Ulcer Bed Research Articles

Gastrointestinal tract ulcers in pediatric intestinal transplantation patients: Etiology and management

One of the observed complications in patients after intestinal transplantation is the occurrence of ulcers in the native or transplanted gastrointestinal tract. Previous reports have described the appearance of ulcers but have not described any systemic approach to accurately diagnose the etiology of the ulcer. We evaluated 112 intestinal transplantation patients at our institution, in which endoscopic examination identified ulcer formation in 11 patients. No common or defining demographic or clinical variables were found in the patients with ulcers. Biopsies were obtained from the ulcer edge as well as the intervening mucosa. The most common changes in the ulcers were compatible with post-transplant lymphoproliferative disorder (PTLD), acute rejection, and viral infections. These changes could occur simultaneously and retrospective analysis showed that ulcers could have concomitant etiologies. Endoscopically directed biopsies of ulcer edges often displayed morphologic changes compatible with acute rejection of the graft. Some patients were treated for rejection based on the changes within the mucosa outside the ulcer bed, and they responded with resolution of the ulcers. Our findings demonstrate that PTLD and acute rejection are the most common causes of chronic ulcer formation and reinforce the concept that biopsy samples should be collected simultaneously from both the ulcer edge and intervening mucosa.

Venous and arterial leg ulcers

Venous leg ulceration is due to sustained venous hypertension, which results from chronic venous insufficiency. In the normal venous system, pressure decreases with exercise as a result of the action...

Therapeutic Outcome of Hyperbaric Oxygen and Basic Fibroblast Growth Factor on Intractable Skin Ulcer in Legs: Preliminary Report

Beneficial effects of hyperbaric oxygen on ischemic vascular diseases have been noted. Acceleration of wound healing with basic fibroblast growth factor has also been reported. The authors employed combination therapy of hyperbaric oxygen and basic fibroblast growth factor in patients with skin ulcer in legs refractory to conventional therapy. Three men and four women were simultaneously treated with hyperbaric oxygen at 2 absolute atmospheric pressures for 90 minutes daily and spray treatment of basic fibroblast growth factor to the ulcer bed daily for an average of 2.6 months. Biopsy specimens obtained from ulcer tissues were divided into two pieces, one for histologic examination and the other for measuring fibrous protein. Ulcers were completely cured in five of seven patients. Two patients showed shrinkage of ulcer size. This combined therapy induced proliferation of connective tissue of the ulcer tissues, especially collagen and noncollagenous protein. Combined treatment with hyperbaric oxygen and basic fibroblast growth factor may be useful in patients with intractable skin ulcers in legs, and the shrinkage effect of this therapy is probably related to the proliferation of granulation tissues of the ulcer lesion.

An esophageal ulcer mimicking advanced esophageal cancer in a patient on alendronate sodium treatment for osteoporosis

We report a case of an esophageal ulcer that mimicked advanced esophageal cancer in a patient who was on alendronate sodium treatment. A 56-year-old woman presented with progressively worsening pain on swallowing. For the past 6 months she had been taking 5 mg/day alendronate sodium (Bonalon) for the treatment of postmenopausal osteoporosis. Upper gastrointestinal endoscopic examination revealed an ulcerative lesion in the lower esophagus that resembled an advanced esophageal cancer (Figure 1 ). The ulcers mucosa was normal, but the ulcer bed was uneven and would not stain with Lugol dye. Biopsy specimens of the ulcer bed showed a marked infiltration of neutrophils and eosinophils in the subepithelial space, but no signs of malignancy (Figure 2). We stopped the alendronate sodium and prescribed a proton-pump inhibitor. Endoscopic examination 2 months later showed marked improvement in the ulcer, with no esophageal stricture.

