Patient Outcomes in Traumatic Subarachnoid Hemorrhage: A Retrospective Analysis.

INTRODUCTION: Patients with isolated traumatic subarachnoid hemorrhage (itSAH) are often transferred to a Level I or II trauma center for neurosurgical evaluation. Recent literature suggests that some patients, such as those with high Glasgow Coma Scale (GCS) scores, may be safely observed without neurosurgical consultation. The objective of this study was to investigate characteristics of patients with itSAH to determine the clinical utility of neurosurgical evaluation and repeat imaging. MATERIALS AND METHODS: A retrospective chart review of 350 patients aged ≥ 18 y with initial computed tomography head (CTH) showing itSAH and GCS scores of 13-15. Patient demographics, medical history, medications, length of stay, transfer status, injury type and severity, and CTH results were extracted for analysis. Bivariate analyses were conducted to determine whether any factors were associated with a worsening repeat CTH. RESULTS: Most patients were female (57.4%) with blunt injuries (99.1%). The median age was 73 y. Neurosurgery was consulted for 342 (97.7%) patients, with one (0.3%) requiring intervention. Of 311 (88.9%) repeat imaging, 16 (5.1%) showed worsening. Factors with statistically significant associations with worsening CTH included injury severity; neurological deficit; lengths of stay; and a history of congestive heart failure, cirrhosis, or substance use disorder. CONCLUSIONS: The findings suggest that patients with itSAH and high GCS scores may be able to be managed safely without neurosurgical oversight. The factors strongly associated with worsening CTH may be useful in identifying patients who need transfer for intensive care. Further research is needed to confirm these findings and develop appropriate management strategies for patients with itSAH.

Hospitalizations Are Increasing in Distal Upper Extremity Fractures.

Introduction Distal upper extremity (DUE) fractures are common and include bony fractures of the wrist, hand, and finger. DUE fractures can require hospital admission for clinical observation or surgical fixation. The trend of hospitalization rate for these injuries may more accurately predict future staffing needs, required resources, and expected revenue for orthopedic surgery hand services. The purpose of this study is to determine the trend of hospitalization percentage from 2009 to 2018 for patients presenting to the United States (US) emergency departments (EDs) with DUE fractures. Methods The National Electronic Injury Surveillance System (NEISS) was utilized to collect data from 138,700 patients with wrist, hand, or finger fractures presenting to the US EDs between 2009 and 2018. A total of 752 patients were excluded for ages less than two years old or no sex entry. The unadjusted and adjusted (age, sex, race, and fracture location) hospitalization rates across years were evaluated using binary logistic regression. Results From 2009 to 2018, 137,948 DUE fractures were reported, of which 4749 (3.4%) were hospitalized. Wrist fractures accounted for the highest amount (2953) and the highest proportion of hospitalized patients (62.2%). Higher hospitalization rates were seen among patients 40 years and older (p < 0.05). Together, the DUE fracture hospitalization rate increased significantly (p < 0.05) in 2016 (OR = 1.215, 95% CI = 1.070-1.380), 2017 (OR = 1.154, 95% CI = 1.016-1.311), and 2018 (OR = 1.154, 95% CI = 1.279-1.638) from 2009. The adjusted results showed hospitalization rate statistically increased (p < 0.05) in 2016 (OR = 1.184, 95% CI = 1.040-1.346) and 2018 (OR = 1.389, 95% CI = 1.225-1.575) compared to 2009. An inconsistent increase in hospitalization rate was seen across locations of fracture: wrist (2012, 2013, 2018), hand (2018), and finger (2016, 2018). Conclusions The hospitalization rate of patients with DUE fractures increased in 2016 and 2018 from 2009. These data may predict a need to increase future staffing and resources for orthopedic surgery hand services as hospitals resume pre-pandemic practices.

A point-of-care ultrasound approach to fascia iliaca nerve block in a patient with a hip fracture.

According to the Centers for Disease Control and Prevention, hip and femoral neck fractures are common fractures seen in older adults. Lower extremity nerve blocks are a tool available for pain control in these patients. One type of block that can be used in this type of fracture is the fascia iliaca compartment block. Clinicians sometimes do not utilize these blocks despite having been shown to produce better pain relief than a standard regimen of intravenous medications. We present a case of a 76-year-old female patient who had inadequate pain relief from intravenous medications. We illustrate the utilization of a standardized approach to a fascia iliaca compartment block using point-of-care ultrasound in the setting of a femoral neck fracture.

