The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study.

The histologic distinction between peritoneal epithelioid mesotheliomas and serous carcinomas diffusely involving the peritoneum may be difficult, but it can be facilitated by the use of immunohistochemistry and electron microscopy. D2-40 and podoplanin are two recently recognized lymphatic endothelial markers that can be expressed in normal mesothelial cells and mesotheliomas. The purpose of this study is to compare the value of these new mesothelial markers with those that are commonly used for discriminating between mesotheliomas and serous carcinomas, and also to determine the current role of electron microscopy in distinguishing between these malignancies. A total of 40 peritoneal epithelioid mesotheliomas and 45 serous carcinomas of the ovary (15 primary, 30 metastatic to the peritoneum) were investigated for the expression of the following markers: D2-40, podoplanin, calretinin, keratin 5/6, thrombomodulin, MOC-31, Ber-EP4, B72.3 (TAG-72), BG-8 (Lewis(Y)), CA19-9, and leu-M1 (CD15). All 40 (100%) of the mesotheliomas reacted for calretinin, 93% for D2-40, 93% for podoplanin, 93% for keratin 5/6, 73% for thrombomodulin, 13% for Ber-EP4, 5% for MOC-31, 3% for BG-8, and none for B72.3, CA19-9, or leu-M1. All 45 (100%) serous carcinomas were positive for Ber-EP4, 98% for MOC-31, 73% for B72.3, 73% for BG-8, 67% for CA19-9, 58% for leu-M1, 31% for keratin 5/6, 31% for calretinin, 13% for D2-40, 13% for podoplanin, and 4% for thrombomodulin. After analyzing the results, it is concluded that Ber-EP4 and MOC-31 are the best negative mesothelioma markers for differentiating between epithelioid mesotheliomas and serous carcinomas. The best discriminators among the positive markers for mesotheliomas are D2-40, podoplanin, and calretinin. From a practical point of view, Ber-EP4 and MOC-31, in combination with calretinin, and/or D2-40 or podoplanin allow the differential diagnosis to be established between mesothelioma and serous carcinoma in nearly all instances. As a clear distinction could be made between these two malignancies in all of the cases in which electron microscopy was performed, this technique can be very useful in establishing the correct diagnosis when the immunohistochemical results are equivocal or further support of a diagnosis of either mesothelioma or serous carcinoma is needed.     

Utilization of common inflammatory markers in new, symptomatic, primary care outpatients based on their cost-effectiveness.

Few studies have demonstrated the optimal usage of common inflammatory markers, alone or in combination, based on the cost-effectiveness. We analyzed the yield and cost of C-reactive protein (CRP), white blood cell count (WBC), erythrocyte sedimentation rate (ESR), sialic acid, and protein fractionation in 177 new primary care outpatients with inflammation-related symptoms. A useful result (UR) was assigned if tests contributed to a change in physician's diagnosis or decision-making. Costs of testing were calculated based on either single or simultaneous measurement. Five inflammatory markers generated 147 URs in 123 patients. CRP showed the best contribution to generation of UR, followed by sialic acid, protein fractionation, WBC, and ESR. CRP demonstrated poor correlation with WBC (r = 0.458), while sialic acid strongly correlated with total absolute amount of alpha1 and alpha2 fractions in protein fractionation (r = 0.855) and moderately with ESR (r = 0.651). The combination of CRP and WBC produced the best cost-effectiveness at a cost of Yen 1169 (US dollars 9.6 or Euro 9.7)/additional UR against CRP testing alone. Sialic acid, an automated multichannel analyzer-based test, demonstrated the favorable cost-effectiveness over ESR or protein fractionation when combined with CRP (and WBC). Our results indicate that the optimal usage of these inflammatory markers should involve careful cost-effectiveness considerations.     

Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZO/Hl)?

