Training in the Conduct of Population-Based Multi-Site and Multi-Disciplinary Studies: the Cancer Research Network's Scholars Program
Expanding research capacity of large research networks within health care delivery systems requires strategically training both embedded and external investigators in necessary skills for this purpose. Researchers new to these settings frequently lack the skills and specialized knowledge conducive to multi-site and multi-disciplinary research set in delivery systems. This report describes the goals and components of the Cancer Research Network (CRN) Scholars Program, a 26-month training program developed to increase the capacity for cancer research conducted within the network's participating sites, its progression from training embedded investigators to a mix of internal and external investigators, and the content evolution of the training program. The CRN Scholars program was launched in 2007 to assist junior investigators from member sites develop independent and sustainable research programs within the CRN. Resulting from CRN's increased emphasis on promoting external collaborations, the 2013 Scholars program began recruiting junior investigators from external institutions committed to conducting delivery system science. Based on involvement of this broader population and feedback from prior Scholar cohorts, the program has honed its focus on specific opportunities and issues encountered in conducting cancer research within health care delivery systems. Efficiency and effectiveness of working within networks is accelerated by strategic and mentored navigation of these networks. Investing in training programs specific to these settings provides the opportunity to improve multi-disciplinary and multi-institutional collaboration, particularly for early-stage investigators. Aspects of the CRN Scholars Program may help inform others considering developing similar programs to expand delivery system research or within large, multi-disciplinary research networks.
Magnitude, treatment, and impact of diabetes mellitus in patients hospitalized with non-ST segment elevation myocardial infarction: A community-based study
PURPOSE OF THE STUDY: To examine differences in the characteristics, treatment practices and in-hospital outcomes of patients with and without previously diagnosed diabetes hospitalized for non-ST segment elevation myocardial infarction.
KEY METHODS: The study cohort consisted of 3916 patients diagnosed with non-ST segment elevation myocardial infarction at all 11 central MA medical centres between 1999 and 2009, of whom 1475 (38%) had been previously diagnosed with diabetes. MAIN
RESULTS: Diabetic patients were more likely to have received treatment with effective cardiac medications, and to have undergone coronary bypass surgery, but were less likely to have received a percutaneous coronary intervention, than non-diabetic patients. Patients with a history of diabetes were more likely to have developed cardiogenic shock, heart failure and died during their index hospitalization than non-diabetic patients.
MAIN CONCLUSION: Diabetic patients presenting with non-ST segment elevation myocardial infarction remain at high risk of developing significant clinical complications during hospitalization.
Disorganized Systematic Reviews and Meta-analyses: Time to Systematize the Conduct and Publication of These Study Overviews
The number of meta-analyses published annually has increased more than 20-fold between 1994 (n = 386) and 2014 (n = 8203). In examining how much of this increase in meta-analysis publication has genuinely represented novel contributions to clinical medicine and public health, it became clear that there was an abundance of redundant and disorganized meta-analyses, creating confusion and generating considerable debate. Ironically, meta-analyses, which should prevent redundant research, have become a victim of it. Recently, 17 meta-analyses were published based on the results of only 3 randomized controlled trials that studied the role of transcatheter closure of patent foramen ovale for prevention of cryptogenic stroke. In our search of the published literature, we identified at least 10 topics that were the subject of 10 meta-analyses. In the context of overlapping meta-analyses, one questions what needs to be done to put this "runaway train" back on track. In this review we examine the practice of redundant meta-analyses and the reasons for its disturbing "popularity." The registration of systematic reviews should be mandatory in prospective registries, such as PROSPERO, and the PRISMA checklist should be updated to incorporate new evidence and mandate the reference of previously published reviews and rationale for any new study.
BACKGROUND: We examined Veterans Affairs (VA) health care experiences among contemporary women veteran patients receiving care at a VA medical center. Specifically, we examined women veteran patients' satisfaction with VA care along dimensions in line with patient-centered medical home (patient-aligned care teams [PACT] in VA) priorities, and pathways through which women initially accessed VA care.
METHODS: We used a mixed methods research design. First, 249 racially diverse women (ages 22-64) who were past-year users of primary care at a VA medical center completed interviewer-administered surveys in 2012 assessing ratings of satisfaction with care in the past year. We then conducted in-depth qualitative interviews of a subset of women surveyed (n = 25) to gain a deeper understanding of perspectives and experiences that shaped satisfaction with care and to explore women's initial pathways to VA care.
