Splicing of the c-src N1 exon is repressed by the polypyrimidine tract binding protein (PTB or PTBP1). During exon repression, the U1 snRNP binds properly to the N1 exon 5′ splice site but is made inactive by the presence of PTB. Examining the patterns of nuclease protection at this 5′ splice site, we find that the interaction of U1 is altered by the adjacent PTB. Interestingly, UV-crosslinking identifies a direct contact between the pre-mRNA-bound PTB and the U1 snRNA. EMSA, ITC and NMR studies show that PTB RRMs 1 and 2 bind the pyrimidine-rich internal loop of U1 snRNA stem loop 4. The PTB/U1 interaction prevents further assembly of the U1 snRNP with spliceosomal components downstream. This precise interaction between a splicing regulator and an snRNA component of the spliceosome points to a range of different mechanisms for splicing regulation.
In the context of image-guided left atrial fibrillation therapy, relatively very little work has been done to consider the changes that occur in the tissue during ablation in order to monitor therapy delivery. Here we describe a technique to predict the lesion progression and monitor the radio-frequency energy delivery via a thermal ablation model that uses heat transfer principles to estimate the tissue temperature distribution and resulting lesion. A preliminary evaluation of the model was conducted in ex vivo skeletal beef muscle tissue while emulating a clinically relevant tissue ablation protocol. The predicted temperature distribution within the tissue was assessed against that measured directly using fiberoptic temperature probes and showed agreement within 5°C between the model-predicted and experimentally measured tissue temperatures at prescribed locations. We believe this technique is capable of providing reasonably accurate representations of the tissue response to radio-frequency energy delivery.
atrial fibrillation therapy; image-guided catheter navigation; image-based radio-frequency ablation modeling; temperature distribution and lesion characterization
Patient-reported outcomes (PROs) capture how patients perceive their health and their health care; their use in clinical research is longstanding. Today, however, PROs increasingly are being used to inform the care of individual patients, and document the performance of health care entities. We recently wrote and internally distributed an institutional position statement titled “Harmonizing and Consolidating the Measurement of Patient-Reported Outcomes at Mayo Clinic: A Position Statement for the Center for the Science of Health Care Delivery”. The statement is meant to educate clinicians, clinical teams, and institutional administrators about the merits of using PROs in a systematic manner for clinical care and quality measurement throughout the institution. The present article summarizes the most important messages from the statement, describing PROs and their use, identifying practical considerations for implementing them in routine practice, elucidating potential barriers to their use, and formulating strategies to overcome these barriers. The lessons learned from our experience – including pitfalls, challenges, and successes – may inform other health care institutions that are interested in systematically using PROs in health care delivery science and practice.
patient-reported outcomes; questionnaire; patient-centered; quality of life; health care quality
Alternative splicing (AS) enables programmed diversity of gene expression across tissues and development. We show here that binding in distal intronic regions (>500 nucleotides (nt) from any exon) by Rbfox splicing factors important in development is extensive and is an active mode of splicing regulation. Similarly to exon-proximal sites, distal sites contain evolutionarily conserved GCATG sequences and are associated with AS activation and repression upon modulation of Rbfox abundance in human and mouse experimental systems. As a proof of principle, we validated the activity of two specific Rbfox enhancers in KIF21A and ENAH distal introns and showed that a conserved long-range RNA-RNA base-pairing interaction (an RNA bridge) is necessary for Rbfox-mediated exon inclusion in the ENAH gene. Thus we demonstrate a previously unknown RNA-mediated mechanism for AS control by distally bound RNA-binding proteins.
Vacuum-assisted closure induces microdeformations of the wound surface and accelerates healing of complex wounds; however, a thorough understanding of the biology of cellular mechanotransduction is lacking. We hypothesized that fibroblast shape and function can be altered in an in vitro vacuum-assisted closure device.
A 3-dimensional fibrin matrix with cultured murine fibroblasts and an intervening polyurethane foam was exposed to 125 mm Hg suction and compared with similar wells without suction. We measured fibroblast proliferation and morphology using fluorescence microscopy and gene expression change using real-time reverse-transcriptase polymerase chain reaction at 24, 48, and 72 hours.
