Immunological profiling of patients with ulcerative colitis leads to identification of two inflammatory conditions and CD1a as a disease marker.

BACKGROUND: Conventional approaches to understand mechanisms underlying the development of pathological manifestations in ulcerative colitis (UC) mostly rely on identification of certain cell types and cytokines followed by verification of their roles in vitro and in vivo. In light of the highly dynamic processes in UC, requiring the cross talk of immune cells, epithelial-, endothelial-, muscle cells and fibrocytes, this approach might neglect temporal and spatial connectivity of individually differing inflammatory responses. METHODS: We undertook a more holistic approach whereby we designed a flow cytometric analysis- and ELISA panel and determined the immunological profiles of UC patients in comparison to Non UC donors. This panel consisted of B-cells, T-cells, macrophages, monocytes, NK- and NK T-cells and subtypes thereof, the cytokines TGFß1 and HGF, the chemokine TARC and periostin. Blood was collected from 41 UC patients and 30 non-UC donors. Isolated PBMC were subjected to flow cytometric analysis and sera were analyzed by ELISA. Data were analysed by cluster- and correlation analysis. To corroborate that the identified cells reflected the inflammatory condition in the colon of UC patients, leucocytes were isolated from colons of UC patients and subjected to the same flow cytometric analysis. RESULTS: Immunological profiling followed by cluster- and correlation analysis led to the identification of two inflammatory conditions: An 'acute' condition characterized by adaptive immune cells as plasma cells,  TSLPR expressing CD11b+ macrophages, CD64 and CCR2 expressing CD14+ monocytes, HGF and TARC and a 'remodeling' condition signified by NK T-cells and TLSPR expressing CD14+ monocytes, TGFß1 and periostin. ROC analysis identified TARC and TGFß1 as biological markers with high potential to discriminate between these two conditions (Δ = -6687.72 ng/ml; p = 1E-04; AUC = 0.87). In addition, CD1a+ CD11b+ macrophages (Δ = 17.73% CD1a+ CD11b+; p = 5E-04; AUC = 0.86) and CD1a+ CD14+ monocytes (Δ = 20.35; p = 0.02, AUC = 0.75) were identified as markers with high potential to discriminate between UC and Non UC donors. CD1a+ CD11b+ macrophages and NK T-cells were found to be significantly increased in inflamed colons of UC patients as compared to non-UC control samples (p = 0.02). CONCLUSIONS: Immunological profiling of UC patients might improve our understanding of the pathology underlying individual manifestations and phases of the disease. This might lead to the development of novel diagnostics and therapeutic interventions adapted to individual needs and different phases of the disease. In addition, it might result in stratification of patients for clinical trials.

No effect of the cyclooxygenase-2 inhibitor etoricoxib on pre-emptive and post-operative analgesia in visceral surgery: results of a randomized controlled trial.

BACKGROUND: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design. METHODS: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection. RESULTS: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups. CONCLUSIONS: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery.

The route to pathologies in chronic inflammatory diseases characterized by T helper type 2 immune cells.

T helper type 2 (Th2)-characterized inflammatory responses are highly dynamic processes initiated by epithelial cell damage resulting in remodelling of the tissue architecture to prevent further harm caused by a dysfunctional epithelial barrier or migrating parasites. This process is a temporal and spatial response which requires communication between immobile cells such as epithelial, endothelial, fibroblast and muscle cells and the highly mobile cells of the innate and adaptive immunity. It is further characterized by a high cellular plasticity that enables the cells to adapt to a specific inflammatory milieu. Incipiently, this milieu is shaped by cytokines released from epithelial cells, which stimulate Th2, innate lymphoid and invariant natural killer (NK) T cells to secrete Th2 cytokines and to activate dendritic cells which results in the further differentiation of Th2 cells. This milieu promotes wound-healing processes which are beneficial in parasitic infections or toxin exposure but account for increasingly dysfunctional vital organs, such as the lung in the case of asthma and the colon in ulcerative colitis. A better understanding of the dynamics underlying relapses and remissions might lead ultimately to improved therapeutics for chronic inflammatory diseases adapted to individual needs and to different phases of the inflammation.

[Structured teaching of surgery the LMU model in Munich]. / Strukturierte Lehre in der Chirurgie am Beispiel des Humanmedizinstudiums an der Ludwig-Maximilians-Universität München.