RESULTS: Ratings of satisfaction with VA care were generally high, with some variation by demographic characteristics. Qualitative interviews revealed perceptions of care centered on the following themes: 1) barriers to care delay needed medical care, while innovative care models facilitate access, 2) women value communication and coordination of care, and 3) personalized context of VA care, including gender sensitive care shapes women's perceptions. Pathways to VA care were characterized by initial delays, often attributable to lack of knowledge or negative perceptions of VA care. Informal social networks were instrumental in helping women to overcome barriers.
CONCLUSIONS: Findings highlight convergence of women's preferences with PACT priorities of timely access to care, provider communication, and coordination of care, and suggest areas for improvement. Outreach is needed to address gaps in knowledge and negative perceptions. Initiatives to enhance women veterans' social networks may provide an information-sharing resource.
BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking.
METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis.
RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 +/- 3.1 mIU/L) compared with placebo (-0.1 +/- 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain.
CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.
INTRODUCTION: It is unknown how the timing between doses might affect nicotine's impact on neural activity. Our objective was to examine how the interdose interval affects nicotine's impact on resting-state functional connectivity (rsFC).
MATERIALS AND METHODS: Adult male Sprague-Dawley rats were administered nicotine daily (0.4 mg/kg) over 6 days while control animals received saline vehicle. Functional magnetic resonance imaging was used to measure rsFC before and after a challenge dose of nicotine (0.4 mg/kg) delivered for the first time and 3, 6, 12, or 24hr after the previous dose.
RESULTS: As the interval between nicotine doses increased from 3 to 24hr, the strength of rsFC increased in some circuits, particularly the nucleus accumbens and prefrontal circuits, and decreased in others, namely the interpeduncular nucleus, hippocampus, caudoputamen, retrosplenial cortex, ventral tegmental, and the insular circuits.
CONCLUSIONS: These data indicate that the effect that nicotine has on the brain is affected by the amount of time that has passed since the previous dose. The effect on rsFC of cumulative doses is not additive. This may have important implications for the study of nicotine addiction as it implies that the same dose of nicotine might have a different impact on the brain depending on the time elapsed from the previous exposure.
CONTEXT: Family caregivers (FCGs) are often at the frontline of symptom management for patients with advanced illness in home hospice. FCGs' cognitive, social, and technical skills in complex medication management have been well studied in the literature; however, few studies have tested existing frameworks in clinical cases in home hospice.
OBJECTIVES: This study sought to assess the applicability of caregiver medication management skills framework by Lau et al. in the context of family caregiving in home hospice to further the understanding of FCGs' essential medication management skills.
METHODS: This was a secondary data analysis of 18 audio recorded home hospice visits transcribed verbatim; deductive content analysis of caregiver-nurse interactions was conducted. The target sample included FCGs of hospice patients who had cancer diagnoses in hospices located in the greater urban area of the Rocky Mountain West. Caregiver medication management skills were identified and categorized into the five domains of caregiver expertise. Exemplars of each domain were identified.
RESULTS: An average of four medications (SD = 3.5) was discussed at each home hospice visit. Medication knowledge skills were observed in most home hospice visits (15 of 18). Teamwork skills were observed in 11 of 18 cases, followed by organizational and personhood skills (10 of 18). Symptom management skills occurred in 12 of 18 cases. An additional two subconstructs of the personhood domain-1) advocacy for the caregiver and 2) skills in discontinuing medications-were proposed.
CONCLUSION: These findings support framework by Lau et al. for caregiver medication management skills and expands on the existing domains proposed. Future interventions to assess FCGs' skills are recommended.
Plasmodium falciparum Protein Microarray Antibody Profiles Correlate With Protection From Symptomatic Malaria in Kenya
BACKGROUND: Immunoglobulin G antibodies (Abs) to Plasmodium falciparum antigens have been associated with naturally acquired immunity to symptomatic malaria.
METHODS: We probed protein microarrays covering 824 unique P. falciparum protein features with plasma from residents of a community in Kenya monitored for 12 weeks for (re)infection and symptomatic malaria after administration of antimalarial drugs. P. falciparum proteins recognized by Abs from 88 children (aged 1-14 years) and 86 adults (aged > /= 18 years), measured at the beginning of the observation period, were ranked by Ab signal intensity.
RESULTS: Abs from immune adults reacted with a total 163 of 824 P. falciparum proteins. Children gradually acquired Abs to the full repertoire of antigens recognized by adults. Abs to some antigens showed high seroconversion rates, reaching maximal levels early in childhood, whereas others did not reach adult levels until adolescence. No correlation between Ab signal intensity and time to (re)infection was observed. In contrast, Ab levels to 106 antigens were significantly higher in children who were protected from symptomatic malaria compared with those who were not. Abs to antigens predictive of protection included P. falciparum erythrocyte membrane protein 1, merozoite surface protein (MSP) 10, MSP2, liver-stage antigen 3, PF70, MSP7, and Plasmodium helical interspersed subtelomeric domain protein.
