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1.  Efficacy of vedolizumab as induction therapy in refractory IBD patients: Amulticenter cohort 
Inflammatory bowel diseases  2015;21(12):2879-2885.
Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease (IBD) in a multicenter cohort of patients.
Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300mg) was administered at weeks 0, 2, 6 and 14. Efficacy was assessed using the Harvey Bradshaw index (HBI) for CD, the simple clinical colitis activity index (SCCAI) for UC and physician assessment, along with C-reactive protein (CRP) and decrease of corticosteroid therapy. Clinical response was defined as decrease in HBI ≥ 3 and SCCAI ≥ 3 and remission as HBI ≤ 4, SCCAI ≤ 2 and physician assessment of response and remission.
Our study included 172 patients (107 CD, 59 UC, 6 IBD-U, male 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had an ostomy and 9 an ileoanal pouch and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14. Adverse events occurred in 10.5%.
VDZ is safe and well tolerated in refractory IBD patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.
PMCID: PMC4745906  PMID: 26288002
Vedolizumab; Crohn's disease; ulcerative colitis
2.  Malaria intervention scale-up in Africa: effectiveness predictions for health programme planning tools, based on dynamic transmission modelling 
Malaria Journal  2016;15:417.
Scale-up of malaria prevention and treatment needs to continue to further important gains made in the past decade, but national strategies and budget allocations are not always evidence-based. Statistical models were developed summarizing dynamically simulated relations between increases in coverage and intervention impact, to inform a malaria module in the Spectrum health programme planning tool.
The dynamic Plasmodiumfalciparum transmission model OpenMalaria was used to simulate health effects of scale-up of insecticide-treated net (ITN) usage, indoor residual spraying (IRS), management of uncomplicated malaria cases (CM) and seasonal malaria chemoprophylaxis (SMC) over a 10-year horizon, over a range of settings with stable endemic malaria. Generalized linear regression models (GLMs) were used to summarize determinants of impact across a range of sub-Sahara African settings.
Selected (best) GLMs explained 94–97 % of variation in simulated post-intervention parasite infection prevalence, 86–97 % of variation in case incidence (three age groups, three 3-year horizons), and 74–95 % of variation in malaria mortality. For any given effective population coverage, CM and ITNs were predicted to avert most prevalent infections, cases and deaths, with lower impacts for IRS, and impacts of SMC limited to young children reached. Proportional impacts were larger at lower endemicity, and (except for SMC) largest in low-endemic settings with little seasonality. Incremental health impacts for a given coverage increase started to diminish noticeably at above ~40 % coverage, while in high-endemic settings, CM and ITNs acted in synergy by lowering endemicity. Vector control and CM, by reducing endemicity and acquired immunity, entail a partial rebound in malaria mortality among people above 5 years of age from around 5–7 years following scale-up. SMC does not reduce endemicity, but slightly shifts malaria to older ages by reducing immunity in child cohorts reached.
Health improvements following malaria intervention scale-up vary with endemicity, seasonality, age and time. Statistical models can emulate epidemiological dynamics and inform strategic planning and target setting for malaria control.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-016-1461-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4991118  PMID: 27538889
Malaria; Prevention; Treatment; Vector control; Mortality; Morbidity; Health impact; Insecticide-treated mosquito nets; Indoor residual spraying; Programme planning; Modelling
3.  Environment shapes the fecal microbiome of invasive carp species 
Microbiome  2016;4:44.
Although the common, silver, and bighead carps are native and sparsely distributed in Eurasia, these fish have become abundant and invasive in North America. An understanding of the biology of these species may provide insights into sustainable control methods. The animal-associated microbiome plays an important role in host health. Characterization of the carp microbiome and the factors that affect its composition is an important step toward understanding the biology and interrelationships between these species and their environments.