Risk Factors Associated With Neurosurgical Intervention in Patients With Mild Traumatic Intracranial Hemorrhage.

INTRODUCTION: Community centers commonly transfer patients with traumatic intracranial hemorrhage (ICH) to level 1 and 2 trauma centers for neurosurgical evaluation regardless of the degree of injury. Determining risk factors leading to neurosurgical intervention (NSI) may reduce morbidity and mortality of traumatic ICH and the transfer of patients with lower risk of NSI. METHODS: A retrospective chart review was performed on patients admitted or transferred to a level 1 trauma center from October 2015 to September 2019 with Glassgow Coma Scale score 13-15 and traumatic ICH on initial head computerized tomography (CTH) scan. Bivariate analyses and multivariable regression were used to identify factors associated with progression to NSI. RESULTS: Of 1542 included patients, 8.2% required NSI. A greater proportion were male (69.1% versus 52.3%, P = 0.0003), on warfarin (37.7% versus 21.6%, P = 0.0023), presented with subdural hemorrhage (98.4% versus 63.3%, P < 0.0001, larger subdural hemorrhage size (median 19 mm [interquartile range {IQR}: 14-25] versus 5 mm [IQR: 3-8], P < 0.0001), and had a worsening repeat CTH (24.4% versus 13%, P < 0.0001). On physical examination, more patients had confusion (40.5% versus 31.4%, P = 0.0495) and hemiparesis (16.2% versus 2.6%, P < 0.0001). CTH findings of midline shift (80.2% versus 10.8%, P < 0.0001) and shift size (median 8.0 mm [IQR: 5.0-12.0] versus 4 mm [IQR: 3-5], P < 0.0001) were significantly associated with NSI. CONCLUSIONS: Clinical factors and patient characteristics can be used to infer a greater risk of requiring NSI. These factors could reduce unnecessary transfers and hasten the transfer of patients more likely to progress to NSI.

Comparative Benefits and Risks Associated with Currently Authorized COVID-19 Vaccines.

This article provides a systematic assessment of the efficacy, risks, and methodological quality of evidence from five major publicly available vaccine trials. Results from Pfizer-BioNTech mRNA, Moderna-US NIH mRN-1273, AstraZeneca-Oxford ChAdOx1 nCov-19, Gamaleya GamCovidVac (Sputnik V), and Ad26.COV2.S Johnson & Johnson vaccines were included. Extracted benefits and risks data from each trial were summarized using the GRADE approach denoting the overall certainty of evidence along with relative and absolute effects. Relative risk reduction across all five vaccine trials ranged from 45% to 96%. Absolute risk reduction in symptomatic COVID-19 ranged from 6 to 17 per 1000 across trials. None of the vaccines were associated with a significant increase in serious adverse events compared to placebo. The overall certainty of evidence varied from low to moderate. All five vaccines are effective and safe, but suggest room for improvement in the conduct of large-scale vaccine trials. Certainty of evidence was downrated due to risk of bias, which can be mitigated by improving transparency and thoroughness in conduct and reporting of outcomes.

Nailfold Capillaroscopy as a Biomarker in the Evaluation of Pediatric Inflammatory Bowel Disease.

BACKGROUND: Noninvasive screening and disease monitoring are an unmet need in pediatric inflammatory bowel disease (IBD). Nailfold capillaroscopy (NFC) is a validated technique for microvascular surveillance in rheumatologic diseases. NFC uses magnified photography to examine nail bed capillaries called end row loops (ERL). We aimed to identify variations in NFC in pediatric IBD patients and their associations with disease activity. METHODS: Pediatric patients with Crohn's disease (CD) or ulcerative colitis (UC) and healthy controls were recruited. NFC was performed on patients with newly diagnosed IBD prior to initiating therapy, patients with established IBD, and controls. ERLs were quantified along with a 3mm distance on 8 nailfolds. Serum biomarker levels of disease activity and symptoms activity indexes were correlated with average ERL density digits on both hands. Statistics were performed using chi-squared, ANOVA, and linear regression. RESULTS: Fifty-one IBD patients and 16 controls were recruited. ERL density was significantly decreased in IBD (Control: 19.2 ERL/3mm vs UC: 15.6 ERL/3mm vs CD: 15.4 ERL/3mm; P < .0001). ERL density was lower in UC patients with lower albumin levels (P = .02, r 2 = 0.29).The change in ERL density over time predicted the change in pediatric CD activity index among CD patients (P = .048, r 2 = 0.58) with treatment. CONCLUSIONS: Our data demonstrate ERL density is reduced in IBD compared to controls. Lower albumin levels correlated with lower ERL density in UC. In newly diagnosed CD, ERL density increases over time as disease activity improves with therapy. NFC may be a feasible biomarker of disease activity and utilized for monitoring IBD.

