An International Continence Society (ICS) report on the terminology for single-use body worn absorbent incontinence products.

AIMS: In 2016, the International Continence Society (ICS) Standardization Steering Committee appointed a working group to address the confusing plethora of synonyms currently used to describe single-use body worn absorbent incontinence products by recommending preferred terminology. METHODS: An online questionnaire was posted in 2016/17 inviting input from stakeholders internationally. The data were analyzed and conclusions progressively refined through working group discussions, an open meeting at the 2017 annual ICS conference, and a review of further iterations-including from the parent ICS Standardization Committee-until consensus was reached. Partway in, the International Organization for Standardization started a project with similar scope and the two organizations liaised to harmonize their conclusions while respecting each other's processes. RESULTS: A hundred people from 18 countries responded to the questionnaire. About a third (32.2%) of those declaring their nationality were from the UK and a further third (34.5%) from other English-speaking countries. Two-thirds (67.8%) lived in Europe; around a quarter (23%) in North America; and 9.2% in Australasia. Seven main design categories of products were identified and, while clear consensus was readily achieved in naming some of them, others required more work to determine the best term among multiple contenders. CONCLUSIONS: The working group concluded that the seven product design categories should be called: (a) pads; (b) unbacked pads; (c) male pads; (d) male pouches; (e) pull-on pads (protective underwear); (f) all-in-ones (wrap-around pads, adult briefs); and (g) belted pads (belted products), in which the bracketed terms are judged acceptable (though not preferred) alternatives.

STAT3 genotypic variation and cellular STAT3 activation and colon leukocyte recruitment in pediatric Crohn disease.

OBJECTIVES: Genotypic variation in signal transducer and activator of transcription 3 (STAT3) increases risk for inflammatory bowel disease (IBD), and STAT3-dependent inflammatory networks are induced in the colon in these patients. We hypothesized that STAT3 "A" risk allele carriage would be associated with increased cellular STAT3 activation and colon leukocyte recruitment. METHODS: Colonic expression of genes regulating STAT3 signaling and leukocyte recruitment and function was measured in pediatric patients with Crohn disease (CD) stratified by STAT3 genotype. The frequency of colonic pSTAT3* and CXCR2* neutrophils was determined using immunohistochemistry. STAT3 tyrosine phosphorylation (pSTAT3) was measured in circulating leukocytes by flow cytometry, and mechanisms regulating STAT3 activation were tested in IBD Epstein-Barr virus (EBV)-transformed lymphocytes (EBL). RESULTS: Colonic expression of interleukin 6 (IL-6), the STAT3 target gene SOCS3, the neutrophil chemoattractants IL-8, CXCL1, and CXCL3, and the neutrophil products S100A8, S100A9, and S100A12 were increased in patients carrying the STAT3 "A" risk allele. The frequency of neutrophils expressing the cognate receptor for IL-8, CXCR2, was increased in colonic biopsies from patients carrying the risk allele, and the frequency of pSTAT3* or CXCR2* neutrophils correlated with histologic severity. The frequency of CD4 lymphocytes and granulocytes expressing pSTAT3 was increased in patients carrying the STAT3 "A" risk allele. EBLs from patients carrying the STAT3 "A" risk allele exhibited increased basal and IL-6-stimulated STAT3 tyrosine phosphorylation, increased transcription of STAT3 and SOCS3 after IL-6 stimulation, and increased membrane localization of the IL-6 receptor, GP130, and Janus-associated kinase 2. CONCLUSIONS: The STAT3 "A" risk allele is associated with increased cellular STAT3 activation and upregulation of pathways that promote recruitment of CXCR2* neutrophils to the gut.

Alanyl-glutamine promotes intestinal epithelial cell homeostasis in vitro and in a murine model of weanling undernutrition.

