Inflamed fibronectin: an altered fibronectin enhances neutrophil adhesion

Recent investigations have emphasized the role of activated granulocytes in mediating vascular endothelial injury in the pathogenesis of shock lung. In vitro studies have indicated that tight adherence of the neutrophil to the endothelium is crucial for the development of cellular injury. Fibronectin is critical to cell-to- substratum and cell-to-cell interactions. Since fibronectin resides in plasma, on endothelial cell surfaces and is secreted into cell matrices, the adhesive properties of fibronectin must be modulated, lest universal cell agglomeration occur, yet be enhanced when cell attachment is appropriate. In these studies, treatment of fibronectin- coated surfaces with neutrophil release products increased the adhesion of activated neutrophils. Similarly, endothelial cells treated with neutrophil release products become a more adherent substrate for neutrophils. This enhanced adherence generated by treatment of fibronectin with neutrophil supernatants is inhibitable by heat and the lysosomal proteinase inhibitor, pepstatin-A. Neutrophil release products cause proteolytic fragmentation of fibronectin and enhanced fibronectin immunofluorescence on endothelial cells. In addition, neutrophils are more injurious to endothelial cells that have been pretreated with neutrophil release products. Neutrophils may enhance their own adherence to endothelial cells by altering fibronectin, and this altered, or "inflamed," fibronectin may serve as an amplifier of inflammation.     

Classical transplantation tolerance in the adult: the interaction between myeloablation and immunosuppression.

Allogeneic bone marrow transplantation in the neonate is an effective way of inducing permanent tolerance to donor tissue. To do the same in the immunocompetent adult requires immunosuppression to counter host-versus-graft alloreactivity. Conditioning with monoclonal antibodies (mAb) to CD4 and CD8 has been sufficient where donor and recipient are mismatched at only multiple "minor" histocompatibility loci, or at major histocompatibility complex (MHC) class I plus "minor" loci, but not where the mismatch involves the entire MHC. Tolerance across the MHC barrier requires extra conditioning with agents that happen to be both immunosuppressive and myeloablative, so obscuring the assessment of which effect is important. By using dimethylmyleran as a selective "space"-creating myeloablative agent, and CD4 plus CD8 mAb as sole immunosuppressive agents, we have been able to dissect the relative requirements for immunosuppression and myeloablation. We show here that transplantation tolerance could only be achieved when both types of agent were combined together so as to guarantee sufficient donor-type hemopoietic chimerism. We argue that the donor marrow, given sufficient space, will engraft and provide a sustained source of tolerogen overriding any host resistance that antibodies cannot control.     

A retrospective analysis of immunohistochemical staining in identification of poorly differentiated round cell and spindle cell tumors--results, reagents and costs.

Immunohistochemistry has rapidly established a significant role in diagnostic pathology. We use immunohistochemistry as an adjunct to morphological diagnosis and employ a "panel approach" to the classification of poorly differentiated tumors. This retrospective analysis was conducted to examine the efficacy of such an approach, using, as an example, the two most common categories of poorly differentiated tumors, namely, the poorly differentiated round cell tumors and spindle cell tumors. Five hundred and fifty-seven consecutive cases of such tumors, collected over a two-yr period, had been subjected to immunohistochemical staining because specific or definitive categorization of the tumor was not possible on the basis of the examination of hematoxylin and eosin stained sections. The clinical history, gross and microscopic findings, as well as the results of immunohistochemical stains were analyzed. Immunohistochemistry allowed a definitive diagnosis to be assigned in 420 cases (75.4%). It was particularly useful in identifying malignant melanoma of both epithelioid and spindle types and distinguished between melanoma, lymphoma and poorly differentiated carcinoma in 126 cases of such lesions occurring in adult lymph nodes. It was also useful in identifying tumors in small biopsies where poor cytomorphological preservation or small size precluded accurate categorization. The application of appropriately chosen panels of antibodies tailored to a narrow list of differential diagnoses helped to identify myogenous, vascular, nerve sheath and fibrocystic lesions among the group of spindle cell tumors. Immunohistochemistry provided definitive diagnoses in 70% of round cell tumors and 92% of spindle cell tumors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Should patients with asymmetrical noise‐induced hearing loss be screened for vestibular schwannomas?

Should patients with asymmetrical noise‐induced hearing loss be screened for vestibular schwannomas? The Peterborough ENT department receives many referrals for MoD personnel who have suffered hearing loss from occupational noise exposure. Those patients with asymmetrical sensorineural hearing loss are routinely screened for vestibular schwannomas by MRI scanning. Scan reports from the past 5 years have been reviewed and out of 152 scans, four revealed vestibular schwannomas giving a pick‐up rate of 2.5%, which compares favourably with other published pick‐up rates. Review of the audiograms in these cases suggests that they can be misleading in this context. The conclusion is that patients with noise‐induced asymmetrical hearing loss should be screened for acoustic neuromas.     

