This is a retrospective noncomparative interventional case series. Medical records of consecutive cases of vitrectomy for retained lens fragments over a period of 4 years were reviewed. Main outcome measures were incidence of breaks, visual acuity outcome, and occurrence of postoperative complications. We included 89 consecutive cases in 89 patients. The median interval between cataract surgery and vitrectomy was 2 days (range, 0-106 days). Visual acuity at last follow-up was ≥ 0.5 in 70% of cases. During surgery, retinal breaks were found in 29% of cases. Induction of a posterior vitreous detachment, the use of a fragmatome, or delay between cataract surgery and vitrectomy did not influence retinal break incidence. Postoperative retinal detachment occurred in only 2% of cases. Other complications were intraoperative choroidal hemorrhage in 1 case, postoperative macular pucker in 2, postoperative macular edema in 1, and glaucoma in 2 cases. We identified a high number of retinal breaks during vitrectomy for retained lens fragments. Prophylactic treatment of breaks and other areas of retinal traction seem to reduce the risk of postoperative retinal detachment.


Further evidence of close correspondence for alcohol demand decision making for hypothetical and incentivized rewards.
Alcohol purchase tasks (APTs) are increasingly being used to assess behavioral economic demand for alcohol. Prior studies utilizing APTs have typically assessed demand for hypothetical outcomes, making the extent to which these hypothetical measures reflect preferences when actual rewards are at stake an important empirical question. This study examined alcohol demand across hypothetical and incentivized APTs. Nineteen male heavy drinkers completed two APTs - one for hypothetical alcohol and another in which one randomly-selected outcome was provided. Participants were given an opportunity to consume the alcohol associated with their choice on the incentivized APT during a self-administration period in a simulated bar environment. Results indicated generally close correspondence between APT versions, though participants were more sensitive to increases in price and tended to consume more at low prices on the incentivized version. Estimated consumption on the incentivized APT was highly correlated with the amount of alcohol consumed in the laboratory (r=.87, p<.001), suggesting that APT responses are valid indicators of actual drinking behavior. These results provide further evidence of congruence of demand-based decision-making when rewards are hypothetical vs. actually available. Implications for behavioral economic approaches to addictive behavior and directions for future research are discussed.


First-line treatment of chronic lymphocytic leukemia: role of alemtuzumab.
The CD52-targeting antibody alemtuzumab is established in clinical practice with convincing activity in relapsed and refractory chronic lymphocytic leukemia (CLL), particularly in patients with high-risk features and adverse prognosis. In the CAM307 study alemtuzumab was tested and finally approved as a first-line single agent, even though the hurdle with chlorambucil as the contender was not set very high. Within clinical trials, the drug demonstrated an excellent ability to eliminate minimal residual disease in blood and bone marrow, which has been correlated with a corresponding survival advantage in patients. However, in the maintenance setting, infectious complications due to severe T cell suppression have been highlighted and do not allow clinicans to use alemtuzumab outside of clinical trials. This review discusses potential therapeutic niches and future applications of alemtuzumab with a focus on CLL front-line treatment.


Involvement of C2H2 zinc finger proteins in the regulation of epidermal cell fate determination in Arabidopsis.
Cell fate determination is a basic developmental process during the growth of multicellular organisms. Trichomes and root hairs of Arabidopsis are both readily accessible structures originating from the epidermal cells of the aerial tissues and roots respectively, and they serve as excellent models for understanding the molecular mechanisms controlling cell fate determination and cell morphogenesis. The regulation of trichome and root hair formation is a complex program that consists of the integration of hormonal signals with a large number of transcriptional factors, including MYB and bHLH transcriptional factors. Studies during recent years have uncovered an important role of C2H2 type zinc finger proteins in the regulation of epidermal cell fate determination. Here in this minireview we briefly summarize the involvement of C2H2 zinc finger proteins in the control of trichome and root hair formation in Arabidopsis.


Deciphering phylogenetic relationships of and delimiting species boundaries within the controversial ciliate genus Conchophthirus using an integrative morpho-evo approach.
The phylum Ciliophora (ciliates) comprises about 2600 symbiotic and over 5500 free-living species. The inclusion of symbiotic ciliates in phylogenetic analyses often challenges traditional classification frameworks due to their morphological adaptions to the symbiotic lifestyle. Conchophthirus is such a controversial obligate endocommensal genus whose affinities to other symbiotic and free-living scuticociliates are still poorly understood. Using uni- and multivariate morphometrics as well as 2D-based molecular and phylogenetic analyses, we attempted to test for the monophyly of Conchophthirus, study the boundaries of Conchophthirus species isolated from various bivalves at mesoscale, and reveal the phylogenetic relationships of Conchophthirus to other scuticociliates. Multidimensional analyses of morphometric and cell geometric data generated the same homogenous clusters, as did phylogenetic analyses based on 144 new sequences of two mitochondrial and five nuclear molecular markers. Conchophthirus is not closely related to 'core' scuticociliates represented by the orders Pleuronematida and Philasterida, as assumed in the past using morphological data. Nuclear and mitochondrial markers consistently showed the free-living Dexiotricha and the mouthless endosymbiotic Haptophrya to be the nearest relatives of Conchophthirus. These three highly morphologically and ecologically dissimilar genera represent an orphan clade from the early radiation of scuticociliates in molecular phylogenies.