CONCLUSIONS: Protein microarrays may be useful in the search for malaria antigens associated with protective immunity.
Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice
BACKGROUND and AIMS: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1beta production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH.
METHODS: Wild-type mice, ATP receptor 2x7 (P2rx7)-KO mice, or mice overexpressing uricase were fed Lieber-DeCarli ethanol or control diet. We also implemented a pharmacological approach in which mice were treated with probenecid or allopurinol.
RESULTS: The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1beta. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was achieved in mice treated with probenecid, which depletes uric acid and blocks ATP-induced P2rx7 signaling. We found that alcohol-damaged hepatocytes released uric acid and ATP in vivo and in vitro and that these sterile danger signals activated the inflammasome in LPS-exposed liver mononuclear cells.
CONCLUSIONS: Our data indicate that the second signal in inflammasome activation and IL-1beta production in ASH results from the endogenous danger signals, uric acid and ATP. Inhibition of signaling triggered by uric acid and ATP may have therapeutic implications in ASH.
Bone Mineral Density as a Predictor of Subsequent Wrist Fractures: Findings From the Women's Health Initiative Study
CONTEXT: Wrist fractures are common among postmenopausal women. Associations of bone mineral density (BMD) and 10-year predicted risk of major osteoporotic fracture (MOF) with wrist fractures are poorly characterized.
OBJECTIVE: The objective was to examine associations between the Fracture Risk Assessment Tool (FRAX)-predicted risk of MOF, BMD, BMD change, and wrist fracture.
DESIGN: This was a prospective observational study with a mean follow-up of 8.5 years.
SETTING: This study included 40 US centers.
PARTICIPANTS: A total of 11 392 participants from the Women's Health Initiative BMD Cohort aged 50-79 years at baseline were included in this study.
MAIN OUTCOME: The goal was to measure incident wrist fracture.
RESULTS: A FRAX-predicted MOF risk > /=9.3% identified 17% of the women aged < 65 years who subsequently experienced wrist fracture. Each one standard deviation lower BMD was associated with higher wrist fracture risk, with adjusted hazard ratio (95% confidence interval) of 1.66 (1.42-1.93) for femoral neck (FN) BMD and 1.45 (1.28-1.64) for lumbar spine BMD. Compared with FN BMD T score > /= -1.0, wrist fracture adjusted hazard ratios (95% confidence interval) were: 1.51 (1.06-2.16) for a T score between -1.01 and -1.49; 1.93 (1.36-2.72) for T score between -1.50 and -1.99; 2.52 (1.77-3.60) for a T score between -2.00 and -2.49; and 2.65 (1.78-3.95) for a T score < /= -2.5. Decrease in FN BMD between baseline and year 3 was associated with increased risk of subsequent wrist fracture; however, change in lumbar spine BMD was not.
CONCLUSIONS: Lumbar spine and femoral neck BMDs were associated with incident wrist fracture, but the FRAX threshold recommended to identify screening candidates did not identify the majority of women who subsequently experienced wrist fracture. Improved understanding of determinants of wrist fractures is warranted.
Wrist fractures are common in postmenopausal women and are associated with functional decline. Fracture patterns after wrist fracture are unclear. The goal of this study was to determine the frequency and types of fractures that occur after a wrist fracture among postmenopausal women. We carried out a post hoc analysis of data from the Women's Health Initiative Observational Study and Clinical Trials (1993-2010) carried out at 40 US clinical centers. Participants were postmenopausal women aged 50 to 79 years at baseline. Mean follow-up duration was 11.8 years. Main measures included incident wrist, clinical spine, humerus, upper extremity, lower extremity, hip, and total non-wrist fractures and bone mineral density (BMD) in a subset. Among women who experienced wrist fracture, 15.5% subsequently experienced non-wrist fracture. The hazard for non-wrist fractures was higher among women who had experienced previous wrist fracture than among women who had not experienced wrist fracture: non-wrist fracture overall (hazard ratio [HR] = 1.40, 95% confidence interval [CI] 1.33-1.48), spine (HR = 1.48, 95% CI 1.32-1.66), humerus (HR = 1.78, 95% CI 1.57-2.02), upper extremity (non-wrist) (HR = 1.88, 95% CI 1.70-2.07), lower extremity (non-hip) (HR = 1.36, 95% CI 1.26-1.48), and hip (HR = 1.50, 95% CI 1.32-1.71) fracture. Associations persisted after adjustment for BMD, physical activity, and other risk factors. Risk of non-wrist fracture was higher in women who were younger when they experienced wrist fracture (interaction p value 0.02). Associations between incident wrist fracture and subsequent non-wrist fracture did not vary by baseline BMD category (normal, low bone density, osteoporosis). A wrist fracture is associated with increased risk of subsequent hip, vertebral, upper extremity, and lower extremity fractures. There may be substantial missed opportunity for intervention in the large number of women who present with wrist fractures.