Heregulin-α and heregulin-β expression is linked to a COX-2-PGE2pathway in human gastric fibroblasts

We have previously shown heregulin (HRG)-alpha expression in human gastric fibroblasts and its stimulation of gastric epithelial cell growth. Although cyclooxygenase (COX)-2 has also been shown to stimulate growth factor production in these cells, the interaction between COX-2 and HRG remains unknown. Conditioned media (CM) from gastric fibroblasts incubated with PGE(2) or interleukin (IL)-1beta, a well known COX-2 inducer, were analyzed for their effect on erbB3 tyrosine phosphorylation in MKN28 gastric epithelial cells. HRG protein expression in fibroblast lysates and CM was also examined by western blot. HRG-alpha and HRG-beta mRNA expression in gastric fibroblasts and human gastric tissue was examined by real-time quantitative PCR. HRG and COX-2 expressions in surgical resections of human gastric ulcer tissue were examined immunohistochemically. CM from fibroblasts incubated with PGE(2), or IL-1beta, stimulated erbB3 phosphorylation in MKN28 cells. Preincubation of the fibroblasts with celecoxib, a selective COX-2 inhibitor, suppressed CM-induced erbB3 phosphorylation. This inhibition was reversed by exogenous PGE(2). As with erbB3 phophorylation, IL-1beta stimulated both HRG-alpha and HRG-beta mRNA expression, as well as HRG release into gastric fibroblast CM. IL-1beta-stimulated HRG expression and release were also inhibited by celecoxib, and exogenous PGE(2) restored this inhibitory effect, suggesting the activation of an IL-1beta-COX-2-PGE(2) pathway that culminates in the release of HRG from fibroblasts. HRG-alpha and HRG-beta mRNA levels were significantly higher in gastric ulcer tissue than in normal gastric mucosa. HRG immunoreactivity was found in interstitial cells of the gastric ulcer bed and coexpressed with COX-2. These results suggest that HRG might be a new member of the growth factor family involved in the COX-2-dependent ulcer repair process.

The debridement of hard to heal leg ulcers by means of a new device based on Fluidjet technology

Debridement plays an essential role in the wound-bed preparation of necrotic and sloughy ulcers, being a mandatory step to achieve a well-debrided bed, proceeding towards healing. This study reports our experience with Versajet [Versajet Hydrosurgery System (Smith & Nephew, Hull, UK)], a new device for the debridement of exudating ulcers, based on Fluidjet technology, which excises and aspirates the unwanted tissue by using the Venturi effect. In a 10-month time period, a total of 68 patients, out of a setting of 167 patients, hospitalised as affected by chronic, hard-to-heal leg ulcers, stuck in the inflammatory phase, were treated with Versajet. Based on ulcer characteristics and clinical conditions, the remaining 99 patients underwent traditional debridement with moist dressings (controls). In the majority of Versajet-treated cases (46), an adequately debrided wound bed was achieved with one operative procedure; two and three procedures were required in 17 and 5 patients, respectively. Almost all the procedures were performed in the ward at the patient's bedside. This procedure is quick (mean time per treatment is about 5 minutes); when compared with a traditional treatment with moist dressings, Versajet considerably shortens the in-hospital stay and promotes a quicker healing process. When used by an experienced surgeon, Versajet allows a selective debridement, as it makes it possible to remove only the tissue centred in the working end and spare the healthy tissue. Debriding with Versajet is highly effective in reducing the bacterial load of the ulcer bed. The pain caused by Versajet is well tolerated, especially when set for gentle debridement. If multiple treatments are required, the combined use with moist dressings is synergistic, as the dressings soften the necrotic tissue, thus facilitating the following Versajet debridement. The results indicate that Versajet offers more precision than standard mechanical debridement and, at high settings, offers an alternative to surgical debridement.

The Role of Cyclooxygenase in Gastric Mucosal Protection

COX-1 and COX-2 are two cyclooxygenase enzymes responsible for prostanoid production. COX-2 is expressed in inflammatory cells and fibroblasts of the gastric mucosa, and through the production of various growth factors including hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), plays a key role in the tissue repair process. Aspirin induces and acetylates COX-2 to produce 15-(R)-epi-lipoxinA4, an anti-inflammatory mediator thought to protect the gastric mucosa against aspirin-induced injury. Recently, three different PGE synthases have been identified, that convert COX-2 metabolites into PGE2. mPGE synthase (mPGES)-1 has been shown to be inducible, and to colocalize with COX-2 in fibroblasts and macrophages infiltrating the gastric ulcer bed. cPGES and mPGES-2 have been found expressed in normal gastric mucosa, with no change in expression levels seen in gastritis or gastric ulcer tissue. Finally, this review discusses the role of these enzymes in the pathophysiology of the gastric mucosa, as well as the biologcal significance of their inhibition.