The medical curriculum (MeCuM) of the Ludwig Maximilian University (LMU) in Munich is a dynamic curriculum aimed to support the learning process of all students with their different learning styles. It is based on interactive, activating teaching methods in order to increase students' interest, and on repetitive evaluation of teaching units to modify the teaching in order to meet students' needs and wishes. In this context the teaching of surgery at our faculty takes place. Besides interdisciplinary lessons where diseases are taught in cooperation with our colleagues from internal medicine, indications for surgery, complications and consequences of surgery for the patients are analysed in PBL tutorials, online cases, bedside teachings and practical teaching on the ward. Surgical skills like suturing are demonstrated in videos, practiced on models or during practical teaching on the ward and they are tested in OSCEs. During the "praktisches Jahr", the students in the last year of their medical studies are supposed to apply their practical skills besides repeating theoretical knowledge in order to pass the final examination. For this purpose they are taught in a revision course called "LMU-StaR" (revision course for the Staatsexamen). In this paper we describe in detail the teaching of surgery at our faculty.

Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) mice engrafted with human peripheral blood mononuclear cells.

Oxazolone-induced colitis in mice has become a recognized model to study the efficacy of therapeutics targeting the immunological response underlying the development of inflammatory bowel disease. However, this model cannot be used when therapeutics designed to address human targets do not interact with the respective murine counterpart. In this study, we examined the induction of oxazolone mediated colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) (NOD-SCID IL2Rγ(null)) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from ulcerative colitis (UC), atopic dermatitis (AD) and healthy volunteers. NOD-SCID IL2Rγ (null) mice were engrafted with hPBMC followed by challenge with oxazolone or ethanol vehicle. Mice developed the same symptoms as observed previously in immunocompetent mice. The clinical activity score increased and the colon architecture was characterized by the development of oedema, fibrosis, crypt loss and dense infiltration of predominantly T cells into the lamina propria. Fluorescence activated cell sorter (FACS) analysis of lymphocytes in the colon identified natural killer (NK) T cells as a major constituent. In contrast to studies with immunocompetent mice, we observed the same phenotype in the group challenged with ethanol vehicle. The phenotype was most pronounced in mice engrafted with PBMC derived from a patient suffering from UC, suggesting that the immunological history of the donors predisposes the engrafted mice to react to ethanol. The model described here has the potential to study the efficacy of therapeutics targeting human lymphocytes in a model which is more reflective of the human disease. In addition, it might be developed to elucidate molecular mechanisms underlying the disease.

Long-term outcome of an unusual haemophilic pseudotumour.

Haemophilia, a lifelong congenital bleeding disease, is a highly demanding disorder, due to the costs of its replacement therapy. In the absence of this pivotal treatment, life expectancy and quality of life are deleteriously affected. As illustration, we present a 14 years long follow-up of a patient with severe haemophilia A, treated sporadically with fresh plasma, cryoprecipitate and factor concentrates, who developed a giant iliopsoas pseudotumor. Since he was an infant, under on demand therapy with fresh frozen plasma, cryoprecipitate and low doses of factor concentrates he presented many spontaneous bleedings, developing multiple disabling arthropathies. At the age of 14 years, an iliopsoas hematoma occurred, which relapsed several times, developing an iliopsoas pseudotumour. After 5 years, sepsis with Klebsiella was diagnosed. A CT scan revealed fistula between the pseudotumor and the gut. Under antibiotics, the evolution of sepsis improved, but over a period of 10 months 5 episodes of haematemesis and melena, followed by one episode of macroscopic haematuria occurred; two months later he developed an inguino-crural mass, which fistulized through the abdominal wall. A mixt german-romanian team solved the clinical concern. After 108 hospitalization days and consumption of 104840 IU factor VIII he left the clinic in good condition. One year later, the temporary colostomy with anus praeter was closed. The follow-up reveals now, after almost 10 years with favourable outcome, that the patient is well, active within his family and profession.

The use of chicken legs for teaching wound closure skills.

OBJECTIVE: Training models are required to impart surgical skills, like wound closure techniques, prior to practice in patients. In an ideal case, the tissue characteristics of the model are close to those of humans, easy to create and of low cost. METHODS: Here, we describe a model to train students in wound closure technique using conventional chicken legs obtained from the supermarket. RESULTS: The described model has good tissue characteristics, does not require any lavish preparation and is of minimal cost (0.62 Euro or 0.78 USD). CONCLUSIONS: Chicken legs appear to be an appropriate tool for teaching wound closure techniques.

Natural history, clinical pattern, and surgical considerations of pneumatosis intestinalis.

