Diabetes Is Associated with Worse Clinical Presentation in Tuberculosis Patients from Brazil: A Retrospective Cohort Study
BACKGROUND: The rising prevalence of diabetes mellitus (DM) worldwide, especially in developing countries, and the persistence of tuberculosis (TB) as a major public health issue in these same regions, emphasize the importance of investigating this association. Here, we compared the clinical profile and disease outcomes of TB patients with or without coincident DM in a TB reference center in Brazil.
METHODS: We performed a retrospective analysis of a TB patient cohort (treatment naive) of 408 individuals recruited at a TB primary care center in Brazil between 2004 and 2010. Data on diagnosis of TB and DM were used to define the groups. The study groups were compared with regard to TB disease presentation at diagnosis as well as to clinical outcomes such as cure and mortality rates upon anti-tuberculosis therapy (ATT) initiation. A composite score utilizing clinical, radiological and microbiological parameters was used to compare TB severity between the groups.
RESULTS: DM patients were older than non-diabetic TB patients. In addition, diabetic individuals more frequently presented with cough, night sweats, hemoptysis and malaise than those without DM. The overall pattern of lung lesions assessed by chest radiographic examination was similar between the groups. Compared to non-diabetic patients, those with TB-diabetes exhibited positive acid-fast bacilli in sputum samples more frequently at diagnosis and at 30 days after ATT initiation. Notably, higher values of the TB severity score were significantly associated with TB-diabetes comorbidity after adjustment for confounding factors. Moreover, during ATT, diabetic patients required more frequent transfers to TB reference hospitals for complex clinical management. Nevertheless, overall mortality and cure rates were indistinguishable between the study groups.
CONCLUSIONS: These findings reinforce the idea that diabetes negatively impacts pulmonary TB severity. Our study argues for the systematic screening for DM in TB reference centers in endemic areas.
RUNX1 a member of the family of runt related transcription factors (RUNX), is essential for hematopoiesis. The expression of RUNX1 gene is controlled by two promoters; the distal P1 promoter and the proximal P2 promoter. Several isoforms of RUNX1 mRNA are generated through the use of both promoters and alternative splicing. These isoforms not only differs in their temporal expression pattern but also exhibit differences in tissue specificity. The RUNX1 isoforms derived from P2 are expressed in a variety of tissues, but expression of P1-derived isoform is restricted to cells of hematopoietic lineage. However, the control of hematopoietic-cell specific expression is poorly understood. Here we report regulation of P1-derived RUNX1 mRNA by RUNX1 protein. In silico analysis of P1 promoter revealed presence of two evolutionary conserved RUNX motifs, 0.6kb upstream of the transcription start site, and three RUNX motifs within 170bp of the 5'UTR. Transcriptional contribution of these RUNX motifs was studied in myeloid and T-cells. RUNX1 genomic fragment containing all sites show very low basal activity in both cell types. Mutation or deletion of RUNX motifs in the UTR enhances basal activity of the RUNX1 promoter. Chromatin immunoprecipitation revealed that RUNX1 protein is recruited to these sites. Overexpression of RUNX1 in non-hematopoietic cells results in a dose dependent activation of the RUNX1 P1 promoter. We also demonstrate that RUNX1 protein regulates transcription of endogenous RUNX1 mRNA in T-cell. Finally we show that SCL transcription factor is recruited to regions containing RUNX motifs in the promoter and the UTR and regulates activity of the RUNX1 P1 promoter in vitro. Thus, multiple lines of evidence show that RUNX1 protein regulates its own gene transcription.
