Role of blood- and tissue-associated inducible nitric-oxide synthase in colonic inflammation

There is evidence that inducible nitric-oxide synthase (iNOS)-derived NO contributes to the pathophysiology of intestinal inflammation. The aims of this study were to assess the role of iNOS in the development of dextran sodium sulfate (DSS)-induced colonic inflammation and to define the contribution of tissue-specific iNOS expression to this inflammatory response. Study groups included: 1) wild-type (WT) mice; 2) WT=>WT bone marrow chimeras with normal iNOS function; 3) WT=>iNOS-/- chimeras (with functional blood cell iNOS, but iNOS-deficient tissue); 4) iNOS-/-=>WT chimeras (with iNOS-deficient blood cells, but normal tissue iNOS activity); and 5) iNOS-deficient mice. In WT mice and WT=>WT chimeras, DSS-induced colonic inflammation was characterized by bloody diarrhea and a high disease activity index. However, WT=>iNOS-/- and iNOS-/-=>WT chimeras and iNOS-/- mice exhibited an attenuated disease activity index, with parallel changes in histopathology. Colonic myeloperoxidase (MPO) was comparably elevated in DSS-treated WT mice (30.1+/-1.7) and WT=>WT chimeras (29.0+/-1), whereas MPO was significantly reduced in iNOS-/- mice and iNOS-/-=>WT chimeras (9.5+/-1.7 and 15.6+/-2.2, respectively). WT=>iNOS-/- chimeras exhibited the lowest MPO activity (3.7+/-0.6). Our findings implicate both blood cell- and tissue-derived iNOS in DSS-induced colonic inflammation, with tissue-associated iNOS making a larger contribution to the recruitment of inflammatory cells.     

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0–0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.This work was supported by DK 43785 (to M.B.G., Project 6), DK 33720 (to R.D.S.), and DK 40249 (to R.B.S.).     

The distinctiveness of compulsive hoarding from obsessive-compulsive disorder

The present study investigated the relation of compulsive hoarding to other obsessive-compulsive disorder (OCD) symptoms in a sample of 162 patients with OCD. Obsessions and compulsions reported on the Anxiety Disorders Interview Schedule for DSM-IV were submitted to an exploratory factor analysis. Results suggested a four-factor model: "Certainty," "Contamination," "Obsessions," and "Numbers/Ordering." Hoarding did not load on any factor. The sample was divided into three groups: pure hoarding, nonhoarding OCD, and mixed OCD and hoarding. The hoarding group endorsed significantly less anxiety, worry, stress, and negative affect on self-report measures than the mixed and nonhoarding groups. Although hoarding sometimes functions as a compulsion among individuals with OCD, hoarding in the absence of other OCD symptoms may be a clinically distinct syndrome.     

Nitric oxide and the gut

Nitric oxide (NO) has been implicated as a modulator of blood flow, motility, electrolyte and water transport, and the function of endothelial cells, platelets, mast cells, and macrophages within the digestive system. In addition, a number of reports have demonstrated that NO possesses potent anti-inflammatory properties, whereas results from an equally impressive number of studies suggest that NO may promote inflammation-induced cell and tissue dysfunction. Consideration of the physiologic chemistry of NO and its interaction with molecuclar oxygen and/or superoxide may allow us to identify which of the NOdependent reactions are important in modulating physiologic and pathophysiologic responses in the gut.     

Role of appendix and spleen in experimental colitis.

