Stem cell therapy in acute respiratory distress syndrome.
Acute respiratory distress syndrome is characterized by an acute pulmonary inflammatory process induced by the presence of a direct (pulmonary) insult that affects lung parenchyma, or an indirect (extrapulmonary) insult that results from an acute systemic inflammatory response. It is believed that an efficient therapy for the acute respiratory distress syndrome should attenuate inflammatory response and promote adequate repair of the lung injury. This article presents a brief review on the use of stem cells and their potential therapeutic effect on the acute respiratory distress syndrome. This systematic review was based upon clinical and experimental acute respiratory distress syndrome studies included in the MedLine and SciElO database during the last 10 years. Stem cell transplant lead to an improvement in lung injury and fibrotic process by inducing adequate tissue repair. This includes alveolar epithelial cell differentiation,and also reduces pulmonary and systemic inflammatory mediators and secretion of growth factors. Stem cells could be a potential therapy for acute respiratory distress syndrome promoting lung repair and attenuating the inflammatory response. However, mechanisms involving their anti-inflammatory and antifibrinogenic effects require better elucidation, limiting their immediate clinical use in acute respiratory distress syndrome.


Structure-activity relationships of selected pyridines. I. Substituent constant analysis.
Twenty-two four-position derivatives of pyridine (C5H5N) were tested following an acute static regime with biological response being monitored as population growth of Tetrahymena pyriformis. The vinyl derivative was the most active and the hydroxy derivative was the least active. Structure-activity relationships were examined using substituent constants as molecular descriptors. Size/shape parameters and hydrophobic/hydrophilic parameters were found to be more important descriptors than electronic parameters. Following the deletion of the outliers, 4-vinylpyridine and 4-nitropyridine, molar refractivity was found to be the best single descriptor explaining 62.5% of the variability in biological response. Based on highest adjusted r2 value the best model is log BR = 0.0055 (MR) - 0.3699 (Ha) - 1.0124, r2 = 0.709 (BR, biological response; MR, molar refractivity; Ha, hydrogen acceptance). Models using Pi (hydrophobic substituent constant) as the descriptor and comparisons with previously assayed naphthalenes are discussed.


[Reliability and validity of Subjective Well-Being Scale].
In this study, a subjective well-being scale was developed, and its reliability and validity evaluated. The Subjective Well-Being Scale (SWBS) had twelve items which covered four domains. It was administered to 1005 adults and 520 college students. Results indicated that for the students, college life satisfaction and self-esteem had positive correlations with SWBS score. For the adults, marital satisfaction, workplace satisfaction, and household income satisfaction had positive correlations with the score. These findings showed considerable constructive validity for SWBS. In addition, internal consistency was sufficiently high, indicating the measure's high reliability. SWBS may be a simple but reliable and valid measure, and it is useful for examining subjective well-being of both adults and college students.


NDRG2 positively regulates E-cadherin expression and prolongs overall survival in colon cancer patients.
To discover the molecular mechanism of N-Myc downstream-regulated gene 2 (NDRG2), a newly found differentiation-related tumor suppressor, the relationships between NDRG2 and E-cadherin were investigated in tumor cells and tissues. Positive correlations between the expression of E-cadherin and NDRG2 were shown in several colon cancer cell lines as well as in colon cancer tissues. According to the transcription assays using a reporter plasmid containing E-cadherin promoter region (-368~+51), NDRG2 introduction into colon cancer cell lines induced upregulation of E-cadherin promoter activity and its transcription. On the contrary, inhibition of NDRG2 expression by siRNA treatment caused the decrease of E-cadherin transcription. Snail, a zinc-finger transcriptional repressor, was shown to be a mediator of NDRG2-regulated E-cadherin expression. The enhancement of glycogen synthase kinase 3β (GSK-3β) activity by NDRG2 overexpression caused proteasomal degradation of Snail transcription factor followed by transcriptional de-repression of E-cadherin. We also found that NDRG2 could mediate cell density-regulated E-cadherin expression. The increase of NDRG2 expression with cell density preceded E-cadherin expression, and the regulation of Snail activity by GSK-3β was also related to this process.


What sedation to use during endoscopic procedure.
Many endoscopists sometimes prefer to perform endoscopies without anaesthetic support, using only benzodiazepines. Endogenous opioid peptides are believed to play an important role in the modulation of pain within the endogenous analgesic system. A group of 40 patients undergoing diagnostic and therapeutic Endoscopic Retrograde Cholangiography and Pancreatography (ERCP) was recruited. Patients were divided into 2 groups according to Visual Analog Scale: pain 1-5 (Group A) and pain 6-10 (Group B). The beta-endorphin baseline values were significantly different between patients of Group A and Group B. Our data show that patients with levels of beta-endorphin over 8 pmol/L were less sensitive to pain, so that they become candidates for a traditional utilization of the benzodiazepines. However in the patients with beta-end levels less of 8 pmol/L should be suitable an anaesthetic as propofol because strong pain might provoke neurohumoral reflexes, cardiovascular alterations, and even a heart attack.


DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion.
Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLγB, the accessory subunit of the POLγ holoenzyme. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLγB acts to stabilize POLγA and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POLγ subunits. We suggest that targeting POLγA turnover can be exploited as a target for the development of future therapies.


[Insulin resistance and evolution].
Both infections and injuries activate the immunity system, leading to a series of metabolic changes which place the organism at a disadvantage and contribute to its elimination, thus facilitating the repair of the injured tissue. The study of the actions of tumour necrosing factor alpha (TNF-alpha) and interleukin-6 (IL-6), classically implicated in inflammatory processes and in fighting infection, has revealed numerous metabolic effects. Some gene polymorphisms of TNF-alpha and IL-6 (associated with a different TNF-alpha or IL-6 transcription rate) and the plasma concentrations of the soluble TNF-alpha receptor are found to be simultaneously associated with resistance to insulin, the proportion of body fat and with the mortality linked with different chronic infections. Therefore, it seems that the immune system is designed to fight infections effectively and to provide certain survival advantages during periods of intermittent fasting so frequent in the past. By inducing a resistance to insulin in the muscles, the energy substrates would thus be reserved for neuronal metabolism. In the presence of an insulin-resistance genotype and a westernization of the environment (carbohydrate-rich diet, an increase in saturated fat, low fibre and sedentary lifestyle), a genotype with a high cytokine response will contribute to a worsening of the resistance to insulin and, finally, to type 2 diabetes mellitus and atherosclerosis. The advantages for our ancestors of a large cytokine response (eradication of the lesion) or moderate resistance to insulin (protection against food shortage) have led in the present day to the development of atherosclerosis now that the characteristics of the environment have changed. It is contended that these changes constitute examples of good adaptation to the environment or poor concordance between our current lifestyle and our genome.


Pharyngeal Gonorrhea in female sex workers: Response to a single 2-g dose of azithromycin.
A sharp increase in the incidence of gonorrhea has been observed in Tel Aviv, Israel, since 1999. Almost one half of interviewed patients admitted contracting the infection from a sex worker. In two thirds of the cases, oral sex (fellatio) was the most probable route of acquiring the disease. In the current study, we assessed the prevalence of pharyngeal gonorrhea among sex workers in Tel Aviv and evaluated the efficacy of a single 2-g dose of azithromycin in eradicating the infection. Throat specimens were obtained for gonococcal culture from 301 female sex workers practicing in brothels. A questionnaire covering demographic and sexual behavior information was administered to all participants, and a single 2-g dose was administered orally under supervision. Women with positive cultures were reexamined a week later for eradication of Neisseria gonorrhoeae. N gonorrhoeae was isolated from 27 women (9%). The median age of women with pharyngeal gonorrhea was 23 years (range, 18-32 years); 85% were born in former Soviet Union (mostly Russia, Ukraine, Moldavia). Regular condom use in vaginal sex was reported by 88% of the participants, whereas only 60% reported always using condoms in oral sex. All isolates were susceptible to azithromycin (MIC < or = 0.5 microg/ml). Gonococci were eradicated in 20/21 individuals (95%). A high carriage rate of gonococci in the throat and a low rate of condom use in oral sex were documented among sex workers in Tel Aviv. A single 2 g dose of azithromycin was very effective in eradicating gonococci from the throat.


Effects of isradipine, a dihydropyridine-class calcium-channel antagonist, on d-methamphetamine's subjective and reinforcing effects.
In healthy human volunteers, we have previously shown that isradipine, a dihydropyridine-class calcium-channel antagonist, reduces some methamphetamine-induced positive subjective effects associated with its abuse liability, presumably by antagonizing cortico-mesolimbic dopamine pathways. In the present study, we combined acute immediate-release (IR) isradipine with repeated sustained-release (SR) isradipine pretreatment to determine whether isradipine could antagonize methamphetamine's positive subjective and reinforcing effects in methamphetamine-dependent research subjects. We included 18 non-treatment-seeking, methamphetamine-dependent subjects aged between 18 and 51 years in this double-blind, within-subject, cross-over study, which was done in a human laboratory. Intravenous methamphetamine (0, 15 and 30 mg) was administered on three different days after 5 days of double-blind cross-over treatment with either isradipine or matching placebo. Subjects received oral isradipine 30 mg SR at bedtime, plus 15 mg IR administered 2 h before methamphetamine infusion. Self-report questionnaires measured drug liking, euphoria, craving, stimulation, and methamphetamine preference. Methamphetamine reinforcement was measured by a behavioural procedure involving choices between methamphetamine and money. For those who received isradipine second and placebo first as the pretreatment paradigm but not vice versa, methamphetamine-induced drug liking, elation, and preference were reduced significantly by isradipine. Depending upon conditioning status, isradipine can reduce some methamphetamine-induced positive subjective and reinforcing effects associated with its abuse liability in methamphetamine addicts.