Nasal High-flow Oxygen Versus Conventional Oxygen Therapy for Acute Severe Asthma Patients: A Pilot Randomized Controlled Trial.
Nasal high flow (NHF) has demonstrated efficacy in relieving dyspnea in various patients with hypoxemic and hypercapnic respiratory failure. It may also reduce dyspnea in patients with acute severe asthma in the emergency department (ED). The aim of the study was to compare the efficacy of NHF with conventional oxygen therapy (COT) in improving dyspnea in acute severe asthma patients with hypoxemia in the ED. This pilot nonblinded randomized controlled trial was conducted involving 37 patients aged ≥ 18 years with acute severe asthma and hypoxemia in the ED of Siriraj Hospital, Bangkok, Thailand (TCTR20180926003). The participants were randomly allocated to receive either COT (n = 18) or NHF (n = 19) for 120 minutes. The primary outcome was comparing the intervention effects on the patients' degree of dyspnea measured using the modified Borg scale (MBS). The secondary outcomes were comparing the interventions based on the numeric rating scale (NRS) of dyspnea, the dyspnea scale assessing accessory muscle use, vital signs, and blood gas results. The intention-to-treat analysis included 37 patients (COT group n = 18 and NHF group n = 19). The baseline mean MBS was 7.8 in both groups. At 120 minutes, the mean (±SD) MBSs in patients receiving COT and NHF were 3.3 (±2.5) and 1.4 (±2.5), respectively (mean difference = 1.9 [95% CI = 0.2 to 3.8], p = 0.043). The trends in NRS and dyspnea score results were similar to those of MBS. Respiratory rates were lower with NHF (mean difference = 4.7 [95% CI = 1.5 to 7.8], p = 0.001). No between- or within-group differences in blood gas results were found. Nasal high flow reduced the severity of dyspnea and respiratory rate in hypoxemic patients with acute severe asthma in the ED.


Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure.
Antimicrobial peptides are endogenous antibiotics that directly inactivate microorganisms and in addition have a variety of receptor-mediated functions. LL-37/hCAP-18 is the only cathelicidin found in humans and is involved in angiogenesis and regulation of the innate immune system. The aim of the present study was to characterize the role of the peptide LL-37 in the regulation of wound closure of the airway epithelium in the cell line NCI-H292 and primary airway epithelial cells. LL-37 stimulated healing of mechanically induced wounds in monolayers of the cell line and in differentiated primary airway epithelium. This effect was detectable at concentrations of 5 mug/ml in NCI-H292 and 1 mug/ml in primary cells. The effect of LL-37 on wound healing was dependent on the presence of serum. LL-37 induced cell proliferation and migration of NCI-H292 cells. Inhibitor studies in the wound closure and proliferation assays indicated that the effects caused by LL-37 are mediated through epidermal growth factor receptor, a G protein-coupled receptor, and MAP/extracellular regulated kinase. In conclusion, LL-37 induces wound healing, proliferation, and migration of airway epithelial cells. The peptide is likely involved in the regulation of tissue homeostasis in the airways.


Scanning laser ophthalmoscopy in the early diagnosis of vitreoretinal interface syndrome.
The purpose of this study was to estimate if and to what extent scanning laser ophthalmoscopy can help in the early diagnosis and follow-up management of the vitreoretinal interface syndrome, which includes disorders such as cellophane maculopathy, pseudomacular hole, macular pucker, and macular hole. The 35 fellow eyes of 35 patients with vitreoretinal interface syndromes in the first eye underwent scanning laser ophthalmoscopy microperimetry and argon, helium-neon, and infrared scanning laser ophthalmoscopy. Fellow eyes were defined as clinically positive or negative for vitreoretinal interface syndrome. Fellow eyes then were classified based on scanning laser ophthalmoscopy techniques. Patients were observed for an average of 18 months (range, 10-26 months). Thirty-two of the 35 fellow eyes were classified as clinically negative, and three of the 35 were classified as clinically positive. Fifteen of the 32 clinically negative fellow eyes were redefined as positive on scanning laser ophthalmoscopy. None of the clinically positive eyes proved to be negative on scanning laser ophthalmoscopy. During the average follow-up period (18 months), the condition of five of 18 fellow eyes that were positive on scanning laser ophthalmoscopy worsened. None of the 17 eyes that were negative on scanning laser ophthalmoscopy worsened. Scanning laser ophthalmoscopy can produce beautifully clear images of structures that are otherwise difficult to see and document, such as posterior hyaloid and the inner retinal layers. Despite a relatively limited number of cases and the short duration of the follow-up period, the present study suggests that scanning laser ophthalmoscopy has good sensitivity and specificity for the early diagnosis of vitreoretinal interface syndromes.


Preliminary clinical observations on the use of piroxicam in the management of rectal tubulopapillary polyps.
Rectal tubulopapillary polyps were diagnosed in eight dogs following proctoscopy and mucosal pinch biopsy. Histological examination of the pinch biopsies revealed evidence of malignant transformation in three of the cases. The remaining cases were diagnosed as benign polyps. Inflammatory changes were observed in four cases. Seven dogs were treated with piroxicam suppositories and one with oral piroxicam. All dogs were re-examined after four to six weeks of piroxicam therapy and the extent of haematochezia, tenesmus and faecal mucus production was reduced in all cases. The owners of seven of the dogs considered the improvement in clinical signs to be good or excellent. Cases with and without evidence of inflammation responded equally well. This finding supports the hypothesis that piroxicam has an antineoplastic effect due to apoptosis and alteration in the cell cycle. Medical management with piroxicam may provide a non-invasive treatment option for dogs with rectal polyp formation in which surgical treatment is likely to be associated with complications such as incontinence, infection and wound breakdown, or where the owner declines such treatment.


Determinants of institutional delivery among young married women in Nepal: Evidence from the Nepal Demographic and Health Survey, 2011.
To identify the determinants of institutional delivery among young married women in Nepal. Nepal Demographic and Health Survey (NDHS) data sets 2011 were analysed. Bivariate and multivariate logistic regression analyses were performed using a subset of 1662 ever-married young women (aged 15-24 years). Place of delivery. The rate of institutional delivery among young married women was 46%, which is higher than the national average (35%) among all women of reproductive age. Young women who had more than four antenatal care (ANC) visits were three times more likely to deliver in a health institution compared with women who had no antenatal care visit (OR: 3.05; 95% CI: 2.40 to 3.87). The probability of delivering in an institution was 69% higher among young urban women than among young women who lived in rural areas. Young women who had secondary or above secondary level education were 1.63 times more likely to choose institutional delivery than young women who had no formal education (OR: 1.626; 95% CI: 1.171 to 2.258). Lower use of a health institution for delivery was also observed among poor young women. Results showed that wealthy young women were 2.12 times more likely to deliver their child in an institution compared with poor young women (OR: 2.107; 95% CI: 1.53 to 2.898). Other factors such as the age of the young woman, religion, ethnicity, and ecological zone were also associated with institutional delivery. Maternal health programs should be designed to encourage young women to receive adequate ANC (at least four visits). Moreover, health programs should target poor, less educated, rural, young women who live in mountain regions, are of Janajati ethnicity and have at least one child as such women are less likely to choose institutional delivery in Nepal.


Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth.
The clinical success of the nucleoside analogs 5-aza-cytidine (5-azaC) and 5-aza-2'deoxycytidine (5-aza-dC) as DNA methyltransferase (DNMT) inhibitors has spurred interest in the development of non-nucleoside inhibitors with improved pharmacologic and safety profiles. Because DNMT catalysis features attack of cytosine bases by an enzyme thiol group, we tested whether disulfiram (DSF), a thiol-reactive compound with known clinical safety, demonstrated DNMT inhibitory activity. Inhibition of DNMT1 activity by DSF was assessed using methyltransferase activity assays with recombinant DNMT1. Next, prostate cancer cell lines were exposed to DSF and assessed for: i) reduction of global 5-methyl cytosine ((5me)C) content using liquid chromatography/tandem mass spectrometry (LC-MS/MS); ii) gene-specific promoter demethylation by methylation-specific PCR (MSP); and iii) gene-reactivation by real-time RT-PCR. DSF was also tested for growth inhibition using prostate cancer cell lines propagated in vitro in cell culture and in vivo as xenografts in nude mice. Disulfiram showed a dose-dependent inhibition of DNMT1 activity on a hemimethylated DNA substrate. In prostate cancer cells in culture, DSF exposure led to reduction of global genomic (5me)C content, increase in unmethylated APC and RARB gene promoters, and associated re-expression of these genes, but did not significantly alter prostate-specific antigen (PSA) expression. DSF significantly inhibited growth and clonogenic survival of prostate cancer cell lines in culture and showed a trend for reduced growth of prostate cancer xenografts. Disulfiram is a non-nucleoside DNMT1 inhibitor that can reduce global (5me)C content, reactivate epigenetically silenced genes, and significantly inhibit growth in prostate cancer cell lines.


Gonorrhea and Chlamydia in emergency departments: screening, diagnosis, and treatment.
Failure to screen sexually active adolescents and adults for gonorrhea and chlamydia at the time of acute care visits to urban emergency departments (ED) results in missed treatment opportunities for 38% to 82% of infected persons. The prevalence of gonorrhea and chlamydia infections among ED patients presenting with genitourinary or pregnancy-related complaints or providing urine specimens as part of routine medical care ranges from 4.3% to 16.4%. Notably, prevalence among general ED patients is similar (9.7%-14.3%). Due to the asymptomatic or nonspecific presentation of these infections, expanded screening is recommended to increase detection, treatment, and partner notification. A lower threshold of empiric treatment in the ED setting is recommended due to the difficulty and incompleteness of follow-up subsequent to ED discharge. Specific recommendations to improve the quality of ED care for sexually transmitted infections and to expand detection are provided.


Associations between level and change in physical function and brain volumes.
Higher levels of fitness or physical function are positively associated with cognitive outcomes but the potential underlying mechanisms via brain structure are still to be elucidated in detail. We examined associations between brain structure and physical function (contemporaneous and change over the previous three years) in community-dwelling older adults. Participants from the Lothian Birth Cohort 1936 (N=694) underwent brain MRI at age 73 years to assess intracranial volume, and the volumes of total brain tissue, ventricles, grey matter, normal-appearing white matter, and white matter lesions. At ages 70 and 73, physical function was assessed by 6-meter walk, grip strength, and forced expiratory volume. A summary 'physical function factor' was derived from the individual measures using principal components analysis. Performance on each individual physical function measure declined across the three year interval (p<0.001). Higher level of physical function at ages 70 and 73 was associated with larger total brain tissue and white matter volumes, and smaller ventricular and white matter lesion volumes (standardized β ranged in magnitude from 0.07 to 0.17, p<0.001 to 0.034). Decline in physical function from age 70 to 73 was associated with smaller white matter volume (0.08, p<0.01, though not after correction for multiple testing), but not with any other brain volumetric measurements. Physical function was related to brain volumes in community-dwelling older adults: declining physical function was associated with less white matter tissue. Further study is required to explore the detailed mechanisms through which physical function might influence brain structure, and vice versa.


Intracanalicular Vestibular Schwannoma: A Systematic Review and Meta-analysis of Therapeutics Outcomes.
To perform a systematic review and meta-analysis summarizing the current evidence on the management of intracanalicular vestibular schwannoma. Embase (1947-), Medline (1946-), Cochrane library (1947-), Scopus (2010-), and CINAHL (1961-) were searched from 1969 to October 5, 2019 (50 years). A search strategy was performed to identify patients with vestibular schwannoma confined to the internal auditory canal without extension to the cerebellopontine angle. Studies with patients aged less than 18, Neurofibromatosis type 2, revision cases, and non-English language were excluded. A standardized collection sheet was used for the extracted data and a quality assessment was performed using the Newcastle-Ottawa Scale with the comparability criterion omitted. Seventy-one studies were included with 24 on observation, 14 on radiotherapy, and 34 on surgery. The primary outcome was serviceable hearing preservation. Secondary outcomes were preservation of facial nerve function, growth, involution, and dizziness. Sub-analysis on the type of surgery and type of radiotherapy were performed. Excel 2016 with MIX 2.0 Pro add-on package was used to analyze the data and create forest plots. Data were presented in proportion with a 95% confidence interval. Serviceable hearing was observed in 31% of patients after observation, 56% after radiotherapy, and 51% after surgical treatment with mean follow-up time of 4.04 years, 4.92 years, and 2.23 years, respectively. Facial nerve function was found to be best preserved in both observation and radiotherapy groups. Vestibular schwannoma growth occurred in 33% of patients under observation. Involution occurred in 2% of patients under observation and in 38% after radiotherapy.


T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.
T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αβT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.