The New Zealand obese mouse (NZO/Hl) is characterised by hereditary obesity and type-2 diabetes, including insulin resistance, hyperinsulinaemia, and glucose intolerance. In other diabetic models, it has been revealed that the proper functioning of the glucose transporter isoform 2 (GLUT2) is essential for adequate secretion of insulin. The aim of this study was to compare the distribution of islet cells and GLUT2, as well as the expression of GLUT2-mRNA, in the pancreas of NZO mice and metabolically unimpaired NMRI (Naval Medical Research Institute) mice. Pancreas tissue was obtained from different stages of development. For molecular determination of the expression level of GLUT2-mRNA, total-RNA was extracted from the pancreas and analysed by quantitative real-time RT-PCR. All investigated NZO mice displayed increased weight, elevated hyperinsulinaemia, and slightly enhanced blood glucose levels compared with the NMRI control mice. By means of immunofluorescence microscopy drastically reduced insulin levels were detected, which might be compensated by the observed islet cell hyperplasia and hypertrophy. Furthermore, the normally peripheral localisation of the alpha-cells within islets was disturbed. By contrast, there were no changes in somatostatin cell distribution. However, considerable differences appeared with regard to GLUT2: whereas the beta-cells of NMRI mice showed dense immunostaining of the GLUT2 transporter on the cell surface, in all age groups of NZO mice, GLUT2 on the plasma membranes was reduced and dispersed in the cytoplasm. These findings agree with the molecular biological results, which displayed decreased mRNA-expression of GLUT2. In summary, the observed alteration of islet morphology and of GLUT2 expression in diabetic mice complements our previous results from a superfusion protocol and further clarifies the mechanisms of diabetogenesis in NZO mice.     

Altered apoptosis in bronchoalveolar lavage lymphocytes after allergen exposure of atopic asthmatic subjects.

The increased number of lymphocytes in airways during an asthmatic response is believed to be the result of increased recruitment of these cells. However, it is possible that a decreased apoptotic rate could also contribute to the increased number. The aim of the present study was to investigate whether allergen airway provocation influences the apoptotic phenotype of lung and peripheral blood lymphocytes (PBL) in subjects with atopic asthma. Bronchoalveolar lavage (BAL) lymphocytes and PBL from 12 asthmatic subjects previously challenged with allergen (n = 7) or saline (n = 5) were exposed to the apoptotic stimulus tributyltin (TBT) in vitro and assayed for apoptosis. Airway allergen provocation resulted in decreased sensitivity of BAL lymphocytes to TBT-induced apoptosis, with 42.2% (range 33.9-62.5%) apoptotic cells before challenge versus 23.5% (range 15.3-42.4%) after challenge, while PBL were unaffected. The increased apoptosis resistance correlated with higher numbers of Bcl-2-expressing lymphocytes. Interestingly, baseline caspase-3-like activity was significantly elevated in viable BAL lymphocytes compared with viable PBL, and was unaltered by allergen exposure. In conclusion, allergen inhalation renders bronchoalveolar lavage lymphocytes more resistant to apoptosis while peripheral blood lymphocytes were not influenced at all, indicating that the apoptotic phenotype of airway lymphocytes may play a role in asthmatic inflammation.     

Aggressive behavior linked to corticotropin-reactive autoantibodies.

BACKGROUND: Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior, but the underlying biological mechanisms are unclear. We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects. METHODS: Using enzyme-linked immunosorbent assay, we studied whether autoAbs directed against corticotropin (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), oxytocin, and vasopressin are present in serum of male subjects with conduct disorder and prisoners with history of violence. Healthy blood donors served as control subjects. RESULTS: Both conduct disorder and prisoners groups displayed strongly increased levels of ACTH-reactive immunoglobulin G (IgG) and immunoglobulin M (IgM) autoAbs compared with control subjects. Levels of oxytocin-reactive IgM autoAbs were slightly increased in both groups of aggressive subjects, whereas levels of vasopressin-reactive IgG and IgM autoAbs were lower only in conduct disorder. No differences in the levels of alpha-MSH-reactive autoAbs were found between aggressive and control subjects. CONCLUSIONS: High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.     

The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses.