Wells exposed to suction induced significant proliferation of fibroblasts and morphologic changes visible by larger, rounder, and notable dendrite-like branching and process extensions. Type 1 collagen alpha 1 (COL1A1), fibroblast growth factor 2 (FGF2, bFGF), and transforming growth factor beta 1 (TGFβ1) were all up-regulated after 48 hours of exposure to suction. Smooth muscle actin alpha 2 (Acta2, α-SMA) was up-regulated after 72 hours.
Microdeformations produced by the combination of polyurethane foam and suction are associated with increased fibroblast proliferation and up-regulation of gene expressions in fibroblasts.
vacuum-assisted closure (VAC); mechanotransduction; microdeformations; wound healing; fibroblast; collagen; smooth muscle actin; fibroblast growth factor; transforming growth factor; myofibroblast
Obtaining an orthopaedic surgery residency is competitive. Advisors must understand what factors may help unmatched candidates reapply successfully.
We determined (1) the attitude of leaders of orthopaedic surgery residency programs toward interviewing unmatched students; (2) whether a surgical internship or a research year is preferred in considering reapplicants; (3) the importance of United States Medical Licensing Examination (USMLE) scores, recommendations, and Alpha Omega Alpha (AOA) membership; and (4) whether academic and nonacademic programs evaluate reapplicants differently.
We sent an anonymous 19-question survey to 151 Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopaedic surgery residency programs in five waves, 1 week apart (December 5, 2009–January 5, 2010). Investigators were blinded to the respondents’ identities.
Ninety-one of the 151 programs (60%) responded. Sixty-eight of the 91 programs (75%) stated they rarely accept unmatched applicants. Sixty-eight programs (75%) agreed an unmatched applicant should do a surgery internship for 1 year. Of the 36 programs that recommended a research year, 32 were academic programs. Academic programs were more likely than nonacademic programs to view as important new recommendations (85% versus 67%), minimum scores of 220 on Step I (67% versus 49%) and Step II (64% versus 36%), and AOA membership (85% versus 67%).
By completing a surgical internship, unmatched students may increase their chances of matching. Students considering academic programs should ensure their academic record meets certain benchmarks and may consider a research year but risk limiting their acceptance to academic programs.
Chronic users of cannabis often report withdrawal symptoms after abstinence from use, but little is known about cannabis withdrawal in people with schizophrenia.
Cannabis use patterns and withdrawal symptoms in adults with schizophrenia who had at least weekly cannabis use before attempting to quit without formal treatment were assessed with the Marijuana Quit Questionnaire (MJQQ), a 176-item, semi-structured questionnaire.
120 participants, predominantly African–American (62.5%) and male (76.7%), met inclusion criteria. 20.1% reported that their first regular cannabis use (median age 15 years [range 8–48]) preceded their age at first psychotic symptoms (20 [4–50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble failing asleep (33.3%). One hundred-and-four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use.
Cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse, and deserves greater attention in treatment and research. Clinical Trials registration NCT00679016.
Schizophrenia; Marijuana; Co-morbidity; Cannabis; Withdrawal
The present study examined the extent to which sleep assessed soon after a trauma predicted subsequent physical health and immune functioning in rescue workers.
Participants included 159 men and women who performed rescue and clean-up operations at the site of a major airplane crash. One hundred twenty-eight participants were retained for a one-year follow-up. Self-report measures of sleep quality and psychological distress were obtained within 2 months of the crash, and a physical health questionnaire was completed at one-year follow-up. Natural killer (NK) cell number and cytotoxicity were assessed using blood samples collected from a subset of participants (n=51) at the one-year follow-up.
After adjusting for gender, age, BMI, and initial distress, initial sleep quality complaints were associated with more physical symptoms (β=.32, p<.001), poorer perceived health (β= −.27, p=.009), and increased health care utilization (β=.31, p=.003) at follow-up. In contrast, initial sleep quality was not associated with NK cell number (r=.10, p=.55) or activity (r=.02, p=.90). Change in sleep quality over the year following the crash was not a significant predictor of health or immune outcomes.
