Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease.

Infiltrating monocytes and macrophages contribute to the initiation and perpetuation of mucosal inflammation characteristic for human inflammatory bowel disease (IBD). Peripheral blood monocytes expressing the low-affinity Fcgamma receptor CD16 have been identified previously as a major proinflammatory cell population, based on their unique cytokine secretion profile. However, the contribution of these cells to the pathogenesis of inflammatory bowel disease remains to be elucidated. Thus, in this study we investigated whether the peripheral CD16(+) monocyte count correlates with common IBD disease parameters, and whether these cells infiltrate the intestinal mucosa under inflammatory conditions. We observed that CD16(+) peripheral blood monocytes are increased significantly in active Crohn's disease, particularly in patients with high Crohn's disease activity index and colonic involvement. Furthermore, we found that CD16(+) cells are a major contributor to the inflammatory infiltrate in Crohn's disease mucosa, although their spontaneous migration through primary human intestinal endothelial cells is limited. Our data suggest that lamina propria, but not peripheral blood, CD16(+) monocytes are a crucial proinflammatory cell population in IBD, and a potential target for anti-inflammatory therapy.

CCR6 identifies lymphoid tissue inducer cells within cryptopatches.

The chemokine receptor CCR6 is expressed by dendritic cells, B and T cells predominantly within the organized structures of the gut-associated lymphatic tissue. Its ligand CCL20 is synthesized by the follicle-associated epithelium and is crucial for the development of M cells within Peyer's patches. In addition, lineage-negative c-kit positive lymphocytes within cryptopatches (CP) express CCR6. CCR6-deficient mice exhibit an altered intestinal immune system containing increased amounts of intraepithelial lymphocytes and show smaller Peyer's patches, while progression of cryptopatches to mature isolated lymphoid follicles (ILF) is inhibited. In this report, we show that lin(-) c-kit(+) lymphocytes express a variety of different chemokine receptors and that CCR6 identifies those cells located within CP. In contrast, cells found outside CP are positive for CXCR3 and exhibit a different surface marker profile, suggesting that at least two different populations of lin(-) c-kit(+) cells are present. The presence of CCR6 does not influence the expression of Notch molecules on lin(-) c-kit(+) cells, nor does it influence Notch ligand expression on bone marrow-derived dendritic cells. In the human gut, CCR6 identifies clusters of lymphocytes resembling murine CP. CCR6 seems to have an important role for lin(-) c-kit(+) cells inside CP, is expressed in a regulated manner and identifies potential human CP.

Granulocyte chemotactic protein 2 (gcp-2/cxcl6) complements interleukin-8 in periodontal disease.

BACKGROUND AND OBJECTIVE: Mucosal inflammatory responses are orchestrated largely by pro-inflammatory chemokines. The chemokine granulocyte chemotactic protein 2 (CXCL6) is involved in neutrophil recruitment and migration. Previous studies have shown that granulocyte chemotactic protein 2 is up-regulated during mucosal inflammation (e.g. in inflammatory bowel disease), similarly to the functionally and structurally related chemokine interleukin-8. Nevertheless, unlike interleukin-8, a role of granulocyte chemotactic protein 2 in gingival inflammation has not been yet demonstrated. In this study we aimed to evaluate the expression of the chemokine granulocyte chemotactic protein 2 in clinically healthy vs. diseased gingival tissues and to explore possible correlations with clinical and microbiological markers of periodontitis. MATERIAL AND METHODS: Gene expression in 184 'diseased' and 63 'healthy' gingival tissue specimens from 90 patients with periodontitis was analyzed using Affymetrix U133Plus2.0 arrays. The expression of granulocyte chemotactic protein 2 was further confirmed by real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay, while the localization of granulocyte chemotactic protein 2 in gingival tissues was analyzed by immunohistochemistry. Plaque samples from the adjacent periodontal pockets were collected and evaluated for 11 species of periodontal bacteria using checkerboard DNA-DNA hybridizations. RESULTS: Among all known chemokines, GCP-2 expression was the most up-regulated (3.8-fold, p < 1.1 x 10(-16)), in 'diseased' vs. 'healthy' tissue as compared to a 2.6-fold increased expression of interleukin-8 mRNA (p < 1.2 x 10(-15)). Increased expression of granulocyte chemotactic protein 2 correlated with higher levels of 'red' and 'orange' complex pathogens and with increased probing depth, but not with attachment loss. Immunohistochemistry showed that granulocyte chemotactic protein 2 was expressed in gingival vascular endothelium. CONCLUSION: The level of expression of granulocyte chemotactic protein 2 correlates with the severity of periodontitis and appears to act as a hitherto unrecognized functional adjunct to interleukin-8 in diseased gingival tissues.