Pediatric Gastroenterology, Hepatology, and Nutrition Entrustable Professional Activities: Development of an Assessment Tool and Curricular Resources.

BACKGROUND: Entrustable professional activities (EPAs) are critical activities performed by medical professionals, which can be observed and assessed. Adding on to common EPAs for all pediatric subspecialty trainees, specialty-specific EPAs for pediatric gastroenterology, hepatology, and nutritional fellowship were developed by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) EPA Task Force. METHODS: Having developed specialty-specific EPAs, building EPA assessments is the next logical step, as EPAs are included under a larger umbrella of competency-based assessment. Thus, the NASPGHAN EPA Task Force and Training Committee collaborated on an assessment tool and associated curricular resources to aid in tracking trainees' progression to entrustment within individual EPAs and readiness for independent practice. RESULTS: This manuscript reports the development of an EPA assessment tool, including guiding principles and the theory behind the assessment tool, with a focus on simple, meaningful assessments that can provide crucial performance feedback to trainees. In addition, curricular resources were developed, based on the assessment tool, to support training. Ultimately, it is the hope of the NASPGHAN EPA Task Force and Training Committee that this tool can aid training programs in providing formative feedback for trainees, and can be used by training programs and clinical competency committees for summative evaluation.

Utility of Gastric and Duodenal Biopsies During Follow-up Endoscopy in Children With Eosinophilic Esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disorder of the esophagus. Consensus guidelines recommend obtaining esophageal, gastric, and duodenal biopsies at diagnostic endoscopy when EoE is suspected. The utility of repeated gastric and duodenal biopsies during follow-up endoscopy in patients previously diagnosed with EoE is not established. The aim of the present study was to explore the role of gastric and duodenal biopsies in children with an established diagnosis of EoE undergoing repeat endoscopy to assess histological response to treatment. METHODS: Retrospective chart review of children diagnosed with EoE at a tertiary care center was conducted. A total of 160 patients with EoE with demographic clinical, endoscopic, and histological data at diagnosis and follow-up endoscopy were included. The frequency of gastric and duodenal biopsies at follow-up endoscopy with abnormal histology and their correlation to endoscopic findings was determined. RESULTS: At follow-up endoscopy, 83% (132/160) of patients had gastric and 74% (118/160) had duodenal biopsies. Histology was normal in 81% of gastric and 92% of duodenal biopsies. The most frequent gastric abnormalities were chemical and inactive chronic gastritis. The most frequent duodenal abnormality was villous blunting with increased intraepithelial lymphocytes. Two patients with normal gastric and duodenal histology progressed to eosinophilic gastroenteritis at follow-up endoscopy. CONCLUSIONS: Gastric and duodenal biopsies obtained in EoE patients during follow-up endoscopy show pathology in a minority of patients, increase costs, and may add potential risk of adverse events. Large multicenter, prospective studies of endoscopic practice during follow-up of EoE are warranted to provide evidence supporting best practices.

Epithelial PIK3R1 (p85) and TP53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.

Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of ß-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome.

Antioxidant properties of mesalamine in colitis inhibit phosphoinositide 3-kinase signaling in progenitor cells.