These data suggest that poor sleep quality in the aftermath of trauma signals increased risk for future adverse physical health outcomes, and underscore the importance of addressing sleep complaints soon after trauma to mitigate the negative impact on physical health.
trauma; sleep; health; natural killer cell; rescue worker
The splicing regulator Polypyrimidine Tract Binding Protein (PTBP1) has four RNA binding domains that each binds a short pyrimidine element, allowing recognition of diverse pyrimidine-rich sequences. This variation makes it difficult to evaluate PTBP1 binding to particular sites based on sequence alone and thus to identify target RNAs. Conversely, transcriptome-wide binding assays such as CLIP identify many in vivo targets, but do not provide a quantitative assessment of binding and are informative only for the cells where the analysis is performed. A general method of predicting PTBP1 binding and possible targets in any cell type is needed. We developed computational models that predict the binding and splicing targets of PTBP1. A Hidden Markov Model (HMM), trained on CLIP-seq data, was used to score probable PTBP1 binding sites. Scores from this model are highly correlated (ρ = −0.9) with experimentally determined dissociation constants. Notably, we find that the protein is not strictly pyrimidine specific, as interspersed Guanosine residues are well tolerated within PTBP1 binding sites. This model identifies many previously unrecognized PTBP1 binding sites, and can score PTBP1 binding across the transcriptome in the absence of CLIP data. Using this model to examine the placement of PTBP1 binding sites in controlling splicing, we trained a multinomial logistic model on sets of PTBP1 regulated and unregulated exons. Applying this model to rank exons across the mouse transcriptome identifies known PTBP1 targets and many new exons that were confirmed as PTBP1-repressed by RT-PCR and RNA-seq after PTBP1 depletion. We find that PTBP1 dependent exons are diverse in structure and do not all fit previous descriptions of the placement of PTBP1 binding sites. Our study uncovers new features of RNA recognition and splicing regulation by PTBP1. This approach can be applied to other multi-RRM domain proteins to assess binding site degeneracy and multifactorial splicing regulation.
A key step in the regulation of mammalian genes is the splicing of the messenger RNA precursor to produce a mature mRNA that can be translated into a particular protein needed by the cell. Through the process of alternative splicing, mRNAs encoding different proteins can be derived from the same primary gene transcript. The regulation of this process plays essential roles in the development of differentiated tissues and is mediated by special pre-mRNA binding proteins. To understand how these proteins control gene expression, one must characterize what they recognize in RNA and identify these binding sites across the genome in order to predict their targets. Models that allow this prediction are essential to understanding developmental regulatory programs and their perturbation by disease causing mutations. In this study, we use statistical methods to build models of RNA recognition by the important splicing regulator PTBP1 and then apply these models to predict PTBP1 regulation of new gene transcripts. We show that PTBP1 has different specificity for RNA than was previously recognized and that its target exons are more diverse than was known before. There are many similar splicing regulators in mammalian cells, and these analyses provide a general framework for the computational analysis of their RNA binding and target identification.
The success or failure of programs designed to address alcohol and drug problems can be profoundly influenced by the communities where they are located. Support from the community is vital for long term stability and conflict with the community can harm a program’s reputation or even result in closure. This study examined the community context of sober living houses (SLHs) in one Northern California community by interviewing key stakeholder groups. SLHs are alcohol and drug free living environments for individuals attempting to abstain from substance use. Previous research on residents of SLHs showed they make long-term improvements on measures of substance use, psychiatric symptoms, arrests, and employment. Interviews were completed with house managers, neighbors, and key informants from local government and community organizations. Overall, stakeholders felt SLHs were necessary and had a positive impact on the community. It was emphasized that SLHs needed to practice a “good neighbor” policy that prohibited substance use and encouraged community service. Size and density of SLHs appeared to influence neighbor perceptions. For small (six residents or less), sparsely populated houses, a strategy of blending in with the neighborhood seemed to work. However, it was clear that larger, densely populated houses need to actively manage relationships with community stakeholders. Strategies for improving relationships with immediate neighbors, decreasing stigma, and broadening the leadership structure are discussed. Implications for a broad array of community based programs are discussed.
Sober Living Houses; Residential Treatment; Environmental Influences; Neighborhood; NIMBY
We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2−/− neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron.