The isolation and characterization of a clonally related series of murine retrovirus-infected mouse cells.
Starting with cloned NIH 3T3 mouse cells we have isolated a series of related lines infected with the Kirsten murine sarcoma/leukaemia (MSV/MLV) virus complex. These lines exhibit all three possible infected cell phenotopes: (i) transformed MSV/MLV producers; (ii) non-transformed MLV producers; (iii) transformed non-producers. We have also selected non-transformed revertants from one of the non-producer clones. This series of lines allows the study of the expression of the virus genome against a constant background of cellular gene expression. We have further characterized the lines with regard to anchorage dependence of growth, tumorigenicity and the presence of a rescuable sarcoma genome. The non-producer clones are uniform in their transformed properties. The revertants contain rescuable sarcoma virus, biologically indistinguishable from the original transforming virus, implying that the reversion is due to a change in cellular rather than viurs genetic information.


Women have farther to fall: gender differences between normal elderly and Alzheimer's disease in verbal memory engender better detection of Alzheimer's disease in women.
We analyzed verbal episodic memory learning and recall using the Logical Memory (LM) subtest of the Wechsler Memory Scale-III to determine how gender differences in AD compare to those seen in normal elderly and whether or not these differences impact assessment of AD. We administered the LM to both an AD and a Control group, each comprised of 21 men and 21 women, and found a large drop in performance from normal elders to AD. Of interest was a gender interaction whereby the women's scores dropped 1.6 times more than the men's did. Control women on average outperformed Control men on every aspect of the test, including immediate recall, delayed recall, and learning. Conversely, AD women tended to perform worse than AD men. Additionally, the LM achieved perfect diagnostic accuracy in discriminant analysis of AD versus Control women, a statistically significantly higher result than for men. The results indicate the LM is a more powerful and reliable tool in detecting AD in women than in men.


[Comparative data on the propagation of cells from commercial common and leukemia-free chick embryos].
Certain differences were found in comparative studies of optimal conditions for preparation and propagation of cell cultures from common and leukemia-free chick embryos. The yield of cells per 1 g of tissue was regularly higher by 12-20% with leukemia-free chick embryos than with common chick embryos. The viability of the latter under conditions of roller cultivation was lower. Monolayer cultures of cells from leukemia-free chick embryos formed 1 day earlier than those from cells of common chick embryos. The optimal medium for growth of leukemia-free chick embryo cells was 0.5% lactalbumin hydrolysate, and for common chick embryo cells--Eagle's medium.


[Quantitative characteristics of the migration ability of different types of fibroblast-like cells cultured on substrates with an ordered relief].
Reactions to the geometrical configuration of the underlying surface of fibroblast-like cells of various species (mouse, rat, chick, hamster, human) were compared quantitatively. All normal cells migrated from 25-40 mcm deep grooves but not from the less deep ones -5-15 mcm. Migration ability was the highest in the mouse cells;it was less pronounced in rat and chick cells; hamster and human cells had the lowest migration ability. The offered quantitative method can be used for estimation of the reaction to the ordered relief of the substratum of different minds of cultured cells - normal as well as pathologically changed.


The Use of Text Messaging to Improve the Hospital-to-Community Transition in Acute Coronary Syndrome Patients (Txt2Prevent): Intervention Development and Pilot Randomized Controlled Trial Protocol.
Acute coronary syndrome, including acute myocardial infarction (AMI), is one of the leading causes for hospitalization, with AMI 30-day readmission rates around 20%. Supporting patient information needs and increasing adherence to recommended self-management behaviors during transition from hospital to home has the potential to improve patient outcomes. Text messages have been effective in other interventions and may be suitable to provide support to patients during this transition period. The goal of this study is to pilot test a text messaging intervention program (Txt2Prevent) that supports acute coronary syndrome patients for 60 days postdischarge. The primary objective is to compare self-management, as measured by the Health Education Impact Questionnaire, between patients receiving only usual care versus those who receive usual care plus the Txt2Prevent intervention. The secondary objectives are to compare medication adherence, health-related quality of life, self-efficacy, health care resource use (and associated costs), all-cause and cardiovascular disease (CVD) readmission, and all-cause and CVD mortality rates between the 2 groups. The third objective is to assess acceptability of the text messaging intervention and feasibility of the study protocol. This is a randomized controlled trial with blinding of outcome assessors. The Txt2Prevent program includes automated text messages to patients about standard follow-up care, general self-management, and healthy living. The content of the text messages was informed by and developed based on interviews with patients, discharge materials, theoretical domains of behavior, and a clinical advisory group composed of patients, clinicians, and researchers. We will recruit 76 consecutive cardiac in-patients with acute coronary syndrome who are treated with either medical management or percutaneous coronary intervention from a hospital in Vancouver, Canada. Assessments at baseline will include measures for demographic information, self-management, health-related quality of life, and self-efficacy. Assessments at follow-up will include medication adherence, readmissions, health care resource use, and mortality in addition to the reassessment of baseline measures. Baseline assessments are done in-person while follow-up assessments are completed through a combination of mailed packages and phone calls. Semistructured interviews with participants will also be performed to better understand participant experiences managing their condition and with the text messages. This study will determine preliminary efficacy, feasibility, and acceptability of the Txt2Prevent program to support acute coronary syndrome patients in the transition to home following hospital discharge. The results of this study will be used to inform a larger trial. ClinicalTrials.gov NCT02336919; https://clinicaltrials.gov/ct2/show/NCT02336919 (Archived by WebCite at http://www.webcitation.org/6qMjEqo6O).


Synthesis of Daidzein Glycosides, α-Tocopherol Glycosides, Hesperetin Glycosides by Bioconversion and Their Potential for Anti-Allergic Functional-Foods and Cosmetics.
Daidzein is a common isoflavone, having multiple biological effects such as anti-inflammation, anti-allergy, and anti-aging. α-Tocopherol is the tocopherol isoform with the highest vitamin E activity including anti-allergic activity and anti-cancer activity. Hesperetin is a flavone, which shows potent anti-inflammatory effects. These compounds have shortcomings, i.e., water-insolubility and poor absorption after oral administration. The glycosylation of bioactive compounds can enhance their water-solubility, physicochemical stability, intestinal absorption, and biological half-life, and improve their bio- and pharmacological properties. They were transformed by cultured Nicotiana tabacum cells to 7-β-glucoside and 7-β-gentiobioside of daidzein, and 3'- and 7-β-glucosides, 3',7-β-diglucoside, and 7-β-gentiobioside of hesperetin. Daidzein and α-tocopherol were glycosylated by galactosylation with β-glucosidase to give 4'- and 7-β-galactosides of daidzein, which were new compounds, and α-tocopherol 6-β-galactoside. These nine glycosides showed higher anti-allergic activity, i.e., inhibitory activity toward histamine release from rat peritoneal mast cells, than their respective aglycones. In addition, these glycosides showed higher tyrosinase inhibitory activity than the corresponding aglycones. Glycosylation of daidzein, α-tocopherol, and hesperetin greatly improved their biological activities.


Differential modulation of thermal preference after sensitization by optogenetic or pharmacological activation of heat-sensitive nociceptors.
Common approaches to studying mechanisms of chronic pain and sensory changes in pre-clinical animal models involve measurement of acute, reflexive withdrawal responses evoked by noxious stimuli. These methods typically do not capture more subtle changes in sensory processing nor report on the consequent behavioral changes. In addition, data collection and analysis protocols are often labour-intensive and require direct investigator interactions, potentially introducing bias. In this study, we develop and characterize a low-cost, easily assembled behavioral assay that yields self-reported temperature preference from mice that is responsive to peripheral sensitization. This system uses a partially automated and freely available analysis pipeline to streamline the data collection process and enable objective analysis. We found that after intraplantar administration of the TrpV1 agonist, capsaicin, mice preferred to stay in cooler temperatures than saline injected mice. We further observed that gabapentin, a non-opioid analgesic commonly prescribed to treat chronic pain, reversed this aversion to higher temperatures. In contrast, optogenetic activation of the central terminals of TrpV1+ primary afferents via in vivo spinal light delivery did not induce a similar change in thermal preference, indicating a possible role for peripheral nociceptor activity in the modulation of temperature preference. We conclude that this easily produced and robust sensory assay provides an alternative approach to investigate the contribution of central and peripheral mechanisms of sensory processing that does not rely on reflexive responses evoked by noxious stimuli.


Car seats for children.
Automobile accidents are the most frequent cause of injury and death among young children. The number of injuries or deaths could be decreased by the use of child restraints. Counseling parents about car safety has a positive effect on increasing the use of restraints. Other important factors include passive protection, such as interior design and air bags, appropriate laws for enforcement of proper use and adequate safety testing of existing restraints.


Resistance to hemi-biotrophic F. graminearum infection is associated with coordinated and ordered expression of diverse defense signaling pathways.
Fusarium species cause serious diseases in cereal staple food crops such as wheat and maize. Currently, the mechanisms underlying resistance to Fusarium-caused diseases are still largely unknown. In the present study, we employed a combined proteomic and transcriptomic approach to investigate wheat genes responding to F. graminearum infection that causes Fusarium head blight (FHB). We found a total of 163 genes and 37 proteins that were induced by infection. These genes and proteins were associated with signaling pathways mediated by salicylic acid (SA), jasmonic acid (JA), ethylene (ET), calcium ions, phosphatidic acid (PA), as well as with reactive oxygen species (ROS) production and scavenging, antimicrobial compound synthesis, detoxification, and cell wall fortification. We compared the time-course expression profiles between FHB-resistant Wangshuibai plants and susceptible Meh0106 mutant plants of a selected set of genes that are critical to the plants' resistance and defense reactions. A biphasic phenomenon was observed during the first 24 h after inoculation (hai) in the resistant plants. The SA and Ca(2+) signaling pathways were activated within 6 hai followed by the JA mediated defense signaling activated around 12 hai. ET signaling was activated between these two phases. Genes for PA and ROS synthesis were induced during the SA and JA phases, respectively. The delayed activation of the SA defense pathway in the mutant was associated with its susceptibility. After F. graminearum infection, the endogenous contents of SA and JA in Wangshuibai and the mutant changed in a manner similar to the investigated genes corresponding to the individual pathways. A few genes for resistance-related cell modification and phytoalexin production were also identified. This study provided important clues for designing strategies to curb diseases caused by Fusarium.