Several studies have shown a reduced efficacy of influenza vaccines in the elderly compared to young adults. In this study, we evaluated the immunogenicity and protective efficacy of a commercially available inactivated influenza vaccine (Fluzone(R)) in young adult and aged mice. C57/BL6 mice were administered a single or double immunization of Fluzone(R) with or without CpG and challenged intranasally with H1N1 A/California/09 virus. A double immunization of Fluzone(R) adjuvanted with CpG elicited the highest level of protection in young adult mice which was associated with increases in influenza specific IgG, elevated HAI titres, reduced viral titres and lung inflammation. In contrast, the vaccine schedule which provided fully protective immunity in young adult mice conferred limited protection in aged mice. Antigen presenting cells from aged mice were found to be less responsive to in vitro stimulation by Fluzone and CpG which may partially explain this result. Our data are supportive of studies that have shown limited effectiveness of influenza vaccines in the elderly and provide important information relevant to the design of more immunogenic vaccines in this age group.
How Would Children Register Their Own Births? Insights from a Survey of Students Regarding Birth Registration Knowledge and Policy Suggestions in Kenya
Birth registration and obtaining physical birth certificates impose major challenges in developing countries, with impact on child and community health, education, planning, and all levels of development. However despite initiatives, universal registration is elusive, leading to calls for new approaches to understanding the decisions of parents. In this paper, we report results of a survey of students in grades six to eight (age ~12-16) in an under-registered area of Kenya regarding their own understanding of registration issues and their suggestions for improvement. These students were selected because they themselves were also nearing the age for high school enrollment/entrance examinations, which specifically requires possession of a birth certificate. This assessment was also a companion to our previous representative survey of adults in the same Kenyan region, allowing for parent-child comparison. Results supported previous research, showing that only 43% had birth certificates. At the same time, despite these low totals, students were themselves quite aware of registration factors and purposes. The students also made quite prescient sources for understanding their households' motivations, with many of their suggestions-for focus on communication of pragmatic benefits, or automatic measures shifting responsibility from parents-mirroring our own previous suggestions, and showing a level of pragmatism not witnessed when surveying their parents. This paper therefore adds evidence to the discussion of registration policy planning. More generally, it also builds on an important trend regarding the treatment of children as stakeholders and important sources of information, and raising an intriguing new avenue for future research.
Pre-Travel Medical Preparation of Business and Occupational Travelers: An Analysis of the Global TravEpiNet Consortium, 2009 to 2012
OBJECTIVES: The aim of the study was to understand more about pre-travel preparations and itineraries of business and occupational travelers.
METHODS: De-identified data from 18 Global TravEpiNet clinics from January 2009 to December 2012 were analyzed.
RESULTS: Of 23,534 travelers, 61% were non-occupational and 39% occupational. Business travelers were more likely to be men, had short times to departure and shorter trip durations, and commonly refused influenza, meningococcal, and hepatitis B vaccines. Most business travelers indicated that employers suggested the pre-travel health consultation, whereas non-occupational travelers sought consultations because of travel health concerns.
CONCLUSIONS: Sub-groups of occupational travelers have characteristic profiles, with business travelers being particularly distinct. Employers play a role in encouraging business travelers to seek pre-travel consultations. Such consultations, even if scheduled immediately before travel, can identify vaccination gaps and increase coverage.
Cardiovascular health awareness and the effect of an educational intervention on school-aged children in a rural district of India
BACKGROUND AND OBJECTIVES: India is the second most populous country in the world and two-thirds of its population is less than 35 years old. This survey was conducted to assess the level of health awareness of cardiovascular disease in adolescent school-aged children 14-16 years old, with the goal of establishing school-based health education and development of heart-healthy lifestyle practices.
METHODS: A school-based survey was conducted in the rural district of West Midnapore, India between June and July of 2014. This involved a pre-evaluation of cardiovascular disease (CVD) health awareness, a short presentation on CVD, and a post-evaluation of CVD health awareness.
RESULTS: A total of 2995 students (48% response rate) from 20 schools participated in the survey. The mean age of the students in the study sample was 14.7 years, 46% were male, 53% were in the 9th grade, and the rest were in the 10th grade. After assessing students' awareness in six domains with 20 multiple-choice questions with a maximum score of 100, the mean pre-test score was 41.1 (SD+/-10.5) and the mean post-test score was 48.1 (SD+/-16.9) (p < 0.001).