Cells within the developing brain undergo an extended period of maturation. A neuronal progenitor cell must first migrate to the proper place within the brain and then develop long extensions that become the axon and dendrites used by the mature neuron to communicate with other cells. Finally, the synapses that connect neurons with other neurons must be established. Multiple mechanisms are needed to ensure that all the proteins involved in this process are expressed when and where they are needed.
The production of a protein begins with a region of DNA being transcribed to produce an RNA transcript that consists of segments called exons separated by segments called introns. This transcript then undergoes a process called splicing that involves the introns being removed and the exons being joined together to form a messenger RNA molecule that can be translated into protein. Specialized RNA binding proteins regulate the splicing process, and most RNA transcripts are subject to a form of splicing called alternative splicing that allows a single gene to express more than one messenger RNA molecule and hence more than one protein product.
As neuronal progenitor cells in the brain are induced to mature into neurons, many RNA transcripts are seen to change their splicing patterns. At the same time, the level of a regulatory RNA binding protein called PTBP1 decreases and the level of a related protein called PTBP2 increases. Now Li et al. have studied mutant mice that lack PTBP2, and have found that structures of the forebrain that normally undergo extensive development after birth instead experience tissue degeneration when PTBP2 is absent. Similarly, when neurons lacking PTPB2 are grown in culture, they fail to develop correctly and die.
Li et al. also found that messenger RNAs from many genes involved in postnatal brain development—affecting processes such as the growth of axons and dendrites and the formation of synapses—exhibit defective alternative splicing in the mutant mice. Specifically, protein variants that would normally be expressed only in adult brains were being expressed much earlier.
By inhibiting the expression of adult forms of proteins until neurons have matured, PTBP2 plays an essential role in controlling the brain’s early development. Further work is now required to determine how individual changes in messenger RNA and protein structure controlled by PTBP2 might alter protein function between immature and mature neurons.
alternative splicing; RNA binding protein; neuronal development; gene regulation; mouse
Elevated atmospheric CO2 can change foliar tissue chemistry. This alters leaf litter palatability to macroinvertebrate detritivores with consequences for decomposition, nutrient turnover, and food-web structure. Currently there is no consensus on the link between CO2 enrichment, litter chemistry, and macroinvertebrate-mediated leaf decomposition. To identify any unifying mechanisms, we presented eight invertebrate species from aquatic and terrestrial ecosystems with litter from Alnus glutinosa (common alder) or Betula pendula (silver birch) trees propagated under ambient (380 ppm) or elevated (ambient +200 ppm) CO2 concentrations. Alder litter was largely unaffected by CO2 enrichment, but birch litter from leaves grown under elevated CO2 had reduced nitrogen concentrations and greater C/N ratios. Invertebrates were provided individually with either (i) two litter discs, one of each CO2 treatment (‘choice’), or (ii) one litter disc of each CO2 treatment alone (‘no-choice’). Consumption was recorded. Only Odontocerum albicorne showed a feeding preference in the choice test, consuming more ambient- than elevated-CO2 birch litter. Species’ responses to alder were highly idiosyncratic in the no-choice test: Gammarus pulex and O. albicorne consumed more elevated-CO2 than ambient-CO2 litter, indicating compensatory feeding, while Oniscus asellus consumed more of the ambient-CO2 litter. No species responded to CO2 treatment when fed birch litter. Overall, these results show how elevated atmospheric CO2 can alter litter chemistry, affecting invertebrate feeding behaviour in species-specific ways. The data highlight the need for greater species-level information when predicting changes to detrital processing–a key ecosystem function–under atmospheric change.
Individuals with alcohol problems often receive pressure to change their drinking. However, when they enter treatment it is unclear how often it is because of the pressure they received or other reasons.
A secondary analysis was conducted using four cross sectional National Alcohol Surveys (NASs) collected at 5-year intervals between 1995 and 2010. Treatment seekers (N=476) were interviewed about 1) all reasons for seeking treatment, 2) their primary reason, 3) lifetime heavy drinking, and 4) whether they ever received pressure from six different sources (spouse, family, friends, doctor, work and police).