Management of bone metastases.
Bone metastases are only apparently similar lesions, considering the large varieties of istotypes and the spread of the primary tumour. Although these metastases develop early and are not terminal events, they have to be considered as severe complications. When possible, surgical treatment can improve the history of the patient in terms of life expectancy and quality of life. The approach to these lesions should be multidisciplinary in collaboration with oncologists and radiotherapists. In fact the average of survival of these patients has increased in recent years. The evolution of anesthesiological techniques permits surgical treatments that once were considered prohibitive. The application of new adjuvant therapies increases the effectiveness for surgical treatment. Controversy exists over the most appropriate treatment for patients with bone metastatic disease. The purpose was to determine the best sequential process to arrive at the most appropriate treatment considering the individual general conditions and the parameters of the metastases. As the number of treatment options for metastatic bone disease has grown, it has become clear that effective implementation of these treatments can only be achieved by a multidisciplinary approach.


An outbreak of Escherichia coli O157 infection following exposure to a contaminated building.
Infection with Escherichia coli O157 causes an estimated 70 000 diarrheal illnesses per year in the United States and can result in hemolytic-uremic syndrome and death. Environmental contamination with E coli O157 may be a public health problem. To determine risk factors for E coli O157 infection during an outbreak investigation at a county fair and to evaluate environmental contamination as a possible cause of the outbreak. Case-control study of 23 patients (median age, 15 years) and 53 age-matched controls who had attended the Lorain County, Ohio, fair between August 20 and August 26, 2001. Case-patients had laboratory-confirmed E coli O157 infection, hemolytic-uremic syndrome, or bloody diarrhea within 7 days of attending the fair; controls attended the fair and did not have diarrhea. Risk factors for infection and isolates of E coli O157 from environmental specimens. Six (26%) case-patients were hospitalized and 2 (9%) developed hemolytic-uremic syndrome. Case-patients were more likely than controls to have visited building A (a multipurpose community facility on the fairgrounds; matched odds ratio [MOR], 21.4 [95% confidence interval [CI], 2.7-170.7]). Among visitors to building A, illness was independently associated with attending a dance in the building (MOR, 7.5; 95% CI, 1.4-41.2), handling sawdust from the floor (MOR, 4.6; 95% CI, 1.1-20.0), or eating and/or drinking in the building (MOR, 4.5; 95% CI, 1.2-16.6). Twenty-four (44%) of 54 specimens collected from building A 6 weeks after the fair grew Shiga toxin-producing E coli O157. Isolates from sawdust, the rafters, and other surfaces were identical by molecular fingerprinting to patient isolates. Sawdust specimens collected 42 weeks after the fair also grew the same E coli O157 strain. Absence of evidence implicating specific food or beverage sources and the recovery of E coli O157 from the rafters suggest that airborne dispersion of bacteria contributed to the contamination. Because E coli O157 can survive in the environment for more than 10 months, humans may be at risk of infection long after an environment is initially contaminated.


The effectiveness of a programme of enhancing resiliency by reducing family boundary ambiguity among children with epilepsy.
The aim of the study was to examine the effect of a programme designed to reduce family boundary ambiguity in families who care for children with epilepsy. When parents are caring for an epileptic child, they may experience unclear perceptions about whether the child is psychologically included in the family and develop unclear expectations regarding role performance in the family. Some studies have identified boundary ambiguity as a possible antecedent to relationship problems that are associated with negative outcomes in the areas of parental well-being and family functioning. There is a need to develop family nursing interventions that will reduce family boundary ambiguity when the family is caring for children with epilepsy. A pretest, post-test, one group, quasi-experimental design was used in this study. This study was made up of three phases: first, the establishing of a parental needs checklist and the development of a parental education information handbook; second, the carrying out of a family assessment including the analysis of the meaning of their experiences and needs and the construction of an educational dialogue and finally, an outcomes evaluation after three months. Seventeen mothers participated in the study. The study found that there were statistically significant improvements in family boundary ambiguity and maternal depression was reduced. This study illustrates nursing intervention that involves the integrating of phenomenological principles into the nursing care process. Specifically, Husserlian phenomenology is able to be helpful to nursing practice, especially the concepts of intentionality, intersubjectivity, empathy and bracketing. This study supported the conceptual framework involved in the construction of the meaning of the situation, the enhancement of mastery over the situation and reconstruction of identity. These items are resiliency factors that provided a mechanism that helps to reduce boundary ambiguity when a family is caring for a child with epilepsy.


Identifying Potentially Preventable Emergency Department Visits by Nursing Home Residents in the United States.
To identify and describe potentially preventable emergency department (ED) visits by nursing home (NH) residents in the United States. These visits are important because they are common, frequently lead to hospitalization, and can be associated with significant cost to the patient and the health care system. Retrospective analysis of the 2005-2010 National Hospital Ambulatory Care Survey (NHAMCS), comparing ED visits by nursing home residents that did not lead to hospital admission (potentially preventable) with those that led to admission (less likely preventable). Nationally representative sample of US EDs; federal hospitals and hospitals with fewer than 6 beds were excluded. Older (age ≥65 years) NH residents with an ED visit during this time period. Patient demographics, ED visit information including testing performed, interventions (both procedures and medications) provided, and diagnoses treated. Older NH residents accounted for 3857 of 208,956 ED visits during the time period of interest (1.8%). When weighted to be nationally representative, these represent 13.97 million ED visits, equivalent to 1.8 ED visits annually per NH resident in the United States. More than half of visits (53.5%) did not lead to hospital admission; of those discharged from the ED, 62.8% had normal vital signs on presentation and 18.9% did not have any diagnostic testing before ED discharge. Injuries were 1.78 times more likely to be discharged than admitted (44.8% versus 25.3%, respectively, P < .001), whereas infections were 2.06 times as likely to be admitted as discharged (22.9% versus 11.1%, respectively). Computed tomography (CT) scans were performed in 25.4% and 30.1% of older NH residents who were discharged from the ED and admitted to the hospital, respectively, and more than 70% of these were CTs of the head. NH residents received centrally acting, sedating medications before ED discharge in 9.4% of visits. This nationally representative sample of older NH residents suggests ED visits for injury, those that are associated with normal triage vital signs, and those that are not associated with any diagnostic testing are potentially preventable. Those discharged from the ED often undergo important testing and receive medications that may alter their physical examination on return to the nursing facility, highlighting the need for seamless communication of the ED course to NHs.


Wanderings in biochemistry.
My Ph.D. thesis in the laboratory of Severo Ochoa at New York University School of Medicine in 1962 included the determination of the nucleotide compositions of codons specifying amino acids. The experiments were based on the use of random copolyribonucleotides (synthesized by polynucleotide phosphorylase) as messenger RNA in a cell-free protein-synthesizing system. At Yale University, where I joined the faculty, my co-workers and I first studied the mechanisms of protein synthesis. Thereafter, we explored the interferons (IFNs), which were discovered as antiviral defense agents but were revealed to be components of a highly complex multifunctional system. We isolated pure IFNs and characterized IFN-activated genes, the proteins they encode, and their functions. We concentrated on a cluster of IFN-activated genes, the p200 cluster, which arose by repeated gene duplications and which encodes a large family of highly multifunctional proteins. For example, the murine protein p204 can be activated in numerous tissues by distinct transcription factors. It modulates cell proliferation and the differentiation of a variety of tissues by binding to many proteins. p204 also inhibits the activities of wild-type Ras proteins and Ras oncoproteins.


Folding of a misfolding-prone beta-galactosidase in absence of DnaK.
In absence of chaperone DnaK, bacterially produced misfolding-prone proteins aggregate into large inclusion bodies, but still a significant part of these polypeptides remains in the soluble cell fraction. The functional analysis of the model beta-galactosidase fusion protein VP1LAC produced in DnaK(-) cells has revealed that the soluble version exhibits important folding defects and that it is less stable and less active than when produced in wild-type DnaK(+) cells. In addition, we have observed that the induction of gene expression at the very late exponential phase enhances twofold the stability of VP1LAC, a fact that in DnaK(-) background results in a dramatic increase of its specific activity up to phenotypically detectable levels. These results indicate that the chaperone DnaK is critical for the folding of misfolding-prone proteins and also that the soluble form reached in its absence by a fraction of polypeptides is not necessarily supportive of biological activity. In the case of E. coli beta-galactosidase, the catalytic activity requires assembling into tetramers and the fine organization of the activating interfaces holding the active sites, what might not be properly reached in absence of DnaK.


Open syntaxin docks synaptic vesicles.
Synaptic vesicles dock to the plasma membrane at synapses to facilitate rapid exocytosis. Docking was originally proposed to require the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) proteins; however, perturbation studies suggested that docking was independent of the SNARE proteins. We now find that the SNARE protein syntaxin is required for docking of all vesicles at synapses in the nematode Caenorhabditis elegans. The active zone protein UNC-13, which interacts with syntaxin, is also required for docking in the active zone. The docking defects in unc-13 mutants can be fully rescued by overexpressing a constitutively open form of syntaxin, but not by wild-type syntaxin. These experiments support a model for docking in which UNC-13 converts syntaxin from the closed to the open state, and open syntaxin acts directly in docking vesicles to the plasma membrane. These data provide a molecular basis for synaptic vesicle docking.


Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia.
Aceruloplasminemia is an autosomal recessive disorder of iron metabolism characterized by progressive neurodegeneration of the retina and basal ganglia in association with inherited mutations of the ceruloplasmin gene. To begin to elucidate the pathogenesis of this disease, ceruloplasmin gene expression was examined in human brain and retinal tissue. RNA blot analysis and RNAse protection studies demonstrate ceruloplasmin-specific transcripts in multiple regions of the human brain, and biosynthetic studies reveal ceruloplasmin synthesis and secretion in these same regions. Consistent with these observations, in situ hybridization of central nervous system tissue utilizing ceruloplasmin cRNA probes reveals abundant ceruloplasmin gene expression in specific populations of glial cells associated with the brain microvasculature, surrounding dopaminergic melanized neurons in the substantia nigra and within the inner nuclear layer of the retina. Taken in the context of the clinical and pathological features observed in patients with aceruloplasminemia, these data reveal that glial cell-specific ceruloplasmin gene expression is essential for iron homeostasis and neuronal survival in the human central nervous system.