Granulocyte/macrophage colony-stimulating factor treatment of human chronic ulcers promotes angiogenesis associated withde novovascular endothelial growth factor transcription in the ulcer bed

Summary Background Granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine with pleiotropic functions, has been successfully employed in the treatment of chronic skin ulcers. The biological effects underlying GM-CSF action in impaired wound healing have been only partly clarified. Objectives To investigate the effects of GM-CSF treatment of chronic venous ulcers on lesion vascularization and on the local synthesis of the angiogenic factors vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF). Methods Patients with nonhealing venous leg ulcers were treated with intradermal injection of recombinant human GM-CSF, and biopsies were taken at the ulcer margin before and 5 days after administration. Wound vascularization was analysed by immunohistochemistry using antiplatelet endothelial cell adhesion molecule-1/CD31 and anti-alpha-smooth muscle actin antibodies. VEGF and PlGF transcription was assessed by in situ hybridization. To identify the cell populations transcribing VEGF within the ulcer bed, the VEGF hybridization signal was correlated with the immunostaining for different cell type markers on serial sections. Direct induction of VEGF transcription by GM-CSF was investigated in GM-CSF-treated cultured macrophages and keratinocytes. Results Blood vessel density was significantly increased in the ulcer bed following GM-CSF treatment. VEGF transcripts were localized in keratinocytes at the ulcer margin both before and after GM-CSF treatment, whereas a VEGF hybridization signal was evident within the ulcer bed only following administration. PlGF mRNA was barely detectable in keratinocytes at the ulcer margin and was not visibly increased after treatment. Unlike VEGF, a specific PlGF hybridization signal could not be detected in cells within the ulcer following GM-CSF administration. Monocytes/macrophages were the main cell population transcribing VEGF after GM-CSF treatment. In vitro analysis demonstrated that VEGF transcription can be directly stimulated by GM-CSF in a differentiated monocytic cell line, but not in keratinocytes. Conclusions Our data show that increased vascularization is associated with GM-CSF treatment of chronic venous ulcers and indicate that inflammatory cell-derived VEGF may act as an angiogenic mediator of the healing effect of GM-CSF in chronic ulcers.

Dystrophic calcification as a cause for non healing leg ulcers

Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.

Developing an accurate system of measuring colour in a venous leg ulcer in order to assess healing

To develop a standardised method of assessing venous ulceration, based on the colour of an ulcer bed and the surrounding skin. This pilot study involved taking three sequential digital photographs during an episode of care and measuring the colour using image analysis software. Ten episodes of care were used for data collection. Based on previous research, a threshold of < or =3 degrees of colour and 3% of saturation was selected to indicate the reliability of the system. The mean of the colour measurements was inside the reliability threshold when measuring an ulcer bed, but outside the threshold for measuring the surrounding skin. The results indicate that the system provides consistent visual representation of a venous leg ulcer.

Microbiology of Chronic Leg and Pressure Ulcers: Clinical Significance and Implications for Treatment

Chronic pressure ulcers and leg ulcers are common, especially in the elderly, and are a source of much distress and disability. Health care providers must distinguish between clinically unimportant but predictable colonization of these wounds and clinically relevant infection.Infection may present as increased local pain, cellulitis, local abscess,necrotizing fasciitis, osteomyelitis, bacteremia, or sepsis. For most of these conditions, systemic antibiotics are necessary. The use of topical antimicrobial agents as a means of promoting healing in clinically uninfected wounds is a subject of active investigation at this time. Currently, evidence is insufficient to support routine use of anti-microbial agents for this purpose. A quantitative tissue culture taken from the ulcer bed, revealing greater than 10(5) organisms/g of tissue appears to increase the risk of failure of ulcer wound closure by graft or flap. A short course of topical or systemic antibiotics before surgery in these instances is advisable.