OBJECTIVE: Pneumatosis intestinalis has been increasingly detected in recent years with the more frequent use of computed tomography for abdominal imaging of the intestine. The underlying causes of the gas found during radiographic studies of the bowel wall can vary widely and different hypotheses regarding its pathophysiology have been postulated. Pneumatosis intestinalis often represents a benign condition and should not be considered an argument for surgery. However, it can also require life-threatening surgery in some cases, and this can be a difficult decision in some patients. METHODS: The spectrum of pneumatosis intestinalis is discussed here based on various computed tomographic and surgical findings in patients who presented at our University Medical Centre in 2003-2008. We have also systematically reviewed the literature to establish the current understanding of its aetiology and pathophysiology, and the possible clinical conditions associated with pneumatosis intestinalis and their management. RESULTS: Pneumatosis intestinalis is a primary radiographic finding. After its diagnosis, its specific pathogenesis should be ascertained because the appropriate therapy is related to the underlying cause of pneumatosis intestinalis, and this is sometimes difficult to define. Surgical treatment should be considered urgent in symptomatic patients presenting with an acute abdomen, signs of ischemia, or bowel obstruction. In asymptomatic patients with otherwise inconspicuous findings, the underlying disease should be treated first, rather than urgent exploratory surgery considered. Extensive and comprehensive information on the pathophysiology and clinical findings of pneumatosis intestinalis is provided here and is incorporated into a treatment algorithm. CONCLUSIONS: The information presented here allows a better understanding of the radiographic diagnosis and underlying aetiology of pneumatosis intestinalis, and may facilitate the decision-making process in this context, thus providing fast and adequate therapy to particular patients.

Diagnostic and treatment options for skin and soft tissue abscesses in injecting drug users with consideration of the natural history and concomitant risk factors.

OBJECTIVE: Skin and soft tissue abscesses are common findings in injecting drug users (IDUs) who present to the surgical emergency department for evaluation and treatment. Although most cases can be managed by incision and drainage, they do require special considerations as compared to abscesses which are not caused by intravenous drug abuse. METHODS: Skin and soft tissue abscesses treated in the emergency department between 2005 and 2007 were reviewed and a systematic literature search of skin and soft tissue abscesses in IDUs was conducted, including the etiology, occurrence, risk factors, and treatment options, thus providing the rationale for the treatment algorithm presented herein. RESULTS: The drugs injected, the technique by which they were injected, the attendant circumstances, as well as the immunological status of the IDUs were major factors for the development of abscesses. Skin and soft tissue abscesses in IDUs should be incised and drained under local or general anesthesia depending on the size, location, and association with neurovascular structures. Different factors have been taken into account when treating soft tissue abscesses in this population which predict their specific risks and therefore further therapy needs. The incidence of tetanus is high among IDUs compared to the general population, giving rise to the recommendation for a strict booster policy if the vaccination status is unclear when the patient presents to the emergency department. The presence of fever requires hospitalisation and evaluation for the presence of endocarditis. Foreign bodies, such as broken needles, should be ruled out by radiography, and duplex sonography should be performed to identify the presence of vascular complications. Prior to incision and drainage, prophylactic antimicrobial agents should be administered to every patient and as therapy for high-risk patients, such as immunocompromised patients and patients with fevers and chills. CONCLUSIONS: IDUs presenting with skin and soft tissue abscesses can be managed safely if some special issues are taken in account. The presented algorithm may help facilitate the decision-making in this context.

Tissue attachment strength and adhesion formation of intraabdominal fixed meshes with cyanoacrylat glues.