CONCLUSIONS: Awareness of CVD and its risk factors was far from optimal among the adolescent school-aged children in this study. A school-based educational program may help improve awareness of CVD and reduce the future disease burden in the community. The results of this study may be useful in formulating a nationwide school health program to deal with the emerging epidemic of CVD in countries such as India.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1(G93A) transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1(G93A) mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans.
T-Cell Immunity to Influenza in Older Adults: A Pathophysiological Framework for Development of More Effective Vaccines
One of the most profound public health consequences of immune senescence is reflected in an increased susceptibility to influenza and other acute respiratory illnesses, as well as a loss of influenza vaccine effectiveness in older people. Common medical conditions and mental and psychosocial health issues as well as degree of frailty and functional dependence accelerate changes associated with immune senescence. All contribute to the increased risk for complications of influenza infection, including pneumonias, heart diseases, and strokes that lead to hospitalization, disability, and death in the over 65 population. Changes in mucosal barrier mechanisms and both innate and adaptive immune functions converge in the reduced response to influenza infection, and lead to a loss of antibody-mediated protection against influenza with age. The interactions of immune senescence and reduced adaptive immune responses, persistent cytomegalovirus infection, inflammaging (chronic elevation of inflammatory cytokines), and dysregulated cytokine production, pose major challenges to the development of vaccines designed to improve T-cell-mediated immunity. In older adults, the goal of vaccination is more realistically targeted to providing clinical protection against disease rather than to inducing sterilizing immunity to infection. Standard assays of antibody titers correlate with protection against influenza illness but do not detect important changes in cellular immune mechanisms that correlate with vaccine-mediated protection against influenza in older people. This article will discuss: (i) the burden of influenza in older adults and how this relates to changes in T-cell function, (ii) age-related changes in different T-cell subsets and immunologic targets for improved influenza vaccine efficacy in older, and (iii) the development of correlates of clinical protection against influenza disease to expedite the process of new vaccine development for the 65 and older population. Ultimately, these efforts will address the public health need for improved protection against influenza in older adults and "vaccine preventable disability."
Antiretroviral therapy (ART) has transformed the clinical profile of human immunodeficiency virus (HIV) from an acute infection with a high mortality into a treatable, chronic disease. As a result, the clinical sequelae of HIV infection are changing as patients live longer. HIV-associated cardiomyopathy (HIVAC) is a stage IV, HIV-defining illness and remains a significant cause of morbidity and mortality among HIV-infected individuals despite ART. Causes and clinical manifestations of HIVAC depend on the degree of host immunosuppression. Myocarditis from direct HIV toxicity, opportunistic infections, and nutritional deficiencies are implicated in causing HIVAC when HIV viral replication is unchecked, whereas cardiac autoimmunity, chronic inflammation, and ART cardiotoxicity contribute to HIVAC in individuals with suppressed viral loads. The initiation of ART has dramatically changed the clinical manifestation of HIVAC in high income countries from one of severe, left ventricular systolic dysfunction to a pattern of subclinical cardiac dysfunction characterized by abnormal diastolic function and strain. In low and middle income countries, however, HIVAC is the most common HIV-associated cardiovascular disease. Clear diagnostic and treatment guidelines for HIVAC are currently lacking but should be prioritized given the global burden of HIVAC.
Physical Activity-Related Policy and Environmental Strategies to Prevent Obesity in Rural Communities: A Systematic Review of the Literature, 2002-2013
INTRODUCTION: Health disparities exist between rural and urban residents; in particular, rural residents have higher rates of chronic diseases and obesity. Evidence supports the effectiveness of policy and environmental strategies to prevent obesity and promote health equity. In 2009, the Centers for Disease Control and Prevention recommended 24 policy and environmental strategies for use by local communities: the Common Community Measures for Obesity Prevention (COCOMO); 12 strategies focus on physical activity. This review was conducted to synthesize evidence on the implementation, relevance, and effectiveness of physical activity-related policy and environmental strategies for obesity prevention in rural communities.
