Number, fixation properties, dye-binding and protease expression of duodenal mast cells: comparisons between healthy subjects and patients with gastritis or Crohn's disease

There is an accumulation of evidence to suggest that mast cells may play a key role in gastrointestinal inflammation. We have investigated the numbers and heterogeneity in staining properties of mast cells in biopsies of the duodenum of normal subjects (n = 10), and of normal duodenum from patients with Crohn's disease of the ileum and/or colon (n = 7) or with Helicobacter-associated gastritis of the antrum/corpus (n = 6). In normal donors, two subsets of mast cells, one located in the duodenal mucosa and the other in the submucosa, were clearly distinguished by their morphology and dye-binding properties. Whereas submucosal mast cells stained metachromatically with Toluidine Blue after neutral formalin fixation and emitted a yellow fluorescence after staining with Berberine sulphate, those in the mucosa were invisible using these stains. In patients with gastritis or Crohn's disease, there were marked changes in the numbers of mucosal mast cells compared with control subjects even though the duodenal biopsies were from apparently uninvolved tissue. Gastritis was associated with increased mucosal mast cell numbers (controls: 187 +/- 23 cells mm-2; gastritis: 413 +/- 139 cells mm-2; p = 0.0004), but mean mucosal mast cell counts in the uninvolved duodenum of Crohn's patients were actually decreased (34 +/- 30 cells mm-2, p = 0.0147). The clear differentiation between mucosal and submucosal mast cells on the basis of metachromasia with Toluidine Blue was not seen in biopsies from the patients with gastritis or Crohn's disease. Previous studies which have suggested that there are no distinct mucosal and submucosal mast cell subsets in the human intestine may, therefore, have been affected by the use of tissue from diseased subjects. Heterogeneity in the expression of mast cell tryptase and chymase was seen by immunohistochemistry using specific antibodies, but the relative numbers of mast cell subsets were critically dependent on the methods used. Using a sensitive staining procedure, the majority of mucosal mast cells stained positively for chymase as well as for tryptase, an observation confirmed by immunoelectron microscopy and immunoabsorption studies. Our findings suggest that early stages in intestinal inflammation may be reflected in changes in mast cell numbers and in their staining properties, and call for a reappraisal of mast cell heterogeneity in the human intestinal tract.     

Ultrasound surveillance for asymptomatic deep venous thrombosis after total joint replacement

Prospective data on 202 consecutive patients who had a total of 123 total hip and ninety-four total knee arthroplasties were collected from two university medical centers. The findings of routine surveillance for deep venous thrombosis performed with ascending contrast venography were compared with those of surveillance with duplex ultrasonography complemented with color-flow Doppler imaging. All of the studies were performed between the third and seventh postoperative days. Of the 202 patients (342 extremities) who were examined, fifty-five (27 per cent) were found to have deep venous thrombosis; fifty-two (95 per cent) of the thrombi were in the calf and three (5 per cent) were in the proximal veins. All of the thrombi were clinically asymptomatic and all were nonocclusive, allowing passage of contrast medium around an intraluminal filling defect. Duplex ultrasonography with color-flow Doppler imaging correctly identified two of the three proximal thrombi and five of the fifty-two thrombi in the calf (sensitivity, 10 per cent). The sensitivity for the detection of thrombi in the calf was zero of sixteen at one of the institutions involved in the study and 14 per cent (five of thirty-six) at the other. There were two false-positive findings on ultrasonographic examination; one involved a proximal thrombus and one, a distal thrombus. We believe that the interinstitutional variability and insensitivity of duplex ultrasonography with color-flow Doppler imaging for the detection of asymptomatic deep venous thrombi in the calf after total joint replacement make it unreliable as a routine surveillance tool after total hip or knee arthroplasty.     

