K.-M. Müller

Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen.

OBJECTIVES The aim of our study was to analyze the cellular components of neointimal tissue regeneration after coronary stenting. BACKGROUND High restenosis rates are a major limiting factor of coronary stenting. To reduce the occurrence of restenoses, more insights into the mechanisms leading to proliferation and expression of extracellular matrix are necessary. METHODS Twenty-one autopsy cases with coronary stents implanted 25 h to 340 days before death were studied. The stented vessel segments were analyzed postmortem by light microscopy and immunohistochemical staining. RESULTS In the initial phase stents are covered by a thin multilayered thrombus. Alpha-actin-positive smooth muscle cells (SMCs) are found as the main cellular component of the neointimal tissue. Later (>6 weeks) extracellular matrix increases and fewer SMCs can be found. In every phase the SMC layers are loosely infiltrated by inflammatory cells (T lymphocytes). In the early postinterventional phase all endothelial cells are destroyed. The borderline between the vessel lumen and the vascular wall is constituted by a thin, membranous thrombus. Six weeks after stenting, SMCs form the vessel surface. Complete reendothelialization is first found 12 weeks after stenting. CONCLUSIONS Stent integration is a multifactorally triggered process with proliferating SMCs generating regenerative tissue. In the early phase predominantly thrombotic material can be observed at the site of stenting, followed by the invasion of SMCs, T lymphocytes and macrophages. The incidence of delayed reendothelializations and the occurrence of deep dissections may be associated with excessive SMC hyperplasia.

Interstitial lung disease in a baby with a de novo mutation in the SFTPC gene

Mutations in the surfactant protein C gene (SFTPC) were recently reported in patients with interstitial lung disease. In a 13‐month-old infant with severe respiratory insufficiency, a lung biopsy elicited combined histological patterns of nonspecific interstitial pneumonia and pulmonary alveolar proteinosis. Immunohistochemical and biochemical analyses showed an intra-alveolar accumulation of surfactant protein (SP)‐A, precursors of SP‐B, mature SP‐B, aberrantly processed proSP‐C, as well as mono- and dimeric SP‐C. Sequencing of genomic DNA detected a de novo heterozygous missense mutation of the SFTPC gene (g.1286T>C) resulting in a substitution of threonine for isoleucine (I73T) in the C‐terminal propeptide. At the ultrastructural level, abnormal transport vesicles were detected in type‐II pneumocytes. Fusion proteins, consisting of enhanced green fluorescent protein and wild-type or mutant proSP‐C, were used to evaluate protein trafficking in vitro. In contrast to wild-type proSP‐C, mutant proSP‐C was routed to early endosomes when transfected into A549 epithelial cells. In contrast to previously reported mutations, the I73T represents a new class of surfactant protein C gene mutations, which is marked by a distinct trafficking, processing, palmitoylation, and secretion of the mutant and wild-type surfactant protein C. This report heralds the emerging diversity of phenotypes associated with the expression of mutant surfactant C proteins.

Saline-irrigated, cooled-tip radiofrequency ablation is an effective technique to perform the maze procedure.

BACKGROUND We evaluated the effectiveness of the saline-irrigated-cooled-tip-radiofrequency ablation (SICTRA) to produce linear intraatrial lesions. METHODS Thirty patients with chronic atrial fibrillation and mitral valve disease were consecutively randomized to have mitral valve operation either with a Maze procedure (group A) or without (group B). Intraatrial linear lesions were made with an SICTRA catheter (20 to 32 W; 200 to 320 mL/h saline). An echocardiography and 24-hour electrocardiogram were obtained 12 months postoperatively. RESULTS The cumulative frequencies of sinus rhythm in group A and B were 0.80 and 0.27 (p < 0.01). Restored biatrial contraction was present in 66.7% (6 of 9) of the group A patients in sinus rhythm. One patient from each group received a permanent pacemaker because of bradycardia. A fatal renal bleeding and mediastinitis occurred in 2 group A patients, 6 weeks postoperatively. One group A patient had sudden cardiac death at home, 4 months after operation. One patient from each group had lethal respiratory failure, 7 and 10 months after operation. Survival after 12 months for group A and B was 73% and 93% (p = 0.131). CONCLUSIONS The SICTRA appeared to be an effective technique to perform the Maze procedure.

Differential pattern of DNA-Aneuploidy in human malignancies

The differential pattern of DNA-aneuploidy, detected by flow cytometry (FCM) regarding its frequency, grade and multiclonality, was investigated and correlated to tumor type, malignancy grade, tumor stage and prognosis in a multi-institutional study at the University of Münster. High resolution measurements using admixed normal blood reference cells were undertaken in 2413 cases of 13 different malignant diseases and in 776 benign lesions or samples. The incidence of DNA-aneuploidy was highest in melanomas, carcinomas, testicular tumors, sarcomas (75%-95%) and myelomas (65%). Acute leukemias showed an intermediate DNA-aneuploidy rate of 40% with special subgroups represented by common ALL (44%), p less than 0.05) and myelomonocytic/monocytic AML (47%, p less than 0.01). The lowest DNA-aneuploidy-rate was found in basal cell skin carcinomas (19%) and congenital melanocytic nevi (9%). No case of DNA-aneuploidy was observed in the 776 benign lesions or samples.--DNA-indices giving the grade of DNA-aneuploidy with 1.0 for normal diploid G1/0 cells were found distributed predominantly between 1.0 and 2.0 in the solid tumors, except testicular tumors, clustering around a triploid maximum at 1.5. DNA-indices of myelomas and acute leukemias generally ranged below 1.25 with lower DNA-aneuploidy grades in AML than in ALL (p less than 0.01).--In melanomas the aneuploidy rate was higher (86%) in metastases than in the primary tumors (54%, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of calcitonin gene-related peptide and nitric oxide in the gastroprotective effect of capsaicin in the rat.