We compared the fecal microbiomes of common, silver, and bighead carps from wild and laboratory environments using Illumina sequencing of bacterial 16S ribosomal RNA (rRNA). The fecal bacterial communities of fish were diverse, with Shannon indices ranging from 2.3 to 4.5. The phyla Proteobacteria, Firmicutes, and Fusobacteria dominated carp guts, comprising 76.7 % of total reads. Environment played a large role in shaping fecal microbial community composition, and microbiomes among captive fishes were more similar than among wild fishes. Although differences among wild fishes could be attributed to feeding preferences, diet did not strongly affect microbial community structure in laboratory-housed fishes. Comparison of wild- and lab-invasive carps revealed five shared OTUs that comprised approximately 40 % of the core fecal microbiome.
The environment is a dominant factor shaping the fecal bacterial communities of invasive carps. Captivity alters the microbiome community structure relative to wild fish, while species differences are pronounced within habitats. Despite the absence of a true stomach, invasive carp species exhibited a core microbiota that warrants future study.
Electronic supplementary material
The online version of this article (doi:10.1186/s40168-016-0190-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4981970  PMID: 27514729
Fecal microbiome; Invasive carp; Microbiota; Community structure; 16SrRNA gene
4.  An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease 
Science translational medicine  2015;7(300):300ra128.
There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.
PMCID: PMC4825054  PMID: 26268315
5.  The Bacterial Communities of Full-Scale Biologically Active, Granular Activated Carbon Filters Are Stable and Diverse and Potentially Contain Novel Ammonia-Oxidizing Microorganisms 
Applied and Environmental Microbiology  2015;81(19):6864-6872.
The bacterial community composition of the full-scale biologically active, granular activated carbon (BAC) filters operated at the St. Paul Regional Water Services (SPRWS) was investigated using Illumina MiSeq analysis of PCR-amplified 16S rRNA gene fragments. These bacterial communities were consistently diverse (Shannon index, >4.4; richness estimates, >1,500 unique operational taxonomic units [OTUs]) throughout the duration of the 12-month study period. In addition, only modest shifts in the quantities of individual bacterial populations were observed; of the 15 most prominent OTUs, the most highly variable population (a Variovorax sp.) modulated less than 13-fold over time and less than 8-fold from filter to filter. The most prominent population in the profiles was a Nitrospira sp., representing 13 to 21% of the community. Interestingly, very few of the known ammonia-oxidizing bacteria (AOB; <0.07%) and no ammonia-oxidizing Archaea were detected in the profiles. Quantitative PCR of amoA genes, however, suggested that AOB were prominent in the bacterial communities (amoA/16S rRNA gene ratio, 1 to 10%). We conclude, therefore, that the BAC filters at the SPRWS potentially contained significant numbers of unidentified and novel ammonia-oxidizing microorganisms that possess amoA genes similar to those of previously described AOB.
PMCID: PMC4561712  PMID: 26209671
6.  CD117+ Dendritic and Mast Cells Are Dependent on RasGRP4 to Function as Accessory Cells for Optimal Natural Killer Cell-Mediated Responses to Lipopolysaccharide 
PLoS ONE  2016;11(3):e0151638.
Ras guanine nucleotide-releasing protein-4 (RasGRP4) is an evolutionarily conserved calcium-regulated, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. While an important intracellular signaling protein for CD117+ mast cells (MCs), its roles in other immune cells is less clear. In this study, we identified a subset of in vivo-differentiated splenic CD117+ dendritic cells (DCs) in wild-type (WT) C57BL/6 mice that unexpectedly contained RasGRP4 mRNA and protein. In regard to the biologic significance of these data to innate immunity, LPS-treated splenic CD117+ DCs from WT mice induced natural killer (NK) cells to produce much more interferon-γ (IFN-γ) than comparable DCs from RasGRP4-null mice. The ability of LPS-responsive MCs to cause NK cells to increase their expression of IFN-γ was also dependent on this intracellular signaling protein. The discovery that RasGRP4 is required for CD117+ MCs and DCs to optimally induce acute NK cell-dependent immune responses to LPS helps explain why this signaling protein has been conserved in evolution.
