The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

Simple nutrients bypass the requirement for HLH-30 in coupling lysosomal nutrient sensing to survival.

Lysosomes are ubiquitous acidified organelles that degrade intracellular and extracellular material trafficked via multiple pathways. Lysosomes also sense cellular nutrient levels to regulate target of rapamycin (TOR) kinase, a signaling enzyme that drives growth and suppresses activity of the MiT/TFE family of transcription factors that control biogenesis of lysosomes. In this study, we subjected worms lacking basic helix-loop-helix transcription factor 30 (hlh-30), the Caenorhabditis elegans MiT/TFE ortholog, to starvation followed by refeeding to understand how this pathway regulates survival with variable nutrient supply. Loss of HLH-30 markedly impaired survival in starved larval worms and recovery upon refeeding bacteria. Remarkably, provision of simple nutrients in a completely defined medium (C. elegans maintenance medium [CeMM]), specifically glucose and linoleic acid, restored lysosomal acidification, TOR activation, and survival with refeeding despite the absence of HLH-30. Worms deficient in lysosomal lipase 2 (lipl-2), a lysosomal enzyme that is transcriptionally up-regulated in starvation in an HLH-30-dependent manner, also demonstrated increased mortality with starvation-refeeding that was partially rescued with glucose, suggesting a critical role for LIPL-2 in lipid metabolism under starvation. CeMM induced transcription of vacuolar proton pump subunits in hlh-30 mutant worms, and knockdown of vacuolar H+-ATPase 12 (vha-12) and its upstream regulator, nuclear hormone receptor 31 (nhr-31), abolished the rescue with CeMM. Loss of Ras-related GTP binding protein C homolog 1 RAGC-1, the ortholog for mammalian RagC/D GTPases, conferred starvation-refeeding lethality, and RAGC-1 overexpression was sufficient to rescue starved hlh-30 mutant worms, demonstrating a critical need for TOR activation with refeeding. These results show that HLH-30 activation is critical for sustaining survival during starvation-refeeding stress via regulating TOR. Glucose and linoleic acid bypass the requirement for HLH-30 in coupling lysosome nutrient sensing to survival.

Effect of leg lift on stroke volume index in children 11-17 years old before and after induction of general anesthesia.

BACKGROUND: Fluid administration in ERAS is one component which anesthesiologists have control. Change in stroke volume index (SVI) is used to assess fluid responsiveness. This study sought the effect of perioperative fluid responsiveness in pediatric patients. The Cheetah NICOM™ (noninvasive CO monitor) was employed because of correlation with other CO monitors. AIMS: The Cheetah NICOM™ is an FDA-approved device in adults. Its indications in children are unknown. 24 enrolled patients (age 11-17) were ASA 1 or 2 without cardiopulmonary disease. The study examined changes in SVI, HR, SBP, and DBP between the semi-recumbent and legs lifted positions, both awake and after anesthesia. METHODS: Each patient had baseline vital signs measured and fluid responsiveness determined with the Cheetah NICOM™ monitor. Stroke volume index (SVI) was measured in both the semi-recumbent position and after passive leg lift. Measurements were repeated immediately after induction of general anesthesia. Twenty-one of 24 patients received inhalation induction with sevoflurane and three patients received intravenous propofol followed by sevoflurane. Airway management included intubation in 19 of 24 and a laryngeal mask airway (LMA) in five of 24 patients. RESULTS: There was a 25% increase in SVI after leg lift from 54.8 ml/m2 to 68.0 ml/m2 in awake patients (p < 0.001). Diastolic pressure decreased by 15.4% from 67.9 mm Hg to 58.2 mm Hg from semi-recumbent position and leg lift, respectively (p = .004). No significant change in heart rate or SBP was found. Following induction, patient SVI increased with leg lift by 25.6% from 42.6 ml/m2 to 53.5 ml/m2 after leg lift (p = .003). Heart rate decreased by 9.3% and SBP increased 2.8% with leg lift. CONCLUSIONS: 96% of normal 11-17-year-old children were fluid responsive while awake and 79% after induction of general anesthesia.

Changes in Presentation of Celiac Disease in Ireland From the 1960s to 2015.