Prosthetic replacement of the inferior vena cava for malignancy

PURPOSE: Invasion of the inferior vena cava (IVC) by tumor is generally considered a criterion of unresectability. This study was designed to review the outcomes of a strategy of aggressive resection of the vena cava to achieve complete tumor resection coupled with prosthetic graft placement to re-establish caval flow. METHODS: Retrospective review of patients treated at a university referral center. Ten patients (mean age 54; eight females, two males) underwent tumor resection that involved circumferential resection of the IVC and immediate prosthetic replacement with ringed polytetrafluoroethylene (PTFE) grafts ranging in diameter from 12 to 16 mm. RESULTS: Seven patients had replacement of the infrarenal IVC, two of their suprarenal IVC, and one had reconstruction of the IVC bifurcation. Four of the 10 patients received preoperative chemotherapy, and none received radiotherapy. The most common (7/10) pathologic diagnosis was leiomyosarcoma arising from the IVC or retroperitoneum. Additional diagnoses included teratoma (one), renal cell carcinoma (one), and adrenal lymphoma (one). There were no perioperative deaths, and one complication (prolonged ileus) occurred. Mean length of stay was 8.1 days. Anticoagulation was not routinely used intraoperatively or postoperatively. Follow-up (mean duration = 19 months) demonstrated that survival was 80% (8/10) and 88% (7/8) of patients were free of venous obstructive symptoms. CONCLUSION: Resection of the IVC with prosthetic reconstruction allows for complete tumor resection and provides durable relief from symptoms of venous obstruction.     

Scalp autografts and hair transfer to the face in the burned child

Hair transfer from split-thickness skin grafts harvested from the scalp is not a widely reported problem. The authors present their experience with hair transfer from scalp autografts in a pediatric burn population, with particular emphasis on hair transfer to the face. They retrospectively reviewed 3307 acute and reconstructive pediatric burn admissions over a 4-year period at a single institution and identified 109 cases in which the scalp had been used as a donor site and in which the patient survived the acute burn period. Data from 73 male and 36 female patients were analyzed with respect to age, race, sex, percent total body surface area burned, graft thickness, number of scalp harvests and time between harvests, and presence of donor site alopecia. Eighteen of the 109 patients had noticeable hair growth from their scalp grafts (17 percent). Fourteen of 18 cases of hair growth involved face or neck grafts (13 percent); the remaining 4 patients had hair growth elsewhere on the body. There was no difference between the two groups (hair growth versus no hair growth) when compared by age, sex, or graft thickness. There was a correlation between larger burn size and greater incidence of hair growth. Those who had multiple harvests of the same scalp donor site were more than twice as likely to have hair transfer (9 of 34 versus 9 of 75 patients), although time between harvests was not a significant variable. Caucasian children represented 77 percent of the study population yet 100 percent of the cases of problem hair growth. Thirty-three percent of the hair growth group (6 of 18 patients) and 4 percent of the remaining patients (4 of 91) had some degree of donor site alopecia. The scalp is a reliable and valuable donor site for skin grafting in children, particularly for facial burns. The authors note a moderate incidence of hair transfer (17 percent) and propose both suggestions for prevention and recommendations for management.     

Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression

Stimulation of antitumor immune mechanisms is the primary goal of cancer immunotherapy, and accumulating evidence suggests that effective alteration of the host-tumor relationship involves immunomodulating cytokines and also the presence of costimulatory molecules. To examine the antitumor effect of direct in vivo gene transfer of murine interleukin 12 (IL-12) and B7-1 into tumors, we developed an adenovirus (Ad) vector, AdIL12-B7-1, that encodes the two IL-12 subunits in early region 1 (E1) and the B7-1 gene in E3 under control of the murine cytomegalovirus promoter. This vector expressed high levels of IL-12 and B7-1 in infected murine and human cell lines and in primary murine tumor cells. In mice bearing tumors derived from a transgenic mouse mammary adenocarcinoma, a single intratumoral injection with a low dose (2.5 x 10(7) pfu/mouse) of AdIL12-B7-1 mediated complete regression in 70% of treated animals. By contrast, administration of a similar dose of recombinant virus encoding IL-12 or B7-1 alone resulted in only a delay in tumor growth. Interestingly, coinjection of two different viruses expressing either IL-12 or B7-1 induced complete tumor regression in only 30% of animals treated at this dose. Significantly, cured animals remained tumor free after rechallenge with fresh tumor cells, suggesting that protective immunity had been induced by treatment with AdIL12-B7-1. These results support the use of Ad vectors as a highly efficient delivery system for synergistically acting molecules and show that the combination of IL-12 and B7-1 within a single Ad vector might be a promising approach for in vivo cancer therapy.     

