Tau released from paired helical filaments with formic acid or guanidine is susceptible to calpain-mediated proteolysis

Paired helical filaments (PHFs), a characteristic neuropathologic finding in Alzheimer's disease brain, are abnormal fibrillary forms of hyperphosphorylated tau (PHF-tau), which have been shown to be highly resistant to calpain digestion. Either excessive phosphorylation or fibrillary arrangement of tau proteins in PHFs may play a role in proteolytic resistance by limiting access to calpain recognition/digestion sites. To determine the contribution of the fibrillary conformation, isolated PHFs were subjected to treatment with either formic acid or guanidine. Both procedures effectively abolished the fibrillary structure of PHF but preserved PHF-tau immunoreactivity using a panel of antibodies that recognize nonphosphorylated and phosphorylated epitopes. These treatments also significantly increased the sensitivity of PHF-tau polypeptides to calpain proteolysis as shown by significant decreases in the half-life (t(1/2)) from the infinite with native PHF to 44 min and 4.4 min in formic acid- or guanidine-treated samples, respectively. In contrast, the sensitivity of normal fetal tau (3.4 min) was either decreased (5.9 min) or unaffected (3.6 min) by similar treatment. Our results indicate that after guanidine treatment, the sensitivity of PHF to calpain resembles that of fetal tau. These results strongly suggest that the fibrillary structure of PHF-tau, rather than hyperphosphorylation, is the major factor responsible for the resistance of abnormal filaments to calpain-mediated proteolysis.     

Helicobacter pylori attachment to gastric cells induces cytoskeletal rearrangements and tyrosine phosphorylation of host cell proteins

The consequences of Helicobacter pylori attachment to human gastric cells were examined by transmission electron microscopy and immunofluorescence microscopy. H. pylori attachment resulted in (i) effacement of microvilli at the site of attachment, (ii) cytoskeletal rearrangement directly beneath the bacterium, and (iii) cup/pedestal formation at the site of attachment. Double-immunofluorescence studies revealed that the cytoskeletal components actin, alpha-actinin, and talin are involved in the process. Immunoblot analysis showed that binding of H. pylori to AGS cells induced tyrosine phosphorylation of two host cell proteins of 145 and 105 kDa. These results indicate that attachment of H. pylori to gastric epithelial cells resembles that of enteropathogenic Escherichia coli. Coccoid H. pylori, which are thought to be terminally differentiated bacterial forms, are capable of binding and inducing cellular changes of the same sort as spiral H. pylori, including tyrosine phosphorylation of host proteins.     

The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics

The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial examining the effect of a low-fat (20% of total energy intake), high-fiber (18 g/1000 kcal), high-vegetable and -fruit (5-8 daily servings) dietary pattern on the recurrence of adenomatous polyps of the large bowel, precursors of most colorectal malignancies. Eligibility criteria include one or more adenomas removed within 6 months of randomization; complete nonsurgical polyp removal and complete colonic examination to the cecum at the qualifying colonoscopy: age 35 years of more; no history of colorectal cancer, inflammatory bowel disease, or large bowel resection; and satisfactory completion of a food frequency questionnaire and 4-day food record. Of approximately 38,277 potential participants with one or more polyps recently resected, investigators at eight clinical centers randomized 2,079 (5.4%; 1,037 in the intervention and 1,042 in the control arm) between June 1991 and January 1994, making the PPT the largest adenoma recurrence trial ever conducted. Of PPT participants, 35% are women and 10% are minorities. At study entry, participants averaged 61.4 years of age; 14% of them smoked, and 22% used aspirin. At the baseline colonoscopy, 35% of participants had two or more adenomas, and 29% had at least one large (> of = 1 cm) adenoma. Demographic, behavioral, dietary, and clinical characteristics are comparable across the two study arms. Participants have repeat colonoscopies after 1 (T(1)) and 4 (T(4)) years of follow-up. The primary end point is adenoma recurrence; secondary end points include number, size, location, and histology of adenomas. All resected lesions are reviewed centrally by gastrointestinal pathologists. The trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate. The primary analytic period, on which sample size calculations were based is 3 years (T(1) to T(4)), which permits a 1-year lag time for the intervention to work and allows a more definitive clearing of lesions at T(1), given that at least 10-15% of polyps may be missed at baseline. The final (T(4)) colonoscopies are expected to be completed in early 1998.     

Morbidity during the first year of life in small for gestational age infants

OBJECTIVE: To study the effect of early postnatal dexamethasone (days 1-3) on the incidence and severity of chronic lung disease in preterm infants with respiratory distress syndrome. METHODS: A multicentre, randomised, placebo controlled, blinded study was carried out in 18 neonatal intensive care units in Israel. The primary outcome measure was survival to discharge without requirement for supplemental oxygen therapy beyond 28 days of life. The secondary outcome measures were requirement for mechanical ventilation at 3 and 7 days, duration of ventilation or oxygen therapy, need for subsequent steroids for established chronic lung disease and incidence of major morbidities. RESULTS: The study consisted of 248 infants (dexamethasone n = 132; placebo n = 116). No differences were found in the outcome variables except for a reduction in requirement for mechanical ventilation at age 3 days in treated infants (dexamethasone 44%, placebo 67%; P = 0.001). Gastrointestinal haemorrhage, hypertension, and hyperglycaemia were more common in treated infants, but no life threatening complications, such as gastrointestinal perforation, were encountered. CONCLUSIONS: These data do no support the routine use of early postnatal steroids, but may justify further study in a selected, high risk group of infants.     