Alanyl-glutamine (Ala-Gln) has recently been shown to enhance catch-up growth and gut integrity in undernourished children from Northeast Brazil. We hypothesized that the intestinal epithelial effects of Ala-Gln in malnourished weanling mice and mouse small intestinal epithelial (MSIE) cells would include modulation of barrier function, proliferation, and apoptosis. Dams of 10-day-old suckling C57BL/6 pups were randomized to a standard diet or an isocaloric Northeast Brazil "regional basic diet," moderately deficient in protein, fat, and minerals. Upon weaning to their dam's diet on day of life 21, pups were randomized to Ala-Gln solution or water. At 6 wk of age, mice were killed, and jejunal tissue was collected for morphology, immunohistochemistry, and Ussing chamber analysis of transmucosal resistance and permeability. Proliferation of MSIE cells in the presence or absence of Ala-Gln was measured by MTS and bromodeoxyuridine assays. MSIE apoptosis was assessed by annexin and 7-amino-actinomycin D staining. Pups of regional basic diet-fed dams exhibited failure to thrive. Jejunal specimens from undernourished weanlings showed decreased villous height and crypt depth, decreased transmucosal resistance, increased permeability to FITC-dextran, increased claudin-3 expression, and decreased epithelial proliferation and increased epithelial apoptosis (as measured by bromodeoxyuridine and cleaved caspase-3 staining, respectively). Undernourished weanlings supplemented with Ala-Gln showed improvements in weight velocity, villous height, crypt depth, transmucosal resistance, and epithelial proliferation/apoptosis compared with unsupplemented controls. Similarly, Ala-Gln increased proliferation and reduced apoptosis in MSIE cells. In summary, Ala-Gln promotes intestinal epithelial homeostasis in a mouse model of malnutrition-associated enteropathy, mimicking key features of the human disease.

Paired immunoglobulin-like receptor B (PIR-B) negatively regulates macrophage activation in experimental colitis.

BACKGROUND & AIMS: Innate and adaptive immune responses are regulated by cross talk between activation and inhibitory signals. Dysregulation of the inhibitory signal can lead to aberrant chronic inflammatory diseases such as the inflammatory bowel diseases (IBD). Little is known about negative regulation of innate intestinal immune activation. We examined the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of macrophage function in innate intestinal immunity. METHODS: We examined the susceptibility of Pirb-/- and wild-type (WT) mice to dextran sodium sulfate (DSS)-induced colitis. We assessed proinflammatory cytokine release and mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) activation in Pirb-/- and WT macrophages following Escherichia coli stimulation. Macrophage transfer experiments were performed to define the role of PIR-B in the negative regulation of macrophage function in DSS-induced colitis. We also assessed expression of PIR-B human homologues (immunoglobulin-like transcript [ILT]-2 and ILT-3) in colon biopsy samples from healthy individuals (controls) and patients with IBD. RESULTS: Pirb-/- mice had increased susceptibility to DSS-induced colitis. In vitro analysis showed increased production of proinflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor alpha) and activation of MAPK and NF-kappaB in Pirb-/- macrophages following bacterial activation. Adoptive transfer of bone marrow-derived Pirb-/- macrophages into WT mice was sufficient to increase disease susceptibility. ILT-2 and ILT-3 were expressed on CD68+ and CD68- mononuclear cells and intestinal epithelium in colon biopsy samples from patients and controls. CONCLUSIONS: PIR-B negatively regulates macrophage functions in response to pathogenic bacteria and chronic intestinal inflammatory responses. Inhibitory receptors such as PIR-B might be used as therapeutic targets for treatment of patients with IBD.

Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn's disease.

BACKGROUND & AIMS: Genetic variations that affect innate immunity increase risk of ileal Crohn's disease (CD). However, the penetrance of susceptibility genes, including NOD2, is low, suggesting additional risk factors. Neutralizing autoantibodies (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) reduce neutrophil antimicrobial function in patients with primary alveolar proteinosis (PAP). We investigated whether GM-CSF Ab regulates neutrophil function in CD. METHODS: Serum samples from 354 adult and pediatric patients with inflammatory bowel disease (IBD) were analyzed for GM-CSF Ab and IBD markers. Levels of GM-CSF Ab were compared with patients' CD features and neutrophil function. Intestinal barrier function and nonsteroidal anti-inflammatory drug (NSAID)-induced injury were assessed in GM-CSF-null and NOD2-null mice. RESULTS: Median GM-CSF Ab levels increased from 0.4 microg/mL in control serum to 2.4 microg/mL in pediatric CD and 11.7 microg/mL in adult CD serum and were associated with ileal involvement (P<.001). Ileal location, duration of disease, and increased GM-CSF Ab levels were associated with stricturing/penetrating behavior (odds ratio, 2.2; P=.018). The positive and negative predictive values of GM-CSF Ab for stricturing/penetrating behavior were comparable with that of other IBD serum markers. CD patients with increased GM-CSF Ab had reduced neutrophil phagocytic capacity and increased accumulation of pSTAT3+ neutrophils in the affected ileum. GM-CSF-null mice and NOD2-null mice in which GM-CSF was neutralized had defects in mucosal barrier function and developed a transmural ileitis following NSAID exposure. CONCLUSIONS: GM-CSF regulates ileal homeostasis in CD and in mouse models. CD patients with increases in serum GM-CSF Ab might benefit from GM-CSF administration.