Safety, immunogenicity, and efficacy against cholera challenge in humans of a typhoid-cholera hybrid vaccine derived from Salmonella typhi Ty21a.
A live oral vaccine consisting of attenuated Salmonella typhi Ty21a expressing Vibrio cholerae O1 Inaba lipopolysaccharide (LPS) O antigen was constructed and tested in volunteers for safety, immunogenicity, and efficacy. Fourteen adults ingested three doses of 10(10) viable organisms with buffer. One month later, 8 vaccinees and 13 unimmunized controls were challenged with 10(6) pathogenic V. cholerae O1 E1 T or Inaba organisms. No significant adverse reactions to vaccination were observed. All volunteers had significant rises in serum immunoglobulin G (IgG) antibody to S. typhi LPS. Only 2 (14%) of 14 had significant rises in serum IgA or IgG antibody to Inaba LPS, and 5 (36%) of 14 had fourfold rises in vibriocidal antibody. In the challenge study, diarrhea occurred in 13 of 13 controls and 6 of 8 vaccinees (vaccine efficacy, 25%; P = 0.13). The vaccine significantly reduced the severity of the clinical illness (P less than 0.05) and caused decreased excretion of challenge vibrios (P less than 0.05). Although the typhoid-cholera hybrid vaccine did not provide significant protection overall against experimental cholera, this study demonstrates the importance of antibody to V. cholerae O antigen in ameliorating clinical illness and illustrates the use of an S. typhi carrier vaccine strain expressing a foreign antigen.


A role for the migrating sperm surface antigen PH-20 in guinea pig sperm binding to the egg zona pellucida.
After the acrosome reaction, the PH-20 surface antigen of guinea pig sperm migrates from its original location on the posterior head surface to a new location on the inner acrosomal membrane (Myles, D.G., and P. Primakoff, 1984, J. Cell Biol., 99:1634-1641). We have isolated three monoclonal antibodies (MAbs) of the IgG1 subclass, PH-20, PH-21, and PH-22, that bind to the PH-20 antigen. The PH-20 MAb strongly inhibited (approximately 90%) sperm binding to the guinea pig egg zona pellucida at saturating antibody concentrations (greater than 20 micrograms/ml). Half-maximal inhibition of sperm binding to the zona was obtained with approximately 2 micrograms/ml PH-20 MAb. The PH-21 MAb at saturating concentration (50 micrograms/ml) partially inhibited (approximately 45%) sperm-zona binding, and the PH-22 MAb (50 micrograms/ml) did not inhibit (0%) sperm-zona binding. Essentially the same amounts of the three MAbs were bound to sperm under the conditions where inhibition (PH-20, PH-21) or no inhibition (PH-22) of sperm-zona binding was observed, which indicates that the different levels of inhibition did not arise from different levels of MAb binding. Competition binding assays with 125I-labeled MAbs showed that PH-21 binding to sperm was not affected by the binding of PH-20 or PH-22. However, that PH-20 and PH-22 blocked each other's binding to sperm suggests that their recognized determinants may be relatively close to one another. The results indicate that the migrating PH-20 antigen has a required function in sperm binding to the zona pellucida and that the PH-20 MAb affects is active site.


How Schools Affect Student Well-Being: A Cross-Cultural Approach in 35 OECD Countries.
A common approach for measuring the effectiveness of an education system or a school is the estimation of the impact that school interventions have on students' academic performance. However, the latest trends aim to extend the focus beyond students' acquisition of knowledge and skills, and to consider aspects such as well-being in the academic context. For this reason, the 2015 edition of the international assessment system Programme for International Student Assessment (PISA) incorporated a new tool aimed at evaluating the socio-emotional variables related to the well-being of students. It is based on a definition focused on the five dimensions proposed in the PISA theoretical framework: cognitive, psychological, social, physical, and material. The main purpose of this study is to identify the well-being components that significantly affect student academic performance and to estimate the magnitude of school effects on the well-being of students in OECD countries, the school effect being understood as the ability of schools to increase subjective student well-being. To achieve this goal, we analyzed the responses of 248,620 students from 35 OECD countries to PISA 2015 questionnaires. Specifically, we considered non-cognitive variables in the questionnaires and student performance in science. The results indicated that the cognitive well-being dimension, composed of enjoyment of science, self-efficacy, and instrumental motivation, as well as test anxiety all had a consistent relationship with student performance across countries. In addition, the school effect, estimated through a two-level hierarchical linear model, in terms of student well-being was systematically low. While the school effect accounted for approximately 25% of the variance in the results for the cognitive dimension, only 5-9% of variance in well-being indicators was attributable to it. This suggests that the influence of school on student welfare is weak, and the effect is similar across countries. The present study contributes to the general discussion currently underway about the definition of well-being and the connection between well-being and achievement. The results highlighted two complementary concerns: there is a clear need to promote socio-emotional education in schools, and it is important to develop a rigorous framework for well-being assessment. The implications of the results and proposals for future studies are discussed.


Lymphokine-activated killer (LAK) cells. V. 8-Mercaptoguanosine as an IL-2-sparing agent in LAK generation.
Guanine ribonucleosides, substituted at the C8 position with either a bromine or a thiol group, have recently been shown to regulate several immunologic responses. We have previously shown that 8-mercaptoguanosine (8MG) can replace the requirement for cytokines in the generation of MHC-restricted CTL. In this paper, we examined the ability of 8MG to induce MHC-nonrestricted killer cells. We found that 8MG did not induce significant lytic activity from normal resting lymphocytes. However, 8MG was able to synergize with minimal amounts of IL-2 in inducing lytic activity similar to lymphokine-activated killers (LAK) in that both NK-sensitive and NK-resistant tumor cells were killed. Both the precursors and effectors of 8MG-LAK activity were similar to NK cells and were CD4- CD8- asialo-GM1+ NK1.1+. Similar to IL-2-induced LAK, 8MG-LAK were B220+. 8MG appeared to "stage" these precursor lymphocytes to become more responsive to IL-2 because optimal induction of 8MG-LAK required preincubation with 8MG before the addition of IL-2. This "staging" appeared to be due to the release of a "second signal" since it was readily inhibited by cyclosporine A. Anti-IFN-alpha beta was as efficient as cyclosporine A in inhibiting 8MG-LAK generation, whereas anti-IFN-gamma and anti-IL-1 did not exhibit significant inhibition. These findings suggest that 8MG can be of possible utility as an IL-2-sparing agent in LAK generation from NK cells.


Cytotoxic and antineoplastic activity of timosaponin A-III for human colon cancer cells.
The potential antitumor activity of timosaponin A-III (1), a steroidal saponin from the rhizomes of Anemarrhena asphodeloides, was investigated in human colorectal cancer HCT-15 cells both in cell culture and in an in vivo murine xenograft model. Compound 1 inhibited the proliferation of cancer cells with cell-cycle arrest and induction of apoptosis. Cell-cycle arrest in the G0/G1 and G2/M phase by 1 was correlated with the down-regulation of cyclin A, cyclin B1, cyclin-dependent kinase 2 (CDK2), CDK4, proliferating cell nuclear antigen, and c-Myc. The increase of the sub-G1 peak by 1 was also closely related to the induction of apoptosis, which was evidenced by the induction of DNA fragmentation, activation of caspases, induction of cleaved poly-(ADP ribose) polymerase, and suppression of Bcl-xL and Bcl-2 expression. In an in vivo xenograft model, treatment with 1 (2 or 5 mg/kg body weight, three times/week, ip administration) for four weeks significantly suppressed tumor growth in athymic nude mice bearing HCT-15 cells, without any overt toxicity. Cell-cycle arrest and induction of apoptosis might be plausible mechanisms of actions for the observed antineoplastic activity of 1.


Relationship between upregulation of CD40 system and restenosis in patients after percutaneous coronary intervention.
To investigate whether the increasing CD40-CD40 ligand system is related to restenosis in patients after percutaneous coronary intervention (PCI). Twenty normal controls and 120 patients with PCI were investigated. The expression of CD40 and the CD40 ligand (CD40L) on platelets was analyzed by indirectimmunofluorescence flow cytometry. The serum level of soluble CD40L (sCD40L) and C-reactive protein (CRP) was determined by commercially available enzyme linked immunosorbent assay. Restenosis was observed in 120 patients within a 6 month follow-up period after PCI surgery. Restenosis occurred in 29 patients (24.2%). Patients who developed restenosis showed higher levels of CD40-CD40L system compared with non-restenotic patients before PCI. All restenotic patients showed a significant increase in CD40 [66.9 +/-4.8, mean fluorescence intensity (MFI)] and CD40L (14.9 +/-1.8, MFI) co-expression on platelets as well as sCD40L (13.7 +/-1.7 ng/mL) compared with non-restenotic patients and controls during the 6 month follow-up period (P<0.01). Elevated sCD40L and CD40L were significantly correlated with the serum level of CRP after percutaneous transluminal coronary angioplasty and with lumen loss during the 6 month followup period. The level of CD40L was associated with late restenosis after PCI indicating that restenosis is an inflammatory disorder.


Nanochannel-based heterometallic {ZnIIHoIII}-organic framework with high catalytic activity for the chemical fixation of CO2.
The exquisite combination of ZnII and HoIII generated the highly robust [ZnHo(CO2)6(OH2)]-based heterometallic framework of {[ZnHo(TDP)(H2O)]·5H2O·3DMF} n (NUC-30, H6TDP = 2,4,6-tri(2',4'-dicarboxyphenyl)pyridine), which featured outstanding physicochemical properties, including honeycomb nanochannels, high porosity, large specific surface area, the coexistence of highly open Lewis acid-base sites, good thermal and chemical stability, and resistance to most organic solvents. Due to its extremely unsaturated metal tetra-coordinated Zn(ii) ions, hepta-coordinated Ho(iii) and high faveolate void volume (61.3%), the conversion rate of styrene oxide and CO2 into cyclic carbonates in the presence of 2 mol% activated NUC-30 and 5 mol% n-Bu4NBr reached 99% under the mild conditions of 1.0 MPa and 60 °C. Furthermore, the luminescence sensing experiments proved that NUC-30 could be used as a fast, sensitive and highly efficiency sensor for the detection of Fe3+ in aqueous solution. Therefore, these results prove that nanoporous MOFs assembled from pyridine-containing polycarboxylate ligands have wide applications, such as catalysis and as luminescent materials.