Instructional intranets in graduate medical education

Changes in medicine, medical education, and technology have influenced graduate medical education (GME) and have altered many traditional concepts of resident training. Three issues in particular have led to changes. The first is the shortage of time that academic and community physicians have to devote to medical teaching because of the demands to bring in revenue through clinical practice. The second is the limited exposure that residents have to various medical conditions due to a shift in training venues from hospitals to ambulatory care settings. Last is residents' lack of training in using information technologies. The resultant deficits the exist in GME make it more difficult for residents to practice medicine in the most efficient manner. Hence, there is a need for health care professionals' education to address the coming demands of the 21st century. Instructional computer technology can be useful in bridging this gap. Intranets, internal organizational networks, are private versions of the World Wide Web that are often available only to members of a particular organization. This paper reviews changes in medicine and medical education, describes how instructional intranets can be incorporated into GME, and discusses the impact intranet and Internet technologies can have on GME.     

Distribution of beta-amyloid precursor and B-cell lymphoma protooncogene proteins in the rat retina after optic nerve transection or vascular lesion

The expression of beta-amyloid precursor protein (APP) and B-cell lymphoma protooncogene protein (Bcl-2) in retinal cells in the rat was studied using immunocytochemistry at different times after intraorbital optic nerve transection or vascular lesion. Three hours to one month after transection of the optic nerve, a significant increase in APP and Bcl-2 immunostaining was observed in retinal Müller glia but not in retinal neurons. In contrast, injury to blood vessels that supply the eye without cutting the optic nerve resulted in a complete loss of APP and Bcl-2 immunostaining in Müller cells and an increase in immunoreactivity in distinct populations of retinal neurons. The overall pattern of APP immunostaining in Müller cells and neurons was essentially the same as that of Bcl-2 under identical experimental conditions. These results suggest that the expression of APP and Bcl-2 in retinal cells is dependent on the nature and severity of injury, and that rapid and common mechanisms are involved in regulating the expression of these molecules.     

Integration of a laser diode with a polymer-based waveguide forphotonic integrated circuits

The fabrication and characterization of BRS lasers monolithically integrated with butt-coupled polymer-based buried strip waveguides is presented. Threshold currents of lasers with one cleaved and one etched mirror facets are 15-18 mA and waveguide output powers are in excess of 5 mW at 100 mA laser driving currents and for 600 μm long waveguides. The device exhibits a total waveguide insertion loss less than 5 dB. The integrated device is potentially suitable as a building-block for photonic integrated circuits     

Critical carotid artery stenosis: diagnosis, timing of surgery, and outcome

PURPOSE: Patients with critical carotid artery stenoses have been considered to be at high risk for carotid artery occlusion necessitating urgent or emergency endarterectomy once the stenosis is identified. Included in this group of patients are those with carotid string sign or atheromatous pseudoocclusion (APO). This review was conducted to determine the impact of the severity of stenosis including APO on the treatment and outcome of patients undergoing carotid endarterectomy. METHODS: The records of 203 consecutive carotid endarterectomies performed in 197 patients were reviewed in detail. Patients were stratified into a critical stenosis group (80% to 99% diameter) and noncritical stenosis group based on noninvasive vascular laboratory and carotid arteriography results. Comparisons were performed of demographic data, atherosclerotic risk factors, carotid artery disease presentation, interval between arteriography and endarterectomy, operative details, and surgical results between the critical and noncritical groups and between patients in the critical group with and without APO. RESULTS: Carotid endarterectomies were performed on 91 critical carotid artery stenoses and 112 noncritical stenoses. The groups did not differ significantly with regards to demographics, risk factors, carotid artery disease presentation, mean back pressure, and operative use of shunt or patch closure. For the critical group the interval between arteriography and endarterectomy was 8.63 +/- 2.38 days compared with 9.64 +/- 2.14 days for the noncritical group (mean +/- SEM, p = 0.75). No patient in either group progressed to occlusion in the interval between arteriography and endarterectomy. Perioperative strokes occurred in two patients (2%) in the critical group and four patients (3.6%) in the noncritical group (p = 0.09). Likewise, no significant difference was demonstrated in these variables when comparing patients with critical carotid artery stenosis and APO with those without APO. CONCLUSIONS: The presence of a critical carotid artery stenosis including APO did not impact on the treatment or outcome of patients requiring endarterectomy nor did it imply the need for emergency intervention to prevent thrombosis. Surgical intervention can proceed after evaluation and optimization of comorbid conditions without undue concern for interval thrombosis.