PMCID: PMC4794117  PMID: 26982501
7.  Evaluating the effect of sample type on American alligator (Alligator mississippiensis) analyte values in a point-of-care blood analyser 
Conservation Physiology  2016;4(1):cov065.
Point-of-care blood analyzers provide researchers with the opportunity to collect blood biochemistry data for a variety of non-domesticed organisms while in the field. We investigated the use of an i-STAT analyzer and CG4+ cartridge to analyze whole blood, fresh plasma, and previously frozen plasma samples collected from American alligators.
The assessment of wildlife health has been enhanced by the ability of point-of-care (POC) blood analysers to provide biochemical analyses of non-domesticated animals in the field. However, environmental limitations (e.g. temperature, atmospheric humidity and rain) and lack of reference values may inhibit researchers from using such a device with certain wildlife species. Evaluating the use of alternative sample types, such as plasma, in a POC device may afford researchers the opportunity to delay sample analysis and the ability to use banked samples. In this study, we examined fresh whole blood, fresh plasma and frozen plasma (sample type) pH, partial pressure of carbon dioxide (PCO2), bicarbonate (HCO3−), total carbon dioxide (TCO2), base excess (BE), partial pressure of oxygen (PO2), oxygen saturation (sO2) and lactate concentrations in 23 juvenile American alligators (Alligator mississippiensis) using an i-STAT CG4+ cartridge. Our results indicate that sample type had no effect on lactate concentration values (F2,65 = 0.37, P = 0.963), suggesting that the i-STAT analyser can be used reliably to quantify lactate concentrations in fresh and frozen plasma samples. In contrast, the other seven blood parameters measured by the CG4+ cartridge were significantly affected by sample type. Lastly, we were able to collect blood samples from all alligators within 2 min of capture to establish preliminary reference ranges for juvenile alligators based on values obtained using fresh whole blood.
PMCID: PMC4922256  PMID: 27382469
American alligator; biochemistry; i-STAT; lactate; plasma; point-of-care
8.  Clinical presentation of eating disorders in young males at a tertiary setting 
Young males with eating disorders are a neglected study population in eating disorders. The aim of this study was to provide knowledge about the clinical presentation of eating disorders in young males.
The data source was the Helping to Outline Paediatric Eating Disorders (HOPE) Project (N ~ 1000), a prospective, ongoing registry comprising consecutive paediatric (<18 years) tertiary eating disorder referrals. Young males with DSM-5 eating disorders (n = 53) were compared with young females with eating disorders (n = 704).
There was no significant difference in the prevalence of diagnosis of bulimia nervosa (2 % vs 11 %, p = 0.26) among sexes. Males had comparable duration of illness (9 months; p = 0.28) and a significantly earlier age of onset (M = 12 years; p <0.001). Shape concern (2.39 vs 3.57, p <0.001) and weight concern (1.97 vs 3.09, p <0.001) were lower in males, and body mass index z score (−1.61 vs −1.42, p = 0.29) and medical compromise (odds ratio [OR] = 0.64, 95 % CI: 0.36, 1.12) were comparable. Males had a two-folder higher odds of being diagnosed with unspecified feeding or eating disorders (40 % vs 22 % for females, p = 0.004). Driven exercise to control weight and shape was common and comparable in prevalence among males and females (51 % vs 47 %, p = 0.79) and males were less likely to present with self-induced vomiting (OR = 0.23, 95 % CI: 0.09, 0.59).
Boys with eating disorders are an understudied group with similarities and differences in clinical presentation from girls with eating disorders. Parents and physicians are encouraged to consider changes in weight, disturbed vital signs, and driven, frequent exercise for the purposes of controlling weight or shape, as possible signs of eating disorders among male children. Diagnostic classification, assessment instruments, conceptualisation, and treatment methods need to be refined to improve application to young males.
PMCID: PMC4640410  PMID: 26557990
Child; Clinical presentation; Eating disorders; HOPE Project; Males; Paediatric
9.  Update on biologic pathways in inflammatory bowel disease and their therapeutic relevance 
Journal of gastroenterology  2012;47(1):1-8.