BACKGROUND: Mesalamine, 5-aminosalicylic acid (5-ASA), is a potent antioxidant and is known to enhance peroxisome proliferator-activated receptor γ activity in the intestine. Our previous studies suggested reduced Phosphoinositide 3-Kinase (PI3K)/ß-catenin signaling as a mechanism for 5-ASA chemoprevention in chronic ulcerative colitis (CUC). We now hypothesize that 5-ASA mediates changes in intestinal epithelial cell (IEC) reactive oxygen species during colitis to affect phosphatase and tensin homolog (PTEN), PI3K, and ß-catenin signaling. METHODS: Here, we examined effects of 5-ASA on oxidant-induced cell signaling pathways in HT-29 cells, IECs from mice, and biopsy tissue from control and CUC patients. Samples were selected to control for inflammation between untreated and 5-ASA-treated CUC patients. RESULTS: Direct evaluation of IEC in H2O2-stimulated whole colonic crypts indicated that 5-ASA reduces reactive oxygen species levels in lower crypt IECs where long-lived progenitor cells reside. Analysis of biopsies from patient samples revealed that 5-ASA increases expression of the antioxidant catalase in CUC patients. Also, 5-ASA increased nuclear peroxisome proliferator-activated receptor γ protein and target gene expression. Data showed 5-ASA-induced peroxisome proliferator-activated receptor γ DNA binding to the PTEN promoter (chromatin immunoprecipitation) and reduced both phosphorylated and oxidized (inactive) PTEN protein levels. Analysis of patient samples revealed 5-ASA that also reduced levels of active phosphorylated Akt in inflamed colitis tissue. Reduced PI3K/Akt signaling and expression of ß-catenin target genes in 5-ASA-treated CUC patients additionally suggests enhanced PTEN activity as well. CONCLUSIONS: Therefore, 5-ASA reduces CUC-induced reactive oxygen species in colonic progenitor cells and enhances PTEN activity, thus attenuating PI3K/Akt signaling. These data suggest that the antioxidant properties of 5-ASA may be the predominant mechanism for 5-ASA chemoprevention.

P-selectin glycoprotein ligand-1 is needed for sequential recruitment of T-helper 1 (Th1) and local generation of Th17 T cells in dextran sodium sulfate (DSS) colitis.

BACKGROUND: Activated effector T cells contribute to tissue injury observed in inflammatory bowel disease. T cells are recruited to effector sites after activation in peripheral lymph nodes directs expression of tissue-specific homing receptors. One such mechanism for effector T cell recruitment employs activation-induced fucosylation of P-selectin glycoprotein ligand (PSGL)-1 that mediates binding to endothelial P-selectin. Here we examine the differential role of PSGL-1 in recruiting effector T-cell subsets in colitis. METHODS: C57BL/6 wildtype and PSGL-1 mice received 2.5% dextran sodium sulfate (DSS) for 6 days and were euthanized 7 and 14 days after the initiation of DSS. Disease activity was monitored throughout. Histologic colitis scores, colonic CD4+ accumulation, and cytokine production were assessed at days 7 and 14. Recruitment of T-helper (Th) subsets was assessed by enumerating adoptively transferred Th1 or Th17 CD4+ cells 2 days after transfer to DSS-treated mice. RESULTS: DSS colitis increases CD4+ T cells in colonic tissue and induces Th1 (interferon gamma [IFN-γ], tumor necrosis factor [TNF]) and Th17 (interleukin [IL]-17, IL-22) cytokines. Loss of PSGL-1 attenuates DSS colitis, decreases colonic CD4+ T cell numbers, and reduces both Th1 and Th17 cytokine production. Colitis increases recruitment of Th1 (19-fold) and Th17 (2.5-fold) cells. PSGL-1 deficiency in transferred T cells abrogates colonic recruitment of Th1 cells in DSS colitis, whereas Th17 recruitment is unaffected. CONCLUSIONS: PSGL-1 selectively controls Th1 recruitment in colitis. Whereas Th17 recruitment is independent of PSGL-1, generation of colonic Th17 cytokine requires initial Th1 recruitment. Therefore, attenuating PSGL-1 binding may prevent colonic recruitment of disease-causing Th1 cells that promote local Th17 generation.

Milk fat globule-EGF factor 8 is a critical protein for healing of dextran sodium sulfate-induced acute colitis in mice.

Milk fat globule-EGF factor 8 (MFG-E8) has been shown to play an important role in maintaining the integrity of the intestinal mucosa and to accelerate healing of the mucosa in septic mice. Herein, we (a) analyzed the expression of MFG-E8 in the gut of wild-type (WT) C57BL/6 (MFG-E8(+/+)) mice with and without dextran sulfate sodium (DSS)-induced colitis, (b) characterized the pathological changes in intestinal mucosa of MFG-E8(+/+) and MFG-E8(-/-) mice with DSS-induced colitis and (c) examined the therapeutic role of MFG-E8 in inflammatory bowel disease by using DSS-induced colitis model. Our data documented that there was an increase in colonic and rectal MFG-E8 expression in MFG-E8(+/+) mice during the development of DSS colitis. MFG-E8 levels in both tissues decreased to below baseline during the recovery phase in mice with colitis. Changes in MFG-E8 gene expression correlated to the levels of inflammatory response and crypt-epithelial injury in both colonic and rectal mucosa in MFG-E8(+/+) mice. MFG-E8(-/-)mice developed more severe crypt-epithelial injury than MFG-E8(+/+) mice during exposure to DSS with delayed healing of intestinal epithelium during the recovery phase of DSS colitis. Administration of MFG-E8 during the recovery phase ameliorated colitis and promoted mucosal repair in both MFG-E8(-/-) and MFG-E8(+/+) mice, indicating that lack of MFG-E8 causes increased susceptibility to colitis and delayed mucosal healing. These data suggest that MGF-E8 is an essential protective factor for gut epithelial homeostasis, and exogenous administration of MFG-E8 may represent a novel therapeutic target in inflammatory bowel disease.