A randomized controlled trial of growth hormone in active pediatric Crohn disease.

OBJECTIVES: Growth hormone (GH) may reduce symptoms and improve growth in Crohn disease (CD). The effect on mucosal inflammation is not known. We hypothesized that GH would improve both clinical and mucosal disease activity and stimulate linear growth in pediatric CD. PATIENTS AND METHODS: Twenty patients ages 7 to 18 receiving corticosteroids (CTX) for active CD were randomized to begin GH, 0.075 mg x kg(-1) x day(-1) (group A), or continue CTX alone (group B). Clinical and endoscopic disease activities were assessed after 12 weeks. Group B began GH at 12 weeks, and clinical disease activity was assessed at 24 weeks. Subjects who experienced a clinical response after 12 weeks of GH therapy continued treatment for an additional 52 weeks, and linear growth was assessed. RESULTS: Sixty-five percent of patients receiving GH achieved clinical remission, compared with 20% treated with CTX alone (P = 0.03). Although endoscopic disease activity trended toward an improvement at week 12 in group A, this did not differ between the groups. Sixty-one percent of week 12 GH responders maintained their clinical response through week 64. Mean (95th confidence interval) height z score on GH increased from -1.1 (-1.6, -0.6) to -0.4 (-1, 0.2), P = 0.004 during this 52-week extension phase. GH was well tolerated with no unexpected safety signals. CONCLUSIONS: The addition of GH to CTX therapy did not induce a reduction in mucosal inflammation, relative to CTX alone. However, GH was safe and effective as an adjunct to CTX for treatment of clinical disease activity and growth failure in pediatric CD.

The APC tumor suppressor is required for epithelial integrity in the mouse mammary gland.

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor has been associated with mammary tumorigenesis in mouse models and through epidemiological studies of human breast cancers, but the normal role for APC in mammary development has not been thoroughly characterized. We report here that Apc(Min/+) mice containing one functional allele of Apc have severely disrupted lobuloalveolar development during pregnancy and lactation, time points at which Apc gene expression is at its highest levels in normal mice. This phenotype was accompanied by altered proliferation during pregnancy and involution, increased apoptosis throughout lactation, the formation of preneoplastic lesions and changes in specific genes associated with each of these processes. Neither modifications in beta-catenin localization, nor the expression of beta-catenin transcriptional target genes, were observed in Apc(Min/+) mammary tissues; however, tissues from lactating Apc(Min/+) mice had a significantly altered epithelial architecture, including disrupted localization of junctional proteins and polarization. Consistent with these findings, APC knockdown in non-transformed mouse mammary epithelial cells in vitro resulted in altered monolayer formation and proliferation without changes in beta-catenin-mediated transcription. These results suggest that APC expression is tightly regulated during mammary gland development and is required for normal mammary homeostasis and tumor suppression primarily through maintaining epithelial integrity.

Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice.