Low-Temperature Curing Strength Enhancement in Cement-Based Materials Containing Limestone Powder.
With the ongoing sustainability movement, the incorporation of limestone powder in cementitious binders for concrete in the U.S. has become a subject of renewed interest. In addition to accelerating the early age hydration reactions of cementitious systems by providing additional surfaces for nucleation and growth of products, limestone powder is also intriguing based on its influence on low-temperature curing. For example, previous results have indicated that the utilization of limestone powder to replace one quarter of the fly ash in a high volume fly ash mixture (40 % to 60 % cement replacement) produces a reduction in the apparent activation energy for setting for temperatures below 25 °C. In the present study, the relationship between heat release and compressive strength of mortars at batching/curing temperatures of 10 °C and 23 °C is investigated. For Portland-limestone cements (PLC) with limestone additions on the order of 10 %, a higher strength per unit heat release is obtained after only 7 d of curing in lime water. Surprisingly, in some cases, the absolute strength of these mortar cubes measured at 7 d is higher when cured at 10 °C than at 23 °C. Solubilities vs. temperature, reaction stoichiometries and enthalpies, and projected phase distributions based on thermodynamic modeling for the cementitious phases are examined to provide some theoretical insight into this strength enhancement. For a subset of the investigated cements, thermogravimetric analysis (TGA), quantitative X-ray diffraction (XRD), and scanning electron microscopy (SEM) are conducted on 7-d paste specimens produced at the two temperatures to examine differences in their reaction rates and the phases produced. The strength enhancement observed in the PLC cements is related to the cement hydration products formed in the presence of carbonates as a function of temperature.


Does ceasing exercise induce depressive symptoms? A systematic review of experimental trials including immunological and neurogenic markers.
Regular exercise in adults improves depressive symptoms (DS) and major depressive disorder (MDD), however the clinical effects of ceasing exercise are largely unknown. Seven databases were searched from inception to December 2017. Eligibility criteria included English language studies investigating the effects of ceasing exercise on DS or MDD in regularly active adults with or without prior DS or MDD. Blood based markers related to exercise cessation (EC) were assessed, if recorded. Studies investigating exercise follow-up periods were excluded. No studies investigated EC in MDD. Six studies including two RCTS and three studies investigating neurogenic and immune biological markers associated with DS met inclusion criteria (152 healthy adults, females n = 50/32.89%). Compared to baseline, EC increased DS after three days, one week, and two weeks. Female participants had significantly more DS than male participants. Following EC, no changes in brain derived neurotrophic factor (BDNF) or tumour necrosis factor alpha (TNF) were evident, however C-reactive protein (CRP) at week one and interleukin 6 (IL6) at week two were reduced. Quality concerns including risks of attrition and reporting bias limit our confidence in these results. Ceasing regular exercise increases DS in healthy adults, with greater DS in females than males. Contrary to the cytokine/inflammatory hypothesis of depression, DS were associated with reduced CRP and IL6 and without increased TNF. High quality trials are needed to extend this field of research in both healthy and MDD populations.


A systematic review of variables associated with the relationship between obesity and depression.
Obesity is one of the leading causes of preventable diseases and disability worldwide, and depression is among the leading causes of burden of disease. Both disorders are increasingly prevalent and comorbid. This comorbidity compounds associated health. While there is consistent evidence of a bidirectional obesity depression relationship, little is known about the biopsychosocial variables associated with this relationship. A systematic review was undertaken to identify variables associated with the relationship between obesity (Body mass index > 30 kg m(-2) ) and depression. Forty-six studies were identified. Obesity, educational attainment, body image, binge eating, physical health, psychological characteristics and interpersonal effectiveness were consistently associated with the relationship between obesity and depression. The current review identified potential biopsychosocial variables associated with the relationship between obesity and depression. This knowledge can inform future research examining moderators, mediators and mechanisms of the relationship between obesity and depression. Improved understanding of this relationship will inform identification, prevention and intervention efforts.


Age and other risk factors for corneal infiltrative and inflammatory events in young soft contact lens wearers from the Contact Lens Assessment in Youth (CLAY) study.
To describe age and other risk factors for corneal infiltrative and inflammatory events (CIEs) in young, soft contact lens (SCL) wearers and to model the age-related risk. A multicenter, retrospective chart review of 3549 SCL wearers (8-33 years at first observed visit, +8.00 to -12.00D, oversampling <18 years) captured CIEs from January 2006 to September 2009. The review noted age, sex, SCL worn, use of lens care products, and SCL wearing history. Event diagnoses were adjudicated to consensus by reviewers masked to wearer identity, age, and SCL parameters. Significant univariate risk factors for CIEs were subsequently tested in multivariate generalized estimating equations. Charts from 14,305 visits observing 4,663 SCL years yielded 187 CIEs in 168 wearers. Age was a significant nonlinear risk factor, peaking between 15 and 25 years (P < 0.008). Less than 1 year of SCL use was protective versus longer years of wear (P < 0.0003). Use of multipurpose care products (2.86×), silicone hydrogels (1.85×), and extended wear (2.37×) were significantly associated with CIEs in the multivariate model (P < 0.0001 each). Patient age, years of lens wear, use of multipurpose care products, silicone hydrogels, and extended wear were all significantly associated with CIEs with SCL wear. Use of SCLs in young patients aged 8 to 15 years was associated with a lower risk of infiltrative events compared with teens and young adults. In terms of safety outcomes, SCLs appear to be an acceptable method of delivering optics designed to manage myopia progression in children and young teens in the future.


Acinetobacter dijkshoorniae is a later heterotypic synonym of Acinetobacter lactucae.
Acinetobacter lactucae and Acinetobacter dijkshoorniae were recently described as novel species, and both were reported to be closely related to Acinetobacter pittii. Because they were reviewed and published almost concurrently, their descriptions did not include a specific comparison between these two novel species. Genomic data were provided in both initial descriptions, which simplifies the comparisons. Genome comparisons based on in silico DNA-DNA hybridizations, average nucleotide identity and core genome phylogeny of the type strain genomes establish that these strains are conspecific. Based on the rules of priority, A. dijkshoorniae should be reclassified as a later heterotypic synonym of A. lactucae.


Evaluation of two different methods for per-oral gastrostomy tube placement in patients with motor neuron disease (MND): PIG versus PEG procedures.
Placement of a gastrostomy tube remains the gold standard procedure to maintain nutrition in patients with motor neuron disease (MND) and bulbar muscle weakness. Percutaneous endoscopic gastrostomy (PEG) is the most commonly used procedure in this context. Per-oral image guided gastrostomy (PIG) is a new hybrid technique used successfully in non-MND patients. We have modified the PIG technique to improve patient tolerability and have undertaken a pilot evaluation of PIG compared to PEG in MND patients. Nineteen PIG and 16 PEG procedures performed over a period of four years were evaluated. Pre-procedural forced vital capacity (FVC), procedural oxygen saturation, post-procedural complications and survival duration were recorded. Results showed that a gastrostomy tube was successfully placed in 95% of the PIG group and 80% of the PEG group. Rates of minor complications were comparable in both groups (21% in PIG, 23% in PEG). No life-threatening complications occurred in either group. Procedural mean oxygen saturations were higher in the PIG group compared to the PEG group (p < 0.001). No significant survival differences were observed. This study provides evidence for the use of the PIG procedure as a safe and well tolerated alternative to PEG in MND patients.


Potassium metabolism in the normal and ischemic heart cell.
Potassium is an important electrolyte in heart cells and has the greatest membrane permeability in the unexcited state. Hence it is responsible for th generation of the resting membrane potential. Clinical disorders of conduction and impulse formation occur within physiological values of serum potassium. Potassium is indirectly involved in excitation-contraction coupling, and its relation to intracellular calcium metabolism is reviewed. While potassium movements within the cell are metabolic-dependent, it is also true that the activity of metabolic pathways is affected by changes in potassium concentration. During anoxia and ischemia, sodium and calcium are gained by the myocyte, and potassium and magnesium are lost by the cell. At the same time, the action potential duration is abbreviated, the slope of the action potential downstroke (phase 2) is increased, and the resting membrane potential may be reduced. A relationship between disturbances in intracellular potassium and ischemic arrhythmias appears likely.


Variations in axial, proximal, and distal motor response to L-dopa in multisystem atrophy and Parkinson's disease.
The purpose of this study was to quantitatively compare the motor response to L-dopa in Parkinson's disease (PD) and striatonigral-type multisystem atrophy (MSA) patients. Ten consecutive MSA patients were compared with nine PD patients selected to have similar overall motor compromise, age, and mental state. The performance of simple repetitive axial movements plus bilateral proximal and distal limb movements; overall motor response assessed by the Unified Parkinson Disease Rating Scale (UPDRS); as well as scores from the UPDRS items evaluating speech/facial expression, postural stability, and posture/gait were assessed 90 min and 12 h (baseline) after L-dopa administration. The total UPDRS score, all subcategory scores, and all body movements improved significantly in the PD group. Proximal and distal limb akinesias and speech/facial expression improved in some MSA patients. Lack of response of axial akinesia to L-dopa in MSA correlates with a presumed greater loss of postsynaptic dopaminergic receptors in the dorsolateral putamen, while improvement in distal and proximal limb muscle akinesias in MSA patients may be related to relative preservation of the ventral putamen.