Epithelial phosphatidylinositol-3-kinase signaling is required for ß-catenin activation and host defense against Citrobacter rodentium infection.

Citrobacter rodentium infection of mice induces cell-mediated immune responses associated with crypt hyperplasia and epithelial ß-catenin signaling. Recent data suggest that phosphatidylinositol-3-kinase (PI3K)/Akt signaling cooperates with Wnt to activate ß-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-ß-catenin(552)). Our aim was to determine whether epithelial PI3K/Akt activation is required for ß-catenin signaling and host defense against C. rodentium. C57BL/6 mice were infected with C. rodentium and treated with dimethyl sulfoxide (DMSO) (vehicle control) or with the PI3K inhibitor LY294002 or wortmannin. The effects of infection on PI3K activation and ß-catenin signaling were analyzed by immunohistochemistry. The effects of PI3K inhibition on host defense were analyzed by the quantification of splenic and colon bacterial clearance, and adaptive immune responses were measured by real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Increased numbers of P-ß-catenin(552)-stained epithelial cells were found throughout expanded crypts in C. rodentium colitis. We show that the inhibition of PI3K signaling attenuates epithelial Akt activation, the Ser552 phosphorylation and activation of ß-catenin, and epithelial cell proliferative responses during C. rodentium infection. PI3K inhibition impairs bacterial clearance despite having no impact on mucosal cytokine (gamma interferon [IFN-γ], tumor necrosis factor [TNF], interleukin-17 [IL-17], and IL-1ß) or chemokine (CXCL1, CXCL5, CXCL9, and CXCL10) induction. The results suggest that the host defense against C. rodentium requires epithelial PI3K activation to induce Akt-mediated ß-catenin signaling and the clearance of C. rodentium independent of adaptive immune responses.

Regulation of induced colonic inflammation by Lactobacillus acidophilus deficient in lipoteichoic acid.

Imbalance in the regulatory immune mechanisms that control intestinal cellular and bacterial homeostasis may lead to induction of the detrimental inflammatory signals characterized in humans as inflammatory bowel disease. Induction of proinflammatory cytokines (i.e., IL-12) induced by dendritic cells (DCs) expressing pattern recognition receptors may skew naive T cells to T helper 1 polarization, which is strongly implicated in mucosal autoimmunity. Recent studies show the ability of probiotic microbes to treat and prevent numerous intestinal disorders, including Clostridium difficile-induced colitis. To study the molecular mechanisms involved in the induction and repression of intestinal inflammation, the phosphoglycerol transferase gene that plays a key role in lipoteichoic acid (LTA) biosynthesis in Lactobacillus acidophilus NCFM (NCK56) was deleted. The data show that the L. acidophilus LTA-negative in LTA (NCK2025) not only down-regulated IL-12 and TNFα but also significantly enhanced IL-10 in DCs and controlled the regulation of costimulatory DC functions, resulting in their inability to induce CD4(+) T-cell activation. Moreover, treatment of mice with NCK2025 compared with NCK56 significantly mitigated dextran sulfate sodium and CD4(+)CD45RB(high)T cell-induced colitis and effectively ameliorated dextran sulfate sodium-established colitis through a mechanism that involves IL-10 and CD4(+)FoxP3(+) T regulatory cells to dampen exaggerated mucosal inflammation. Directed alteration of cell surface components of L. acidophilus NCFM establishes a potential strategy for the treatment of inflammatory intestinal disorders.

Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis.