Pharmacogenomics of 4-hydroxycoumarin anticoagulants.
Oral anticoagulants of the 4-hydroxycoumarin class, typified by warfarin, are used worldwide to treat thromboembolic disease. These drugs show the beneficial attributes of high efficacy and low cost, but patient management can be complicated by their narrow therapeutic index and wide inter-individual variability in dosing. Our understanding of the latter complication has improved significantly in recent years due to intense investigation of genetic factors influencing drug pharmacokinetics (CYP2C9) and pharmacodynamic response (VKORC1). In particular, the discovery of polymorphisms in the VKORC1 gene that strongly impact oral anticoagulant dose has heightened expectations that genetic testing for a relatively small cadre of warfarin-response genes might substantially enhance patient care in this area, especially during the initiation phase of therapy. However, enthusiasm for genotype-based dosing of oral anticoagulants must be balanced against the ready availability of both a simple phenotypic test (prothrombin time) and an antidote to over-anticoagulation (vitamin K). Wide-spread acceptance of genetically based tests for establishing therapy with warfarin and its congeners will likely require additional evidence that such an approach offers protection against a variety of negative anticoagulation outcomes, especially severe bleeding, as well as offering utility across many racial populations. This article will review recent events in these and other related areas.


Immunostimulatory properties of genomic DNA from different bacterial species.
Bacterial DNA has potent immunological properties because of its content of immunostimulatory sequences centering on CpG motifs. To investigate whether DNA from various bacterial species differ in these properties, the activity of a panel of DNA was assessed in in vitro cultures of murine spleen cells. This panel varied in base composition and included DNA from Clostridium perfringens (CP), Escherichia coli (EC), Micrococcus lysodeikticus (MC), Staphylococcus aureus (SA), and, as a mammalian DNA control, calf thymus (CT) DNA. In assays of IL-12 and IFN-gamma production as well as B cell mitogenesis, these DNA showed marked differences in their immunostimulatory activity. For both cytokine and B cell responses, EC DNA demonstrated the highest activity while CP DNA had the lowest activity among the bacterial DNA. To determine whether differences in stimulatory capacity resulted from differences in cell uptake, the activity of DNA complexed with lipofectin was tested. While the addition of lipofectin to DNA increased stimulation by all DNA, it did not change the relative potency of the DNA tested. These results indicate that bacterial DNA differ in their immunostimulatory capacity, most likely reflecting their content of CpG motifs. These differences could affect the induction of innate immunity as well as the consequences of infection.


Early-term effect of adult chondrocyte transplantation in an osteoarthritis animal model.
In this study, we investigated the efficacy of the transplantation of autologous articular chondrocytes seeded onto a hyaluronan-based scaffold, known as Hyaff(®)-11, on the treatment of early cartilage lesions in a rabbit osteoarthritis (OA) model. The hypothesis of the study was that this treatment could enhance cartilage repair after OA induction. OA was surgically induced by Anterior Cruciate Ligament Transection (ACLT) in thirty rabbits. Animals were divided into three groups, according to treatment: group 1: ACLT; group 2: Chondrocytes+Hyaff-11; and group 3: Hyaff-11 alone. The animals were euthanized, respectively, at 3 and 6 months after the treatment. Histomorphometrical analyses were performed by means of fibrillation index, cartilage thickness, and subchondral bone thickness evaluations. Histological appearance was scored according to Modified Kraus' Mankin and Osteoarthritis Research Society International (OARSI) scores. Immunohistochemical analyses were carried out for type I and II collagens, MMP-1, and MMP-3. A comparison between groups and follow-up for each outcome was performed with the general linear model with Sidak correction. Histomorphometrical evaluations at 3 and 6 months demonstrated that OA lesions became significantly worse followed by Hyaff-11 treatment, whereas Chondrocytes+Hyaff-11 treatment had the best overall subjective grade. Overall raw histological scores demonstrated a significant improvement with chondro-hyaluronic acid (HA) treatment at 3 months compared with HA in cartilage repair processes. Immunohistochemical analyses displayed a strong positivity for type II collagen in the Chondrocytes+Hyaff-11group at 3 months compared with the HA group. No staining was observed in MMP-3 expression in this group at any experimental point. The use of Chondrocytes+Hyaff-11 for the treatment of early OA lesions produced, already at 3 months, a repair tissue showing better macroscopic, histological, and immunohistochemical results than those observed after Hyaff-11 treatment. Thus, the transplantation of Chondrocytes+Hyaff-11 would seem to be advocated in the very early stage of the OA disease when a precocious action is mandatory.


Multiscale cancer modeling.
Simulating cancer behavior across multiple biological scales in space and time, i.e., multiscale cancer modeling, is increasingly being recognized as a powerful tool to refine hypotheses, focus experiments, and enable more accurate predictions. A growing number of examples illustrate the value of this approach in providing quantitative insights in the initiation, progression, and treatment of cancer. In this review, we introduce the most recent and important multiscale cancer modeling works that have successfully established a mechanistic link between different biological scales. Biophysical, biochemical, and biomechanical factors are considered in these models. We also discuss innovative, cutting-edge modeling methods that are moving predictive multiscale cancer modeling toward clinical application. Furthermore, because the development of multiscale cancer models requires a new level of collaboration among scientists from a variety of fields such as biology, medicine, physics, mathematics, engineering, and computer science, an innovative Web-based infrastructure is needed to support this growing community.


Levels of Physical Activity and Physical Fitness in Pediatric Pacemaker Patients: A Cross-Sectional Study.
Children with heart diseases have reduced physical activity (PA) levels relative to their peers, which in turn increases cardiovascular risk. To the best of our knowledge, physical fitness and objectively measured PA levels have not been previously studied in children with pacemakers. We evaluated PA levels and physical fitness in pediatric pacemaker patients compared to their healthy peers. Twenty-eight pediatric patients with pacemakers (15 female, 13 male; mean age 13.43 ± 3.68 years) and 24 healthy subjects (14 female, 10 male; mean age 13.08 ± 3.67 years) were included. Physical fitness was assessed using the Munich Fitness Test (MFT). SenseWear Armband metabolic Holter device was used to record the PA for 7 consecutive days. MFT total and sub-parameter scores were significantly lower in the patient group (p < 0.05). Patients' total and active energy expenditure, PA level, total distance, number of steps, and vigorous PA were significantly lower than those of healthy children (p < 0.05). Sedentary activity and light, moderate, and very vigorous PA durations were similar in both groups (p > 0.05). Duration of mean moderate to vigorous PA was higher than 60 min/day recommended in PA guidelines in both patients and healthy subjects. These results provide initial data on PA and fitness in children with pacemakers and suggest that physical fitness and activity levels in children with pacemakers are lower than in healthy peers. Appropriate exercise programs may improve PA levels in pediatric pacemaker patients. Awareness of the importance of PA should be raised among the parents and families of these children.