Microsomal prostaglandin E synthase (mPGES)-1, mPGES-2 and cytosolic PGES expression in human gastritis and gastric ulcer tissue

Recently, three different prostaglandin E2 synthases have been identified: microsomal prostaglandin E synthase (mPGES)-1, cytosolic PGES (cPGES), and mPGES-2; however, their role and connection to cyclooxygenase (COX)-2 in the gastric ulcer repair process remain unknown. Therefore, we examined mPGES-1, cPGES, and mPGES-2 expression and localization in the stomach in vitro and in vivo. Tissues were obtained from Helicobacter pylori (H. pylori)-infected patients and consisted of surgical resections of gastric ulcers, or biopsies of gastric ulcers or gastritis. mPGES-1 mRNA and protein expression levels were examined by real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. mPGES-1, cPGES, and mPGES-2 localization were analyzed immunohistochemically. Induction of PGES expression in response to interleukin (IL)-1β was examined in vitro in the cultured human gastric fibroblast line Hs262.St. Real-time PCR analysis of mPGES-1 mRNA expression in biopsy samples showed significantly higher expression levels in open than in closed gastric ulcer tissue. Western blot analysis showed mPGES-1 protein expression limited to open ulcer tissue, while mPGES-2 and cPGES immunoreactivities were seen in both open and closed ulcer tissue. Immunohistochemical analysis showed strong mPGES-1 expression in fibroblasts and macrophages of the ulcer bed, paralleling COX-2 expression. cPGES and mPGES-2 expression levels were seen in both fibroblasts of the ulcer bed and in epithelial cells. Furthermore, stronger cPGES and mPGES-2 immunoreactivities were seen in scattered mast cell-like cells and neuroendocrine-like cells, respectively. Induction of mPGES-1 expression in response to IL-1β was seen in cultured gastric fibroblasts in vitro, and double immunostaining showed mPGES-1 coexpression with COX-2 in fibroblasts of the ulcer bed in vivo. In conclusion, mPGES-1, cPGES, and mPGES-2 are all expressed in gastric ulcer tissue, but only mPGES-1 parallels COX-2 expression in mesenchymal and inflammatory cells of the ulcer bed, suggesting a key role for this enzyme in the ulcer repair process.

Cultured pressure ulcer fibroblasts show replicative senescence with elevated production of plasmin, plasminogen activator inhibitor‐1, and transforming growth factor‐β1

In a 16-patient study, cultured fibroblast populations from normal skin were able to replicate an average of 14.8 +/- 2.2 times before becoming senescent, while fibroblast populations from the ulcer bed reached the end of their replicative life span after 7.2 +/- 1.9 population doublings (p= 0.001). Fibroblast populations from 10 of 16 pressure ulcers became senescent after fewer than five population doublings, whereas when populations of fibroblasts from adjacent normal skin were studied, only 2 of 16 became senescent within this same time period. In addition, only an occasional fibroblast from normal skin stained positively for senescence-associated beta-galactosidase compared to approximately 50% of equally aged ulcer bed fibroblasts (p = 0.0060). Senescent ulcer bed fibroblasts secreted significantly more plasmin than early passage ulcer bed fibroblasts (p= 0.0237), nearly six times as much plasmin as early passage normal skin fibroblasts (p < 0.0001), three and a half times the level of normal skin fibroblasts of the same age (11.52 +/- 4.58 microg/mg protein; p= 0.0003), and more than one and a half times the level of senescent normal skin fibroblasts (p= 0.0525). Senescent pressure ulcer fibroblasts generated significantly more plasminogen activator inhibitor-1 (1179.27 +/- 25.37 ng/mg protein) than normal skin fibroblasts of the same age (132.16 +/- 16.20 ng/mg protein; p = 0.0357). Also, senescent ulcer bed fibroblasts produced higher levels of transforming growth factor-beta1, but these were not significantly different from senescent normal skin fibroblasts. Although senescent ulcer fibroblasts produce elevated levels of plasminogen activator inhibitor-1 and transforming growth factor-beta1, the ratio of these factors to plasmin levels suggests that this may have little influence on extracellular matrix synthesis or maintenance in the chronic wound. These data show that cultured fibroblasts from most patient pressure ulcers profile a wound environment that is associated with an increasing population of senescent fibroblasts; however, factors within the chronic wound environment that promote cellular senescence remain unclear. We have proposed that a prolonged inflammatory response may be a contributing factor to the chronic wound condition.