Over 90% of the sample received pressure from at least one source. Thirty-four percent identified legal problems/felt forced as their primary reason for seeking treatment. Other primary reasons included a desire to improve relationships (25%) and health (15%). When asked about all reasons, 46% endorsed five or more reasons and 74% included legal problems/felt forced. When pressure was received from police it was often the primary reason for seeking treatment. When pressure was received from physicians or work, legal problems/felt forced was less likely to be the primary reason. Most reasons, including legal problems/felt forced, did not change significantly over time.
A primary reason for seeking alcohol treatment is drinking-related legal problems or feeling forced. However, legal problems/feeling forced occurs along with a variety of additional reasons. Future research should assess pathways between receipt of pressure from different sources, recognition of different types of problems, and reasons given for seeking treatment.
treatment entry; alcohol services; reasons for seeking help; treatment barriers; drinking Pressure
Clinical pharmacy services have been shown to reduce adverse drug events and health care costs. However, few studies have assessed their effect on patient outcomes in the intensive care unit (ICU).
To describe characteristics of ICU patients with documented pharmacist interventions and to evaluate the relationships between patients’ complexity level and pharmacists’ interventions and between pharmacists’ interventions and mortality rate.
Inpatient records of admissions between January 1, 2004, and March 31, 2007, were analyzed to identify the presence of clinical pharmacy notes (CPNs). The characteristics of patients with and without CPNs were compared using descriptive statistics. For primary analysis of the association between patient complexity level and presence of CPNs, logistic regression modelling was performed to adjust for potential confounding. Logistic regression was also used to explore the possible association between CPNs and mortality. Finally, mortality analysis was carried out for patients with and without CPNs, with matching by complexity level.
The main study cohort comprised 1561 patients: 333 (21.3%) with CPNs and 1228 (78.7%) with no CPNs. A greater proportion of those with a CPN had the highest complexity level: 295 (88.6%) of those with CPNs versus 660 (53.7%) of those with no CPNs. After adjustment for age and sex, the odds ratio for having a CPN among patients with complexity level 4 (relative to patients with lower complexity levels) was 8.20 (95% confidence interval 5.44–12.38). Mortality rates were not significantly different between the 2 groups: 26.7% (89/333) among patients with CPNs and 27.9% (343/1228) among those without CPNs (p = 0.66). After adjustment for age, sex, complexity level, and length of stay in the ICU, the presence of a CPN was not significantly associated with mortality. Mortality rates in the matched cohort (n = 1078) were also similar between patients with and without CPNs (89/333 [26.7%] and 226/745 [30.3%], respectively; p = 0.23), and the presence of a CPN was not significantly associated with mortality after adjustments for potential confounding factors.
Documenting clinical pharmacy activities is essential for assessing pharmacists’ impact on patient outcomes. These data suggest that ICU pharmacists prioritize clinical activities to care for the sickest patients.
clinical pharmacy; documentation; patient outcomes; interventions; mortality; length of stay; pharmacie clinique; consignation; résultats thérapeutiques; interventions; mortalité; durée du séjour
We develop a Bayesian model for the alignment of two point configurations under the full similarity transformations of rotation, translation and scaling. Other work in this area has concentrated on rigid body transformations, where scale information is preserved, motivated by problems involving molecular data; this is known as form analysis. We concentrate on a Bayesian formulation for statistical shape analysis. We generalize the model introduced by Green and Mardia for the pairwise alignment of two unlabeled configurations to full similarity transformations by introducing a scaling factor to the model. The generalization is not straight-forward, since the model needs to be reformulated to give good performance when scaling is included. We illustrate our method on the alignment of rat growth profiles and a novel application to the alignment of protein domains. Here, scaling is applied to secondary structure elements when comparing protein folds; additionally, we find that one global scaling factor is not in general sufficient to model these data and, hence, we develop a model in which multiple scale factors can be included to handle different scalings of shape components.
Morphometrics; protein bioinformatics; similarity transformations; statistical shape analysis; unlabeled shape analysis
Colorectal cancer (CRC) can be prevented by the early detection and removal of advanced adenomas (AAs) by colonoscopy. Our aim was to evaluate peripheral blood leukocyte (PBL) telomere length as a potential biomarker for the presence of AAs.