There is growing clinical evidence suggesting that certain secondary lymphoid tissues (e.g., appendix and spleen) contribute to the initiation and/or perpetuation of ulcerative colitis. In this study, the importance of secondary lymphoid tissues in inducing colitis was assessed experimentally by removing the spleen and/or appendix (or sham operation) prior to inducing colitis in mice. Feeding 2.5% dextran sulphate sodium (DSS) in drinking water over 7 days induced colitis. Clinical disease activity was assessed based on weight loss, stool consistency, and presence of blood in stools. Additional measurements included white blood cell count and hematocrit, and myeloperoxidase activity (MPO) in colon samples. Colonic injury was assessed by histology and computerized image analysis. DSS treatment in sham-operated mice produced colitis associated with weight loss, bloody diarrhea, and mucosal ulceration. Clinical assessment of DSS-treated mice subjected to appendectomy or combined appendectomy/splenectomy exhibited a delayed onset and course of disease activity. Histomorphologic examination revealed significantly lower damage scores and a reduction in ulcerated mucosal surface area. Colonic MPO activity, which correlated with tissue injury and disease activity, was lowest in appendectomized mice. No beneficial effects of splenectomy were observed after 7 days of colitis. These findings support the hypothesis that appendicular lymphoid tissue, but not the spleen, contributes to the development of colitis.     

Saccadic tracking skills of poor readers in high school.

BACKGROUND: Oculomotor control has been implicated as a factor when reading is poor, but few studies exist for adolescents. METHODS: The saccadic eye movement efficiency of 684 ninth grade students, identified as poor readers in 5 California high schools, was quantified using the Developmental Eye Movement test. Frequency distributions were produced from scores on vertical and horizontal components, and gender and test-retest factors were considered during analysis. RESULTS: Vertical times were within 1 standard deviation of normal for eighth grade. However, horizontal (saccadic) times were typical of grade 3, and the average number of errors on the horizontal test was typical of grade 2. Boys and girls performed similarly. Results of retests showed slightly improved horizontal times and fewer errors, but the grade level equivalents remained dramatically low. Overall, fewer than 10% of students scored above the 50th percentile for eighth grade. CONCLUSION: The results indicate that poor readers in high school may be at high risk for poor saccadic tracking skill.     

Nurses Improving Care for Healthsystem Elders (NICHE): using outcomes and benchmarks for evidenced-based practice

This article describes Nurses Improving Care for Healthsystem Elders (NICHE), a project begun in 1992 with four pilot hospitals. These pilot hospitals gathered baseline data using a geriatric institutional assessment profile (GIAP) with a pre- and postdesign to capture changes in staff attitudes, knowledge, and perceptions of the care of older adults. Based on the success of the pilot effort, NICHE, now in its eighth year, has evolved into a program that involves 32 health systems comprising 105 hospitals nationally. To date, more than 10,000 GIAPs have been collected by NICHE hospital staff. All NICHE settings are able to benchmark their GIAP data against comparable institutions (eg, urban, rural, university, community settings) to understand how they compare and then interpret the data at their unique sites. The opportunities for continuous quality improvement through the NICHE program are described.     

Relationship among circulating leukocytes, platelets, and microvascular responses during induction of chronic colitis

The mechanisms by which microvascular alterations contribute to the pathogenesis of the inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) have not been clearly delineated. The purpose of the current study was to characterize the inflammatory events, microvascular alterations, and blood cell changes that occur in a mouse model of IBD. In this model, CD4⁺ T-lymphocytes obtained from interleukin-10-deficient mice were injected intraperitoneally into lymphopenic, recombinase-activating gene-1 deficient (RAG^−/−) mice. Two groups of control mice were also included: RAG^−/− mice and C57BL/6 mice that were injected with phosphate-buffered saline but did not receive the T-cells. Four weeks later, the RAG^−/− mice that had received the T-cell transfer showed significant signs of colonic inflammation, but without significant decreases in either body weight or mean arterial blood pressure. T-cell transfer increased the volume % of circulating platelets, while decreasing the number of circulating red blood cells. Additionally, the T-cell transfer tended to increase the circulating numbers of both lymphocytes and neutrophils when compared to unmanipulated RAG^−/− mice. First-order colonic arterioles and venules tended to dilate in the colitic mice; however, the dilation was considerably more substantial with higher numbers of circulating leukocytes. The possibility that circulating inflammatory cells initiate the microvascular alterations in colitis warrants further investigation.