Cell proliferation in the gastric epithelium of the ulcer rat

Objective. Cell division is brisk in the ulcer margin and many of the new cells will migrate over and cover the ulcer bed. The aim of this study was to determine how agents that promote or delay gastric ulcer healing influence cell proliferation in the gastric epithelium. Material and methods. Acetic acid ulcers were produced in the rat gastric corpus; non-ulcer rats served as controls. All rats were given a continuous infusion of 3H-thymidine. Some rats were also given gastrin or indomethacin, or infected with Helicobacter pylori. The rats were killed after 1, 2, 6 or 13 days, and the ulcer margin and undamaged corpus were excised for determination of labeling index (LI) by autoradiography. Antrum, duodenum and colon were also studied. Silver grain counting was carried out in some groups. Results. LI in the ulcer margin grew exponentially, reaching 84% after 6 days; gastrin increased, and indomethacin decreased LI significantly. In 6-day ulcer rats that were given 3H-thymidine only during the first day LI was 5%, while in those given 3H-thymidine only during the last day LI was 27%. LI and silver grain counting results indicated that during the first 6 days of healing the epithelial cells in the ulcer margin divide twice. In the undamaged epithelium of the 1-day ulcer rats LI was <one-third, and in the antral epithelium one-half of that in the non-ulcer controls. Conclusions. During the first 6 days of healing, the LI of the non-parietal epithelial cells increases exponentially in the ulcer margin; this is enhanced by gastrin. The unexpected finding in the ulcer rats of decreased LI in undamaged oxyntic and antral epithelium may be caused by a block of the G1 restriction point in the cell cycle. The reason for this remains obscure.

Keratinocyte and dermal vascular endothelial cell capacities remain unimpaired in the margin of chronic venous ulcer

The role of endogenously produced cytokines and growth factors in the impaired healing of chronic leg ulcers remains uncertain. The aim of this study was to determine the functional capacity of skin cells in ulcer bed tissue compared to those in the edge of ulcers and skin distal to ulcers. Biopsies from leg ulcers of ten randomly selected patients were examined immunohistochemically for cytokines and growth factors produced by keratinocytes (KC) and vascular endothelial cells (EC). The phenotype of leukocytes infiltrating venous ulcers and the expression of vascular adhesion molecules responsible for extravasation were also studied. The expression of cytokines and growth factors by KC was similar in areas adjacent and remote from an ulcer. In the dermis adjacent to an ulcer, the expression of IL-1alpha, IL-1beta, IL-1Ra, EGF and PDGFa by EC was higher than the levels of expression in EC from the distant dermis. The expression of IL-6, TNFalpha and GM-CSF was comparable to that in cells from intact dermis. For all these factors staining was cytoplasmic, suggesting production in these areas. Ulcer bed tissue contained few fibroblasts and blood capillaries showing a high staining intensity for CD62E and CD106 EC adhesion molecules but no FGF2 expression (P<0.05). The intensity of staining for scavenging CD15+ elastase+ granulocytes and CD35+ (C3bR) activated macrophages in the ulcer bed was comparable to that in the margin but higher than that in the distant dermis (P<0.05), whereas staining for CD68+, HLA DR+, TGFbeta+ and CD54+ dermal macrophages was similar in all areas. There was reduced staining for CD4+ and CD8+ cells in the ulcer bed (P<0.05). There were no CD1a+ Langerhans cells in the epidermis encroaching upon the granulation tissue and there was reduced CD1a staining in the adjacent epidermis (P<0.05). In conclusion, there is chronic accumulation of scavenging cells with lack of remodeling of the granulation tissue and, at the same time, preserved cytokine and growth factor secretory potential of KC and dermal EC in non-healing venous leg ulcers.