PBL telomere length was measured in patients with AAs (n = 35), in a control group of similar-aged patients who had a normal colonoscopy (n = 145) and in a separate population group with no history of cancer, again similarly aged (n = 495). Telomere measurements were performed using a quantitative PCR assay and reported a ratio of telomere and single copy gene measurements.
Telomere lengths tended to be lower in the patients with AAs than in patients in the normal colonoscopy group (p < 0.001) as well as those in the population group (p = 0.011). A telomere/single copy gene ratio of 0.5 was found to have an estimated 94% sensitivity and 56% specificity for AAs; a combination of sensitivity and specificity for which a value of >0.5 would reduce the odds of a patient having AAs by a factor of 0.11 (the negative likelihood ratio). Thirty three percent of individuals in the population group tested above this cut off and could be considered at low risk for AAs.
PBL telomeres are shortened in patients with colorectal neoplasia suggesting that PBL telomere length could be a promising non-invasive blood biomarker to pre-screen for risk of AAs prior to colonoscopy.
Telomeres; Colorectal polyps; Colorectal adenomas
HMGB1 released from necrotic cells or macrophages functions as a late inflammatory mediator, and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca2+ transients using fluo-3, and L-type calcium currents using whole cell perforate configuration of the patch clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca++ transient within 5 min (p <0.01). The immediate negative inotropic effects HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward L-type calcium currents also was documented by the patch clamp technique. HMGB1 induced the PKCε translocation and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx, and suggest that HMGB1 maybe act as a novel myocardial depressant factor during cardiac injury.
Inflammation; innate immunity; myocardial function; sepsis
The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a pro-inflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.
Tumor necrosis factor; transforming growth factor; myocardial fibrosis; transgenesi
A large majority of women entering addiction treatment present significant symptoms of trauma related to physical or sexual abuse. Despite research indicating that trauma interventions are integral to women’s successful recovery from addiction, many programs do not adequately address violence-related trauma. This chapter provides a review of the literature on trauma among women with addictive disorders and several manual based interventions developed to address co-occurring addiction and trauma-related disorders. One intervention, “Beyond Trauma,” which has become increasingly popular among community based programs is described in detail. Beyond Trauma appears to have several advantages over other therapies for treating trauma and addiction in women, including 1) a theoretical foundation that draws on relational theory as a guide to the intervention, 2) a broad based approach that can be utilized by a variety of professional and paraprofessional staff members, 3) a focus that goes beyond treating women with a formal diagnosis of post traumatic stress disorder to include treatment for an array of symptoms and problems associated with trauma, and 4) gender-appropriate use of expressive arts in its curriculum. The chapter also discusses treatment program environment factors that may be critically important to treatment outcome for women: 1) whether the program is gender specific, 2) the degree of emphasis on peer involvement in recovery, 3) program recognition of the value of knowledge-based recovery experience, 4) program facilitation of cohesion, 5) the empowerment of clients in decisions affecting the program and 6) skills training relevant to managing moods, relationships and a variety of problems that women face during recovery. Possible mechanisms of change for Beyond Trauma are explored with particular emphasis on the variety of ways the intervention attempts to impact problem areas experienced by women (e.g., mental health functioning self esteem and social support). Recommendations for future research in the treatment of trauma and addiction-related disorders in women are outlined.
Trauma; Women; Addiction; Recovery; Post Traumatic Stress Disorder
Trace elements have been hypothesised to be involved in the pathogenesis of Multiple Sclerosis and volcanic degassing is the major natural sources of trace elements. Both incidence of Multiple Sclerosis in Catania and volcanic activity of Mount Etna have been significantly increased during the last 30 years. Due to prevailing trade winds direction, volcanic gases from Etna summit craters are mostly blown towards the eastern and southern sectors of the volcano.
To evaluate the possible association between Multiple Sclerosis and exposure to volcanogenic trace elements.
We evaluated prevalence and incidence of Multiple Sclerosis in four communities (47,234 inhabitants) located in the eastern flank and in two communities (52,210 inhabitants) located in the western flank of Mount Etna, respectively the most and least exposed area to crater gas emissions.