Results of recent genetic and immunologic studies have brought to the forefront several biologic pathways that allow for a better understanding of the mechanisms of tissue homeostasis, on the one hand, and inflammatory bowel disease (IBD) on the other. The explosion of research activity as a result of these newly identified targets is bringing the pathogenesis of these complex disorders into focus as well as creating new therapeutic opportunities. The greatest advances with perhaps the largest impact on our understanding of the etiology of Crohn’s disease are those related to bacterial sensing, such as through nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and its relationships to autophagy and the unfolded protein response as a consequence of endoplasmic reticulum stress. Interestingly, it appears as though these pathways, which are rooted in microbial sensing and regulation, are interrelated. Genetic studies have also renewed interest in previously studied pathways in IBD, such as the formation and function of the inflammasome and its relationship to interleukin (IL) 1-beta signaling. With the recent success of therapeutic agents designed to block tumor necrosis factor, the IL-12/23 pathways, and lymphocyte homing, insights have been gained into the biologic relevance and impact of these various inflammatory pathways in IBD. In this review, the exciting recent advances in these biologic pathways of IBD are discussed, particularly in light of their therapeutic relevance.
PMCID: PMC4592148  PMID: 22215058
Bacterial sensing; Intestinal homeostasis; Inflammatory bowel disease; Crohn’s disease; Autophagy; Ulcerative colitis
10.  Phylogenomically Guided Identification of Industrially Relevant GH1 β-Glucosidases through DNA Synthesis and Nanostructure-Initiator Mass Spectrometry 
ACS Chemical Biology  2014;9(9):2082-2091.
Harnessing the biotechnological potential of the large number of proteins available in sequence databases requires scalable methods for functional characterization. Here we propose a workflow to address this challenge by combining phylogenomic guided DNA synthesis with high-throughput mass spectrometry and apply it to the systematic characterization of GH1 β-glucosidases, a family of enzymes necessary for biomass hydrolysis, an important step in the conversion of lignocellulosic feedstocks to fuels and chemicals. We synthesized and expressed 175 GH1s, selected from over 2000 candidate sequences to cover maximum sequence diversity. These enzymes were functionally characterized over a range of temperatures and pHs using nanostructure-initiator mass spectrometry (NIMS), generating over 10,000 data points. When combined with HPLC-based sugar profiling, we observed GH1 enzymes active over a broad temperature range and toward many different β-linked disaccharides. For some GH1s we also observed activity toward laminarin, a more complex oligosaccharide present as a major component of macroalgae. An area of particular interest was the identification of GH1 enzymes compatible with the ionic liquid 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]), a next-generation biomass pretreatment technology. We thus searched for GH1 enzymes active at 70 °C and 20% (v/v) [C2mim][OAc] over the course of a 24-h saccharification reaction. Using our unbiased approach, we identified multiple enzymes of different phylogentic origin with such activities. Our approach of characterizing sequence diversity through targeted gene synthesis coupled to high-throughput screening technologies is a broadly applicable paradigm for a wide range of biological problems.
PMCID: PMC4168791  PMID: 24984213
11.  The Multifaceted Mast Cell in Inflammatory Bowel Disease 
Inflammatory bowel diseases  2014;20(12):2364-2378.
Mast cells (MCs) are tissue-resident immune cells that carry out protective roles against pathogens. In disease states, such as inflammatory bowel disease, these granulocytes release a diverse array of mediators that contribute to inflammatory processes. They also participate in wound repair and tissue remodeling. In this review, the composition of MCs and how their phenotypes can be altered during inflammation of the gastrointestinal tract is detailed. Animal and human clinical studies that have implicated the participation of MCs in inflammatory bowel disease are reviewed, including the contribution of the cell’s mediators to clinical symptoms, stress-triggered inflammation, and fistula and strictures. Studies that have focused on negating the proinflammatory roles of MCs and their mediators in animal models suggest new targets for therapies for patients with inflammatory bowel disease.