METHODS: A literature search was conducted in PubMed, PsycINFO, Web of Science, CINHAL, and PAIS databases for articles published from 2002 through May 2013 that reported findings from physical activity-related policy or environmental interventions conducted in the United States or Canada. Each article was extracted independently by 2 researchers.
RESULTS: Of 2,002 articles, 30 articles representing 26 distinct studies met inclusion criteria. Schools were the most common setting (n = 18 studies). COCOMO strategies were applied in rural communities in 22 studies; the 2 most common COCOMO strategies were "enhance infrastructure supporting walking" (n = 11) and "increase opportunities for extracurricular physical activity" (n = 9). Most studies (n = 21) applied at least one of 8 non-COCOMO strategies; the most common was increasing physical activity opportunities at school outside of physical education (n = 8). Only 14 studies measured or reported physical activity outcomes (10 studies solely used self-report); 10 reported positive changes.
CONCLUSION: Seven of the 12 COCOMO physical activity-related strategies were successfully implemented in 2 or more studies, suggesting that these 7 strategies are relevant in rural communities and the other 5 might be less applicable in rural communities. Further research using robust study designs and measurement is needed to better ascertain implementation success and effectiveness of COCOMO and non-COCOMO strategies in rural communities.
Fetal Hematopoietic Stem Cell Transplantation Fails to Fully Regenerate the B-Lymphocyte Compartment
B cells are key components of cellular and humoral immunity and, like all lymphocytes, are thought to originate and renew from hematopoietic stem cells (HSCs). However, our recent single-HSC transfer studies demonstrate that adult bone marrow HSCs do not regenerate B-1a, a subset of tissue B cells required for protection against pneumonia, influenza, and other infections. Since B-1a are regenerated by transfers of fetal liver, the question arises as to whether B-1a derive from fetal, but not adult, HSCs. Here we show that, similar to adult HSCs, fetal HSCs selectively fail to regenerate B-1a. We also show that, in humanized mice, human fetal liver regenerates tissue B cells that are phenotypically similar to murine B-1a, raising the question of whether human HSC transplantation, the mainstay of such models, is sufficient to regenerate human B-1a. Thus, our studies overtly challenge the current paradigm that HSCs give rise to all components of the immune system.
Culturally adaptive storytelling method to improve hypertension control in Vietnam - "We talk about our hypertension": study protocol for a feasibility cluster-randomized controlled trial
BACKGROUND: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. At present, the major risk factors for cardiovascular disease (CVD) are either on the rise or at alarming levels in Vietnam; inasmuch, the burden of CVD will continue to increase in this country unless effective prevention and control measures are put in place. A national survey in 2008 found that the prevalence of hypertension (HTN) was approximately 25 % among Vietnamese adults and it increased with advancing age. Therefore, novel, large-scale, and sustainable interventions for public health education to promote engagement in the process of detecting and treating HTN in Vietnam are urgently needed.
METHODS: A feasibility randomized trial will be conducted in Hung Yen province, Vietnam to evaluate the feasibility and acceptability of a novel community-based intervention using the "storytelling" method to enhance the control of HTN in adults residing in four rural communities. The intervention will center on stories about living with HTN, with patients speaking in their own words. The stories will be obtained from particularly eloquent patients, or "video stars," identified during Story Development Groups. The study will involve two phases: (i) developing a HTN intervention using the storytelling method, which is designed to empower patients to facilitate changes in their lifestyle practices, and (ii) conducting a feasibility cluster-randomized trial to investigate the feasibility, acceptability, and potential efficacy of the intervention compared with usual care in HTN control among rural residents. The trial will be conducted at four communes, and within each commune, 25 individuals 50 years or older with HTN will be enrolled in the trial resulting in a total sample size of 100 patients.