Electron Microscopic Study of Anterior Lens Capsule Allotransplants in Chronic Corneal Ulcers

This study provides ultrastructural morphology and quantitative analysis of allotransplants of anterior lens capsule in the treatment of recurrent corneal ulcers. Mechanical ulcers of uniform size were created with a 6-mm corneal trephine in 9 eyes at one-third corneal depth in 6 white New Zealand male rabbits. Following initial epithelial regrowth, an identical injury was created in the same area of each cornea a second time. In 6 eyes (treated group), an anterior lens capsule from a healthy donor rabbit was sutured into the ulcer bed, followed by antibiotic/steroid drops 3 times daily for 1 week. The remaining 3 control eyes were allowed to heal without surgical intervention using the same antibiotic/steroid drops only. Slit-lamp examination, histopathology, and electron microscopic findings with hemidesmosome counts and size were recorded over a 3-month follow-up period. The control injured group had discontinuous epithelial basement membrane with significant reduction in hemidesmosome count compared with noninjured controls (P<0.0001). The treated subgroup 7 days after surgery showed linear basement membrane with identifiable lamina lucida and densa and newly-formed hemidesmosomes, which were significantly more numerous than in the injured but nontreated group (P<0.0001). Numerous hemidesmosomes and firm adhesion of epithelium to underlying stroma were seen in this group with lens capsule allografts 3 months after surgery. The number and size of hemidesmosomes did not significantly differ between groups 7 days and 3 months after surgery. On the ultrastructural level, anterior lens capsule allotransplants in mechanically induced corneal ulcer heal with continuously formed epithelial basement membrane and numerous hemidesmosomes. This enables significant reformation of hemidesmosomes that are identical in size to hemidesmosomes in healthy corneas and helps forming a stronger apposition for epithelial cells to underlying structures in eyes where epithelial basement membrane has been destroyed from chronic ulceration.

Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases

A specialized system for a new method for enteroscopy, the double-balloon method, was developed. The aim of this study was to evaluate the usefulness of this endoscopic system for small-intestinal disorders. The double-balloon endoscopy system was used to perform 178 enteroscopies (89 by the anterograde approach and 89 by the retrograde approach) in 123 patients. The system was assessed on the basis of the rates of success in jejunal and ileal insertion and the entire examination of the small intestine, diagnostic yields, ability to perform treatment, and complications. Insertion of the endoscope beyond the ligament of Treitz or ileocecal valve was possible in all 178 procedures. It was possible to observe approximately one half to two thirds of the entire small intestine by each approach, and observation of the entire small intestine was possible in 24 (86%) of 28 trials. The source of bleeding was identified in 50 (76%) of 66 patients with GI bleeding, scrutiny of strictures was possible in 23 patients, and a tumor was examined endoscopically in 17 patients. Two complications (1.1%) occurred. Endoscopic therapies in the small intestine including hemostasis (12 cases), polypectomy (1 case), endoscopic mucosal resection (1 case), balloon dilation (6 cases), and stent placement (2 cases) were performed successfully. Double-balloon endoscopy permits the exploration of the small intestine with a high success rate of total enteroscopy. The procedure is safe and useful, and it provides high diagnostic yields and therapeutic capabilities.

Angiogenesis, cell proliferation and apoptosis in gastric ulcer healing. Effect of a selective cox-2 inhibitor

To elucidate the role of cyclooxygenase-2, we compared the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, and ibuprofen, a nonselective cyclooxygenase inhibitor, on the evolution of acetic-acid-induced gastric ulcers in rats, evaluating growth factor expression, the angiogenic process, cell proliferation and cell apoptosis. Levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), angiogenesis and cell proliferation were analysed by immunohistochemical methods, and apoptosis was evaluated by an enzyme immunoassay. Both growth factors and microvessels appeared to be abundant in the granulation tissue of the ulcer bed. Rofecoxib (2.5 mg/kg/day) and ibuprofen (100 mg/kg/day) delayed ulcer healing, but only rofecoxib treatment provoked a reduction of bFGF expression and inhibition of the development of new microvessels. No changes in VEGF expression were detected. Results also showed that proliferation and apoptosis were increased in control ulcerated animals. Rofecoxib reduced significantly both processes. These findings demonstrate that a reduction of bFGF expression and an antiangiogenic action, as well as proliferation/apoptosis inhibition, are some of the mechanisms possibly implicated in the delay in ulcer healing seen after the administration of the highly selective COX-2 inhibitor rofecoxib.