Impact of health risk factors on healthcare resource utilization, work-related outcomes and health-related quality of life of Australians: a population-based longitudinal data analysis.
Health risk factors, including smoking, excessive alcohol consumption, overweight, obesity, and insufficient physical activity, are major contributors to many poor health conditions. This study aimed to assess the impact of health risk factors on healthcare resource utilization, work-related outcomes and health-related quality of life (HRQoL) in Australia. We used two waves of the nationally representative Household, Income, and Labor Dynamics in Australia (HILDA) Survey from 2013 and 2017 for the analysis. Healthcare resource utilization included outpatient visits, hospitalisations, and prescribed medication use. Work-related outcomes were assessed through employment status and sick leave. HRQoL was assessed using the SF-6D scores. Generalized estimating equation (GEE) with logit or log link function and random-effects regression models were used to analyse the longitudinal data on the relationship between health risk factors and the outcomes. The models were adjusted for age, sex, marital status, education background, employment status, equilibrium household income, residential area, country of birth, indigenous status, and socio-economic status. After adjusting for all other health risk factors covariates, physical inactivity had the greatest impact on healthcare resource utilization, work-related outcomes, and HRQoL. Physical inactivity increased the likelihood of outpatient visits (AOR = 1.60, 95% CI = 1.45, 1.76 p < 0.001), hospitalization (AOR = 1.83, 95% CI = 1.66-2.01, p < 0.001), and the probability of taking sick leave (AOR = 1.31, 95% CI = 1.21-1.41, p < 0.001), and decreased the odds of having an above population median HRQoL (AOR = 0.48, 95% CI = 0.45-0.51, p < 0.001) after adjusting for all other health risk factors and covariates. Obesity had the greatest impact on medication use (AOR = 2.02, 95% CI = 1.97-2.29, p < 0.001) after adjusting for all other health risk factors and covariates. Our study contributed to the growing body of literature on the relative impact of health risk factors for healthcare resource utilization, work-related outcomes and HRQoL. Our results suggested that public health interventions aim at improving these risk factors, particularly physical inactivity and obesity, can offer substantial benefits, not only for healthcare resource utilization but also for productivity.


Identification of the dynamics of time-varying phase aberrations from time histories of the point-spread function.
To optimally compensate for time-varying phase aberrations with adaptive optics, a model of the dynamics of the aberrations is required to predict the phase aberration at the next time step. We model the time-varying behavior of a phase aberration, expressed in Zernike modes, by assuming that the temporal dynamics of the Zernike coefficients can be described by a vector-valued autoregressive (VAR) model. We propose an iterative method based on a convex heuristic for a rank-constrained optimization problem, to jointly estimate the parameters of the VAR model and the Zernike coefficients from a time series of measurements of the point-spread function (PSF) of the optical system. By assuming the phase aberration is small, the relation between aberration and PSF measurements can be approximated by a quadratic function. As such, our method is a blind identification method for linear dynamics in a stochastic Wiener system with a quadratic nonlinearity at the output and a phase retrieval method that uses a time-evolution-model constraint and a single image at every time step.


En Route Critical Care Transfer From a Role 2 to a Role 3 Medical Treatment Facility in Afghanistan.
En route care is the transfer of patients requiring combat casualty care within the US military evacuation system. No reports have been published about en route care of patients during transfer from a forward surgical facility (role 2) to a combat support hospital (role 3) for comprehensive care. To describe patients transferred from a role 2 to a role 3 US military treatment facility in Afghanistan. A retrospective review of data from the Joint Trauma System Role 2 Database was conducted. Patient characteristics were described by en route care medical attendants. More than one-fourth of patients were intubated at transfer (26.9%), although at transfer fewer than 10% of patients had a base deficit of more than 5 (3.5%), a pH of less than 7.3 (5.2%), an international normalized ratio of more than 2 (0.8%), or temporary abdominal or chest closure (7.4%). The en route care medical attendant was most often a nurse (35.5%), followed by technicians (14.1%) and physicians (10.0%). Most patients (75.3%) were transported by medical evacuation (on rotary-wing aircraft). This is the first comprehensive review of patients transported from a forward surgical facility to a more robust combat support hospital in Afghanistan. Understanding the epidemiology of these patients will inform provider training and the appropriate skill mix for the transfer of postsurgical patients within a combat setting.


Self-management of heart failure in dementia and cognitive impairment: a systematic review.
The cornerstone of effective management in heart failure (HF) is the ability to self-care. Aims include i) To determine factors influencing self-care in HF patients with cognitive impairment (CI) and ii) to determine the influence of cognitive domains on self-care in patients with HF and CI. MEDLINE, CINAHL, EMBASE, EBSCOHost, PsychINFO, ProQuest Research Library, Health Technology Assessment Database, The Cochrane Library, Web of Science and Scopus databases were systematically searched. Original research describing the relationship between cognition and HF self-care in community-dwelling older persons with dementia/CI in English, published in a peer-reviewed journal from 1stJanuary(2000)-22ndMarch(2016) was identified. Study and population characteristics, data sources, self-care processes, methods of cognitive assessment, cognitive domains affected, study outcomes, impact of impairment, and other risk factors of self-care impairment were abstracted by two reviewers. Of 10,688 studies identified, 14 met the inclusion criteria. Patients with HF and CI ranged from 14 to 73%. Where reported, self-care maintenance adequacy ranged from 50 to 61%; self-care management adequacy ranged from 14 to 36% and self-care confidence adequacy ranged from 0 to 44% on the Self-care of Heart Failure Index (SCHFI). All but one study predicted poor self-care ability according to poor outcome on cognitive testing. Additionally, specific cognitive domain deficits impaired self-care. Subjects with lower cognitive scores were less likely to seek assistance while subjects with depression had poor self-care abilities. Clinicians must consider the type and severity of impairments in cognitive domains to tailor management. Awareness of depression, self-confidence and support access may modulate self-care ability.