Previously we derived independent estimates of the effect of the dopamine D2 receptor (DRD2) Ser311Cys polymorphism on risk for schizophrenia using fixed- and random-effects meta-analyses. Both analyses identified a significant association between the Cys allele and schizophrenia, but neither included all available data. Furthermore, genotype data were not evaluated in either analysis, thus precluding any determination of the mode of inheritance. The present study was conducted to resolve discrepancies between the existing meta-analyses, and provide more comprehensive and accurate estimates of the nature and magnitude of the influence of the Ser311Cys polymorphism on risk for schizophrenia. All discrepancies between the two sets of previously meta-analyzed studies were identified and resolved to the mutual satisfaction of the authors, and the final dataset was analyzed independently by fixed- and random-effects meta-analyses. A total of 27 samples, comprising 3,707 schizophrenia patients and 5,363 control subjects, were included in the analyses of allelic association, while smaller numbers of studies and subjects were included in each of the genotypic association analyses. A significant effect of the Cys allele was observed under both fixed-effects (odds ratio [OR] = 1.4; P = 0.002) and random-effects (OR = 1.4; P = 0.007) models. Cys/Ser heterozygotes were at elevated risk for schizophrenia when compared to Ser/Ser homozygotes (fixed- and random-effects OR = 1.4, p(s) or= 0.948). There was no evidence of heterogeneity, excessive influence of any single study, or publication bias in any of the analyses, suggesting that the effect of this DRD2 polymorphism on schizophrenia risk is reliable and uniform across populations, and our estimates of its magnitude are robust and accurate.     

Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: a retrospective analysis of potential risk factors.

PURPOSE: In children with locally advanced or recurrent malignant tumours, prognosis can be improved by regional deep hyperthermia (RHT) in combination with platin-based chemotherapy. However, because of the increasing number of patients that achieve long-time remission with this therapy, it is necessary to evaluate long-term sequelae of thermochemotherapy. During the years 1993-2004 one has observed avascular osteonecrosis (AON) of the femoral head after RHT in seven children with pelvic germ cell tumours or rhabdomyosarcomas. METHODS: Although AON may develop in patients with malignancies treated with chemo- or radiotherapy alone, RHT might nevertheless contribute to the occurrence of AON. In order to determine potential risk factors for AON after RHT, this study analysed the relationship of AON to the patient's age, medical history and treatment parameters such as thermal dose equivalent and power output. RESULTS AND CONCLUSIONS: In the present study AON was associated with young age as well as intensity of hyperthermia indicated by high power levels that exceed 20 W per kg body weight and/or application of eight or more heat sessions as well as additional radiotherapy. Based on this observation, it was assumed that an optimized three dimensional thermal field modelling may be helpful to avoid hazardous temperatures in the femoral heads during RHT treatment and to reduce AON of the femoral heads.     

LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.     

Bifid mandibular canal.

PURPOSE: To determine the incidence and characteristics of bifid mandibular canals. METHODS: A retrospective study was performed using panoramic radiographs of 2012 patients subjected to dental treatment in the Dental Clinic of the Valencia University Dental School (Valencia, Spain) between 1996 and 1999. The goal was to investigate the presence of double mandibular canals. RESULTS: The extraoral panoramic radiographs revealed a total of 7 images suggestive of bifid canals. Mandibular computed tomography revealed the existence of this anatomic variant in 2 of 3 patients. An analysis was performed on the incidence of this type of image in extraoral panoramic radiography, its possible interpretations, and the clinical implications of bifid mandibular canals. CONCLUSIONS: In this study, 0.35% of canals were bifid. All cases were in women.     

Predictive factors of stroke in patients undergoing coronary bypass grafting: statins are protective.

BACKGROUND: Despite major improvement in surgical techniques and intensive care management, stroke remains one of the most devastating complications of coronary artery bypass grafting (CABG). We aimed to determine factors predicting the occurrence of stroke during CABG. A special interest was focused on preoperative therapies. METHODS: We prospectively enrolled 810 consecutive candidates for CABG alone in a specific database, including all pre- and perioperative data (history, clinical, therapeutic, cardiac catheterization, surgical and intensive care data). Univariate tests and then multiple logistic regression analysis were used to determine independent predictive factors. RESULTS: During the first postoperative month, stroke occurred in 11 cases and transient ischemic attack (TIA) in 4 additive cases (cumulative rate: 1.85%). After the multivariate analysis, the following factors remained significant (p<0.05) in the predictive model, with corresponding odds ratios between brackets: redo cardiac surgery (7.45), unstable cardiac status (4.74), past history of cerebrovascular disease (4.14), past history of peripheral arterial disease (3.55), whereas the presence of preoperative statins was protective (0.24, 95% IC: 0.07-0.78). The addition of perioperative data (aortic calcification, postoperative arrhythmia, on/off-pump surgery) did not change the final predictive model. CONCLUSION: To our knowledge, this is the first real-world observational report highlighting the interest of statins for the prevention of stroke in the very special situation of CABG. Even though according to randomized trials coronary patients have a benefit from these drugs, a special level of interest should be directed towards those presenting the above-mentioned risk factors.