DISCUSSION: This feasibility trial will provide the necessary groundwork for a subsequent large-scale, fully powered, cluster-randomized controlled trial to test the efficacy of our novel community-based intervention. Results from the full-scale trial will provide health policy makers with practical evidence on how to combat a key risk factor for CVD using a feasible, sustainable, and cost-effective intervention that could be used as a national program for controlling HTN in Vietnam and other developing countries.
TRIAL REGISTRATION: ClinicalTrials.gov.
REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT02483780 (registration date June 22, 2015).
Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression
Chrysotile, like other types of asbestos, has been associated with mesothelioma, lung cancer and asbestosis. However, the cellular abnormalities induced by these fibers involved in cancer development have not been elucidated yet. Previous works show that chrysotile fibers induce features of cancer cells, such as aneuploidy, multinucleation and multipolar mitosis. In the present study, normal and cancer derived human cell lines were treated with chrysotile and the cellular and molecular mechanisms related to generation of aneuploid cells was elucidated. The first alteration observed was cytokinesis regression, the main cause of multinucleated cells formation and centrosome amplification. The multinucleated cells formed after cytokinesis regression were able to progress through cell cycle and generated aneuploid cells after abnormal mitosis. To understand the process of cytokinesis regression, localization of cytokinetic proteins was investigated. It was observed mislocalization of Anillin, Aurora B, Septin 9 and Alix in the intercellular bridge, and no determination of secondary constriction and abscission sites. Fiber treatment also led to overexpression of genes related to cancer, cytokinesis and cell cycle. The results show that chrysotile fibers induce cellular and molecular alterations in normal and tumor cells that have been related to cancer initiation and progression, and that tetraploidization and aneuploid cell formation are striking events after fiber internalization, which could generate a favorable context to cancer development.
Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3)
OBJECTIVE: To evaluate apremilast treatment in patients with active psoriatic arthritis, including current skin involvement, despite prior therapy with conventional disease-modifying antirheumatic drugs and/or biologic agents.
METHODS: Patients (N=505) were randomised (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. Rescue therapy with apremilast was designated at week 16 for placebo patients not achieving 20% improvement in swollen and tender joint counts. At week 24, the remaining placebo patients were then randomised to apremilast 20 mg twice daily or 30 mg twice daily. The efficacy and safety of apremilast were assessed over 52 weeks.
RESULTS: At week 16, significantly more patients receiving apremilast 20 mg twice daily (28%) and 30 mg twice daily (41%) achieved 20% improvement in American College of Rheumatology response criteria versus placebo (18%; p=0.0295 and p < 0.0001, respectively), and mean decrease in the Health Assessment Questionnaire-Disability Index score was significantly greater with apremilast 30 mg twice daily (-0.20) versus placebo (-0.07; p=0.0073). In patients with baseline psoriasis body surface area involvement > /=3%, significantly more apremilast 30 mg twice daily patients achieved 50% reduction from baseline Psoriasis Area and Severity Index score (41%) versus placebo (24%; p=0.0098) at week 16. At week 52, observed improvements in these measures demonstrated sustained response with continued apremilast treatment. Most adverse events were mild to moderate in severity; the most common were diarrhoea, nausea, headache and upper respiratory tract infection.
CONCLUSIONS: Apremilast demonstrated clinically meaningful improvements in psoriatic arthritis and psoriasis at week 16; sustained improvements were seen with continued treatment through 52 weeks. Apremilast was generally well tolerated and demonstrated an acceptable safety profile.
TRIAL REGISTRATION NUMBER: NCT01212770.
Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans
Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1. The nsy-1(gf) allele caused hyperinduction of p38 MAPK PMK-1-dependent immune effectors, had greater levels of phosphorylated p38 MAPK, and was more resistant to killing by the bacterial pathogen Pseudomonas aeruginosa compared to wild-type controls. In addition, the nsy-1(gf) mutation was toxic to developing animals. Together, these data suggest that the activity of the MAPKKK NSY-1 is tightly regulated as part of a physiological mechanism to control p38 MAPK-mediated innate immune hyperactivation, and ensure cellular homeostasis in C. elegans.
Patients are increasingly using online social networks (ie, social media) to connect with other patients and health care professionals--a trend called peer-to-peer health care. Because online social networks provide a means for health care professionals to communicate with patients, and for patients to communicate with each other, an opportunity exists to use social media as a modality to deliver behavioral interventions. Social media-delivered behavioral interventions have the potential to reduce the expense of behavioral interventions by eliminating visits, as well as increase our access to patients by becoming embedded in their social media feeds. Trials of online social network-delivered behavioral interventions have shown promise, but much is unknown about intervention development and methodology. In this paper, we discuss the process by which investigators can translate behavioral interventions for social media delivery. We present a model that describes the steps and decision points in this process, including the necessary training and reporting requirements. We also discuss issues pertinent to social media-delivered interventions, including cost, scalability, and privacy. Finally, we identify areas of research that are needed to optimize this emerging behavioral intervention modality.
Incidence of Dengue Virus Infection in Adults and Children in a Prospective Longitudinal Cohort in the Philippines
BACKGROUND: The mean age of dengue has been increasing in some but not all countries. We sought to determine the incidence of dengue virus (DENV) infection in adults and children in a prospective cohort study in the Philippines where dengue is hyperendemic.
METHODOLOGY/PRINCIPAL FINDINGS: A prospective cohort of subjects > /=6 months old in Cebu City, Philippines, underwent active community-based surveillance for acute febrile illnesses by weekly contact. Fever history within the prior seven days was evaluated with an acute illness visit followed by 2, 5, and 8-day, and 3-week convalescent visits. Blood was collected at the acute and 3-week visits. Scheduled visits took place at enrolment and 12 months that included blood collections. Acute samples were tested by DENV PCR and acute/convalescent samples by DENV IgM/IgG ELISA to identify symptomatic infections. Enrolment and 12-month samples were tested by DENV hemagglutination inhibition (HAI) assay to identify subclinical infections. Of 1,008 enrolled subjects, 854 completed all study activities at 12 months per-protocol undergoing 868 person-years of surveillance. The incidence of symptomatic and subclinical infections was 1.62 and 7.03 per 100 person-years, respectively. However, in subjects > 15 years old, only one symptomatic infection occurred whereas 27 subclinical infections were identified. DENV HAI seroprevalence increased sharply with age with baseline multitypic HAIs associated with fewer symptomatic infections. Using a catalytic model, the historical infection rate among dengue naive individuals was estimated to be high at 11-22%/year.
CONCLUSIONS/SIGNIFICANCE: In this hyperendemic area with high seroprevalence of multitypic DENV HAIs in adults, symptomatic dengue rarely occurred in individuals older than 15 years. Our findings demonstrate that dengue is primarily a pediatric disease in areas with high force of infection. However, the average age of dengue could increase if force of infection decreases over time, as is occurring in some hyperendemic countries such as Thailand.