BACKGROUND: Intestinal epithelial cell (IEC) STAT3 is required for wound healing following acute dextran sodium sulfate (DSS) injury. We hypothesized that loss of IEC STAT3 would promote the development of chronic colitis following acute DSS injury. METHODS: Colitis was induced in IEC-specific STAT3-deficient mice (STAT3)[INCREMENT]IEC and littermate controls (STAT3 Flx/Flx) with 4% DSS for 7 days, followed by water consumption for 21 days. Epithelial and immune mediators and severity of colitis were determined. RESULTS: Survival, colon length, and histologic injury were significantly worse at day 28 in STAT3[INCREMENT]IEC mice. IEC proliferation and apoptosis did not vary by genotype at day 14 or day 28. The colonic lamina propria frequency of pSTAT3* cells was increased at day 28 and correlated with histologic injury in STAT3 [INCREMENT]IEC mice. The frequency of colonic F480* pSTAT3* macrophages and CD3* pSTAT3* T lymphocytes were increased in STAT3[INCREMENT]IEC mice as compared with STAT3 Flx/Flx controls. In STAT3[INCREMENT]IEC mice, colonic expression of STAT3 target genes Reg3ß and Reg3γ, which mediate epithelial restitution, were significantly decreased, whereas expression of interleukin (IL)-17a, IFNγ, CXCL2, CXCL10, and CCL2 were significantly increased and correlated with the increase in histologic severity at day 28(P < 0.05). IL-17a expression also correlated with the increased lamina propria frequency of CD3* pSTAT3* T lymphocytes. CONCLUSIONS: Loss of intestinal epithelial STAT3 leads to more severe chronic inflammation following acute injury, which is not accounted for by a sustained defect in epithelial proliferation or apoptosis 7 or 21 days after 1 cycle of DSS but rather defective REG3 expression and expansion of pSTAT3* lymphocytes and IL-17A expression.

Completely humanizing prolactin rescues infertility in prolactin knockout mice and leads to human prolactin expression in extrapituitary mouse tissues.

A variety of fundamental differences have evolved in the physiology of the human and rodent prolactin (PRL) systems. The PRL gene in humans and other primates contains an alternative promoter, 5.8 kbp upstream of the pituitary transcription start site, which drives expression of PRL in "extrapituitary" tissues, where PRL is believed to exert local, or paracrine, actions. Several of these extrapituitary PRL tissues serve a reproductive function (eg, mammary gland, decidua, prostate, etc), consistent with the hypothesis that local PRL production may be involved in, and required for, normal reproductive physiology in primates. Rodent research models have generated significant findings regarding the role of PRL in reproduction. Specifically, disruption (knockout) of either the PRL gene or its receptor causes profound female reproductive defects at several levels (ovaries, preimplantation endometrium, mammary glands). However, the rodent PRL gene differs significantly from the human, most notably lacking the alternative promoter. Understanding of the physiological regulation and function of extrapituitary PRL has been limited by the absence of a readily accessible experimental model, because the rodent PRL gene does not contain the alternative promoter. To overcome these limitations, we have generated mice that have been "humanized" with regard to the structural gene and tissue expression of PRL. Here, we present the characterization of these animals, demonstrating that the human PRL transgene is responsive to known physiological regulators both in vitro and in vivo. More importantly, the expression of the human PRL transgene is able to rescue the reproductive defects observed in mouse PRL knockout (mPRL(-)) females, validating their usefulness in studying the function or regulation of this hormone in a manner that is relevant to human physiology.

Innate dysfunction promotes linear growth failure in pediatric Crohn's disease and growth hormone resistance in murine ileitis.

BACKGROUND: Growth failure remains a common complication of pediatric Crohn's disease (CD) and has been associated with small bowel involvement and need for surgery. We have reported that patients with elevated (≥ 1.6 µg/mL) granulocyte macrophage colony stimulating factor autoantibodies (GM-CSF Ab) are more likely to experience complicated ileal disease requiring surgery. We hypothesized that concurrent GM-CSF Ab and CARD15 risk allele carriage (C15(+) GMAb(+) ) would be associated with growth failure in CD and growth hormone (GH) resistance in murine ileitis. METHODS: We enrolled 229 pediatric CD patients at two sites and determined CARD15 genotype, serum GM-CSF Ab, and GH binding protein (GHBP), and height (HTz) and weight (WTz) z-scores at diagnosis. Ileitis was induced in card15-deficient mice by GM-CSF neutralization and nonsteroidal antiinflammatory drug (NSAID) exposure. Hepatic GH receptor (GHR) abundance and GH-dependent Stat5 activation were determined by western blot and Igf-I mRNA expression by real-time polymerase chain reaction (PCR). RESULTS: Mean (95% confidence interval [CI]) HTz at diagnosis was reduced to -0.48 (-4.2, 2.3) in C15(+) GMAb(+) patients, compared to -0.07 (-4.9, 3.4) in disease controls (P ≤ 0.05). Circulating GHBP, as a marker for tissue GHR abundance, was reduced in C15(+) GMAb(+) patients. Hepatic GHR abundance, GH induction of Stat5 tyrosine phosphorylation, and Igf-I mRNA expression were reduced in male card15-deficient mice with ileitis due to GM-CSF neutralization and NSAID exposure. CONCLUSIONS: Innate dysfunction due to concurrent genetic variation in CARD15 and neutralizing GM-CSF Ab is associated with linear growth failure in pediatric CD, and hepatic GH resistance in murine ileitis.