Immune control of SV40-induced tumors in mice.
The ability of mice to mount a cytotoxic T-lymphocyte (CTL) immune response to SV40 T-antigen is determined by the H-2 haplotype of the host; H-2b and k mice are high responders and H-2d mice are low responders. Mice of these 3 H-2 haplotypes were challenged with SV40 and their ability to generate and sustain an antibody response to SV40 T-antigen was found to be equivalent. To investigate the role of the different components of the host immune response in controlling growth of SV40-induced tumors, the tumorigenic potential of freshly established cell lines, obtained by SV40 transformation of cells from normal tissues of inbred strains of mice of 6 H-2 haplotypes, was assessed. Each cell line was tumorigenic in athymic and newborn mice but not in adult syngeneic immunocompetent mice. Cells from these initial SV40-transformed lines were then passaged in athymic (nu/nu) mice, re-established in vitro and again transferred into syngeneic animals. Transfer of H-2d SV40 transformants to low or non-responder mice of the H-2d haplotype resulted in tumor formation in some animals. Cells derived from these tumors expressed both the viral encoded T-antigen and the H-2Dd restriction element. Furthermore, the proportion of animals with tumors varied with the strength of their CTL-responsiveness to SV40 T-antigen in association with H-2Dd. Therefore, in H-2d animals, tumor cell growth appears to result from escape of cells from inefficient CTL surveillance. No tumors were formed by transfer of the in vivo selected H-2b or H-2k SV40 transformants to syngeneic high-responder mice. We therefore investigated the role of CTL in the selection of SV40-transformed cells able to escape immune surveillance. Under conditions of stringent immune selection by CTLs, tumorigenic cells that no longer expressed the relevant H-2 class-I restriction element were obtained. Although interaction between the various immune effector mechanisms may play a role in the recognition and elimination of SV40 transformants, our results were consistent with the hypothesis that the SV40-specific CTL response is the predominant control of SV40 tumor growth.


Movement related desynchronisation pattern preceding voluntary movement in untreated Parkinson's disease.
To study planning of movement in Parkinson's disease. The spatiotemporal pattern of movement related desynchronisation (MRD) preceding a self paced voluntary wrist flexion was compared between two groups of 10 untreated right and left hemiparkinsonian patients receiving no treatment and 10 control subjects. The MRD was computed in the 9 to 11 Hz frequency band from 11 source derivations covering the frontocentral, central, and parietocentral areas, during two successive left and right experimental conditions. In the two patient groups the desynchronisation appeared over the primary sensorimotor area contralateral to the affected side with a shorter latency (750 ms before movement onset for the right hemiparkinsonian group and 875 ms for the left hemiparkinsonian group) than in the control group (1750 ms), only when the movements were performed with the akinetic hand. For the non-affected hand, the same latency as in the control group was noted (1750 ms). The delay of appearance of MRD in Parkinson's disease confirmed that the programming of movement is affected, thus partially explaining akinesia.


Simultaneous needle catheter selection and dwell time optimization for preplanning of high-dose-rate brachytherapy of prostate cancer.
Needle catheter positions critically affect the quality of treatment plans in prostate cancer high-dose-rate (HDR) brachytherapy. The current standard needle positioning approach is based on human intuition, which cannot guarantee a high-quality plan. This study proposed a method to simultaneously select needle catheter positions and determine dwell time for preplanning of HDR brachytherapy of prostate cancer. We formulated the needle catheter selection problem and inverse dwell time optimization problem in a unified framework. In addition to the dose objectives of the planning target volume (PTV) and organs at risk (OARs), the objective function incorporated a group-sparsity term with a needle-specific adaptive weighting scheme to generate high-quality plans with the minimal number of needle catheters. The optimization problem was solved by a fast-iterative shrinkage-thresholding algorithm. For validation purposes, we tested the proposed algorithm on 10 patient cases previously treated at our institution and compared the resulting plans with plans generated using needle catheters selected manually. Compared to the plan with manually selected needle catheters, when normalizing both plans to the same PTV coverage V 100% = 95%, the plans generated by the proposed algorithm reduced median V 125% from 65% to 64%, but increased median V 150% from 35% to 38%, and V 200% from 14% to 16%. All planning objectives were met. All clinically important dosimetric parameters of OARs were reduced. D 1cc of bladder and rectum were reduced from 8.57 Gy to 8.50 Gy and from 7.24 Gy to 6.80 Gy, respectively. D max of urethra was reduced from 15.85 Gy to 15.77 Gy. The median number of selected needle catheters was reduced by two. The computational time for solving the proposed optimization problem was ∼90 s using MATLAB. The proposed algorithm was able to generate plans for prostate cancer HDR brachytherapy preplanning with increased median conformity index (0.73-0.77) and slightly lower median homogeneity index (0.64-0.62) with the number of selected needles reduced by two compared to the manual needle selection approach.


Relationship between floating marine debris accumulation and coastal fronts in the Northeast coast of the USA.
Floating marine debris (FMD) is one of the world's most concerning issues due to its potential impact on biodiversity, communities, and ecosystem services. FMD transport and concentrations are driven by fronts, generated by oceanographic processes, and the accumulation of FMD has been reported in gyres, eddies, tidal fronts, salinity fronts, and coastal fronts. This study explores the relationship between fronts and FMD accumulation in the Gulf of Maine (GoM) and the surrounding coastal areas (USA). Frontal edge detection algorithms were applied to sea surface temperature (SST) imagery from the Moderate-resolution Imaging Spectroradiometer (MODIS) between 2002 and 2012. Frontal location is spatially correlated with FMD concentrations collected by the Sea Education Association. Higher concentrations of FMD are associated with frontal frequencies (FF) of 5-10 %. FMD is trapped between fronts and the coastline in accumulation zones. These results highlight the need to consider coastal FMD hotspots, given these are areas of high biodiversity value.


Function of Ikaros as a tumor suppressor in B cell acute lymphoblastic leukemia.
The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL.