PMCID: PMC4428674  PMID: 25401721
inflammatory bowel disease; ulcerative colitis; Crohn’s disease; mast cell; tryptase; chymase
12.  Fecal Microbiota Transplantation via Colonoscopy for Recurrent C. difficile Infection 
Fecal Microbiota Transplantation (FMT) is a safe and highly effective treatment for recurrent and refractory C. difficile infection (CDI). Various methods of FMT administration have been reported in the literature including nasogastric tube, upper endoscopy, enema and colonoscopy. FMT via colonoscopy yields excellent cure rates and is also well tolerated. We have found that patients find this an acceptable and tolerable mode of delivery. At our Center, we have initiated a fecal transplant program for patients with recurrent or refractory CDI. We have developed a protocol using an iterative process of revision and have performed 24 fecal transplants on 22 patients with success rates comparable to the current published literature. A systematic approach to patient and donor screening, preparation of stool, and delivery of the stool maximizes therapeutic success. Here we detail each step of the FMT protocol that can be carried out at any endoscopy center with a high degree of safety and success.
PMCID: PMC4396937  PMID: 25549239
Immunology; Issue 94; C.difficile; colonoscopy; fecal transplant; stool; diarrhea; microbiota
13.  Western Juniper Management: Assessing Strategies for Improving Greater Sage-grouse Habitat and Rangeland Productivity 
Environmental Management  2015;56(3):675-683.
Western juniper (Juniperus occidentalis subsp. occidentalis) range expansion into sagebrush steppe ecosystems has affected both native wildlife and economic livelihoods across western North America. The potential listing of the greater sage-grouse (Centrocercus urophasianus) under the U.S. Endangered Species Act has spurred a decade of juniper removal efforts, yet limited research has evaluated program effectiveness. We used a multi-objective spatially explicit model to identify optimal juniper removal sites in Northeastern California across weighted goals for ecological (sage-grouse habitat) and economic (cattle forage production) benefits. We also extended the analysis through alternative case scenarios that tested the effects of coordination among federal agencies, budgetary constraints, and the use of fire as a juniper treatment method. We found that sage-grouse conservation and forage production goals are somewhat complementary, but the extent of complementary benefits strongly depends on spatial factors and management approaches. Certain management actions substantially increase achievable benefits, including agency coordination and the use of prescribed burns to remove juniper. Critically, our results indicate that juniper management strategies designed to increase cattle forage do not necessarily achieve measurable sage-grouse benefits, underscoring the need for program evaluation and monitoring.
Electronic supplementary material
The online version of this article (doi:10.1007/s00267-015-0521-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4527980  PMID: 25957623
Centrocercus urophasianus; Juniperus occidentalis subsp. occidentalis; Multi-objective management; Optimization modeling; Resource management; U.S. Endangered Species Act
14.  Gastrointestinal Behçet's disease: A review 
Behçet’s disease (BD) is an idiopathic, chronic, relapsing, multi-systemic vasculitis characterized by recurrent oral and genital aphthous ulcers, ocular disease and skin lesions. Prevalence of BD is highest in countries along the ancient silk road from the Mediterranean basin to East Asia. By comparison, the prevalence in North American and Northern European countries is low. Gastrointestinal manifestations of Behçet’s disease are of particular importance as they are associated with significant morbidity and mortality. Although ileocecal involvement is most commonly described, BD may involve any segment of the intestinal tract as well as the various organs within the gastrointestinal system. Diagnosis is based on clinical criteria - there are no pathognomonic laboratory tests. Methods for monitoring disease activity on therapy are available but imperfect. Evidence-based treatment strategies are lacking. Different classes of medications have been successfully used for the treatment of intestinal BD which include 5-aminosalicylic acid, corticosteroids, immunomodulators, and anti-tumor necrosis factor alpha monoclonal antibody therapy. Like inflammatory bowel disease, surgery is reserved for those who are resistant to medical therapy. A subset of patients have a poor disease course. Accurate methods to detect these patients and the optimal strategy for their treatment are not known at this time.