BACKGROUND & AIMS: Celiac disease is an immune-mediated enteropathy characterized with high heterogeneity in presentation among genetically predisposed individuals. In recent years, a change in the phenotypic presentation of celiac disease has been reported. We studied clinical presentation, from 1960 through 2015, in Ireland, which has a high incidence of celiac disease. METHODS: We performed a retrospective analysis of medical charts from patients diagnosed with celiac disease at 5 secondary referral centers in Ireland from 1960 through 2015 (n = 749; median age, 56 years; age range, 18-91 years). The cohort was divided into 5 groups based on year of diagnosis (≤1985, 1986-1995, 1996-2005, 2006-2010, or 2011 and later). We collected findings from clinical presentation at diagnosis; serology tests; small intestinal biopsy analyses; and patients' demographic, clinical, and family data. Presentations at diagnosis were classified according to the Oslo criteria as follows: classical (patients presenting with malabsorption), nonclassical (no signs or symptoms of malabsorption at presentation), or subclinical (below the threshold of clinical detection). The primary outcome was change in clinical presentation of celiac disease over time. RESULTS: Of the 749 patients studied, 512 were female and 237 were male (ratio of 2.2:1). Female patients were diagnosed at younger ages than male patients (42 vs 47 years, respectively; P = .004), and had more immune-mediated conditions than male patients (35.7% for female patients vs 21.5% for male patients; P < .001). For patients diagnosed as adults (after the age of 18 years), the median age of diagnosis increased from 34.0 years during the period ≤1985 to median ages of 44-46 years after 1985 (P < .002). A smaller proportion of patients presented with classical features of celiac disease after 2010 (48.4%) than ≤1985 (85.2%); the proportion of patients with nonclassical or subclinical celiac disease increased from 14.8% ≤1985 to 51.6% after 2010 (P = .006 for each). Biopsies categorized as Marsh 3c decreased, from 52.2% in the period 1996-2005 to 22.5% in the period after 2010 (P = .003). The prevalence of associated thyroid disease has decreased during the study period, from 36.6% ≤1985 to 17.1% after 2010 (P = .039), whereas body mass index at diagnosis increased from 21.5 kg/m2 ≤1985 to 24.8 kg/m2 after 2010 (P < .001). CONCLUSIONS: We found the clinical presentation of celiac disease changed significantly in Ireland from 1960 through 2015. The age of presentation in adulthood increased over this time period, as did the proportions of patients with nonclassical or subclinical disease.

FOXM1 cistrome predicts breast cancer metastatic outcome better than FOXM1 expression levels or tumor proliferation index.

FOXM1 is a key transcription factor regulating cell cycle progression, DNA damage response, and a host of other hallmark cancer features, but the role of the FOXM1 cistrome in driving estrogen receptor-positive (ER+) versus estrogen receptor-negative (ER-) breast cancer clinical outcomes remains undefined. Chromatin immunoprecipitation sequencing (ChIP-Seq) coupled with RNA sequencing (RNA-Seq) analyses was used to identify FOXM1 target genes in breast cancer cells (MCF-7) where FOXM1 expression was either induced by cell proliferation or repressed by p53 upregulation. The prognostic performance of these FOXM1 target genes was assessed relative to FOXM transcript levels and a 61-gene proliferation score (PS) for their ability to dichotomize a pooled cohort of 683 adjuvant chemotherapy-naïve, node-negative breast cancer cases (447 ER+, 236 ER-). Differences in distant metastasis-free survival (DMFS) between the dichotomized expression groups were determined by Cox proportional hazard modeling. Proliferation-associated FOXM1 upregulation induced a set of 145 differentially bound and expressed genes (direct targets), and these demonstrated minimal overlap with differentially bound and expressed genes following FOXM1 repression by p53 upregulation. This proliferation-associated FOXM1 cistrome was not only better at significantly predicting metastatic outcome of ER+ breast cancers (HR: 2.8 (2.0-3.8), p = 8.13E-10), but was the only parameter trending toward significance in predicting ER- metastatic outcome (HR: 1.6 (0.9-2.9), p = 0.087). Our findings demonstrate that FOXM1 target genes are highly dependent on the cellular context in which FOXM1 expression is modulated, and a newly identified proliferation-associated FOXM1 cistromic signature best predicts breast cancer metastatic outcome.

Designing and implementing the objective structured clinical examination in anesthesiology.