BACKGROUND Capsaicin-sensitive neurons contain various peptides including calcitonin gene-related peptide. This study examines (1) whether calcitonin gene-related peptide is involved in capsaicin-induced gastroprotection and (2) whether nitric oxide and prostaglandin are required for calcitonin gene-related peptide to prevent mucosal injury. METHODS Gastroprotection by capsaicin or calcitonin gene-related peptide against ethanol-induced gross and histological damage was studied after pretreatment with the calcitonin gene-related peptide receptor antagonist, human calcitonin gene-related peptide8-37, anti-calcitonin gene-related peptide antibodies, and NG-nitro-L-arginine. RESULTS Protection by capsaicin was dose-dependently (50% inhibitory dose, 305 pmol.kg-1.min-1) antagonized by human calcitonin gene-related peptide8-37 and significantly attenuated by anti-calcitonin gene-related peptide antibodies. NG-nitro-L-arginine dose-dependently inhibited the protective effect of calcitonin gene-related peptide (50% inhibitory dose, 0.9 mg/kg), 3 mg/kg completely blocking protection. L-Arginine reversed the effects of NG-nitro-L-arginine. Protection by calcitonin gene-related peptide was neither associated with increased prostaglandin formation nor inhibited by indomethacin. CONCLUSIONS The results suggest that calcitonin gene-related peptide is an essential mediator of the protection elicited by stimulation of capsaicin-sensitive neurons and that the protective effect of calcitonin gene-related peptide is lost after blockade of the nitric oxide system but not the prostaglandin system.

Left atrial versus bi-atrial maze operation using intraoperatively cooled-tip radiofrequency ablation in patients undergoing open-heart surgery: Safety and efficacy

OBJECTIVES We sought to determine whether limited left atrial Maze surgery encircling each of the pulmonary veins, using cooled-tip radiofrequency (RF) ablation, is as effective as the bi-atrial approach? BACKGROUND The original Cox/Maze operation effectively restores sinus rhythm (SR) in patients with atrial fibrillation (AF). Ablation procedures aimed at eliminating pulmonary vein foci have produced promising short-term success. METHODS This was a prospective analysis of patients with chronic AF undergoing open-heart surgery in addition to the Maze operation, using intraoperatively cooled-tip RF ablation either in the left atrium alone (group A) or in both atria (group B). RESULTS Patients in group A (n = 21) and group B (n = 49) did not differ in terms of their baseline characteristics. Concomitant open-heart surgical procedures included mitral valve replacement (3 vs. 25), mitral valve plasty (0 vs. 2), mitral and aortic valve replacement (1 vs. 1), aortic valve replacement (4 vs. 6) and coronary artery bypass grafting (13 vs. 15) in groups A and B, respectively. Follow-up ranged from 1 to 50 months. The overall cumulative rates of SR were 82% in group A and 75% in group B, without a statistically significant difference (p = 0.571). Bi-atrial contraction was revealed in 92.3% of patients in SR in group A and in 79.2% in group B. The cumulative survival rates were 90.5% in group A and 77.9% in group B (p = 0.880). CONCLUSIONS A left or bi-atrial Maze operation using intraoperatively cooled-tip RF ablation can safely be combined with open-heart surgery. A left atrial Maze procedure seems to be as effective as the bi-atrial procedure and restores SR in 82% of patients.

Experimental comparison of monofile light and heavy polypropylene meshes : Less weight does not mean less biological response

BackgroundMesh implantation is a standard procedure in hernia repair. It provides low recurrence rate but increases complication rate due to foreign-body reaction induced by alloplastic materials in surrounding tissues. It is believed that biocompatibility of meshes may be improved by reducing their weight per meter squared (m2) and altering the implant structure.AimThe aim of this study was to evaluate the effect of weight and structure as determinants of mesh biocompatibility.MethodThirty-six Wistar rats were studied. In 12 animals, conventional polypropylene (heavy) meshes (HM) were implanted; in other 12, material-reduced (light) microporous polypropylene meshes (LM); and the remaining 12 served as a sham-operated control group. Meshes were explanted after 21 and 90 days (6 animals per group). All samples were examined by light and electron microscopies. Integration of meshes in surrounding tissue, inflammatory response, fibrotic reactions, and structural changes were recorded. Quantification of the inflammatory response was achieved by CD-68 marking of macrophages and counting their number per surface unit.ResultsAfter 21 days, there was no significant difference in thickness of surrounding connective tissue between meshes in all groups studied. After 90 days, thickness of connective tissue decreased in both groups, and fibrotic reaction in the mesh bed was significantly less in the HM group. Total amount of macrophages per millimeter squared (mm2) decreased with time in HM and LM samples but was significantly lower in the HM group on day 21 (43.5%) and day 90 (46.7%).ConclusionThis study found worse biocompatibility of LM compared with HM. Thus, the amount of implanted mesh was not the main determinant of biocompatibility (expressed as successful incorporation and diminished foreign-body reaction) but the size of the pores.