PMCID: PMC4385527  PMID: 25852265
Behçet syndrome; Behçet disease; Upper gastrointestinal tract; Inflammatory bowel disease; Lower gastrointestinal tract; Ulcer
18.  A decade of data from a specialist statewide child and adolescent eating disorder service: does local service access correspond with the severity of medical and eating disorder symptoms at presentation? 
Eating disorders affect up to 3% of children and adolescents, with recovery often requiring specialist treatment. A substantial literature has accrued suggesting that lower access to health care services, experienced by rural populations, has a staggering effect on health-related morbidity and mortality. The aim of this study was to evaluate whether lower service access foreshadowed a more severe medical and symptom presentation among children and adolescents presenting to a specialist eating disorders program.
The data source was the Helping to Outline Paediatric Eating Disorders (HOPE) Project registry (N ~1000), a prospective ongoing registry study comprising consecutive paediatric tertiary eating disorder referrals. The sample consisted of 399 children and adolescents aged 8 to 16 years (M =14.49, 92% female) meeting criteria for a DSM-5 eating disorder.
Consistent with the hypotheses, lower service access was associated with a lower body mass index z-score and a higher likelihood of medical complications at intake assessment. Contrary to our hypothesis, eating pathology assessed at intake was associated with higher service access. No relationship was observed between service access and duration of illness or percentage of body weight lost.
Lower service access is associated with more severe malnutrition and medical complications at referral to a specialist eating disorder program. These findings have implications for service planning and provision for rural communities to equalize health outcomes.
PMCID: PMC4232640  PMID: 25400911
Adolescent; Child; Eating disorders; HOPE Project; Medical complications; Rural
19.  Resolution of Severe Clostridium difficile Infection Following Sequential Fecal Microbiota Transplantation 
PMCID: PMC3735621  PMID: 23632358
Fecal microbiota transplantation; severe Clostridium difficile infection
20.  Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing 
Advances in immunology  2014;122:211-252.
Mast cells (MCs) are active participants in blood coagulation and innate and acquired immunity. This review focuses on the development of mouse and human MCs, as well as the involvement of their granule serine proteases in inflammation and the connective tissue remodeling that occurs during the different phases of the healing process of wounded skin and other organs. The accumulated data suggest that MCs, their tryptases, and their chymases play important roles in tissue repair. While MCs initially promote healing, they can be detrimental if they are chronically stimulated or if too many MCs become activated at the same time. The possibility that MCs and their granule serine proteases contribute to the formation of keloid and hypertrophic scars makes them potential targets for therapeutic intervention in the repair of damaged skin.
PMCID: PMC4115062  PMID: 24507159
21.  A Clinicopathologic Study of 24 Cases of Systemic Mastocytosis Involving the Gastrointestinal Tract and Assessment of Mucosal Mast Cell Density in Irritable Bowel Syndrome and Asymptomatic Patients 
Counting mast cells in gastrointestinal (GI) mucosal biopsies is becoming an increasingly common practice. The primary reason for this exercise is to evaluate for possible involvement by systemic mastocytosis (SM). However, the features of mastocytosis in GI biopsies are not well described. In addition, recent studies have suggested that increased mast cells may be involved in the pathogenesis of some cases of diarrhea-predominant irritable bowel syndrome (IBS); the term “mastocytic enterocolitis” has been proposed for such cases. As the baseline mast cell density in colonic biopsies from normal patients has not been established in large cohorts, there is no widely accepted threshold for what constitutes increased mucosal mast cells. The aims of this study were (1) to determine the utility of GI biopsies for the diagnosis of SM, (2) to characterize the clinical, histologic, and immunohistochemical features of mastocytosis in the GI tract, (3) to determine mast cell density in normal colonic mucosa from a large cohort of asymptomatic patients, and (4) to compare these findings with those from patients with diarrhea-predominant IBS. Twenty-four patients with SM involving the GI tract, 100 asymptomatic patients, and 100 patients with IBS (the latter 