Comparison between quantitative measurements of diffusion tensor imaging and T2 signal intensity in a large series of cervical spondylotic myelopathy patients for assessment of disease severity and prognostication of recovery.
Cervical spondylotic myelopathy (CSM) is a common cause of spinal cord dysfunction. Recently, it has been shown that diffusion tensor imaging (DTI) may be a better biomarker than T2-weighted signal intensity (T2SI) on MRI for CSM. However, there is very little literature on a comparison between the quantitative measurements of DTI and T2SI in the CSM patient population to determine disease severity and recovery. A prospective analysis of 46 patients with both preoperative DTI and T2-weighted MRI was undertaken. Normalized T2SI (NT2SI), regardless of the presence or absence of T2SI at the level of maximum compression (LMC), was determined by calculating the T2SI at the LMC/T2SI at the level of the foramen magnum. Regression analysis was performed to determine the relationship of fractional anisotropy (FA), a quantitative measure derived from DTI, and NT2SI individually as well their combination with baseline preoperative modified Japanese Orthopaedic Association (mJOA) score and ∆mJOA score at the 3-, 6-, 12-, and 24-month follow-ups. Goodness-of-fit analysis was done using residual diagnostics. In addition, mixed-effects regression analysis was used to evaluate the impact of FA and NT2SI individually. A p value < 0.05 was selected to indicate statistical significance. Regression analysis showed a significant positive correlation between FA at the LMC and preoperative mJOA score (p = 0.041) but a significant negative correlation between FA at the LMC and the ΔmJOA score at the 12-month follow-up (p = 0.010). All other relationships between FA at the LMC and the baseline preoperative mJOA score or ∆mJOA score at the 3-, 6-, and 24-month follow-ups were not statistically significant. For NT2SI and the combination of FA and NT2SI, no significant relationships with preoperative mJOA score or ∆mJOA at 3, 6, and 24 months were seen on regression analysis. However, there was a significant correlation of combined FA and NT2SI with ∆mJOA score at the 12-month follow-up. Mixed-effects regression revealed that FA measured at the LMC was the only significant predictor of ΔmJOA score (p = 0.03), whereas NT2SI and time were not. Goodness-of-fit analysis did not show any evidence of lack of fit. In this large prospective study of CSM patients, FA at LMC appears to be a better biomarker for determining long-term outcomes following surgery in CSM patients than NT2SI or the combination values at LMC.


Primary pineal malignant melanoma.
Primary pineal malignant melanoma is a rare entity, with only thirteen cases reported in the world literature to date. We report a case of a 70-year-old man, who consulted with gait disturbance of six months duration, associated in the last month with dizziness, visual abnormalities and diplopia. No other additional melanocytic lesions were found elsewhere. The magnetic resonance showed a 25 mm expansive mass in the pineal gland that was associated with hydrocephaly, ventricular and transependimary oedema. The lesion was partially excised by a supracerebellar infratentorial approach. The histological examination revealed a melanoma. The patient received radiation therapy, but died of disease 16 weeks later. We herein review the literature on this rare tumour and comment on its clinical, radiological and histopathological features and differential diagnosis.


Myocarditis in Humans and in Experimental Animal Models.
Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against heart-specific antigens. In certain models, myocarditis is followed by the phenotype of dilated cardiomyopathy and the end stage of heart failure. This review describes the most commonly used mouse models of experimental myocarditis with a focus on the role of the innate and adaptive immune systems in induction and progression of the disease. The review discusses also advantages and limitations of individual mouse models in the context of the clinical manifestation and the course of the disease in humans. Finally, animal-free alternatives in myocarditis research are outlined.


Clinical Trial Registration: The Time Has Come.
Note from the AJOT Editor-in-Chief: AJOT has joined several other major rehabilitation and disability journals in a collaborative initiative to mandate clinical trial registration. Authors of manuscripts reporting clinical trials must ensure that the trials are registered before submitting their manuscript. For trials that are underway and are already enrolling patients, registration will be retrospective. This interim step achieves the goals of educating authors about trial registration and providing documentation of original study designs and primary outcome measures. Multiyear studies that were not registered before enrolling participants, are ongoing at the time of this editorial, and will not be completed before the January 1, 2017, deadline may be considered for publication in AJOT with special permission from the Editor-in-Chief. This permission must be obtained before submitting the manuscript for publication. By adopting these standards, we hope to further enhance the quality of AJOT articles. This editorial is reprinted from the Archives of Physical Medicine and Rehabilitation, 96, 2093. http://dx.doi.org/10.1016/j.apmr.2015.09.005.


Pretreatment HIV drug resistance and treatment failure in non-Italian HIV-1-infected patients enrolled in ARCA.
An increase in pretreatment drug resistance (PDR) to first-line antiretroviral therapy (ART) in low-income countries has been recently described. Herein we analyse the prevalence of PDR and risk of virological failure (VF) over time among migrants to Italy enrolled in ARCA. HIV-1 sequences from ART-naive patients of non-Italian nationality were retrieved from ARCA database from 1998 to 2017. PDR was defined by at least one mutation from the reference 2009 WHO surveillance list. Protease/reverse transcriptase sequences from 1,155 patients, mainly migrants from sub-Saharan Africa (SSA; 42%), followed by Latin America (LA; 25%) and Western countries (WE; 21%), were included. PDR was detected in 8.6% of sequences (13.1% versus 5.8% for B and non-B strains, respectively; P<0.001). 2.1% of patients carried a PDR for protease inhibitors (PIs; 2.1% versus 2.3%; P=0.893), 3.9% for nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs; 6.8% versus 2.1%; P<0.001) and 4.3% for non-nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs; 6.3% versus 3.1%; P=0.013). Overall, prevalence of PDR over the years remained stable, while it decreased for PIs in LA (P=0.021) and for NRTIs (P=0.020) among migrants from WE. Having more than one class of PDR (P=0.015 versus absence of PDR), higher viral load at diagnosis (P=0.008) and being migrants from SSA (P=0.001 versus WE) were predictive of VF, while a recent calendar year of diagnosis (P<0.001) was protective for VF. PDR appeared to be stable over the years in migrants to Italy enrolled in ARCA; however, it still remains an important cause of VF together with viral load at diagnosis.


Macular hole opercula. Ultrastructural features and clinicopathological correlation.
To investigate the ultrastructural features of idiopathic full-thickness macular hole (FTMH) opercula excised during vitrectomy and to correlate them with the outcome of surgery. Opercula were collected from eyes undergoing vitrectomy for stage 3 FTMH using noncrushing, cupped foreign body forceps. Following immediate fixation, specimens were processed for transmission electron microscopy. The ultrastructural features were correlated with the clinical data recorded for each patient before and after surgery. Eighteen specimens were studied. Native vitreous collagen was identified on the surface of all 18, while fragments of internal limiting membrane were present in 11 (61%). Eleven (61%) were found to contain only glia, comprising fibrous astrocytes and Müller cells in variable proportions. The remaining 7 (39%) were found to contain, in addition to glia, neurites and synaptic complexes, of which some were typical of cone photoreceptors. The initial surgical closure rate was significantly better in eyes in which only glia were present (9/11 [82%]), compared with those with neurites (1/7 [14%]) (P = .01). Once closure had been achieved with reoperation, the median final visual acuity was 20/60 in both groups (P = .26), although the likelihood of achieving an acuity of 20/40 or better was greater in the former (50%) than the latter group (17%). Two distinct types of opercula occur in association with stage 3 FTMH--those containing only glia (pseudo-opercula), which are probably associated with a foveal dehiscence and little or no loss of foveal tissue, and those containing both glia and a significant number of avulsed foveal cones (true opercula), which arise from a full-thickness foveal tear. Although the loss of foveal tissue in true opercula would seem to explain the worse initial anatomical and more modest visual results in some eyes, significant visual improvement may still be achieved after successful closure. The presence of neurites in true opercula suggests that, in at least some cases, direct traction on the foveal retina leads to macular hole formation.


3 beta-acetoxyandrost-1,5-diene-17-ethylene ketal functions as a potent antiandrogen with marginal agonist activity.
The majority of available antiandrogens have been reported to possess agonist activity to induce prostate-specific antigen, which might result in antiandrogen withdrawal syndrome. Here we report the identification of 3 beta-acetoxyandrost-1,5-diene-17-ethylene ketal (ADEK) from dehydroepiandrosterone metabolites and derivatives as a potent antiandrogen. We found ADEK could interrupt androgen binding to the androgen receptor (AR) and suppress androgen-induced transactivations of WT AR and a mutant AR in prostate cancer cells. ADEK inhibited prostate-specific antigen expression as well as growth in LNCaP prostate cancer cells stimulated by androgen. Importantly, ADEK had only marginal agonist effects, as compared with commonly used antiandrogens such as hydroxyflutamide and bicalutamide, leading to a lower possibility of inducing withdrawal response. Moreover, ADEK could block an adrenal androgen androstenediol-induced AR transactivation that hydroxyflutamide and bicalutamide failed to block. These unique antiandrogenic activities make ADEK a potential therapeutic compound that might be able to inhibit AR-mediated prostate cancer progression. Further in vivo studies might facilitate the development of a better antiandrogen for the treatment of prostate cancer.


[Microacupuncture therapy of pain syndromes of the lumbosacral portion of the peripheral nervous system].
Results of clinical and neurophysiological observations of 96 patients treated by the new method of microacupuncture are presented. This method is a modification of classical acupuncture, and consists of implantation of a specially designed micro-needle into the skin for a long time (one to three weeks). Possible mechanisms of the effects of this therapy method on the body are discussed. Recommendations on practical use of the microacupuncture method for treating vertebrogenic radicular syndromes are given.


No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease.
Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by defects in the activity of the lysosomal enzyme, glucocerebrosidase, resulting in intracellular accumulation of glucosylceramide (GlcCer). Neuronopathic forms, which comprise only a small percent of GD patients, are characterized by neurological impairment and neuronal cell death. Little is known about the pathways leading from GlcCer accumulation to neuronal death or dysfunction but defective calcium homeostasis appears to be one of the pathways involved. Recently, endoplasmic reticulum stress together with activation of the unfolded protein response (UPR) has been suggested to play a key role in cell death in neuronopathic forms of GD, and moreover, the UPR was proposed to be a common mediator of apoptosis in LSDs (Wei et al. (2008) Hum. Mol. Genet. 17, 469-477). We now systematically examine whether the UPR is activated in neuronal forms of GD using a selection of neuronal disease models and a combination of western blotting and semi-quantitative and quantitative real-time polymerase chain reaction. We do not find any changes in either protein or mRNA levels of a number of typical UPR markers including BiP, CHOP, XBP1, Herp and GRP58, in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. We conclude that the proposition that the UPR is a common mediator for apoptosis in all neurodegenerative LSDs needs to be re-evaluated.