Immunosuppression of mice injected with heterologous anti-immunoglobulin heavy chain antisera.
Neonatal injection of mice with rabbit anti-micro antiserum has been shown to produce complete loss of direct and indirect plaque-forming responses to sheep erythrocytes as well as loss of serum IgM and severe depressions of all other serum immunoglobulins. Similar injection of anti-gamma1gamma2 or anti-gamma1 antibodies effects a loss of the indirect response but induces relatively minor alterations in serum Ig levels. Delaying initiation of anti-micro treatment until young adulthood results in a somewhat diminished effect on plaque-forming responses and serum Ig levels but triggers the release of high serum levels of an aberrant micro-bearing protein. Anti-micro suppression of genetically thymusless mice indicates that at least part of the target cells for suppression are bone marrow derived. A working hypothesis for the maturation of humoral antibody-producing cell lines as it relates to these data is discussed.


Stable and Fast-Dissolving Amorphous Drug Composites Preparation via Impregnation of Neusilin® UFL2.
A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin®. The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs.


[The necessity of a surplus in the nitrogen balance in the rumen of cows having high milk production].
The amount of crude protein entering the small intestine (nXP) and the nitrogen balance in the rumen (RNB) are the two components of the German protein evaluation system. Although there is no scientific evidence, feeding strategies for the practice imply an excess in RNB, particularly in diets for high-yielding cows. This study was undertaken to investigate whether cows benefit from an excess in RNB under conditions of sufficient nXP supply. Three rations were used equal in energy (7.2 MJ net energy for lactation per kilogram dry matter; DM) and nXP (173 g/kg DM) and mainly based on silages from maize, grass, and brewer's grains as well as ground barley and solvent extracted meals from rapeseed and soybeans. Three rations were calculated to allow for an RNB of either 0 or 50 g/day. RNB was adjusted by either a supplementation of urea or a change in the proportions of oilseed meals. The intended levels of energy, nXP and RNB in the diets were confirmed under consideration of separate digestibility measurements with wether sheep and a chemical fractionation of dietary crude protein. The rations were offered as total mixed rations. At least 35 cows between days 21 and 98 of lactation were used per treatment. Cows were milked three times daily and had continuous access to feed and water. Feed intake was measured continuously and for each cow individually by a feeder system through which the rations were offered. The average values for the three treatments ranged between 20.1 and 21.7 kg/day for DM intake, 43.0 and 44.0 kg/day for milk yield, and 1.39 and 1.42 kg/day for milk protein yield. No significant treatment effect was detected in any of the monitored criteria. Cows were in a negative energy budget as indicated by a loss in backfat thickness, similar for all treatments. Under inclusion of literature data it is concluded that under conditions of a sufficient nXP supply, dairy cows do not need an excess in RNB in total mixed rations, even at very high levels of milk protein yield.


Late-life depression, mild cognitive impairment, and dementia: possible continuum?
Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.


Takotsubo cardiomyopathy, or broken-heart syndrome.
To report a case of takotsubo cardiomyopathy, also known as apical ballooning syndrome or stress cardiomyopathy. A 68-year-old female with a history of hypertension, hyperlipidemia, and anxiety presented with symptoms that mimicked acute coronary syndrome (ACS); the chief symptom was chest tightness. An electrocardiogram showed normal sinus rhythm, with minimal ST elevation in the anterior leads. The patient was initially treated for ST-segment elevation myocardial infarction and symptoms resolved. Coronary angiography ruled out ACS and confirmed a diagnosis of takotsubo cardiomyopathy. Takotsubo cardiomyopathy is commonly triggered by severe emotional or psychological stress and occurs primarily in postmenopausal women. A reversible contractility abnormality of the left ventricle causes the ventricle to take on a balloon-like appearance; hence the name of takotsubo, a Japanese octopus fishing pot that has a narrow neck and a wide midsection. Signs and symptoms of takotsubo cardiomyopathy mimic those of ACS. Takotsubo cardiomyopathy is best diagnosed with coronary angiography, which can rule out blockage. Treatment usually consists of carvedilol and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocking agent if left ventricular ejection fraction is less than 40%. The syndrome is usually spontaneously reversible and cardiovascular function returns to normal after a few weeks. Takotsubo cardiomyopathy causes a reversible left ventricle dysfunction which occurs most commonly in postmenopausal women with or without cardiovascular disease. Recognition is detected with coronary angiography. It is thought to primarily be due to an abnormally high sympathetic stimulation after emotional or psychological stress. Treatment consists of an angiotensin-converting enzyme inhibitor and/or beta blocker if needed for left ventricular dysfunction and possibly an anxiolytic agent.


Sexual health of ethnic minority MSM in Britain (MESH project): design and methods.
Men who have sex with men (MSM) remain the group most at risk of acquiring HIV infection in Britain. HIV prevalence appears to vary widely between MSM from different ethnic minority groups in this country for reasons that are not fully understood. The aim of the MESH project was to examine in detail the sexual health of ethnic minority MSM living in Britain. The main objectives of the MESH project were to explore among ethnic minority MSM living in Britain: (i) sexual risk behaviour and HIV prevalence; (ii) their experience of stigma and discrimination; (iii) disclosure of sexuality; (iv) use of, and satisfaction with sexual health services; (v) the extent to which sexual health services (for treatment and prevention) are aware of the needs of ethnic minority MSM.The research was conducted between 2006 and 2008 in four national samples: (i) ethnic minority MSM living in Britain; (ii) a comparison group of white British MSM living in Britain; (iii) NHS sexual health clinic staff in 15 British towns and cities with significant ethnic minority communities and; (iv) sexual health promotion/HIV prevention service providers. We also recruited men from two "key migrant" groups living in Britain: MSM born in Central or Eastern Europe and MSM born in Central or South America.Internet-based quantitative and qualitative research methods were used. Ethnic minority MSM were recruited through advertisements on websites, in community venues, via informal networks and in sexual health clinics. White and "key migrant" MSM were recruited mostly through Gaydar, one of the most popular dating sites used by gay men in Britain. MSM who agreed to take part completed a questionnaire online. Ethnic minority MSM who completed the online questionnaire were asked if they would be willing to take part in an online qualitative interview using email.Service providers were identified through the British Association of Sexual Health and HIV (BASHH) and the Terrence Higgins Trust (THT) CHAPS partnerships. Staff who agreed to take part were asked to complete a questionnaire online.The online survey was completed by 1241 ethnic minority MSM, 416 men born in South and Central America or Central and Eastern Europe, and 13,717 white British MSM; 67 ethnic minority MSM took part in the online qualitative interview. In addition 364 people working in sexual health clinics and 124 health promotion workers from around Britain completed an online questionnaire. The findings from this study will improve our understanding of the sexual health and needs of ethnic minority MSM in Britain.


