Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes

To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.     

Rapid transepithelial antigen transport in rat jejunum: impact of sensitization and the hypersensitivity reaction

BACKGROUND & AIMS: Intestine from sensitized rats develops a rapid secretory response to luminal antigen challenge that depends on activation of subepithelial mast cells. The aim of this study was to determine the timing and route of the transepithelial protein antigen transport. METHODS: Rats were sensitized to horseradish peroxidase (HRP). After 10-14 days, jejunal segments were resected, mounted in Ussing chambers, and challenged with HRP on the luminal side. RESULTS: Electron microscopy of tissue specimens fixed at 2 minutes (before mast cell activation) showed enhanced endocytic uptake of HRP in enterocytes of HRP-sensitized rats compared with ovalbumin-sensitized or saline-injected controls. At this time, HRP was distributed throughout epithelial cells and was already evident in the lamina propria. In contrast, HRP was restricted to the apical region of enterocytes in controls. At 30 minutes (after mast cell activation), in HRP-sensitized rats only, HRP was also located within tight junctions and the paracellular region between epithelial cells. Tissue conductance was increased in HRP-sensitized rats beginning 30 minutes after HRP addition and correlated with the overall flux of HRP across the tissue. CONCLUSIONS: The results show that specific sensitization enhances the initial uptake and transcytosis of antigen across intestinal epithelium. Subsequent to activation of mast cells, antigen transport is further enhanced by penetration through the paracellular pathway.     

Metacarpophalangeal joint dislocation: indications for open surgical reduction

In complex dislocations of the metacarpophalangeal joint, the volar plate is separated from the proximal phalanx and the metacarpal head is entrapped within surrounding tissue structures. These complex dislocations must be managed by open surgical reduction to reduce the dislocation and realign the volar plate. A 58-year-old male presented to the emergency department with a complex dislocation of the metacarpophalangeal joint of the left little finger, which was successfully treated by open reduction in the operating room. The indications for open reduction of metacarpophalangeal joint dislocations are reviewed.     

The herpesvirus protease: mechanistic studies and discovery of inhibitors of the human cytomegalovirus protease

This paper is a review of the literature on the possible association between osteoporosis and oral bone loss, with an emphasis on radiological studies. Such an association was first suggested in 1960. Subsequent histomorphometric and microradiographic studies showed that after the age of 50 there was a marked increase in the cortical porosity of the mandible, with this increase being greater in the alveolar bone than the mandibular body; and that with this increase in porosity, there was a concomitant decrease in bone mass, which appeared to be more pronounced in females than in males, with the loss in bone mineral content estimated to be 1.5% per year in females and 0.9% in males. These studies also demonstrated a considerable amount of variation in the amounts of cortical and trabecular bone within and among individuals. Subsequent clinical studies reported associations between the bone densities of jaws and (1) metacarpals, (2) forearm bones, (3) vertebrae and (4) femurs. These studies indicated that women had lower mandibular bone mineral content (BMC) than men and that age-related loss of bone was more pronounced in women after the age of 50 years than in men of the same age, as was the case for the rest of the body. It was suggested that systemic factors responsible for osteoporotic bone loss may combine with local factors (periodontal diseases) to increase rates of periodontal alveolar bone loss. Although not all studies found associations between osteoporosis and oral bone loss, the conclusion of this review is that such an association exists; yet additional longitudinal investigations are needed to confirm this, and before the implications of this association could be fully utilized in clinical dentistry, inexpensive methods must be developed for sensitive and specific measures of oral bone loss.     

Regional blood flow during pulsatile cardiopulmonary bypass and after circulatory arrest in an infant model

BACKGROUND: Pulsatile perfusion systems have been proposed as a means of improving end-organ perfusion during and after cardiopulmonary bypass. Few attempts have been made to study this issue in an infant model. METHODS: Neonatal piglets were subjected to nonpulsatile (n = 6) or pulsatile (n = 7) cardiopulmonary bypass and 60 minutes of circulatory arrest. Cerebral, renal, and myocardial blood flow measurements were obtained at baseline, on bypass before and after circulatory arrest, and after bypass. RESULTS: Cerebral blood flow did not differ between groups at any time and was diminished equally in both groups after circulatory arrest. Renal blood flow was diminished in both groups during bypass but was significantly better in the pulsatile group than in the nonpulsatile group prior to, but not after, circulatory arrest. Myocardial blood flow was maintained at or above baseline in the pulsatile group throughout the study, but in the nonpulsatile group, it was significantly lower than baseline during CPB prior to circulatory arrest and lower compared with baseline and with the pulsatile group 60 minutes after CPB. CONCLUSIONS: Pulsatile bypass does not improve recovery of cerebral blood flow after circulatory arrest, may improve renal perfusion during bypass but does not improve its recovery after ischemia, and may have beneficial effects on myocardial blood flow during bypass and after ischemia compared with nonpulsatile bypass in this infant model.