Since its description in 1974, the Objective Structured Clinical Examination (OSCE) has gained popularity as an objective assessment tool of medical students, residents, and trainees. With the development of the anesthesiology residents' milestones and the preparation for the Next Accreditation System, there is an increased interest in OSCE as an evaluation tool of the six core competencies and the corresponding milestones proposed by the Accreditation Council for Graduate Medical Education.In this article the authors review the history of OSCE and its current application in medical education and in different medical and surgical specialties. They also review the use of OSCE by anesthesiology programs and certification boards in the United States and internationally. In addition, they discuss the psychometrics of test design and implementation with emphasis on reliability and validity measures as they relate to OSCE.

Boon or Bane? Anti-Tumor Necrosis Factor Therapy Complicated by Listeria monocytogenes Meningitis Culminating in Colectomy for Ulcerative Colitis.

Anti-tumor necrosis factor (TNF) biologics have revolutionized the management of inflammatory bowel diseases (IBDs) by promoting mucosal healing and delaying surgical intervention in ulcerative colitis (UC). However, biologics can potentiate the risk of opportunistic infections alongside the use of other immunomodulators in IBD. As recommended by the European Crohn's and Colitis Organisation (ECCO), anti-TNF-α therapy should be suspended in the setting of a potentially life-threatening infection. The objective of this case report was to highlight how the practice of appropriately discontinuing immunosuppression can exacerbate underlying colitis. We need to maintain a high index of suspicion for complications of anti-TNF therapy, so that we can intervene early and prevent potential adverse sequelae. In this report, a 62-year-old female presented to the emergency department with non-specific symptoms including fever, diarrhea and confusion on a background of known UC. She had been commenced on infliximab (INFLECTRA®) 4 weeks earlier. Inflammatory markers were elevated, and Listeria monocytogenes was identified on both blood cultures and cerebrospinal fluid (CSF) polymerase chain reaction (PCR). The patient improved clinically and completed a 21-day course of amoxicillin advised by microbiology. After a multidisciplinary discussion, the team planned to switch her from infliximab to vedolizumab (ENTYVIO®). Unfortunately, the patient re-presented to hospital with acute severe UC. Left-sided colonoscopy demonstrated modified Mayo endoscopic score 3 colitis. She has had recurrent hospital admissions over the past 2 years for acute flares of UC, ultimately culminating in colectomy. To our knowledge, our case-based review is unique in unpacking the dilemma of holding immunosuppression at the risk of IBD worsening.

The ACE-inhibitor drug captopril inhibits ACN-1 to control dauer formation and aging.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in C. elegans , Drosophila , and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNAi promoted dauer larvae formation, suggesting acn-1 is a daf gene. Captopril-mediated lifespan extension xwas abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control. Summary Statement: Captopril and acn-1 control aging. By demonstrating they regulate dauer formation and interact with daf genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.

Cytokine elevation and transaminitis after laparoscopic donor nephrectomy.

Acute kidney injury frequently occurs in the critically ill and often progresses into multiorgan dysfunction syndrome, resulting in high mortality. We previously showed that nephrectomized mice had increased interleukin (IL)-6 and tumor necrosis factor (TNF)-α that directly contributed to systemic inflammation and hepatic injury. In this study, we examined whether patients undergoing laparoscopic donor nephrectomy have increased postoperative cytokine levels with injury to the liver and whether the remaining kidney sustains injury. Serial serum and urine samples were collected from 32 patients undergoing laparoscopic donor nephrectomy and 17 patients undergoing nonrenal laparoscopic surgery. Serum IL-6, IL-18, TNF-α and monocyte chemotactic protein-1 (MCP-1) (markers of systemic inflammation) and urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), MCP-1, and IL-18 (markers of acute kidney injury) were quantified by enzyme-linked immunosorbent assay. We also analyzed serum creatinine, aspartate transaminase (AST), and alanine transaminase to assess liver injury. Patients who underwent donor nephrectomy not only demonstrated increased serum creatinine but also had significant increases in serum IL-6, MCP-1, and AST. Serum TNF-α also trended upward in donor nephrectomy patients. Finally, the donor nephrectomy group showed increased urinary NGAL but not KIM-1 at 24 h. Taken together, our findings of increased serum IL-6, MCP-1, and AST after donor nephrectomy suggest that an acute reduction of kidney function induces systemic inflammation and may have distant effects on the liver. Further studies are needed to correlate increased urinary NGAL after donor nephrectomy both as a potential marker for renal tubular stress and/or hypertrophy in the contralateral kidney.