Heterotaxy, a birth defect involving left-right patterning defects, and primary ciliary dyskinesia (PCD), a sinopulmonary disease with dyskinetic/immotile cilia in the airway are seemingly disparate diseases. However, they have an overlapping genetic etiology involving mutations in cilia genes, a reflection of the common requirement for motile cilia in left-right patterning and airway clearance. While PCD is a monogenic recessive disorder, heterotaxy has a more complex, largely non-monogenic etiology. In this study, we show mutations in the novel dynein gene DNAH6 can cause heterotaxy and ciliary dysfunction similar to PCD. We provide the first evidence that trans-heterozygous interactions between DNAH6 and other PCD genes potentially can cause heterotaxy. DNAH6 was initially identified as a candidate heterotaxy/PCD gene by filtering exome-sequencing data from 25 heterotaxy patients stratified by whether they have airway motile cilia defects. dnah6 morpholino knockdown in zebrafish disrupted motile cilia in Kupffer's vesicle required for left-right patterning and caused heterotaxy with abnormal cardiac/gut looping. Similarly DNAH6 shRNA knockdown disrupted motile cilia in human and mouse respiratory epithelia. Notably a heterotaxy patient harboring heterozygous DNAH6 mutation was identified to also carry a rare heterozygous PCD-causing DNAI1 mutation, suggesting a DNAH6/DNAI1 trans-heterozygous interaction. Furthermore, sequencing of 149 additional heterotaxy patients showed 5 of 6 patients with heterozygous DNAH6 mutations also had heterozygous mutations in DNAH5 or other PCD genes. We functionally assayed for DNAH6/DNAH5 and DNAH6/DNAI1 trans-heterozygous interactions using subthreshold double-morpholino knockdown in zebrafish and showed this caused heterotaxy. Similarly, subthreshold siRNA knockdown of Dnah6 in heterozygous Dnah5 or Dnai1 mutant mouse respiratory epithelia disrupted motile cilia function. Together, these findings support an oligogenic disease model with broad relevance for further interrogating the genetic etiology of human ciliopathies.
Palliative cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion: current clinical practice or misnomer
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) is being used more and more frequently for the management of peritoneal carcinomatosis. Despite significant improvements in oncologic outcomes and the risk of complications and mortality, CRS/HIPEC remains one of the most morbid treatments offered for advanced cancers. Consequently CRS/HIPEC is still considered controversial by many, even in the setting of cancers that are potentially curable. However, as high volume surgical oncologists become more experienced with CRS/HIPEC, the potential role of "palliative CRS/HIPEC" in the management of peritoneal carcinomatosis is being raised. Given the often limited survival benefit expected after CRS/HIPEC, understanding the impact of the treatment on quality of life (QOL) needs to be an essential part of the decision to proceed and is critical to optimizing recovery afterwards. This article reviews the potential definitions of "palliative CRS/HIPEC" in various clinical contexts and describes the current state of the QOL experience after CRS/HIPEC.
Safety of anticoagulation with uninterrupted warfarin vs. interrupted dabigatran in patients requiring an implantable cardiac device
BACKGROUND: The optimal strategy of peri-procedural anticoagulation in patients undergoing permanent cardiac device implantation is controversial. Our objective was to compare the major bleeding and thromboembolic complications in patients managed with uninterrupted warfarin (UW) vs. interrupted dabigatran (ID) during permanent pacemaker (PPM) or implantable cardioverter defibrillators (ICD) implantation.
METHODS: A retrospective cohort study of all eligible patients from July 2011 through January 2012 was performed. UW was defined as patients who had maintained a therapeutic international normalized ratio (INR) on the day of the procedure. ID was defined as stopping dabigatran > /=12 hours prior to the procedure and then resuming after implantation. Major bleeding events included hemothorax, hemopericardium, intracranial hemorrhage, gastrointestinal bleed, epistaxis, or pocket hematoma requiring surgical intervention. Thromboembolic complications included stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, or arterial embolism.
RESULTS: Of the 133 patients (73.4+/-11.0 years; 91 males) in the study, 86 received UW and 47 received ID. One (1.2%) patient in the UW group sustained hemopericardium perioperatively and died. In comparison, the ID patients had no complications. As compared to the ID group, the UW group had a higher median CHADS2 score (2 vs. 3, P=0.04) and incidence of Grade 1 pocket hematoma (0% vs. 7%, P=0.09). Neither group developed any thromboembolic complications.
CONCLUSIONS: Major bleeding rates were similar among UW and ID groups. Perioperative ID appears to be a safe anticoagulation strategy for patients undergoing PPM or ICD implantation.