2 groups with histologically normal colonic biopsies) were included. For the mastocytosis group, 107 biopsies (70 involved by mastocytosis; 67 mucosal, 3 liver) from 20 women and 4 men were evaluated (median age 59 y). The most commonly involved site was the colon (19 patients, 95%), followed by ileum (86%), duodenum (80%), and stomach (54%). In 16 cases (67%), the first diagnosis of SM was made on the basis of GI biopsies. Seventeen patients had documented cutaneous mastocytosis. Fifteen of 17 patients who underwent bone marrow biopsy had marrow involvement by SM. Eighteen patients had indolent disease, and 6 had aggressive disease (including all 3 with liver involvement). The most common GI symptom was diarrhea, followed by abdominal pain, nausea, weight loss, bloating, vomiting, or reflux. Liver disease presented with hepatomegaly and ascites. Endoscopic abnormalities (observed in 62%) included erythema, granularity, and nodules. Histologically, involved biopsies were characterized by infiltrates of ovoid to spindle-shaped mast cells in aggregates or sheets in the lamina propria, sometimes forming a confluent band underneath the surface epithelium; 25% of biopsies had only focal involvement (single aggregate). Prominent eosinophils were seen in 44% of involved colonic/ileal biopsies and 16% of duodenal biopsies. Mast cells were highlighted by diffuse membranous staining for KIT and CD25. In the nonmastocytosis groups, all biopsies contained singly dispersed mast cells with no aggregates. The mean highest mast cell counts (in a single high-power field) for asymptomatic patients and IBS patients were 26 (range, 11 to 55) and 30 (range, 13 to 59), respectively. In summary, GI (especially colonic) biopsies can establish a diagnosis of SM in patients with GI symptoms. GI involvement is usually subtle and is often associated with prominent eosinophils, which may obscure the mast cell infiltrate. KIT and CD25 are invaluable markers for the diagnosis. Mast cell density in colonic mucosa from asymptomatic patients is highly variable. Although patients with diarrhea-predominant IBS on average have mildly increased mast cells, the overlap in range with that of control patients is too great for this difference to be clinically useful. These findings argue against the utility of counting GI mucosal mast cell in patients with chronic diarrhea.
PMCID: PMC4086834  PMID: 24618605
gastrointestinal tract; liver; mast cells; mastocytosis; mast cell activation syndrome; irritable bowel syndrome; urticaria pigmentosa; KIT
22.  Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation 
Microbiome  2014;2:13.
Clostridium difficile is an opportunistic human intestinal pathogen, and C. difficile infection (CDI) is one of the main causes of antibiotic-induced diarrhea and colitis. One successful approach to combat CDI, particularly recurrent form of CDI, is through transplantation of fecal microbiota from a healthy donor to the infected patient. In this study we investigated the distal gut microbial communities of three CDI patients before and after fecal microbiota transplantation, and we compared these communities to the composition of the donor’s fecal microbiota. We utilized phylogenetic Microbiota Array, high-throughput Illumina sequencing, and fluorescent in situ hybridization to profile microbiota composition down to the genus and species level resolution.
The original patients’ microbiota had low diversity, was dominated by members of Gammaproteobacteria and Bacilli, and had low numbers of Clostridia and Bacteroidia. At the genus level, fecal samples of CDI patients were rich in members of the Lactobacillus, Streptococcus, and Enterobacter genera. In comparison, the donor community was dominated by Clostridia and had significantly higher diversity and evenness. The patients’ distal gut communities were completely transformed within 3 days following fecal transplantation, and these communities remained stable in each patient for at least 4 months. Despite compositional differences among recipients’ pre-treatment gut microbiota, the transplanted gut communities were highly similar among recipients post-transplantation, were indistinguishable from that of the donor, and were rich in members of Blautia, Coprococcus, and Faecalibacterium. In each case, the gut microbiota restoration led to a complete patient recovery and symptom alleviation.
We conclude that C. difficile infection can be successfully treated by fecal microbiota transplantation and that this leads to stable transformation of the distal gut microbial community from the one abundant in aerotolerant species to that dominated by members of the Clostridia.
