Analysis of Cardiac Ion Channels to Understand Arrhythmias Which Lead to Sudden Cardiac Death

There are 300,000-400,000 fatalities attributed to sudden cardiac death every year in the U.S. due to a lack of sufficient research on mechanisms causing arrhythmias1. Malfunctions with the ion channels in the heart may lead to lethal arrhythmias. The purpose of this work is to study ion channels and evaluate malfunctions relative to normally functioning hearts. Plasmid insertion in E. coli assayed whether functional ion channels reach the membrane, and confocal fluorescent microscopy was used to illuminate cellular functionality. In addition, genetic analysis was used to determine the extent of hereditary factors in sudden cardiac death. Genes that encode for the voltage-gated sodium, potassium, and calcium ion channels were analyzed at the genetic level using isolated DNA samples and traditional Sanger sequencing methods to identify mutations that may be responsible for sudden cardiac death syndromes. For example, Long QT syndrome, Short QT syndrome, and Brugada syndrome are caused by mutations in these ion channels. Once these mutations are identified, genetic engineering techniques can be used in the generation of new heart cells from the stem cells found in somatic tissue. Generation of such heart cells is important because it could lead to the development of personalized treatment for degenerative diseases such as heart failure in the future. Rubart, M. et al., Mechanisms of Sudden Cardiac Death, 2005. J. clin. invest. 115(9):2305-2315

Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity

We have identified a novel autoantibody specificity in scleroderma that we term anti-chromo. These antibodies recognize several chromosomal antigens with apparent molecular mass of between 23 and 25 kDa, as determined by immunoblots. Anti-chromo autoantibodies occur in 10-15% of sera from patients with anti-centromere antibodies (ACA). We used anti-chromo antibodies to screen a human expression library and obtained cDNA clones encoding a 25 kDa chromosomal autoantigen. DNA sequence analysis reveals this protein to be a human homologue of HP1, a heterochromatin protein of Drosophila melanogaster. We designate our cloned protein HP1Hs alpha. Epitope mapping experiments using both human and Drosophila HP1 reveal that anti-chromo antibodies target a region at the amino terminus of the protein. This region contains a conserved motif, the chromo domain (or HP1/Pc box), first recognized by comparison of Drosophila HP1 with the Polycomb gene product. Both proteins are thought to play a role in creating chromatin structures in which gene expression is suppressed. Anti-chromo thus defines a novel type of autoantibody that recognizes a conserved structural motif found on a number of chromosomal proteins

Adult Development: Capturing New Ways of Thinking About the Life Course

We outline first a brief overview of a four-fold typology of developmental theory (biological, psychological, sociocultural an integrative models). We then discuss work that illustrates two of these frames: the sociocultural, which includes racial and ethnic, and relational aspects of development; and the integrative, focusing on time, development as narrative, and spiritual development. We close with a commentary on the current developmental literature and how this literature challenges our practice as adult educators

Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

SummaryCancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1+ CD11b+ cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1+ CD11b+ cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development—a finding that was dependent on CD8+ T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment

Gender Equity in Transplantation: A Report From the Women in Transplantation Workshop of The Transplantation Society of Australia and New Zealand

The exponential growth of young talented women choosing science and medicine as their professional career over the past decade is substantial. Currently, more than half of the Australian medical doctoral graduates and early career researchers are comprised of women, but less than 20% of all academic professorial staff are women. The loss of female talent in the hierarchical ladder of Australian academia is a considerable waste of government investment, productivity, and scientific innovation. Gender disparity in the professional workforce composition is even more striking within the field of transplantation. Women are grossly underrepresented in leadership roles, with currently no female heads of unit in any of the Australian and New Zealand transplanting centers. At the same time, there is also gender segregation with a greater concentration of women in lower-status academic position compared with their male counterparts. Given the extent and magnitude of the disparity, the Women in Transplantation Committee, a subcommittee of The Transplantation Society of Australia and New Zealand established a workshop comprising 8 female clinicians/scientists in transplantation. The key objectives were to (i) identify potential gender equity issues within the transplantation workforce; (ii) devise and implement potential strategies and interventions to address some of these challenges at a societal level; (iii) set realistic and achievable goals to enhance and facility gender equality, equity, and diversity in transplantation

Probable tacrolimus toxicity from tibolone co-administration in a woman: a case report

Introduction: Tibolone is a synthetic steroid, used with increasing frequency to treat symptoms of menopause, including patients with solid-organ transplants who are taking concurrent immune suppression. To the best of our knowledge, there are no reported drug interactions between tibolone and tacrolimus, one of the principal immune suppressants used in kidney transplantation. Case presentation: We report the case of a 49-year-old Caucasian woman who had received a kidney transplant and who developed acute kidney injury secondary to tacrolimus toxicity 10 days after starting tibolone therapy. No alternative causes were found. Tibolone is known to be a weak competitive inhibitor of CYP3A4, which is involved in tacrolimus metabolism. Conclusions: Despite a careful evaluation, no alternative reason was found for the acute kidney injury, and her kidney function returned to the previous baseline within several days of cessation of the medication, and with no other specific treatment. Using the Drug Interaction Probability Scale we conclude that she experienced a probable drug interaction. We believe that transplant clinicians should utilise frequent therapeutic drug monitoring of tacrolimus in patients starting or stopping tibolone therapy