Phagocyte-specific S100 proteins are released from affected mucosa and promote immune responses during inflammatory bowel disease.

Phagocyte-derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end-products, while complexes of S100A8/S100A9 (myeloid-related proteins, MRP8/14; calprotectin) are ligands of toll-like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohn's disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28-fold enhanced in inflamed tissue when compared to non-inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up-regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte-derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD.

Recurrent obscure gastrointestinal bleeding caused by aorto-enteric fistula.

Aorto-enteric fistulas are rare but serious clinical conditions that may arise as a complication following abdominal aortic surgery. Clinical symptoms in affected patients range from obscure recurrent gastrointestinal bleeding and intermittent unexplained fever attacks to fulminant hematochezia and rapid exsanguination. A high degree of clinical alertness and suspicion is critical for both accurate diagnosis and timely surgical therapy in these patients. This case report describes a patient who was referred to our department six months after abdominal aortic surgery. The patient presented with septic illness and episodes of obscure gastrointestinal bleeding. Diagnostic work-up revealed a retroperitoneal infection of the aortic graft. A false aneurysm led to recurrent duodenal bleeding, which was accompanied by perforation of the obliterated aortic graft into the cecum. After immediate surgical repair, the patient recovered and continues to do well. We present a brief review of the current literature on this entity, outlining different surgical strategies and their outcomes.

Spontaneous splenic rupture, in tertian malaria.

We report a case of tertian malaria in a 36-year-old Caucasian male complicated by spontaneous splenic rupture 2 months after returning from Kenya. The ruptured and enlarged spleen displaying multiple subcapsular hemorrhages was surgically resected. Histological examination revealed a marked enlargement of the red pulp and a reduced white pulp in addition to hyperemia of the spleen. Tertian malaria was diagnosed by peripheral blood smear and elevated antibody titer against Plasmodium vivax. The patient underwent antimalarial therapy with chloroquine and primaquine and the further course was uneventful. Etiopathology, differential diagnosis and therapy of this rare complication in malaria are discussed.

Amelanotic malignant melanoma of the esophagus: case report.

We present the case of a primary malignant esophageal melanoma arising in a 75-year-old male, initially diagnosed as anaplastic squamous cell carcinoma. After resection of the tumor, histological work-up was indicative of a marked morphological heterogeneity, resembling a focally amelanotic primary malignant melanoma. Primary malignant melanomas of the esophagus are exceptionally rare. An exact preoperative diagnosis is critical with respect to the appropriate therapeutic strategy. Clinicopathological features of this entity with a brief review of the literature are presented.

Stable remission after administration of rituximab in a patient with primary hepatic marginal zone B-cell lymphoma.

We describe a case of primary hepatic marginal zone B-cell lymphoma in a 36-year-old Caucasian male with a history of chronic hepatitis B infection. Immunohistochemically, extensive infiltration by a CD20-positive, CD5- negative and CD10-negative lymphoid cell population displaying a follicular arrangement was detected. Molecular analysis of immunoglobulin heavy chain gene rearrangements confirmed the clonal expansion of lymphoma cells. Fourteen months after surgical treatment, the tumour recurred in close proximity to the liver hilus, hampering further surgery. Therefore, we implemented a therapy using the monoclonal anti-CD20-antibody rituximab in a dose of 375 mg/m(2), administered four times once a week. Six, 10, 18, and 26 months later the recurrent lymphoma could no longer be detected as shown by abdominal ultrasonography and CT. This case report demonstrates the difficulties of treating this extremely rare liver disease and shows its response to rituximab therapy.

Ultrasonographic stress test of the metacarpophalangeal joint of the thumb.