Impact of mandibular implant prostheses on the oral health-related quality of life in partially and completely edentulous patients.
To assess the oral health-related quality of life (OHRQoL) of patients provided with mandibular implant fixed partial prostheses (IFPP) for rehabilitation of two adjacent missing posterior teeth and complete denture patients provided with mandibular implant-supported overdenture (ISOD). The response to change in OHRQoL with implant prostheses was additionally compared. In this prospective study, 20 IFPP (mean age 47.0; SD 12.9 years) and 28 ISOD (mean age 61.5; SD 9.1 years) patients received 2 mandibular implants. Metal ceramic nonsplinted fixed prostheses were provided in IFPP group, while in ISOD group, the mandibular overdentures were retained by nonsplinted attachments. Patients rated their oral health-related quality of life using OHIP-14 Malaysian version at baseline (T0), 2-3 months (T1) and 1 year (T2) postimplant treatment. Mean OHIP-14 for total and domain scores between groups and intervals was analysed using repeated-measures ANOVA and t-test. Mann-Whitney and Wilcoxon signed-rank tests were used for the comparison of mean score change and effect size, while the association between pre- and post-treatment scores was determined using multivariate linear regression modelling. The total OHIP and domain scores before implant treatment were significantly higher (lower OHRQoL) in IFPP than in ISOD groups, except for physical pain where this domain showed similar impact in both groups. Postimplant scores between groups at T1 and T2 showed no significant difference. The mean score changes at T0-T1 and T0-T2 for total OHIP-14 and domains were significantly greater in IFPP except in the domains of physical pain and disability which showed no difference. Large effect size (ES) was observed for total OHIP-14 in IFPP while moderate in ISOD. Improved OHRQoL was dependent on the treatment group and pretreatment score. Improvement in OHRQoL occurred following both mandibular implant-supported overdentures and implant fixed partial prostheses.


Epidermal growth factor receptor-mediated membrane type 1 matrix metalloproteinase endocytosis regulates the transition between invasive versus expansive growth of ovarian carcinoma cells in three-dimensional collagen.
The epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas and promotes cellular responses that contribute to ovarian cancer pathobiology. In addition to modulation of mitogenic and motogenic behavior, emerging data identify EGFR activation as a novel mechanism for rapid modification of the cell surface proteome. The transmembrane collagenase membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) is a major contributor to pericelluar proteolysis in the ovarian carcinoma microenvironment and is subjected to extensive posttranslational regulation. In the present study, the contribution of EGFR activation to control of MT1-MMP cell surface dynamics was investigated. Unstimulated ovarian cancer cells display caveolar colocalization of EGFR and MT1-MMP, whereas EGFR activation prompts internalization via distinct endocytic pathways. EGF treatment results in phosphorylation of the MT1-MMP cytoplasmic tail, and cells expressing a tyrosine mutated form of MT1-MMP (MT1-MMP-Y(573)F) exhibit defective MT1-MMP internalization. As a result of sustained cell surface MT1-MMP activity, a phenotypic epithelial-mesenchymal transition is observed, characterized by enhanced migration and collagen invasion, whereas growth within three-dimensional collagen gels is inhibited. These data support an EGFR-dependent mechanism for regulation of the transition between invasive and expansive growth of ovarian carcinoma cells via modulation of MT1-MMP cell surface dynamics.


Anti-Inflammatory Effects of 3-(4'-Hydroxyl-3',5'-Dimethoxyphenyl)Propionic Acid, an Active Component of Korean Cabbage Kimchi, in Lipopolysaccharide-Stimulated BV2 Microglia.
We investigated the protective ability of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), an active principle in Korean cabbage kimchi, against the production of proinflammatory mediators and cytokines, and the mechanisms involved in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. HDMPPA significantly suppressed the production of nitric oxide (NO) and prostaglandin E2, along with the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV2 cells, at concentrations with no cytotoxicity. HDMPPA also attenuated the LPS-induced expression and secretion of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β. Furthermore, HDMPPA inhibited LPS-induced nuclear factor-κB (NF-κB) activation, which was associated with the abrogation of IκB-α degradation and phosphorylation, and subsequent decreases in NF-κB p65 levels. Moreover, the phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt, a downstream molecule of phosphatidylinositol-3-kinase (PI3K), in LPS-stimulated BV2 cells was suppressed markedly by HDMPPA. This effect was associated with a significant reduction in the formation of intracellular reactive oxygen species. The findings in this study suggest that HDMPPA may exert anti-inflammatory responses by suppressing LPS-induced expression of proinflammatory mediators and cytokines through blockage of NF-κB, MAPKs, and PI3K/Akt signaling pathways and oxidative stress in microglia.


Tangential load sharing among fingers during prehension.
The goal of the study was to examine the force sharing among the fingers during static prehension under systematic loading and postural changes. A custom-built handle was constructed that allowed for bi-directional loading (upward and downward) with different load magnitudes (250, 750 and 1250 g). Five- and three-digit grasps were tested. The fingers were spaced 2, 3 or 6 cm apart. The handle was oriented vertically such that the tangential forces acted parallel to the applied load. There were no differences in tangential sharing patterns between males and females. The factors that did affect the sharing pattern (ranked from the smallest to the largest effect) were: TRIAL (i.e., inter-trial variability), LOAD MAGNITUDE, SUBJECT, HAND POSTURE and LOAD DIRECTION. Normal force sharing accounted for much but not all of the variability in tangential sharing. The results suggest that loading direction should be considered when designing tools that require functional tangential forces for successful task completion (e.g., screwdrivers, jar lids, etc.). A hypothesis to account for the directional changes based on the passive properties of the fingers is proposed.