Insurance Does Not Affect Adverse Events While Awaiting Surgery for Ankle Trauma in One System.
Ankle injuries that are not properly cared for can have devastating effects on a patient's health and ability to maintain an active lifestyle. Recommended outpatient surgery may be difficult to obtain for many groups of patients, including those without insurance or minority races. Patients who are of low socioeconomic status also have worse outcomes following trauma. The purpose of this study was to examine whether insurance status impacts the number of adverse events that patients face prior to receiving surgical treatment following an emergency department (ED) visit for an acute ankle injury. We conducted a retrospective chart review at two medical centers within the same healthcare system. The sample included 192 patients presenting to the ED with an unstable ankle injury between October 1, 2015- May 1, 2018. We used chi-square and t-test analysis to determine differences in rates of adverse events occurring while awaiting surgery. Few (4%) patients presented as being self-pay. Neither Medicare (χ2 (1) (N = 192) = 2.389, p = .122), Medicaid (χ2 (1), (N = 192) = .084, p = .772), other insurances (χ2 (1) (N = 192) = .567, p = .452), or private insurance (χ2 (1) (N=192) = .000, p = .982) was associated with a difference in rates of adverse events. Likewise, gender (χ2 (1) (N = 192) = .402, p = .526), race (χ2 (3) (N = 192) = 2.504, p = .475), and all other demographic variables failed to show a difference in occurrence of adverse events. Those admitted to the hospital did show a lower rate of adverse events compared to those sent home from the ED (χ2 (1) (N = 192) = 5.452, p = .020). Sampled patients were admitted to the hospital at a high rate (49%). The sampled facilities did not have adverse event rates that differed based on insurance status or demographic features. These facilities, with hospital-based subsidy programs and higher than expected admission rates, may manage their vulnerable populations well and may indicate their efforts to eliminate health disparity are effective.


Androgen Receptor regulation of Vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-Hydroxyvitamin D5 - a calcitriol analog.
Calcitriol (1,25(OH)(2)D3) is cytostatic for prostate cancer (CaP), but had limited therapeutic utility due to hypercalcemia-related toxicities, leading to the development of low-calcemic calcitriol analogs. We show that one analog, 1-α-Hydroxyvitamin-D5 (1α(OH)D5), induced apoptosis in castration-sensitive LNCaP prostate cancer cells, but unlike calcitriol, did not increase androgen receptor (AR) transcriptional activity. LNCaP-AI, a castrate-resistant (CRCaP) LNCaP subline, was resistant to 1α(OH)D5 in the presence of androgens; however, androgen withdrawal (AWD), although ineffective by itself, sensitized LNCaP-AI cells to 1α(OH)D5. Investigation of the mechanism revealed that the vitamin D receptor (VDR), which mediates the effects of 1α(OH)D5, is downregulated in LNCaP-AI cells compared to LNCaP in the presence of androgens, whereas AWD restored VDR expression. Since LNCaP-AI cells expressed higher AR compared to LNCaP and AWD decreased AR, this indicated an inverse relationship between VDR and AR. Further, AR stimulation (by increased androgen) suppressed VDR, while AR downregulation (by ARsiRNA) stimulated VDR levels and sensitized LNCaP-AI cells to 1α(OH)D5 similar to AWD. Another cell line, pRNS-1-1, although isolated from a normal prostate, had lost AR expression in culture and adapted to androgen-independent growth. These cells expressed the VDR and were sensitive to 1α(OH)D5, but restoration of AR expression suppressed VDR levels and induced resistance to 1α(OH)D5 treatment. Taken together, these results demonstrate negative regulation of VDR by AR in CRCaP cells. This effect is likely mediated by prohibitin (PHB), which was inhibited by AR transcriptional activity and stimulated VDR in CRCaP, but not castrate-sensitive cells. Therefore, in castration sensitive cells, although the AR negatively regulates PHB, this does not affect VDR expression, whereas in CRCaP cells, negative regulation of PHB by the AR results in concomitant negative regulation of the VDR by the AR. These data demonstrate a novel mechanism by which 1α(OH)D5 prolong the effectiveness of AWD in CaP cells.


Redox-sensitive homodimerization of Pex11p: a proposed mechanism to regulate peroxisomal division.
Pex11p (formerly Pmp27) has been implicated in peroxisomal proliferation (Erdmann, R., and G. Blobel. 1995. J. Cell Biol. 128; 509-523; Marshall, P.A., Y.I. Krimkevich, R.H. Lark, J.M. Dyer, M. Veenhuis, and J.M. Goodman, 1995. J. Cell Biol. 129; 345-355). In its absence, peroxisomes in Saccharomyces cerevisiae fail to proliferate in response to oleic acid; instead, one or two large peroxisomes are formed. Conversely, overproduction of Pex11p causes an increase in peroxisomal number. In this report, we confirm the function of Pex11p in organelle proliferation by demonstrating that this protein can cause fragmentation in vivo of large peroxisomes into smaller organelles. Pex11p is on the inner surface of the peroxisomal membrane. It can form homodimers, and this species is more abundant in mature peroxisomes than in proliferating organelles. Removing one of the three cysteines in the protein inhibits homodimerization. This cysteine 3-->alanine mutation leads to an increase in number and a decrease in peroxisomal density, compared with the wild-type protein, in response to oleic acid. We propose that the active species is the "monomeric" form, and that the increasing oxidative metabolism within maturing peroxisomes causes dimer formation and inhibition of further organelle division.


Epipregnanolone and a novel synthetic neuroactive steroid reduce alcohol self-administration in rats.
This study was designed to compare the effects of several neuroactive steroids with varying patterns of modulation of gamma-aminobutyric acid (GABA)(A) and NMDA receptors on operant self-administration of ethanol or water. Once stable responding for 10% (w/v) ethanol was achieved, separate test sessions were conducted in which male Wistar rats were allowed to self-administer ethanol or water following pre-treatment with vehicle or one of the following neuroactive steroids: (3beta,5beta)-3-hydroxypregnan-20-one (epipregnanolone; 5, 10, 20 mg/kg; n=12), (3alpha,5beta)-20-oxo-pregnane-3-carboxylic acid (PCA; 10, 20, 30 mg/kg n=10), (3alpha,5beta)-3-hydroxypregnan-20-one hemisuccinate (pregnanolone hemisuccinate; 5, 10, 20 mg/kg; n=12) and (3alpha,5alpha)-3-hydroxyandrostan-17-one hemisuccinate (androsterone hemisuccinate; 5, 10, 20 mg/kg; n=11). The effect of the 3beta-epimer of PCA, (3beta,5beta)-20-oxo-pregnane-3-carboxylic acid (10, 20, 30 mg/kg; n=9), on ethanol self-administration was also examined. The compounds were administered using a Latin-square design 45 min prior to the weekly test sessions. The effects of the 30 mg/kg dose of the steroidal hemisuccinates on ethanol intake were also examined 5 min after administration of these drugs. Both epipregnanolone and PCA attenuated ethanol self-administration. However, neither of the hemisuccinate compounds significantly altered this behavior. The steroidal hemisuccinates (30 mg/kg; n=7) were also tested 5 min before behavior testing and had no effect on ethanol intake 5 min after administration. The 3beta-epimer of PCA also failed to alter ethanol intake. None of the test compounds altered water intake. In electrophysiological studies, the effects of PCA and androsterone hemisuccinate on evoked GABA(A) receptor-mediated inhibitory postsynaptic currents (GABA(A)-IPSCs) was examined in brain slices of the amygdala. PCA had a stimulatory effect at concentrations of 5 and 25 muM. Androsterone hemisuccinate had no agonist activity. The ability of epipregnanolone and PCA to alter ethanol intake appears to be related to different inhibitory actions of these compounds on either GABA(A) or NMDA receptors, respectively. Thus, dual modulation of these systems by selected neuroactive steroids may offer potential for modifying the reinforcing effects of alcohol.


Stability of the nicotine metabolite ratio in ad libitum and reducing smokers.
The ratio of two nicotine metabolites, cotinine and trans-3'-hydroxycotinine (3-HC), has been validated as a method of phenotyping the activity of the liver enzyme cytochrome P450 (CYP) 2A6 and, thus, the rate of nicotine metabolism. Our objective was to evaluate the correlates and stability of the 3-HC to cotinine ratio in ad libitum and reducing smokers, using nicotine replacement therapy (NRT), over a period of months. Smokers (n = 123, 94% Caucasian) participated in a smoking reduction study, where one-third of the sample smoked ad libitum for 8 weeks (Waitlist phase), before joining the rest of the participants for 12 weeks of cigarette reduction (Reduction phase) using NRT. Urinary nicotine, cotinine, and 3-HC were measured at each visit. The baseline 3-HC to cotinine ratio was significantly but weakly correlated with cigarettes per day (r = 0.19), BMI (r = -0.27), and waking at night to smoke (r = 0.23). As assessed by repeated measure ANOVA, the 3-HC to cotinine ratio was stable in the Waitlist phase [coefficient of variation for 3 to 4 measurements, 38% (range, 5-110%)], whereas minor variation was noted in the Reduction phase [coefficient of variation for 3-5 measurements, 35% (range, 10-107%)]. In nonreducing ad libitum smokers, the 3-HC to cotinine ratio was generally stable, whereas during smoking reduction using NRT, some small variation was detected. Although the current findings are suggestive of the stability of the 3-HC to cotinine ratio in a predominantly Caucasian sample smoking freely or reducing smoking with NRT, additional research is needed in more diverse populations.