Status of confocal laser endomicroscopy in gastrointestinal disease.

Confocal laser endomicroscopy (CLE) is an advanced imaging technique which combines conventional white light endoscopy (WLE) with an integrated or probe based confocal microscope. This allows microscopic examination of the surface epithelium and in vivo diagnosis during endoscopy. Established CLE applications include the diagnosis of Barrett's oesophagus, gastric intestinal metaplasia, coeliac disease and microscopic colitis. CLE can differentiate hyperplastic from adenomatous polyps in the colon and may obviate the need to biopsy all polyps at endoscopy. CLE is particularly helpful in surveillance endoscopy in inflammatory bowel disease where it has been shown to reduce the number of biopsies required and improve the detection of dysplasia. The future of CLE may be with new contrast agents to allow for molecular tagging and improved endoscopic diagnoses. The aim of this review is to describe the technology and techniques involved in CLE, and discuss the evolving applications in obtaining "virtual biopsy" throughout the GI tract.

Control of aging by the renin-angiotensin system: a review of C. elegans, Drosophila, and mammals.

The free-living, non-parasitic nematode Caenorhabditis elegans is a premier model organism for the study of aging and longevity due to its short lifespan, powerful genetic tools, and conservation of fundamental mechanisms with mammals. Approximately 70 percent of human genes have homologs in C. elegans, including many that encode proteins in pathways that influence aging. Numerous genetic pathways have been identified in C. elegans that affect lifespan, including the dietary restriction pathway, the insulin/insulin-like growth factor (IGF) signaling pathway, and the disruption of components of the mitochondrial electron transport chain. C. elegans is also a powerful system for performing drug screens, and many lifespan-extending compounds have been reported; notably, several FDA-approved medications extend the lifespan in C. elegans, raising the possibility that they can also extend the lifespan in humans. The renin-angiotensin system (RAS) in mammals is an endocrine system that regulates blood pressure and a paracrine system that acts in a wide range of tissues to control physiological processes; it is a popular target for drugs that reduce blood pressure, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Emerging evidence indicates that this system influences aging. In C. elegans, decreasing the activity of the ACE homolog acn-1 or treatment with the ACE-inhibitor Captopril significantly extends the lifespan. In Drosophila, treatment with ACE inhibitors extends the lifespan. In rodents, manipulating the RAS with genetic or pharmacological interventions can extend the lifespan. In humans, polymorphisms in the ACE gene are associated with extreme longevity. These results suggest the RAS plays a conserved role in controlling longevity. Here, we review studies of the RAS and aging, emphasizing the potential of C. elegans as a model for understanding the mechanism of lifespan control.

Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.

Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.

Reproductive Aging in Caenorhabditis elegans: From Molecules to Ecology.

Aging animals display a broad range of progressive degenerative changes, and one of the most fascinating is the decline of female reproductive function. In the model organism Caenorhabditis elegans, hermaphrodites reach a peak of progeny production on day 2 of adulthood and then display a rapid decline; progeny production typically ends by day 8 of adulthood. Since animals typically survive until day 15 of adulthood, there is a substantial post reproductive lifespan. Here we review the molecular and cellular changes that occur during reproductive aging, including reductions in stem cell number and activity, slowing meiotic progression, diminished Notch signaling, and deterioration of germ line and oocyte morphology. Several interventions have been identified that delay reproductive aging, including mutations, drugs and environmental factors such as temperature. The detailed description of reproductive aging coupled with interventions that delay this process have made C. elegans a leading model system to understand the mechanisms that drive reproductive aging. While reproductive aging has dramatic consequences for individual fertility, it also has consequences for the ecology of the population. Population dynamics are driven by birth and death, and reproductive aging is one important factor that influences birth rate. A variety of theories have been advanced to explain why reproductive aging occurs and how it has been sculpted during evolution. Here we summarize these theories and discuss the utility of C. elegans for testing mechanistic and evolutionary models of reproductive aging.

Coeliac disease enteropathy and symptoms may be aggravated by angiotensin receptor blockers in patients on a gluten-free diet.