Expression of endothelial cell adhesion molecules on heart valves: up‐regulation in degeneration as well as acute endocarditis

Inflammatory cytokines such as interleukin‐1 (IL‐1) and tumour necrosis factor‐alpha (TNF‐α), as well as shear stress, cause endothelial cells (ECs), to undergo not only functional alterations but also structural reorganizations, which contribute to vascular leakage. Like ECs of the human aorta, ECs on heart valves are exposed to extreme shear stress. However, while ECs expression of cell adhesion molecules (CAMs) in large vessels has been widely studied, it seems that there are no such studies on ECs of heart valves, although this knowledge might be important for our understanding of the aetiological aspects of local inflammatory responses. Using immunohistochemistry, this study characterized the CAM expression of ECs on degenerative, mostly calcified heart valves and on heart valves with florid endocarditis. As expected, the constitutively expressed molecules (ICAM‐1, CD34, CD31) were found both on degenerative and on inflamed valves. Furthermore, marked expression of E‐selectin and VCAM‐1 was found not only on inflamed valves, but also on larger portions of the degenerative valves with no morphological evidence of inflammation. This striking finding might help to explain why patients with fibrotic heart valves are susceptible to recurrent endocarditis. Why the endothelial activation markers E‐selectin and VCAM‐1 are expressed on degenerative heart valves requires further investigation. Copyright

Pathology of small-cell lung cancer

Abstract The morphological differentiation between small-cell and non-small-cell lung cancer has great prognostic and therapeutic significance for the patient. Malignant lung tumors are now classified according to the new 1999 WHO/IASLC classification of lung and pleural tumors. The variant of heterogeneously differentiated “combined small-cell carcinoma” can be distinguished from classical small-cell carcinoma, whereas the subtype of “intermediate cell carcinoma” is no longer used. Together with “large-cell neuroendocrine carcinomas” and typical or atypical carcinoid tumors, small-cell lung cancers are currently histogenetically categorized as neuroendocrine lung tumors. In contrast to large-cell neuroendocrine carcinoma, the immunohistochemical demonstration of neuroendocrine differentiation is not a prerequisite for the diagnosis of small-cell lung cancer. Although electron-microscopical, immunohistochemical, and molecular-biological findings have considerably increased our understanding of the pathogenesis and progression of malignant lung tumors, routine pathological-anatomical diagnostics are still decisively based on light-microscopical evaluation of tissue samples.

Computed Tomography–Navigated Transthoracic Core Biopsy of Pulmonary Lesions: Which Factors Affect Diagnostic Yield and Complication Rates?

RATIONALE AND OBJECTIVES Only a few studies have systematically evaluated risk factors for pneumothorax and pulmonary hemorrhage in computed tomographically (CT)-guided transthoracic lung biopsy (TLB). We evaluated the diagnostic yield of CT-guided TLB and determined risk factors for pneumothorax and hemorrhage. METHODS One hundred seventy-two CT-guided TLBs were performed on 159 patients (mean age 66 +/- 11 years; 72% male) using a 16-gauge core biopsy needle. Lesion and patient characteristics, lung function analysis, CT signs of emphysema, histopathologic diagnoses, and complications were recorded. Statistical analysis was performed with multivariate regression analysis. RESULTS Histopathologic diagnosis was established in 153 cases (89%). Although lesion size was higher (47 +/- 29 vs. 43 +/- 35 mm, P = .191) and depth was lower (22 +/- 23 vs. 6 +/- 23 mm, P = .350) in procedures with histopathologic diagnosis, no parameter showed significant impact on diagnostic yield. Sensitivity and specificity for detection of malignancy were 93% and 100%, respectively, whereas positive and negative predictive values were 100% and 88%. Overall accuracy was 95%. Pneumothorax occurred in 45 procedures (26%). Hemorrhage was recorded in 17 procedures (10%). There was higher frequency of pneumothorax in smaller lesions (35 +/- 23 vs. 50 +/- 31 mm, P = .003; odds ratio = .96) and greater depth (29 +/- 29 vs. 20 +/- 19 mm, P = .05; odds ratio = 1.03). CT signs of emphysema revealed higher incidence of hemorrhage (35% vs. 23%; P = .04; odds ratio=41.03). Other parameters were nonsignificant. CONCLUSIONS The high diagnostic yield of CT-guided TLB was not affected by lesion characteristics or emphysema. Pneumothorax rate was influenced by lesion size and depth. Hemorrhage was associated with CT signs of emphysema.