Pretreatment with anti-VEGF therapy may exacerbate inflammation in experimental acute colitis.

AIM: Our previous investigations of angiogenesis in inflammatory bowel disease showed that vascular endothelial growth factor (VEGF) blockade reduced colonic neovascularization and inflammation. We hypothesized that pretreatment with bevacizumab, a monoclonal anti-VEGF antibody, would attenuate the severity of angiogenesis and inflammation in a murine model of colitis. METHODS: C57BL/6 mice were treated with intraperitoneal injections of bevacizumab (250 µg/dose) before induction of colitis with dextran sulfate sodium (DSS). The colons were examined at predetermined time points. Colonic inflammation and microvessel density were assessed microscopically. RESULTS: All mice acutely developed melena and weight loss (18.8% ± 1.1% control vs 20.2% ± 1.1% treated, P = .37) and regained a similar weight percentage after the recovery (26.5% ± 4.0% vs 20.9% ± 4.4%, P = .37). Microvessel density acutely increased in both groups in response to DSS, with a trend toward inhibited angiogenesis in the treated group at the conclusion of the acute phase (194,100 ± 14,240 vs 149,400 ± 17,590 µm(2), P = .11). Bevacizumab-treated mice exhibited significantly increased inflammation after the acute phase (8.3 ± 0.8 vs 13.0 ± 2.0, P = .05), but were similar to control after the recovery (7.3 ± 1.5 vs 5.5 ± 1.0, P = .27). CONCLUSIONS: Preemptive VEGF inhibition does not significantly attenuate angiogenesis and, in fact, worsens inflammation in a model of acute colitis. Preventive VEGF blockade may disrupt healing and exacerbate injury via alternative angiogenic or inflammatory pathways.

Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis.

BACKGROUND: Systemic exposure to lipopolysaccharide (LPS) has been linked to clinical disease activity in adults with inflammatory bowel disease (IBD). We hypothesized that markers of LPS exposure and the acute phase response (APR) would be increased in pediatric IBD patients with growth failure, and that LPS signaling would be required for induction of the APR in murine colitis. METHODS: Serum markers of LPS exposure, endotoxin core IgA antibody (EndoCAb), and the APR, LPS binding protein (LBP) were quantified in pediatric IBD patients and controls. LBP and cytokine production were determined after administration of trinitrobenzene sulfonic acid (TNBS) enemas to mice with genetic deletion of Toll-Like receptor 4 (TLR4), and wildtype (WT) controls. RESULTS: Serum EndoCAb and LBP were significantly elevated in patients with Crohn's disease (CD), compared to disease controls with ulcerative colitis (UC) and healthy controls (P < 0.001). This was independent of disease activity or location. CD patients with elevated serum EndoCAb and LBP exhibited linear growth failure which persisted during therapy. Serum LBP increased in WT mice following TNBS administration, in conjunction with increased serum TNF-alpha, IL-6, and IL-10, and expansion of regulatory T-cell numbers. Both the APR and expansion of foxp3+ T cells were abrogated in TLR4-deficient mice, in conjunction with a reduction in acute weight loss. CONCLUSIONS: LPS exposure and a persistent APR are associated with growth failure in pediatric CD. LPS signaling is required for the APR in murine colitis. Therapies targeting this pathway may benefit the subset of patients with refractory growth failure.

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.