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Introduction: Management of inflammatory bowel diseases (IBDs) – both Crohn’s disease (CD) and ulcerative colitis (UC) – during pregnancy can be challenging since most monitoring tools available in nonpregnant patients are contraindicated. Objectives: The aim of the study was to test whether fecal inflammatory markers – specifically fecal lactoferrin – physiologically change during normal pregnancy as a prerequisite to use them to monitor IBD activity during pregnancy. Methods: Fecal lactoferrin was tested in healthy pregnant and nonpregnant women from the same geographic area and age range (18–40 years) – all negative for clinical gastrointestinal tract inflammation. A retrospective review of fecal lactoferrin levels contrasted with the Simple Endoscopic Score for CD, and the Disease Activity Index for UC was also performed in women with active IBDs within the same age range and geographical area. Results: In 30 nonpregnant subjects, fecal lactoferrin levels were 0.87 ± 1.08 μg/g. In 49 pregnant subjects, levels were 0.59 ± 0.83, 0.87 ± 1.13, and 0.85 ± 1.06 μg/g during the first, second, and third trimester, respectively (p = 0.64), with average levels for the 3 trimesters of 0.81 ± 1.04 μg/g (p = 0.61 compared to nonpregnant subjects). Sequential fecal lactoferrin levels (n = 26) did not differ from one trimester to the other in the individual subjects (p = 0.80). In 45 female IBD patients (27 with CD and 18 with UC), fecal lactoferrin levels were correlated with disease activity as defined by the endoscopic scores: 218, 688, and 1,175 μg/g for CD and 931, 2,088, and 2,509 μg/g for UC, respectively, for mild, moderate, and severe activity. Conclusions: Fecal lactoferrin levels during normal pregnancy are superimposable to those of nonpregnant women and significantly below levels in women of the same childbearing age with active IBDs. Additional published data – reviewed in this atricle – and our own indicate that fecal lactoferrin and other markers can be potentially used to monitor disease activity in pregnant IBD patients.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn’s disease (CD) and ulcerative colitis (UC) patients.Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD.Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3.Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

The ATP-dependent chromatin-remodeling complex SWR1 exchanges a variant histone H2A.Z/H2B dimer for a canonical H2A/H2B dimer at nucleosomes flanking histone-depleted regions, such as promoters. This localization of H2A.Z is conserved throughout eukaryotes. SWR1 is a 1 megadalton complex containing 14 different polypeptides, including the AAA+ ATPases Rvb1 and Rvb2. Using electron microscopy, we obtained the three-dimensional structure of SWR1 and mapped its major functional components. Our data show that SWR1 contains a single heterohexameric Rvb1/Rvb2 ring that, together with the catalytic subunit Swr1, brackets two independently assembled multisubunit modules. We also show that SWR1 undergoes a large conformational change upon engaging a limited region of the nucleosome core particle. Our work suggests an important structural role for the Rvbs and a distinct substrate-handling mode by SWR1, thereby providing a structural framework for understanding the complex dimer-exchange reaction.

The H2A.Z histone variant, a genome-wide hallmark of permissive chromatin, is enriched near transcription start sites in all eukaryotes. H2A.Z is deposited by the SWR1 chromatin remodeler and evicted by unclear mechanisms. We tracked H2A.Z in living yeast at single-molecule resolution, and found that H2A.Z eviction is dependent on RNA Polymerase II (Pol II) and the Kin28/Cdk7 kinase, which phosphorylates Serine 5 of heptapeptide repeats on the carboxy-terminal domain of the largest Pol II subunit Rpb1. These findings link H2A.Z eviction to transcription initiation, promoter escape and early elongation activities of Pol II. Because passage of Pol II through +1 nucleosomes genome-wide would obligate H2A.Z turnover, we propose that global transcription at yeast promoters is responsible for eviction of H2A.Z. Such usage of yeast Pol II suggests a general mechanism coupling eukaryotic transcription to erasure of the H2A.Z epigenetic signal.

Despite aggressive medical therapy, many patients with Crohn’s disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score ‘per se’ bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn’s disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy.

Introduction The debate format has been infrequently used in resident education. We used the panel debate format as a tool to improve health care professionals' knowledge of the Patient Protection and Affordable Care Act (PPACA). Methods Six physical medicine and rehabilitation resident physician debaters led a 60-minute panel debate about the PPACA. Outcome measures included a survey of the spectators with validated questions on physician attitudes towards health care reform in the US and open-ended questions regarding Americans' views on the US health care system. Results Twenty-nine physician and nonphysician faculty and staff participated as spectators. Responses to the questions on attitudes toward reform of the health care system indicated that zero spectators rated the current US health care system (i.e., the PPACA) as “Excellent,” 25% rated it as “Good,” 42% “Average,” 25% “Poor,” and 8% “Failing.” Half of the respondents indicated they support a US president who advocates making the US health care system more like those of other countries. The majority of respondents (89%) expressed the idea that the US does not have the best health care system in the world. Discussion Approaching a topic as broad as health care reform with the debate format promoted knowledge, reflection, and interaction with both the opposing debaters and audience.

While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)—both ulcerative colitis (UC) and Crohn’s Disease (CD)—as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage—as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients’ first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.