Co-infections of Adenovirus Species in Previously Vaccinated Patients

Adenoviral infections associated with respiratory illness in military trainees involve multiple co-infecting species and serotypes

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

Fetal hemoglobin level is a heritable complex trait that strongly correlates with the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease

Relationships Among Alcohol Outlet Density, Alcohol use, and Intimate Partner Violence Victimization Among Young Women in the United States

Greater access to alcohol has been widely found to be associated with many negative outcomes including violence perpetration. This study examines the relationship between alcohol outlet density, alcohol use, and intimate partner violence (IPV) victimization among young women in the United States. A direct association between alcohol outlet density in one’s neighborhood and the likelihood of IPV victimization was examined. Data were from Wave III of the National Longitudinal Study of Adolescent Health (Add Health), which followed a nationally representative sample of adolescents into adulthood. Participants were young adult females age 18 to 26 at Wave III. Of the 4,571 female respondents who reported a current heterosexual relationship and had IPV data, 13.2% reported having been the victim of physical violence only and 6.5% experienced sexual only or physical and sexual violence in the relationship during the past year. In the regression models tested, there was no significant direct association between neighborhood alcohol outlet density and IPV victimization nor was there an association between outlet density and drinking behaviors, thus eliminating the possibility of an indirect association. Results of fully adjusted models indicate females who drank heavily, whether infrequently or frequently, were at significant risk for experiencing sexual only IPV or sexual and physical IPV. Asians and Native Americans were at significantly greater odds of experiencing sexual only or sexual and physical IPV compared with non-Hispanic Whites, while non-Hispanic Blacks were at significantly greater odds for physical only IPV. We conclude that a continuous measure of alcohol outlet density was not associated with IPV in models controlling for individual and other neighborhood characteristics. Young women who drink heavily, whether infrequently or frequently, have greater odds of experiencing sexual only or sexual and physical compared to abstainers. Similar to previous study findings, young women living with or married to their partner were at far greater risk of experiencing physical only and/or sexual only or sexual and physical IPV. The study adds to the growing body of literature that examines how community characteristics such as outlet density influence the likelihood of IPV

Nerve root block versus surgery (NERVES) for the treatment of radicular pain secondary to a prolapsed intervertebral disc herniation: study protocol for a multi-centre randomised controlled trial

Abstract Background Sciatica is a common condition reported to affect over 3% of the UK population at any time and is often caused by a prolapsed intervertebral disc (PID). Although the duration and severity of symptoms can vary, pain persisting beyond 6 weeks is unlikely to recover spontaneously and may require investigation and treatment. Currently, there is no specific care pathway for sciatica in the National Health Service (NHS), and no direct comparison exists between surgical microdiscectomy and transforaminal epidural steroid injection (TFESI). The NERVES (NErve Root block VErsus Surgery) trial aims to address this by comparing clinical and cost-effectiveness of surgical microdiscectomy and TFESI to treat sciatica secondary to a PID. Methods/design A total of 163 patients were recruited from NHS out-patient clinics across the UK and randomised to either microdiscectomy or TFESI. Adult patients (aged 16–65 years) with sciatic pain endured for between 6 weeks and 12 months are eligible if their symptoms have not been improved by at least one form of conservative (non-operative) treatment and they are willing to provide consent. Patients will be excluded if they present with neurological deficit or have had previous surgery at the same level. The primary outcome is patient-reported disability measured using the Oswestry Disability Questionnaire (ODQ) score at 18 weeks post randomisation and secondary outcomes include disability and pain scales using numerical pain ratings, modified Roland-Morris and Core Outcome Measures Index at 12-weekly intervals, and patient satisfaction at 54 weeks. Cost-effectiveness and quality of life (QOL) will be assessed using the EQ-5D-5 L and self-report cost data at 12-weekly intervals and Hospital Episode Statistics (HES) data. Adverse event data will be collected. Analysis will follow the principle of intention-to-treat. Discussion NERVES is the first trial to evaluate the comparative clinical and cost-effectiveness of microdiscectomy to local anaesthetic and steroid administered via TFESI. The results of this research may facilitate the development of an evidence-based treatment strategy for patients with sciatica. Trial registration ISRCTN, ID: ISRCTN04820368. Registered on 5 June 2014. EudraCT EudraCT2014–002751-25. Registered on 8 October 2014