The role of beta-catenin, TGF beta 3, NGF2, FGF2, IGFR2, and BMP4 in the pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids

A subset of midgut carcinoids (MCs) result in mesenteric angiopathy (MA) and bowel infarction as a consequence of vascular compression caused by extensive mesenteric sclerosis (MS). The goal of this study was to determine whether the level of expression of several fibrosing-related growth factors was related to the finding of MA and/or MS in MCs. Eighteen cases of MC, 6 with both extensive MS and MA (group I), 5 with extensive MS only (group II), and 7 with ordinary MS only (group III), were analyzed for immunoexpression of beta-catenin, transforming growth factor-beta 2 (TGF beta 2), nerve growth factor 2 (NGF2), fibroblast growth factor 2 (FGF2), insulin growth factor receptor (IGFR), and bone morphogenic protein 4 (BMP4) in formalin-fixed, paraffin-embedded sections. Standard immunohistochemical technique was used following antigen retrieval. Immunostaining was scored semiquantitively as the product of the percentage and intensity (0 to 2+) of the immunostaining, giving a possible range of 0 to 200. One-way analysis of variance and Mann-Whitney nonparametric analyses were used for statistical analysis. The mean scores of immunoreactivity of each factor in groups I, II, and III were as follows: 135, 174, and 147 for beta-catenin (cytoplasmic reactivity only); 106, 112, and 92 for TGF beta 3; 1.67, 32, and 36 for NGF-2; 2.5, 48, and 55 for FGF-2; 19, 112, and 66 for IGFR2; 140, 45, and 52 for BMP4. There were significant differences in NGF-2 immunoreactivity between groups I and III (P = 0.0023) and in BMP4 immunoreactivity between groups I and II (P = 0.017) and groups I and III (P = 0.022). All MCs expressed high levels of membranous beta-catenin, moderate levels of TGF beta 3 and IGFR2, and low levels of FGF-2, with no significant differences seen among the groups. MCs with prominent MS and MA (group I) expressed significantly higher BMP4 than those in groups II and III, suggesting a potential role of BMP4 in the pathogenesis of MA. The level of NGF-2 expression was significantly lower in group I than in group III, possibly indicating abnormal angiogenesis in the formation of angiopathy.     

Antibodies against the extracellular enveloped virus B5R protein are mainly responsible for the EEV neutralizing capacity of vaccinia immune globulin

In the event of smallpox bioterrorism, widespread vaccination may be required. Vaccinia immune globulin (VIG) has been used to treat complications from the smallpox vaccine. While the potency of VIG was defined by its ability to neutralize intracellular mature virus, a second form of vaccinia called the extracellular enveloped virus (EEV) is critical for virus spread in the host. The B5R-protein is one of many EEV-specific proteins. Immunoprecipitation and ELISA revealed that VIG recognizes the B5R-protein. An EEV plaque-reduction assay using a recombinant vaccinia that lacks the majority of the extracellular domain of B5R showed that the ability of VIG to neutralize EEV is principally directed at B5R. In addition, absorbing out the anti-B5R antibody present in VIG through the addition of recombinant B5R protein abrogated VIG's ability to significantly neutralize wild-type EEV. This work demonstrates the prominent role of B5R as a target of EEV-neutralizing activity of human antibodies.     

Molecular Analysis of SV-40-CAL,a New Slow Growing SV-40 Strain from the Kidney of a Caged New World Monkey with Fatal Renal Disease

A decline of the Callimico goeldii population in American zoos is presently occurring due to glomerulonephritis of unknown etiology. We hypothesized that this emerging idiopathic fatal renal disease (IFRD) was caused by a virus. We therefore attempted to isolate virus from the kidneys three C. goeldi in Illinois that had IFRD. Along with other viruses, Simian virus 40 (SV-40) strain CAL was isolated. SV-40-CAL is currently the slowest-growing natural isolate of SV-40 in CV-1 cells. Inefficient SV-40-CAL growth in CV-1 cells stems from two features: a suboptimal protoarchetypal regulatory region, and a Large tumor antigen gene sequence like that of SV-40 strain T302, previously considered the slow-growing natural isolate of SV-40. To our knowledge, this is the first documented isolation of SV-40 from a New World monkey outside of a laboratory setting. Though SV-40 is renaltropic, the role of SV-40-CAL in IFRD is uncertain. Transmission of SV-40 to C. goeldii through anthropogenic activity is suspected.     

Prostate implant evaluation using tumour control probability--the effect of input parameters

In this paper, we examine the effect of treatment parameters in a model used to evaluate permanent prostate implants. The model considers the prostate to be composed of 12 sub-sections, each sub-section is assigned a cell density based on the probability of finding cancer foci in that sub-section. Wasted dose as a result of the dose rate from the implant falling below a level adequate to counteract repopulation was found to vary by 2-16% over the range of radiosensitivity and repopulation rates considered. Within the model, applied to five dose distributions, the uncertainty in the tumour control probability (TCP) values calculated for each sub-section as a result of differences in the model parameters, was found to be less than 12% in most cases for the good quality implants. The difference in TCP values was much larger for the poor quality implant. Substituting a heterogeneous distribution of alpha for a single mean value resulted in generally lower TCP values though introducing a cutoff value with a Gaussian distribution had a profound effect on the calculated values. Despite uncertainties in the parameters, the model was able to identify sub-sections at risk of local recurrence but as a result of these uncertainties, the TCP values can only be considered in the relative rather than absolute sense.     