Spatial and Temporal Pattern of Expression of Interstitial Collagenase, Stromelysin/Transin, Gelatinase A, and TIMP-1 during Experimental Gastric Ulcer Healing

Background/Aim: Controlled proteolysis is a prerequisite for cell migration, angiogenesis, and matrix remodelling during gastric ulcer healing. We studied the temporal and spatial expression of three matrix metalloproteinases, gelatinase A (MMP-2), interstitial collagenase (MMP-13), stromelysin (MMP-3), and their major inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1) during experimental gastric ulcer healing induced in rats by acetic acid injection. Methods: Gastric tissue specimens were hybridized with antisense ³⁵S-labelled RNA probes and the autoradiographic signal was analyzed by a computer aided image system. Gelatinase activity was analyzed by in situ and gel zymography. Results: During gastric ulcer healing, MMP-2, MMP-3, and MMP-13 RNA expression was increased in stromal cells of the gastric mucosa bordering the ulcer, suggesting a prevalent role of non-epithelial cells in pericellular proteolysis. Gelatinolytic activity was increased during ulcer healing and it was associated with extracellular matrix of the healing mucosa and newly formed vessels. In contrast to MMP-2 RNA, which was homogeneously distributed in all layers of the ulcer bed, MMP-3 and MMP-13 RNAs were confined to the upper layers of the granulation tissue. TIMP-1 RNA was detected in both epithelial and stromal cells of the gastric mucosa adjacent to the ulcer, as well as in the granulation tissue of the ulcer bed. Both MMP and TIMP-1 expression returned to basal levels during the late stages of tissue remodeling. Conclusion: Gastric ulcer repair is associated with a transient expression of specific metalloproteinases and their inhibitors in a distinct anatomical pattern pointing to complex cellular and cell/matrix interactions in the various layers of the healing mucosa.

TOXOPLASMA COLITIS IN A PATIENT WITH ACQUIRED IMMUNE DEFICIENCY SYNDROME

A 53 y/o black male with HIV disease whose most recent CD4 count was 159 cells/mm3 with viral load of 53,229 RNA copies/mm3 presented with intermittent bright red blood per rectum for three years with increased frequency of rectal bleeding for the previous two weeks before admission. There is no past or family history of inflammatory bowel disease. Other symptoms included diarrhea, weakness, and lightheadedness. On examination: T 37.4°C, BP 106/70 mmHg, HR 123 beats/minute, and RR 19 breaths/minute. Physical exam revealed pale conjunctiva and a nontender abdomen but was otherwise unremarkable. Initial laboratory results were: WBC 5,500 cells/mm3, HGB 6.5 g/dL, HCT 19.9%, MCV 78.6 fL, and PLT count 431,000 cells/mm3. Upper endoscopy revealed whitish plaques coating the esophagus consistent with Candidia esophagitis infection and erythema-tous gastric mucosa. Colonoscopy was performed and demonstrated multiple ulcers with raised margins throughout the colon. Biopsies of the ulcers showed colitis, ulceration, and the presence of Toxoplasma gondii organisms within the ulcer bed confirmed with immunohistochemistry staining. MRI of the brain with gadolinium contrast showed too numerous to count enhancing lesions within the brain parenchyma some with ring enhancement. The patient was treated with pyrimethamine, sulfadiazine, and folate resulting in resolution of diarrhea. In both the United States and Europe, toxoplasma infection has been reported to occur in up to 10–15% of patients with AIDS. Usually the central nervous system (CNS) is involved and infection of organs outside of the CNS is rare. Colonic ulceration is rarely seen. This case demonstrates that Toxoplasma gondii infection should be included in the differential diagnosis of diarrhea and/or lower gastrointestinal bleeding in patients with AIDS.