Chiari osteotomy and shelf augmentation in the treatment of hip dysplasia

The clinical and radiographic results of Chiari osteotomy and shelf augmentation for acetabular dysplasia in 30 hips were reported. The average age at operation was 17 years for Chiari osteotomy and 13.8 years for shelf augmentation. The mean follow-up was 7.1 years for Chiari osteotomy and 4.1 years for shelf augmentation. Of the 14 Chiari osteotomies, 12 had good results by Tonnis clinical grading and 2 had poor results. There were significant improvements in the radiographic parameters measured (p < 0.01). They included center-edge angle of Wiberg, the acetabular angle of Sharp, the percentage of femoral head coverage, and the "c/b" ratio. For the 16 shelf augmentations, there were 8 good, 2 fair, and 6 poor results. The radiographic parameters measured were also all significantly improved (p < 0.01). The final Severin grading of the hips were improved by both Chiari osteotomy and shelf augmentation.     

Computer databases for the sentinel lymph node program

At the University of California San Francisco Comprehensive Cancer Center, a computer database system was created using the FileMaker Pro database program. The system allows the clinical team to bring together data from all aspects of a multidisciplinary effort toward improving daily clinical management, for research, and ultimately, for the clinical standard of care for melanoma patients. With modest objectives during the initiation of the database, its adaptability has allowed it to become an integral link in all the efforts of the melanoma program. For the future, tapping into the immense potential of the Internet has begun to organize multicenter efforts. Through nationwide collaboration, the Sentinel Lymph Node Working Group will be able to follow, on a larger scale, the successes of the FileMaker pro database at the UCSF Comprehensive Cancer Center.     

Effects of dietary fat and a vegetable-fruit mixture on the development of intestinal neoplasia in the ApcMin mouse

The variation in colorectal cancer (CRC) incidence worldwide strongly suggests a role for dietary influences. Based on epidemiological data, protective effects of vegetables and fruit intake on CRC are widely claimed, while other data indicate a possible increased CRC risk from (higher) dietary fat intake. Therefore, we have investigated single and interactive effects of dietary fat and a vegetable-fruit mixture (VFM) in the ApcMin mouse, a mouse model for multiple intestinal neoplasia. In this study, four different diets (A-D) were compared, which were either low in fat (20% energy diets A/B) or high in fat (40% energy diets C/D). In addition, 19.5% (wt/wt) of the carbohydrates in diets B and D were replaced by a freeze-dried VFM. The diets were balanced so that they only differed among each other in fat/carbohydrate content and the presence of specific plant-constituents. Because the initiation of intestinal tumors in ApcMin mice occurs relatively early in life, exposure to the diets was started in utero. Without the addition of VFM, mice maintained at a high-fat diet did not develop significantly higher numbers of small or large intestinal adenomas than mice maintained at a low-fat diet. VFM added to a low-fat diet significantly lowered multiplicity of small intestinal polyps (from 16.2 to 10.2/mouse, 15 animals/group), but not of colon tumors in male ApcMin mice only. Strikingly, addition of VFM to female mice maintained on a low-fat diet and to both sexes maintained on a high-fat diet significantly enhanced intestinal polyp multiplicity (from 16.5 to 26.7 polyps/mouse). In conclusion, our results indicate that neither a lower fat intake nor consumption of VFM included in a high-fat diet decreases the development of polyps in mice genetically predisposed to intestinal tumor development.      

Characterization of breast lesion morphology with delayed 3DSSMT: an adjunct to dynamic breast MRI

The purpose of the study was to determine the sensitivity and specificity of various morphologic criteria in distinguishing malignant from benign breast lesions using a new sequence (3DSSMT) performed immediately after dynamic breast MRI. 3DSSMT combines a water-selective spectral-spatial excitation and an on-resonance magnetization transfer pulse with three-dimensional spoiled gradient-echo imaging. Morphologic features of 87 pathologically confirmed lesions were analyzed. The presence of either skin thickening, or a combination of a spiculated or microlobulated border, with a rim, ductal, linear, or clumped enhancement pattern was 94% specific and 54% sensitive for malignancy. Conversely, the presence of either a perfectly smooth border, a well-defined margin, non-enhancing internal septations, or a macrolobulated border was 97% specific and 35% sensitive for a benign diagnosis. In conclusion, delayed 3DSSMT discriminates a significant number of benign and malignant breast lesions; it has the potential to improve the diagnostic accuracy of dynamic breast MRI.