BACKGROUND & AIMS: Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that serine/threonine protein kinase Akt (Akt) signaling cooperates with Wingless (Wnt) to activate beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-beta-catenin(552)). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of beta-catenin during intestinal inflammation. METHODS: The class IA subunit of PI3K was conditionally deleted from intestinal epithelial cells in mice named I-pik3r1KO. Acute inflammation was induced in mice and intestines were analyzed by biochemical and histologic methods. The effects of chemically blocking PI3K in colitic interleukin-10(-/-) mice were examined. Biopsy samples from patients were examined. RESULTS: Compared with wild-type, I-pik3r1KO mice had reduced T-cell-mediated Akt and beta-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K-Akt signaling increased nuclear total beta-catenin and P-beta-catenin(552) levels and reduced N-terminal beta-catenin phosphorylation, which is associated with degradation. PI3K inhibition in interleukin-10(-/-) mice impaired colitis-induced epithelial Akt and beta-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-beta-catenin(552) throughout expanded crypts and increased messenger RNA expression of beta-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples. CONCLUSIONS: PI3K-Akt signaling cooperates with Wnt to increase beta-catenin signaling during inflammation. PI3K-induced and Akt-mediated beta-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.

Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis.

BACKGROUND & AIMS: Mesalamine is a mainstay therapeutic agent in chronic ulcerative colitis (CUC) in which condition it reverses crypt architectural changes and reduces colitis-associated cancer (CAC). The present study addressed the possibility that mesalamine reduces beta-catenin-associated progenitor cell activation, Akt-phosphorylated beta-catenin(Ser552) (P-beta-catenin), and colitis-induced dysplasia (CID). METHODS: Effects of mesalamine on P-beta-catenin staining and function were assessed by immunohistochemistry and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in biopsy specimens of CUC in mild or "refractory" severe mucosal inflammation. Effects of mesalamine on epithelial proliferation and activation of Akt and beta-catenin were assessed in interleukin (IL)-10(-/-) colitis and CID by immunohistochemistry and Western blotting. Dysplasia was assessed by counting the number and lengths of lesions per colon. RESULTS: Data from IL-10(-/-) and human colitis samples show that mesalamine reduced Akt activation and P-beta-catenin levels in the middle and upper crypt. Reductions in P-beta-catenin in CUC biopsy specimens with severe inflammation suggested that mesalamine reduced P-beta-catenin levels in tissue refractory to mesalamine's anti-inflammatory effects. In IL-10(-/-) mice, mesalamine reduced CID concordant with inhibition of crypt Akt and beta-catenin signaling. CONCLUSIONS: The results are consistent with the model that mesalamine contributes to chemoprevention in CAC by reducing beta-catenin signaling within intestinal progenitors.

Therapeutic benefit of pentostatin in severe IL-10-/- colitis.

BACKGROUND: Pentostatin, an adenosine deaminase (ADA) inhibitor, is a purine antimetabolite used for the treatment of leukemias. ADA inhibition blunts expansion of proliferating lymphocytes and increases adenosine release, a potent anti-inflammatory molecule. Human inflammatory bowel disease (IBD) is driven by expansion of effector T cells (T(eff)) that overwhelm reulatory T cells (T(reg)) and propagate innate immune reponses. Here we study the therapeutic benefits of ADA inhibition to impair T(eff) cell expansion and reduce inflammatory cytokine release in IL-10-deficient (IL-10-/-) mice. METHODS: Colitis was induced in IL-10-/- mice by administering piroxicam for two weeks. Mice were treated with daily pentostatin or phosphate-buffered saline for 1 week and effects on tissue inflammation, lymphocyte numbers and cytokine production examined. RESULTS: Pentostatin reduced inflammation by >50% and nearly normalized serum amyloid A levels. Lymphocyte expansions in the colon and mesenteric lymph node (MLN) (3.5-fold and >5-fold respectively) dropped by >50-90%. Pro-inflammatory factors in the colon and MLN (IL-1beta, IFN-gamma, IL-6, CXCL10, TNF) dropped whereas FoxP3 and TGF-beta were unchanged. Reductions in cytokine production from equivalent numbers of T cells from pentostatin-treated mice after in vitro (36h) or in vivo (3h) activation suggested anti-inflammatory effects of pentostatin independent of lymphodepletion contributed to its therapeutic benefit. Analysis of mucosal lymphocyte subsets suggested pentostatin reduced numbers of effector CD4+ CD69+ T cells, while sparing CD4+ CD62L+ T cells. CONCLUSIONS: Pentostatin dosages that avoid severe lymphocyte depletion effectively treat colitis by impairing T(eff) cell expansion and reducing pro-inflammatory cytokine production while preserving regulatory T(reg) populations and function.