The purpose of this study was to evaluate functional ultrasound as a tool for detecting an ulnar collateral ligament injury of the thumb. The feasability of using ultrasound for imaging the thumb joint space was tested in a pilot study, using ultrasound and dissection in 14 cadaveric hand specimens. To test this method clinically, both metacarpophalangeal joints of the thumb in 461 healthy volunteers were examined using ultrasound (11 MHz) under radial stress. The distance between the innominate tubercle of the first metacarpal head to the proximal phalanx was measured. The mean distance between the first metacarpal head and the proximal phalanx (n = 461) was 4.5 mm (standard deviation, 0.65 mm) on the right side and 4.6 mm (standard deviation, 0.61 mm) on the left side. These data were compared with data of 25 patients with an operative diagnosis of rupture of the ulnar collateral ligament of the thumb. The difference in joint space between the injured and uninjured sides was 2.25 mm (standard deviation, 0.46 mm). The metacarpophalangeal joint space can be reproducibly detected on high-frequency ultrasound. An increased gap seen on ultrasound is indicative of a rupture of the ulnar collateral ligament of the thumb.

[Narrowing of the third extensor tendon compartment in minimal displaced distal radius fractures with impending rupture of the EPL tendon]. / Einengung des dritten Strecksehnenfaches bei gering dislozierter distaler Radiusfraktur mit Gefahr einer Extensor pollicis longus-Sehnenruptur.

Delayed ruptures of the extensor pollicis longus tendon (EPL) occur in about 0.7 percent following undisplaced distal radius fractures. Two possible mechanisms are mainly discussed in the literature: A mechanical irritation of the tendon caused by a sharp edge of the fractured bone and a direct microvascular compromise of the poorly vascularized tendon. In undisplaced fractures, however, a mechanical irritation seems less likely. In the cases here described we were able to demonstrate a fragment displacement in the area of Lister's tubercle suspected by the native X-ray and further evaluated by a CT scan. The use of CT scans even in minor displaced distal radius fractures involving Lister's tubercle may demonstrate a direct contact of the EPL tendon with a sharp edge of this fractured bone and make adequate surgery possible.

Signet-ring cell carcinoma of unknown primary location. Metastatic to lower back musculature - remission following FU/FA chemotherapy.

The detection of gastrointestinal signet-ring cell carcinoma by endoscopy can be a diagnostic challenge. The main clinical features include atypical metastasis and a poor prognosis. We present a case of a metastasizing signet-ring cell carcinoma with unknown primary location arising in 71-year-old female. Following 6 cycles of a routine intravenous FU/FA chemotherapy, an almost complete remission could be observed. After 2 years of follow up, metastatic recurrence was detected to the lower back musculature. This case report emphasizes the difficulties in diagnosing signet-ring cell carcinoma by endoscopy and demonstrates an unusual clinical course.

Accuracy of endoscopic ultrasonography in preoperative staging of esophageal carcinoma.

BACKGROUND: With the advent of stage-adapted multimodal regimens for many gastrointestinal malignancies, accurate staging has become of utmost importance. In esophageal cancer, endoscopic ultrasonography (EUS) emerged as standard to determine T and N stage. OBJECTIVE: Since growth patterns of squamous carcinoma (SC) differs from adenocarcinoma (AC) and lymph nodes are located at various distances from the esophagus in a horizontal plane, we studied the accuracy of esophageal EUS as a function of tumor type and localization of the tumor within the esophagus. RESULTS: Overall staging accuracy was 79% for T and for N staging. Staging was more accurate for T3/4, when compared to T1/2 tumors, and for SC when compared to AC. Histological T1/2 stages were overstaged by EUS in 8/17 patients, mostly in patients with AC (6/10). The sensitivity of retrosternal pain and of dysphagia for extramural disease was 57 and 92% respectively, the specificity of pain for extramural disease was 73%, and of dysphagia 36%. Preoperative weight loss in this series correlated linearly with tumor stages. CONCLUSIONS: The accurate preoperative staging of T2 esophageal endodermal malignancies is crucial for treatment stratification but difficult to achieve by visual analysis of endosonography alone. Postacquisition processing of echoendosonographic images might further increase the accuracy of echoendosonography and aid in the critical differentiation of T2 versus T3 esophageal malignancies. Preoperative weight loss and retrosternal pain are good clinical indicators of extramural disease.