Leukocyte rolling in vivo is mediated by P-selectin glycoprotein ligand- 1

Leukocyte rolling, an early and important step in the inflammatory response, is mediated by the selectin family of adhesion molecules. The selectins bind with low affinity to sialylated and fucosylated glycans such as sialyl Lewisx (sLex), but bind with high affinity to only a few specific glycoproteins on cell surfaces. One such glycoprotein is P- selectin glycoprotein ligand-1 (PSGL-1). The relative contributions of low- and high-affinity ligands to leukocyte rolling in vivo are unknown. We show here that a monoclonal antibody to PSGL-1 (PL1) dramatically reduces rolling of human polymorphonuclear neutrophils (PMN) and promyelocytic HL-60 cells in venules of acutely exteriorized rat mesentery. Control PMN and HL-60 cell rolling flux fractions were 39% +/- 3% and 33% +/- 5%, which were reduced by PL1 to 7% +/- 2% and 6% +/- 2%, respectively. Similar reductions were seen with F(ab) fragments of PL1. PL1-treated PMN rolled at significantly higher mean velocities than untreated PMN owing to intermittent rather that continuous interactions. These findings show that interaction of P- selectin with PSGL-1 is required for rolling of myeloid cells in mesenteric venules at physiologic shear stress in vivo.     

Performance on the internal medicine second-year residency in-training examination predicts the outcome of the ABIM certifying examination

For 223 residents from eight teaching hospitals, the results of the second-year in-training examination and the first-sitting certifying examination of the American Board of Internal Medicine were highly correlated. The results of the in-training examination can serve residents as an important measure of their preparedness for certification and can be useful in identifying the need for more intensive self-study strategies during the subsequent one and a half years     

Progressive Metaplastic and Dysplastic Changes in Mouse Pancreas Induced by Cyclooxygenase-2 Overexpression

Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.     

The relation between smoking and sleep: the influence of smoking level, health, and psychological variables

The relation between smoking and sleep was examined in a randomly selected sample of 769 individuals (379 men and 390 women, ages 20 to 98). Participants completed 2 weeks of sleep diaries, provided a global report on their sleep, indicated the number of cigarettes smoked per day, and supplied information on health, depressive symptoms, anxiety, and caffeine and alcohol use. After controlling for demographic, health, psychological, and behavioral variables, light smoking (< 15 cigarettes per day), but not heavier smoking, was associated with self-reported chronic insomnia and reduced sleep diary total sleep time and time in bed. Smokers did not differ significantly from nonsmokers on diary measures of sleep-onset latency, number of awakenings during the night, wake time after sleep onset, or sleep efficiency.     

Relationship between intermittent claudication, inflammation, thrombosis, and recurrent cardiac events among survivors of myocardial infarction

BACKGROUND: Among coronary disease patients, concomitant peripheral arterial disease is a potent risk factor for future cardiac events and mortality. We sought to determine clinical and biochemical markers that might better elucidate the relationship between coronary and peripheral arterial disease. METHODS: Two months after an index myocardial infarction, 1045 patients provided detailed medical histories and underwent blood testing for selected hemostatic, lipid, and inflammatory markers. Patients were then followed up prospectively for a mean of 26 months. RESULTS: Compared with individuals without intermittent claudication (n = 966), those with claudication (n = 78) (information was unavailable for 1 individual) were significantly older and demonstrated an increased frequency of diabetes mellitus, tobacco use, prior cardiac and cerebrovascular events, and depressed left ventricular function. Individuals with claudication were less likely to receive beta-blocker therapy after the index infarction. Individuals with claudication had evidence of enhanced procoagulant and proinflammatory states manifested by relative elevations in plasma fibrinogen, D-dimer, C-reactive protein, and serum amyloid A concentrations. During follow-up, the presence of claudication was associated with an independent 2-fold increase in the combined end point of death or nonfatal cardiac event (38.5% vs 17.8%, P =.001) and a 5-fold increase in cardiac mortality (19.2% vs 3.6%, P =.001). Patients with intermittent claudication who were not treated with beta-blockers had a significant 3-fold mortality excess relative to those receiving beta-blockers. CONCLUSIONS: Following myocardial infarction, the added presence of intermittent claudication is associated with heightened procoagulant and proinflammatory states and an underuse of beta-blocker therapy and is a strong independent predictor of recurrent cardiovascular events.     

Structural changes at cut ends of earthworm giant axons in the interval between dye barrier formation and neuritic outgrowth

We describe structural changes at the cut ends of invertebrate myelinated earthworm giant axons beginning with the formation of a dye barrier (15 minutes posttransection or postcalcium addition) and ending with the formation of a neuritic outgrowth (2-10 days posttransection). The morphology of the cut end, and the location and morphological configuration of the dye barrier, were assessed by time-lapse confocal, fluorescence microscopy and by electron microscopy. During the interval from 15 to 35 minutes postcalcium addition, the dye barrier continuously migrated away from a cut axonal end; the dye barrier then remained stable for up to 5 hours. The size, packing density, and arrangement of membranous structures were correlated with changes in the dye barrier from 15 to 35 minutes postcalcium addition. During this interval, uptake of an externally placed hydrophilic dye by these membranous structures was also variable. After 35 minutes postcalcium addition, the membranous structures remained stable until they completely disappeared between 1 and 2 days posttransection. The disappearance of membranous structures always preceded neuritic outgrowth, which only arose from cut axonal ends. These results demonstrate that the dye barrier and associated membranous structures, which form after transection of earthworm giant axons, are very dynamic in the short term (35 minutes) with respect to their location and morphological configuration and suggest that axolemmal repair must be completed before neuritic outgrowth can occur.     

Treatment assessment of learning disabled children: is there a role for frequently repeated neuropsychological testing?

Test/retest practice effects among learning disabled (LD) and non-learning disabled (NLD) children were examined using the Halstead Category Test. Two experimental paradigms were performed. The first compared subjects on successive trials. The second paradigm used a control group to compare second trial performance of the experimental group with first trial performance of the controls. Both paradigms provide evidence of the relative inability of LD children to profit from practice. It is suggested that neuropsychological data can be used for short term test/retest as one indication of the efficacy of treatment intervention for learning disabled children without the practice effect being a significantly confounding variable.