Practical Evaluation of Methods for Detection and Specificity of Autoantibodies to Extractable Nuclear Antigens

Detection and specificity of autoantibodies against extractable nuclear antigens (ENA) play a critical role in the diagnosis and management of autoimmune disease. Historically, the detection of these antibodies has employed double immunodiffusion (DID). Autoantibody specificity was correlated with diagnoses by this technique. Enzyme immunoassays have been developed by multiple manufacturers to detect and identify the specificity ENA autoantibodies. To address the relationship of ENA detection by DID and enzyme immunoassay, the performances of five immunoassays were compared. These included two DID and three enzyme-linked immunoassays (ELISA) (both screening and individual antigen profile kits). The sample set included 83 ENA-positive, antinuclear-antibody (ANA)-positive specimens, 77 ENA-negative, ANA-positive specimens, and 20 ENA- and ANA-negative specimens. Sensitivity and specificity were calculated by two methods: first, by using the in-house DID result as the reference standard, and second, by using latent class analysis, which evaluates each kit result independently. Overall, the results showed that the ELISA methods were more sensitive for detection of ENA autoantibodies than DID techniques, but presence and/or specific type of ENA autoantibody did not always correlate with the patient''s clinical presentation. Regardless of the testing strategy an individual laboratory uses, clear communication with the clinical staff regarding the significance of a positive result is imperative. The laboratory and the clinician must both be aware of the sensitivity and specificity of each testing method in use in the clinical laboratory.A diagnosis of autoimmune disease in patients is based upon clinical history, physical examination, and laboratory detection of antinuclear antibodies (ANAs). A particular class of ANAs specific for extractable nuclear antigens (ENA) was initially described in 1959 (3). Since that time, many different anti-ENA antibodies have been described. The detection of these autoantibodies and identification of their specificity have become well-established tools for the laboratory diagnosis of several autoimmune diseases. Studies of patients with ENA antibodies have shown that detection of these autoantibodies may have both diagnostic and prognostic significance, and the detection of anti-ENA antibodies has assumed an important role in the management of these patients (5, 16, 22). In most cases, ENA testing is ordered after an initial ANA screen. The indications for use are to establish a diagnosis in patients with suggestive clinical symptoms, to exclude a diagnosis of autoimmune disease in patients with few or uncertain clinical signs, to subclassify patients with a known diagnosis, and to monitor disease activity.Testing for anti-ENA antibodies has historically relied on gel-based immunoprecipitation techniques such as double immunodiffusion (DID) and counterimmunoelectrophoresis (2, 14). The associations of specific types of ENA autoantibodies with rheumatological diseases were established by using these gel-based immunoassay techniques (15). In the last decade, enzyme-linked immunoassay (ELISA) systems have been developed to detect and determine the specificity of anti-ENA antibodies. ELISA systems permit more rapid processing of more specimens with a faster turnaround time than gel-based assays. ELISA-based methods may also have increased sensitivity for detection of ENA antibodies. However, the increased sensitivity of these ELISAs may influence the clinical relevance of their detection because diagnostic specificity may be reduced (10, 12, 17, 24). As yet, a set of reference standards with known antibody specificities against defined antigen preparations is not available for evaluation of various methods or kits. Serum reference panels are available from the Association of Medical Laboratory Immunologists (4), but the specificities of these sera were determined by consensus results from multiple laboratories. The purpose of this study was to address the relationship between DID and ELISA methods for the detection and identification of anti-ENA antibodies by evaluating and comparing two DID kits and three ELISA kits. We evaluated both screening ELISAs and monospecific antigen ELISAs to determine anti-ENA specificity.     

Diagnosis and management of acute aortic dissection, clinical and radiological follow-up

A clinical series of acute aortic dissections is presented. Twenty cases were of type A and 10 of type B. Acute severe chest pain was common, in type A also blood pressure difference between the arms and aortic regurgitation. The diagnosis was established by echocardiography, computerized tomography and/or aortography. Antihypertensive therapy was instituted immediately after diagnosis and was in type A cases followed by acute surgery unless definite contraindications existed. Of 14 surgically treated type A patients 13 survived the operation. On follow-up 1.5-3.5 years later, 12 patients were still alive and doing well, but the false channel remained open in all cases where it had not been resected totally. Only one of six conservatively treated type A patients survived. Type B dissections were operated on only if conservative therapy failed. Four of five conservatively and two of five surgically treated type B patients survived.     

Solid tumor screening recommendations in trisomy 18

The purpose of this study was to determine whether trisomy 18 patients are at an increased risk of tumor development and require formal tumor screening recommendations. A literature search of trisomy 18 patients with reports of tumors or malignancies, and compilation of all previously reported as well as new unreported cases was performed. 67 patients with trisomy 18 were found to have documented malignancies. 44 patients had hepatoblastomas, 21 patients had Wilms tumors, one patient had a functional neurogenic neoplasia, and one patient had Hodgkins lymphoma. The increasing numbers of reported malignancies in patients with trisomy 18 supports the indication for an early screening process. Specific screening recommendations are outlined consisting of imaging exams and laboratory values performed at specific intervals.     

Ultraviolettes Licht und Entstehung der Hautkrebse

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