OBJECTIVES: To establish Montreal Cognitive Assessment (MoCA) scores that correspond to well-established cut-points on the Mini-Mental State Examination (MMSE).
DESIGN: Cross-sectional observational study.
SETTING: General medical service of a large teaching hospital.
PARTICIPANTS: Individuals aged 75 and older (N = 199; mean age 84, 63% female).
MEASUREMENTS: The MoCA (range 0-30) and the MMSE (range 0-30) were administered within 2 hours of each other. The Abbreviated MoCA (A-MoCA; range 0-22) was calculated from the full MoCA. Scores from the three tests were analyzed using equipercentile equating, a statistical method for determining comparable scores on different tests of a similar construct by estimating percentile equivalents.
RESULTS: MoCA scores were lower (mean 19.3 +/- 5.8) than MMSE scored (mean 24.1 +/- 6.6). Traditional MMSE cut-points of 27 for mild cognitive impairment and 23 for dementia corresponded to MoCA scores of 23 and 17, respectively.
CONCLUSION: Scores on the full and abbreviated versions of the MoCA can be linked directly to the MMSE. The MoCA may be more sensitive to changes in cognitive performance at higher levels of functioning.
Formative Clinical Geriatrics Experiences for First- and Second-Year Medical Students: An Elusive Goal
Providing first- and second-year (preclerkship) medical students with a formative clinical experience that effectively teaches clinical skills poses significant challenges for medical educators.
BACKGROUND: Opioid use disorders are considered a serious public health problem among young adults. Current treatment is limited to long-term opioid substitution therapy, with high relapse rates after discontinuation. This study evaluated the co-administration of memantine to brief buprenorphine pharmacotherapy as a treatment alternative.
METHODS: 13-week double-blind placebo-controlled trial evaluating 80 young adult opioid dependent participants treated with buprenorphine/naloxone 16-4mg/day and randomized to memantine (15mg or 30mg) or placebo. Primary outcomes were a change in the weekly mean proportion of opioid use, and cumulative abstinence rates after rapid buprenorphine discontinuation on week 9.
RESULTS: Treatment retention was not significantly different between groups. The memantine 30mg group was significantly less likely to relapse and to use opioids after buprenorphine discontinuation. Among participants abstinent on week 8, those in the memantine 30mg group (81.9%) were significantly less likely to relapse after buprenorphine was discontinued compared to the placebo group (30%) (p < 0.025). Also, the memantine 30mg group had significantly reduced opioid use (mean=0, SEM+/-0.00) compared to the placebo group (mean=0.33, SEM+/-0.35; p < 0.004) during the last 2 weeks of study participation.
CONCLUSIONS: Memantine 30mg significantly improved short-term treatment with buprenorphine/naloxone for opioid dependent young adults by reducing relapse and opioid use after buprenorphine discontinuation. Combined short-term treatment with buprenorphine/naloxone may be an effective alternative treatment to long-term methadone or buprenorphine maintenance in young adults.
Medical oncologists are internists specializing in the care of the adult cancer patient. They frequently function as a primary care physician for patients with cancer. This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist will review the practice of medical oncology and some general principles followed in the use of chemotherapy. Concepts including goals of chemotherapy treatment, evaluation of the effects of chemotherapy, integration of chemotherapy with other cancer treatments, and use of combinations of chemotherapy drugs will be covered.
Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry
OBJECTIVES: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1-3 repeats (1-3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1-3 DRA.
PARTICIPANTS: 66 index cases and 33 relatives carrying 1-3 DRA.
OUTCOMES: The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk.
RESULTS: No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1-3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment.
CONCLUSIONS: The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.