Clinical decision support with natural language processing facilitates determination of colonoscopy surveillance intervals.
With an increased emphasis on improving quality and decreasing costs, new tools are needed to improve adherence to evidence-based practices and guidelines in endoscopy. We investigated the ability of an automated system that uses natural language processing (NLP) and clinical decision support (CDS) to facilitate determination of colonoscopy surveillance intervals. We performed a retrospective study at a single Veterans Administration medical center of patients age 40 years and older who had an index outpatient colonoscopy from 2002 through 2009 for any indication except surveillance of a previous colorectal neoplasia. We analyzed data from 10,798 reports, with 6379 linked to pathology results and 300 randomly selected reports. NLP-based CDS surveillance intervals were compared with those determined by paired, blinded, manual review. The primary outcome was adjusted agreement between manual review and the fully automated system. κ statistical analysis produced a value of 0.74 (P < .001) for agreement between the full text annotation and the NLP-based CDS system. Fifty-five reports (18.3%; 95% confidence interval, 14.1%-23.2%) differed between manual review and CDS recommendations. Of these, NLP error accounted for 30 (54.5%), incomplete resection of adenomatous tissue accounted for 14 (25.5%), and masses observed without biopsy findings of cancer accounted for 4 (7.2%). NLP-based CDS surveillance intervals had higher levels of agreement with the standard (81.7%) than the level agreement between experts (72% agreement between paired reviewers). A fully automated system that uses NLP and a guideline-based CSD system can accurately facilitate guideline-recommended adherence surveillance for colonoscopy.


Dependency reduction with divisive normalization: justification and effectiveness.
Efficient coding transforms that reduce or remove statistical dependencies in natural sensory signals are important for both biology and engineering. In recent years, divisive normalization (DN) has been advocated as a simple and effective nonlinear efficient coding transform. In this work, we first elaborate on the theoretical justification for DN as an efficient coding transform. Specifically, we use the multivariate t model to represent several important statistical properties of natural sensory signals and show that DN approximates the optimal transforms that eliminate statistical dependencies in the multivariate t model. Second, we show that several forms of DN used in the literature are equivalent in their effects as efficient coding transforms. Third, we provide a quantitative evaluation of the overall dependency reduction performance of DN for both the multivariate t models and natural sensory signals. Finally, we find that statistical dependencies in the multivariate t model and natural sensory signals are increased by the DN transform with low-input dimensions. This implies that for DN to be an effective efficient coding transform, it has to pool over a sufficiently large number of inputs.


Prognostic value of left ventricular mitral annular longitudinal displacement obtained by tissue Doppler imaging in patients with heart failure with reduced ejection fraction.
Tissue Doppler imaging (TDI) can be used to measure the mitral annular longitudinal displacement (LD) during systole. However, the prognostic utility of global and regional LD in patients with heart failure with reduced ejection fraction (HFrEF) is unknown. Echocardiographic examinations from 907 patients with HFrEF were analysed obtaining conventional echocardiographic measurements. Regional LD was obtained from colour TDI projections in six mitral annular regions and global LD was calculated as an average. Mean age was 67 years, 26.9% were women and mean left ventricular ejection fraction was 27%. During a median follow-up period of 40 months, 150 (16.5 %) patients died. The risk of dying increased with decreasing tertile of global LD and was approximately five times higher for patients in the lowest tertile compared with the highest (1. tertile vs 3. tertile, HR 4.9, 95% CI: 3.0 to 7.9, p<0.001).Global LD was a significant independent predictor of mortality after adjusting for age, gender, body mass index, pacemaker, heart rate, atrial fibrillation, diabetes and conventional echocardiographic measures and global longitudinal strain: HR 1.16 (95% CI: 1.00 to 1.34, p=0.044) per 1 mm decrease.For regional measures, inferior LD was also a significant independent predictor in the multivariable model: HR 1.16 (95% CI: 1.04 to 1.29, p=0.006) and adding inferior LD to the conventional measures yielded a significant increase in Harrell's C-statistic (95% CI: 0.75 to 0.78, p=0.009). In patients with HFrEF, global and inferior LD are independent predictors of all-cause mortality. Furthermore, inferior LD proved to be a significant prognosticator when compared with all the conventional echocardiographic parameters.


Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma.
The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is activated by a diverse group of acidic ligands, including many peroxisome proliferator chemicals present in the environment. Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) signaling is activated by multiple cytokines and hormones and leads to the translocation of dimerized STAT proteins to the nucleus where they activate transcription of target genes. Previous studies have shown that growth hormone (GH)-activated STAT5b can inhibit PPAR-regulated transcription. Here, we show that this inhibitory cross-talk is mutual, and that GH-induced, STAT5b-dependent beta-casein promoter-luciferase reporter gene transcription can be inhibited up to approximately 80% by ligand-activated PPARalpha or PPARgamma. Dose-response experiments showed a direct relationship between the extent of PPAR activation and the degree of inhibition of STAT5-regulated transcription. PPAR did not block STAT5b tyrosine phosphorylation or inhibit DNA-binding activity. Both PPARs inhibited the transcriptional activity of a constitutively active STAT5b mutant, indicating that inhibition occurs downstream of the GH-stimulated STAT5 activation step. Transcriptionally inactive, dominant-negative PPAR mutants did not block STAT5b inhibition by wild-type PPAR, indicating that PPAR target gene transcription is not required. PPARalpha retained its STAT5b inhibitory activity in the presence of the histone deacetylase inhibitor trichostatin, indicating that enhanced histone deacetylase recruitment does not contribute to STAT5b inhibition. PPARalpha lacking the ligand-independent AF-1 trans-activation domain failed to inhibit STAT5b, highlighting the importance of the AF-1 region in STAT5-PPAR inhibitory cross-talk. These findings demonstrate the bidirectionality of cross-talk between the PPAR and STAT pathways and provide a mechanism whereby exposure to environmental chemical activators of PPAR can suppress expression of GH target genes.


Decadal changes in blood δ13C values, at-sea distribution, and weaning mass of southern elephant seals from Kerguelen Islands.
Changes in the foraging environment and at-sea distribution of southern elephant seals from Kerguelen Islands were investigated over a decade (2004-2018) using tracking, weaning mass, and blood δ13C values. Females showed either a sub-Antarctic or an Antarctic foraging strategy, and no significant shift in their at-sea distribution was detected between 2004 and 2017. The proportion of females foraging in sub-Antarctic versus Antarctic habitats did not change over the 2006-2018 period. Pup weaning mass varied according to the foraging habitat of their mothers. The weaning mass of sub-Antarctic foraging mothers' pups decreased by 11.7 kg over the study period, but they were on average 5.8 kg heavier than pups from Antarctic foraging mothers. Pup blood δ13C values decreased by 1.1‰ over the study period regardless of their sex and the presumed foraging habitat of their mothers. Together, these results suggest an ecological change is occurring within the Indian sector of the Southern Ocean with possible consequences on the foraging performance of southern elephant seals. We hypothesize that this shift in δ13C is related to a change in primary production and/or in the composition of phytoplankton communities, but this requires further multidisciplinary investigations.


Choroidal neovascular membrane inhibition in a laser treated rat model with intraocular sustained release triamcinolone acetonide microimplants.
To determine if intravitreal microimplants containing triamcinolone acetonide (TAAC) inhibit experimental fibrovascular proliferation (FVP) induced by laser trauma in a rat as a model of choroidal neovascular membranes (CNVMs). 20 anaesthetised male Brown Norway rats received a series of eight krypton red laser lesions per eye (647 nm, 0.05 s, 50 micro m, 150 mW). Three types of sterilised TAAC microimplant designs were evaluated: implant A consisting of 8.62% TAAC/20% polyvinyl alcohol (PVA) matrix (by dry weight); implant B consisting of 3.62% TAAC/20% PVA matrix; and implant C consisting of a dual 8.62% TAAC/20% PVA matrix design combined with a central core (0.5 mm) of compressed TAAC to extend the implant release time. For each animal studied, one eye received one of the three aforementioned TAAC implant designs, while the fellow eye received a control implant consisting of PVA but without TAAC. The animals were sacrificed at day 35 and ocular tissues were processed for histological analysis. Serial histological specimens were methodically assessed in a masked fashion to analyse each laser lesion for the presence or absence of FVP; maximum FVP thickness for each lesion was measured from the choriocapillaris. All three types of TAAC implants inhibited FVP relative to controls in a statistically significant fashion. In the eyes that received implant A (n = 8), the mean thickness of the recovered lesions (n = 36) measured 32 (SD 22) micro m, compared to 52 (30) micro m (p <0.005) for the recovered lesions (n = 40) from the fellow control eyes. In the eyes that received implant B (n = 6), the mean thickness of the recovered lesions (n = 31) measured 28 (15) micro m, compared to 50 (29) micro m (p <0.001) for the lesions (n = 19) recovered from the fellow control eyes. In the eyes that received implant C (n = 6), the mean thickness of the recovered lesions (n = 21) measured 39 (24) micro m, compared to 65 (30) micro m (p <0.001) for the lesions (n = 39) recovered from the fellow control eyes. All three of the tested TAAC microimplant designs produced potent inhibition of FVP in a rat model of CNVMs. There were no differences in inhibition of FVP between the three different types of implants evaluated. This study provides evidence that: (1) corroborates previous investigations that propose TAAC as a potential treatment for CNVMs in humans, and (2) demonstrates TAAC can be effectively delivered via long acting sustained release intraocular microimplants. It should be noted, however, that the FVP observed in this rat laser trauma may not reflect the CNVM observed in human with exudative age related macular degeneration (AMD).


Model selection with multiple regression on distance matrices leads to incorrect inferences.
In landscape genetics, model selection procedures based on Information Theoretic and Bayesian principles have been used with multiple regression on distance matrices (MRM) to test the relationship between multiple vectors of pairwise genetic, geographic, and environmental distance. Using Monte Carlo simulations, we examined the ability of model selection criteria based on Akaike's information criterion (AIC), its small-sample correction (AICc), and the Bayesian information criterion (BIC) to reliably rank candidate models when applied with MRM while varying the sample size. The results showed a serious problem: all three criteria exhibit a systematic bias toward selecting unnecessarily complex models containing spurious random variables and erroneously suggest a high level of support for the incorrectly ranked best model. These problems effectively increased with increasing sample size. The failure of AIC, AICc, and BIC was likely driven by the inflated sample size and different sum-of-squares partitioned by MRM, and the resulting effect on delta values. Based on these findings, we strongly discourage the continued application of AIC, AICc, and BIC for model selection with MRM.