BACKGROUND: Angiotensin receptor blocker-associated enteropathy (ARB-e) is an increasingly recognised clinical entity with symptoms and histological findings identical to coeliac disease (CD). There is evidence to suggest immune-mediated mucosal injury in ARB-e with a high prevalence of DQ2/DQ8; however, as IgA anti-tissue transglutaminase (anti-TTG) is usually negative, an insult other than TTG-mediated injury is suspected. The impact of ARBs on disease activity in patients with CD is not known. OBJECTIVE: To assess the effect of ARB exposure on patients with established CD. METHODS: A patient record search of 1142 individual patients attending a dedicated coeliac clinic from 2010 to the present identified 59 patients treated with ARB. Those with CD confirmed by serology (TTG + ve/EMA + ve) and histopathology (Marsh criteria) were included (n = 40, 0.52%). Data collected included disease duration, compliance with gluten-free diet (GFD), reported symptoms (diarrhoea, weight loss and abdominal pain), surrogate markers of absorption (Vitamin D, Iron, Calcium and Haemoglobin), in addition to anti-TTG titre and histological grade at last follow up. Patients were age and sex-matched in a 1:2 ratio with CD patients not taking ARBs (controls), with comparable rates of disease duration and compliance with GFD. RESULTS: The ARB and control groups were matched in terms of age (mean 66.2 years) and gender (female 63%). Strict compliance with GFD was reported in 55% and 56%, respectively. Persistent symptoms were reported in 10/40 (25%) of the ARB group compared with 7/82 (9%) of controls (p = 0.0181). There were lower rates of mucosal healing (Marsh grade 0) in the ARB group (36% n = 11) compared to controls (55%, n = 33). There was no significant difference in anti-TTG titres. Surrogate markers of absorption were comparable across the groups, except for Vitamin D which was lower in those taking olmesartan (p = 0.0015). CONCLUSIONS: ARBs may aggravate the enteropathy and lead to increased symptoms in patients with bone fide diagnosed CD following a GFD.

Evaluation of 6 candidate genes on chromosome 11q23 for coeliac disease susceptibility: a case control study.

BACKGROUND: Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance). The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23. METHODS: We have evaluated six candidate genes in one of these regions (11q23), namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls. RESULTS: Promotor SNPs (-607, -137) in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P < 0.05). Follow-up analyses of an extended sample supported the same, moderate effect (P < 0.05) for one of these. Haplotype analysis of IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P < 0.0001), which was independently associated in two case-control comparisons. This same haplotype has been noted in rheumatoid arthritis. CONCLUSION: Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.

Nonopioid Modalities for Acute Postoperative Pain in Abdominal Transplant Recipients.

The field of abdominal organ transplantation is multifaceted, with the clinician balancing recipient comorbidities, risks of the surgical procedure, and the pathophysiology of immunosuppression to ensure optimal outcomes. An underappreciated element throughout this process is acute pain management related to the surgical procedure. As the opioid epidemic continues to grow with increasing numbers of transplant candidates on opioids as well the increase in the development of enhanced recovery after surgery protocols, there is a need for greater focus on optimal postoperative pain control to minimize opioid use and improve outcomes. This review will summarize the physiology of acute pain in transplant recipients, assess the impact of opioid use on post-transplant outcomes, present evidence supporting nonopioid analgesia in transplant surgery, and briefly address the perioperative approach to the pretransplant recipient on opioids.

Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing.

BACKGROUND: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. Aim: To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years. METHODS: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time. RESULTS: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time. CONCLUSIONS: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.

Prostate cancer reactivates developmental epigenomic programs during metastatic progression.

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Lifespan Extension in C. elegans Caused by Bacterial Colonization of the Intestine and Subsequent Activation of an Innate Immune Response.

Mechanisms that control aging are important yet poorly defined. To discover longevity control genes, we performed a forward genetic screen for delayed reproductive aging in C. elegans. Here, we show that am117 is a nonsense mutation in the phm-2 gene, which encodes a protein homologous to human scaffold attachment factor B. phm-2(lf) mutant worms have an abnormal pharynx grinder, which allows live bacteria to accumulate in the intestine. This defect shortens lifespan on highly pathogenic bacteria but extends lifespan and health span on the standard E. coli diet by activating innate immunity pathways that lead to bacterial avoidance behavior and dietary restriction. eat-2(lf) mutants displayed a similar phenotype, indicating accumulation of live bacteria also triggers extended longevity in this mutant. The analysis of phm-2 elucidates connections between pathogen response and aging by defining a mechanism of longevity extension in C. elegans-bacterial colonization, innate immune activation, and bacterial avoidance behavior.