PMCID: PMC4030581  PMID: 24855561
Microbiota; Microflora; Clostridium difficile; Fecal microbiota transplantation; Microbiota Array
23.  Restoring the gut microbiome for the treatment of inflammatory bowel diseases 
Fecal microbiota transplantation (FMT) is considered to be a highly successful therapy for recurrent and refractory Clostridium difficile infection (CDI) based on recent clinical trials. The pathogenesis of inflammatory bowel diseases (IBD) is thought to be due in part to perturbations in the gut microflora that disrupt homeostasis. FMT restores essential components of the microflora which could reverse the inflammatory processes observed in IBD. Case reports and series for the treatment of IBD by FMT have shown promise with regards to treatment success and safety despite the limitations of the reporting. Future studies will determine the optimal delivery and preparation of stool as well as the conditions under which the recipient will derive maximal benefit. The long term consequences of FMT with regards to infection, cancer, auto-immune, and metabolic diseases are not known and will require continued regulation and study. Despite these limitations, FMT may be beneficial for the treatment of ulcerative colitis and Crohn’s disease, particularly those with concurrent CDI or with pouchitis.
PMCID: PMC3974513  PMID: 24707129
Crohn’s; Ulcerative colitis; Microbiota; Fecal transplantation; Dysbiosis; Pouchitis; Clostridium difficile; Probiotic
24.  High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria 
Gut Microbes  2013;4(2):125-135.
Fecal microbiota transplantation (FMT) is becoming a more widely used technology for treatment of recurrent Clostridum difficile infection (CDI). While previous treatments used fresh fecal slurries as a source of microbiota for FMT, we recently reported the successful use of standardized, partially purified and frozen fecal microbiota to treat CDI. Here we report that high-throughput 16S rRNA gene sequencing showed stable engraftment of gut microbiota following FMT using frozen fecal bacteria from a healthy donor. Similar bacterial taxa were found in post-transplantation samples obtained from the recipients and donor samples, but the relative abundance varied considerably between patients and time points. Post FMT samples from patients showed an increase in the abundance of Firmicutes and Bacteroidetes, representing 75–80% of the total sequence reads. Proteobacteria and Actinobacteria were less abundant (< 5%) than that found in patients prior to FMT. Post FMT samples from two patients were very similar to donor samples, with the Bacteroidetes phylum represented by a great abundance of members of the families Bacteroidaceae, Rikenellaceae and Porphyromonadaceae, and were largely comprised of Bacteroides, Alistipes and Parabacteroides genera. Members of the phylum Firmicutes were represented by Ruminococcaceae, Lachnospiraceae, Verrucomicrobiaceae and unclassified Clostridiales and members of the Firmicutes. One patient subsequently received antibiotics for an unrelated infection, resulting in an increase in the number of intestinal Proteobacteria, primarily Enterobacteriaceae. Our results demonstrate that frozen fecal microbiota from a healthy donor can be used to effectively treat recurrent CDI resulting in restoration of the structure of gut microbiota and clearing of Clostridum difficile.
PMCID: PMC3595072  PMID: 23333862
fecal microbial transplantation; frozen preparations; DNA sequence analysis; Illumina; microbiota; restoration; Clostridium difficile; firmicutes; bacteroides; curing
25.  Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome 
There is a spectrum of disorders that clinically manifest as a result of mast cell activation. A non-clonal form has emerged in the literature where many of the clinical features of systemic mastocytosis are shared despite having a distinct mast cell biology. In this review, we summarize key features of the science behind mast cell activation relevant to what is now known as non-clonal mast cell activation syndrome (nc-MCAS). We highlight the clinical manifestations of nc-MCAS with a focus on diagnosis and treatment.
PMCID: PMC3545645  PMID: 23212667
Mast cell activation; Non-clonal mast cell activation syndrome; Tryptase; Prostaglandin; Histamine; cKIT; Flushing; Anaphylaxis; Antihistamines; Immunology

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