Simultaneous acquisition of spatial harmonics (SMASH): fast imaging with radiofrequency coil arrays

SiMultaneous Acquisition of Spatial Harmonics (SMASH) is a new fast-imaging technique that increases MR image acquisition speed by an integer factor over existing fast-imaging methods, without significant sacrifices in spatial resolution or signal-to-noise ratio. Image acquisition time is reduced by exploiting spatial information inherent in the geometry of a surface coil array to substitute for some of the phase encoding usually produced by magnetic field gradients. This allows for partially parallel image acquisitions using many of the existing fast-imaging sequences. Unlike the data combination algorithms of prior proposals for parallel imaging, SMASH reconstruction involves a small set of MR signal combinations prior to Fourier transformation, which can be advantageous for artifact handling and practical implementation. A twofold savings in image acquisition time is demonstrated here using commercial phased array coils on two different MR-imaging systems. Larger time savings factors can be expected for appropriate coil designs.     

Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3' kinase were highly apoptotic, suggesting that recruitment of PI-3' kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3' kinase binding site was noted in tumors derived from the strains expressing the PI-3' kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3' kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3' kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.     

Divergent changes in survival for histological types of non-small-cell lung cancer in the southeastern area of The Netherlands since 1975

We studied the incidence and survival rates for the histological subtypes of non-small-cell lung cancer, using data from the Eindhoven Cancer Registry over the period 1975-94. The proportions with adenocarcinoma and large-cell undifferentiated carcinoma increased from 11% to 21% and from 11% to 15%, respectively, while those with squamous cell carcinoma decreased from 78% to 62%. The increase in the proportion with adenocarcinoma was only found among men. Although the overall prognosis for patients with non-small-cell lung cancer has remained unchanged, there have been divergent changes between morphological subtypes. Relative 1- and 5-year survival rates for squamous cell carcinoma have improved slightly from 48% to 51% and from 14% to 16%, respectively, because of an increase in the proportion with localized tumours, while relative 1- and 5-year survival rates for adenocarcinoma have decreased from 59% to 45% and from 28% to 18%, respectively, because of a decrease in localized tumours. The proportion with localized tumours and the relative 1-year survival for large-cell undifferentiated carcinoma (about 18% and 30% respectively) were markedly lower. The divergent trends could partly be explained by changes in the histological classification of tumours, but changes in patterns of risk and biological behaviour of adenocarcinoma cannot be excluded.     

Role of echocardiography in patients undergoing elective cardioversion of atrial fibrillation

BACKGROUND: Performance of endomyocardial biopsy (EMB) to diagnose myocarditis in patients with dilated cardiomyopathy is controversial because of a lack of evidence favoring immunosuppressive therapy. In spite of advances in heart failure treatment, dilated cardiomyopathy carries a poor prognosis, and myocardial inflammation and viral infection are potential therapeutic targets. METHODS: We used decision analysis to determine the efficacy (5-year risk reduction in mortality or transplantation) that a treatment for myocarditis would require to favor a biopsy-guided approach over conventional therapy. Literature-based estimates included prevalence of myocarditis among patients with dilated cardiomyopathy with or without borderline myocarditis (16% and 11%, respectively); probability of 5-year transplantation-free survival (55%); sensitivity (50% and 63%, respectively), specificity (95.4%), and mortality rate (0.4%) of EMB; side effects resulting in withdrawal of immunosuppressive treatment (4%); and a 6-month mortality rate for immunosuppressive treatment (0.1%). All estimates were varied to determine impact on model results (sensitivity analysis). RESULTS: A therapy that decreased the rate of death or transplantation by 12.7% and 7.1% for patients without or with borderline myocarditis, respectively, favored EMB. Sensitivity analysis indicated that therapeutic efficacy was influenced by myocarditis prevalence and biopsy-related death, but not by accuracy of biopsy or probability of immunosuppressive therapy side effects. Randomized trials powered to detect 7% and 25% reductions in death and transplantation would require 5790 and 380 end points, respectively. CONCLUSION: Decreasing the rate of death or transplantation by 7.1% offsets therapy side effects, EMB-related death, and inaccuracies in histologic diagnosis. Prospective randomized trials of treatments for myocarditis may be more feasible during periods of high prevalence or with more sensitive diagnostic techniques.