Transgenic Drosophila for Investigating DUX4 and FRG1, Two Genes Associated with Facioscapulohumeral Muscular Dystrophy (FSHD)
Facioscapulohumeral muscular dystrophy (FSHD) is typically an adult onset dominant myopathy. Epigenetic changes in the chromosome 4q35 region linked to both forms of FSHD lead to a relaxation of repression and increased somatic expression of DUX4-fl (DUX4-full length), the pathogenic alternative splicing isoform of the DUX4 gene. DUX4-fl encodes a transcription factor expressed in healthy testis and pluripotent stem cells; however, in FSHD, increased levels of DUX4-fl in myogenic cells lead to aberrant regulation of target genes. DUX4-fl has proven difficult to study in vivo; thus, little is known about its normal and pathogenic roles. The endogenous expression of DUX4-fl in FSHD-derived human muscle and myogenic cells is extremely low, exogenous expression of DUX4-fl in somatic cells rapidly induces cytotoxicity, and, due in part to the lack of conservation beyond primate lineages, viable animal models based on DUX4-fl have been difficult to generate. By contrast, the FRG1 (FSHD region gene 1), which is linked to FSHD, is evolutionarily conserved from invertebrates to humans, and has been studied in several model organisms. FRG1 expression is critical for the development of musculature and vasculature, and overexpression of FRG1 produces a myopathic phenotype, yet the normal and pathological functions of FRG1 are not well understood. Interestingly, DUX4 and FRG1 were recently linked when the latter was identified as a direct transcriptional target of DUX4-FL. To better understand the pathways affected in FSHD by DUX4-fl and FRG1, we generated transgenic lines of Drosophila expressing either gene under control of the UAS/GAL4 binary system. Utilizing these lines, we generated screenable phenotypes recapitulating certain known consequences of DUX4-fl or FRG1 overexpression. These transgenic Drosophila lines provide resources to dissect the pathways affected by DUX4-fl or FRG1 in a genetically tractable organism and may provide insight into both muscle development and pathogenic mechanisms in FSHD.
Versatility of CRISPR/Cas9-based platforms makes them promising tools for the correction of diverse genetic/epigenetic disorders. Here we contrast the use of these genome editing tools in two myopathies with very different molecular origins: Duchenne muscular dystrophy, a monogenetic disease, and facioscapulohumeral muscular dystrophy, an epigenetic disorder with unique therapeutic challenges.
Imaging is an integral part of the multidisciplinary management of cancer. Radiographic techniques are indispensable for proper staging of cancers and evaluation of the response of tumors to treatment. A wide variety of imaging modalities is available to clinicians. This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist will introduce the role of radiology in the diagnosis and treatment of cancer.
The Epithelial Transmembrane Protein PERP Is Required for Inflammatory Responses to S. typhimurium Infection: A Dissertation
Salmonella enterica subtype Typhimurium (S. Typhimurium) is one of many non-typhoidal Salmonella enterica strains responsible for over one million cases of salmonellosis in the United States each year. These Salmonella strains are also a leading cause of diarrheal disease in developing countries. Nontyphoidal salmonellosis induces gastrointestinal distress that is characterized histopathologically by an influx of polymorphonuclear leukocytes (PMNs), the non-specific effects of which lead to tissue damage and contribute to diarrhea.
Prior studies from our lab have demonstrated that the type III secreted bacterial effector SipA is a key regulator of PMN influx during S. Typhimurium infection and that its activity requires processing by caspase-3. Although we established caspase-3 activity is required for the activation of inflammatory pathways during S. Typhimurium infection, the mechanisms by which caspase-3 is activated remain incompletely understood. Most challenging is the fact that SipA is responsible for activating caspase-3, which begs the question of how SipA can activate an enzyme it requires for its own activity.
In the present study, we describe our findings that the eukaryotic tetraspanning membrane protein PERP is required for the S. Typhimuriuminduced influx of PMNs. We further show that S. Typhimurium infection induces PERP accumulation at the apical surface of polarized colonic epithelial cells, and that this accumulation requires SipA. Strikingly, PERP accumulation occurs in the absence of caspase-3 processing of SipA, which is the first time we have shown SipA mediates a cellular event without first requiring caspase-3 processing. Previous work demonstrates that PERP mediates the activation of caspase-3, and we find that PERP is required for Salmonella-induced caspase-3 activation.
Our combined data support a model in which SipA triggers caspase-3 activation via its cellular modulation of PERP. Since SipA can set this pathway in motion without being cleaved by caspase-3, we propose that PERP-mediated caspase-3 activation is required for the activation of SipA, and thus is a key step in the inflammatory response to S. Typhimurium infection. Our findings further our understanding of how SipA induces inflammation during S. Typhimurium infection, and also provide additional insight into how type III secreted effectors manipulate host cells.