OBJECTIVE: The aim of this study was to evaluate the technique of prosthetic mesh fixation in laparoscopic intraperitoneal incisional and ventral hernia repair using cyanoacrylat glue (Glubran GEM, Viareggio, Italy) in comparison with fixation methods using spiral tacks (Protack 5mm, Tyco) or transabdominal Prolene 4/0 sutures respectively. METHOD: Through a midline laparotomy 3 pieces (3 x 3cm) of mesh (n = 60) where fixed onto the intact peritoneum on either side of a midline laparotomy in 10 New Zealand White rabbits. Two types of meshes where compared: ePTFE meshes (Gore-Tex Dual Mesh W.L. Gore and Associates, Inc. Medical Products Division, Flagstaff, Arizona, USA) and polypropylene/ polyvinylfluorid meshes (Dyna Mesh - IPOM P.J. Dahlhausen and Co. GmbH, Germany). All animals were killed after 12 weeks. Upon scoring of the adhesions the prosthetic materials were excised en bloc with the anterior abdominal wall for tensile strength analysis and histologic evaluation. RESULTS: In contrast to ePTFE meshes fixed with cyanoacrylat glue, PP meshes fixed with transabdominal sutures as well as with spiral tacks showed the highest percentage and tenacity of adhesions (p<0.033). Independent of the method of fixation, ePTFE meshes revealed a significantly higher shrinkage than PP prosthesis (41% vs 17% related to original mesh surface; p<0.033). The strength of the mesh incorporation was significantly higher in PP meshes (p<0.033). Fixation of PP meshes with cyanoacrylat glue showed an equivalent tensile strength as ePTFE meshes fixed with spiral tacks (6.6 +/- 2.7 N vs 6.6 +/- 3.1N). CONCLUSION: In this rabbit model, intraabdominal fixation of PP composite meshes with cyanoacrylat glue was equivalent to ePTFE mesh fixation with spiral tacks concerning tensile strength analysis. Adhesions between mesh and abdominal wall were found more frequently after PP fixation. In contrast, mesh shrinkage was more evident after ePTFE mesh implantation.

Natural history and surgical treatment of brown tumor lesions at various sites in refractory primary hyperparathyroidism.

OBJECTIVE: Nowadays, the occurrence of brown tumor lesions or osteitis fibrosa cystica caused by long-lasting primary hyperparathyroidism are very rare, since measuring serum calcium became available routinely in the mid-1970s. It is a tumor-like lesion that may affect the entire skeleton, often presenting with diffuse focal bone pain or by pathological fracture. METHODS: We describe our experience of brown tumor lesions at different skeletal sites that were treated at our trauma centre within the last two years. This included surgical therapy for the indications (i) pain at the pelvis, (ii) increased risk for pathological fracture at the tibia and (iii) acute radicular symptoms at the lumbar spine. The literature was reviewed for the current understanding of the pathophysiology as well as therapy of brown tumor lesions in primary hyperparathyroidism. RESULTS: Curettage of a left-sided iliac crest brown tumor terminated focal pain. A less invasive stabilisation system and bone cement decreased both patient pain and the fracture risk of brown tumor lesion sites of the shinbone; and internal fixator including laminectomy at the lumbar spine ended radicular symptoms. CONCLUSION: Patients with refractory primary hyperparathyroidism should be monitored closely by endocrinologists and the patient's serum calcium level should be adjusted as far as possible. Radiography is required only if focal bone pain or pathological fractures or radicular symptoms occur. Surgery should be considered if large bone defects with spontaneous fracture risk or increasing pain are present. Tumor curettage, Palacos plombage and less invasive stabilisation systems have proved to be acceptable surgical options.

Malignant melanoma of the anal region.

Malignant melanoma (MM) of the anal region is an uncommon disease. In many cases, the disease is undetected or mistaken for a benign polyp or haemorrhoids until it reaches an advanced state. Owing to delayed diagnosis and early metastases, the prognosis is often poor. In contrast to melanomas of the skin, a history of sun exposure does not seem to have an impact in development of MM in this region. Anorectal melanomas (AM) are most common in the rectum, followed by the anal canal and anal verge. Ras mutations, especially in codon 61 of the N-ras oncogene, are common in CM and rare in melanomas of the vulva and anorectum. The diagnosis of an AM is usually made using a biopsy. Histopathological examinations show spindle-shaped and pleomorphic cells. Adjuvant immunohistological markers are the calcium-binding protein S-100, the melanoma antigen HMB-45, the melanoma-expressed protein Melan A, and microphthalmia-associated transcription factor (MiTF). To date, there are few published guidelines for the correct management of AM, and surgery remains the mainstay of treatment. We report on a 39-year old man who presented with a 5-week history of recurrent prolapse of an anal tumour. The tumour was histologically confirmed to be malignant melanoma.

Treatment procedures for anal fistulous cryptoglandular abscess--how to get the best results.