A higher prevalence was found in the population of the eastern flank compared to the population of the western one (137.6/100,000 versus 94.3/100,000; p-value 0.04). We found a borderline significantly higher incidence risk during the incidence study period (1980–2009) in the population of the eastern flank 4.6/100,000 (95% CI 3.1–5.9), compared with the western population 3.2/100,000 (95% CI 2.4–4.2) with a RR of 1.41 (95% CI 0.97–2.05; p-value 0.06). Incidence risks have increased over the time in both populations reaching a peak of 6.4/100,000 in the eastern flank and of 4.4/100.000 in the western flank during 2000–2009.
We found a higher prevalence and incidence of Multiple Sclerosis among populations living in the eastern flank of Mount Etna. According to our data a possible role of TE cannot be ruled out as possible co-factor in the MS pathogenesis. However larger epidemiological study are needed to confirm this hypothesis.
Ischemic cardiac injury is the leading cause of heart failure and mortality in the US, and a major expense to health care systems. Once the heart is injured, a highly dynamic and coordinated immune response is initiated, which is dependent on both resident and recruited leukocytes. The goal of the inflammatory response is to remove ischemic and necrotic material, and to promote infarct healing. If this system is perturbed, the myocardium heals poorly, leading to significant left ventricular dysfunction. Understanding how inflammatory cells coordinate and interact with each other is required prior to designing therapeutic interventions that target pathological processes at play, and leave untouched those processes that are protective. This review will discuss the intercellular cross talk between cells of the innate immune system following myocardial ischemic injury and how that response is coordinated over time.
Myocardial infarction; innate immunity; monocyte; T cell; neutrophil
Younger women with breast cancer consistently show greater psychological distress than older women. This study examined a range of factors that might explain these age differences. A total of 653 women within 8 months of a first-time breast cancer diagnosis provided data on patient characteristics, symptoms, and psychosocial variables. Chart reviews provided cancer and treatment-related data. The primary outcome was depressive symptomatology assessed by the Beck Depression Inventory. A succession of models that built hierarchically upon each other was used to determine which variables could account for age group differences in depression. Model 1 contained age group only. Models 2–5 successively added patient characteristics, cancer-related variables, symptoms, and psychosocial variables. As expected, in the unadjusted analysis (Model 1) younger women were significantly more likely to report depressive symptomatology than older women (p < 0.0001). Age remained significantly related to depression until Model 4 which added bodily pain and vasomotor symptoms (p = 0.24; R = 0.27). The addition of psychosocial variables in Model 5 also resulted in a model in which age was nonsignificant (p = 0.49; R2 = 0.49). Secondary analyses showed that illness intrusiveness (the degree that illness intrudes on specific areas of life such as work, sex life, recreation, etc.) was the only variable which, considered individually with age, made the age group-depression association nonsignificant. Age differences in risk of depression following a breast cancer diagnosis can be explained by the impact of cancer and its treatment on specific areas of a woman’s life.
Breast; Cancer; Oncology; Depression; Age; Pain; Psychosocial; Survivors
The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Non Matching-to-Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore et al, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought.
Dorsal prefrontal cortex; Delayed Non-matching to Sample; Recognition memory; Rule learning; Rhesus monkey
Disability is the result of interactions between biological and environmental factors including the physical, economic, and social barriers imposed on an individual by society. In low and middle-income countries, limited attention has been given to the situation of individuals with intellectual disabilities, who remain seriously neglected. Given the lack of resources available to address mental disorders, it is essential to examine the role of socioeconomic and socio-cultural factors in the lives of these individuals. We conducted interviews of key informants and community members in a shantytown community in Lima, Peru, to explore public knowledge, perceptions, and attitudes regarding intellectual disability. Findings indicated that the most important concern for community members was the longstanding issues associated with poverty. There was a profound lack of awareness of intellectual disability among the general population and an absence of social integration for these individuals. However, interviewees also recognized the productive potential of persons with intellectual disabilities provided they received currently inaccessible support services. The results suggest that educational efforts and intervention strategies must be mindful of the challenges of chronic poverty in order to successfully facilitate the social integration of individuals with intellectual disabilities into the community.
Disability; Intellectual disability; Poverty; Social integration; Policy