INTRODUCTION: Up to date anal fistulous cryptoglandular abscess is a subject of controversial scientific discussions and the number of medico legal cases dealing with treatment procedures is growing . In principal, there is a dispute whether it is reasonable to perform a primary fistulotomy at the time of abscess drainage or to wait for a secondary fistulotomy. The purpose of this study was to compare studies focussing on the treatment of anal fistulous abscess with regard to different treatment procedures, their outcome (recurrence, incontinence, follow-up) and factors influencing outcome (primary or recurrent fistulous abscess, comorbidity, exclusion criteria, anaesthesia, microbiology, antibiotics, search for internal opening, classification). METHODS: A Medline search included the terms: fistulous abscess, anal abscess, horseshoe abscess, anorectal sepsis, and perianal infection/abscess. RESULTS: In 63 (1964-2004) studies we found 35 different treatment methods: the most often used procedures were incision and drainage (I+D; n = 35) and incision and drainage and primary fistulotomy (I+D+pF; n = 23). Only in ten studies the treatment has been restricted for primary anal fistulous abscess; the remaining studies investigated primary and recurrent anal fistulous abscess. There was a considerable lack of information on morbidity, microbiology, and exclusion criteria. In only 16/63 studies patients were routinely diagnosed and treated under general anaesthesia. We found nine different classifications of fistulous abscess. There is a wide range of recurrence after different treatment procedures: up to 88% after I+D and 21% after I+D+pF. The incontinence rate after I+D ranged from 0-26%, after I+D+pF 0-52%. However, in many studies there was no information on incontinence available. CONCLUSION: A true comparison of different treatment methods is not available. This is mainly due to either a lack of information on important factors influencing outcome, even unclear definitions in some instances. Recent randomized studies have been criticized for missing information and flaws in the randomization procedure. The choice of treatment, e.g., primary or secondary fistulotomy, depends on the clinical experience of the surgeon on duty, the hospital structure (staff, equipment, and anaesthesia), the patient's history and the local anatomical circumstances. On the basis of up to date knowledge there is no reason to condemn primary or secondary fistulotomy without more clinical studies and without knowing the individual situation.

The critical role of aprotinin in controlling haemostasis in conjunction with non-pharmacological blood-saving strategies during routine coronary artery bypass surgery.

OBJECTIVE: Aprotinin, a non-specific serine protease inhibitor, has been confirmed to be safe and effective in reducing intra- and postoperative blood drainage, transfusion requirements, and perioperative morbidity and mortality during coronary artery bypass surgery. It is the only one of the currently available haemo-static agents that is approved by the U.S. Food and Drug Administration (FDA) for use in cardiac surgery. However, one major weakness of currently available trials is the lack of information regarding the concomitant usage of aprotinin with blood-saving strategies that have been used more frequently in recent years. METHODS: Patients undergoing elective first-time coronary artery bypass grafting (n = 172) who were given systemic high-dose aprotinin (n = 85), combined systemic high-dose aprotinin and topical aprotinin (n = 27), or no aprotinin (n = 60) were reviewed retrospectively. The use of all blood-saving procedures was systematically taken in account. RESULTS: Postoperative blood drainage was significantly less in patients treated with aprotinin than controls (P < 0.0001). Concomitant use of topical aprotinin was accompanied by a postoperative blood loss reduction of 35% compared to systemic aprotinin use alone (P < 0.003). The intra- and postoperative donor blood requirements were dramatically reduced in both aprotinin-treated groups compared to controls, although patients received different blood saving strategies as appropriate (P < 0.0001). A trend of up to 20% lower postoperative blood drainage was noted in patients in whom intraoperative haemodilution and autologuos blood transfusions were used (P > 0.05). CONCLUSIONS: The present analysis demonstrates that the local and systemic administration of aprotinin is safe and effective in reducing intra- and postoperative blood drainage and transfusion requirements. In elective CABG procedures, aprotinin should still be used even if blood-saving strategies are employed.

[Capsule endoscopy: indication, diagnosis and patient management in the doctor's office]. / Ambulante Dünndarmdiagnostik. Was leistet die Kapselendoskopie in der Praxis?

In this prospective clinical study, 50 consecutive patients in whom there was an indication for capsule endoscopy were evaluated with regard to indication, examination course, outcome and modifications to patient management, and the data obtained analysed. In 88% of the patients, capsule endoscopy revealed pathological changes. Patient management was modified in 78% of the cases.

AIDS, multicentric Castleman's disease, and plasmablastic leukemia: report of a long-term survival.

Plasmablastic leukemia (PL) as a complication of human herpes virus 8 (HHV8)-associated Castleman's disease is marked by a rapid and fatal outcome. In patients with AIDS, survival of 7 to 14 days after diagnosis has been reported. Prompt splenectomy and chemotherapy might lead to a significant survival benefit. Here we report a case of long-term survival in a patient with AIDS and multicentric Castleman's disease (MCD) complicated by PL.