The effect of observer experience on magnetic resonance imaging interpretation and localization of triangular fibrocartilage complex lesions.

This study investigates the effect of experience of the interpreter on the ability of magnetic resonance imaging (MRI) to identify the presence and anatomic location of a triangular fibrocartilage complex (TFCC) lesion. Fifty-one patients who underwent wrist arthroscopy with preoperative MRI studies were reviewed retrospectively. Two radiologists with different levels of training and experience evaluated the MRI scans in a blinded manner. The sensitivity rates of the 2 observers for detection of TFCC lesions were 86% and 80%. The specificity rates were 96% and 80%. The accuracy rates for prediction of a TFCC tear were 83% and 61% for the 2 observers. The correct location of a TFCC lesion was predicted by the more experienced observer for 12 of 19 central, 3 of 4 radial, and 6 of 12 peripheral lesions. The less experienced observer correctly identified 8 of 19 central, 2 of 4 radial, and 2 of 12 peripheral tears. The overall accuracy rates for prediction of a TFCC lesion and its location were 69% and 37%. Our data indicate that the published accuracy rates for prediction of TFCC lesion location may be reproducible only in very specialized centers.

Developing and implementing a comprehensive program for children and adolescents with eating disorders.

TOPIC: Treatment of eating disorders in children and adolescents across a continuum of care. PURPOSE: To describe the development and implementation of a comprehensive pilot program for children and adolescents with eating disorders. SOURCES: Published literature and clinical experience. CONCLUSIONS: The pilot program to provide comprehensive care to children and adolescents has been successful. As of November 2000, the inpatient modal eating disorder census has been 4 (highest = 10, lowest = 1). With the focus on prevention and early intervention, the multidisciplinary team continues to educate the public and providers.

Difluoro ketone peptidomimetics suggest a large S1 pocket for Alzheimer's gamma-secretase: implications for inhibitor design.

The final step in the generation of the amyloid-beta protein (Abeta), implicated in the etiology of Alzheimer's disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by gamma-secretase. Although considered an important target for therapeutic design, gamma-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alcohol transition-state analogue inhibitors suggest that gamma-secretase is an aspartyl protease with loose sequence specificity. To further characterize the active site of gamma-secretase, we prepared a series of difluoro ketone peptide analogues with varying steric bulkiness in the P1 position and tested the ability of these compounds to inhibit Abeta production in APP-transfected cells. Incorporation of bulky, aliphatic P1 side chains, such as sec-butyl or cyclohexylmethyl, led to increased gamma-secretase inhibitory potency, suggesting a large S1 pocket to accommodate these substituents and providing further evidence for loose sequence specificity. The cyclohexylmethyl P1 substituent allowed N-terminal truncation to a low-molecular-weight compound (<600 Da) that effectively blocked Abeta production (IC(50) approximately 5 microM). This finding suggests that optimal S1 binding may allow the development of potent inhibitors with ideal pharmaceutical properties. Moreover, a difluoro alcohol analogue with a cyclohexylmethyl P1 substituent was equipotent with its difluoro ketone counterpart, providing strong evidence that gamma-secretase is an aspartyl protease. All new analogues inhibited total Abeta and Abeta(42) production with the same rank order of potency and increased Abeta(42) production at low concentrations, providing further evidence for distinct gamma-secretases that are nevertheless closely similar with respect to active site topology and mechanism.

Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease.

The amyloid beta-protein (Abeta), implicated in the pathogenesis of Alzheimer's disease (AD), is a proteolytic metabolite generated by the sequential action of beta- and gamma-secretases on the amyloid precursor protein (APP). The two main forms of Abeta are 40- and 42-amino acid C-terminal variants, Abeta40 and Abeta42. We recently described a difluoro ketone peptidomimetic (1) that blocks Abeta production at the gamma-secretase level [Wolfe, M. S., et al. (1998) J. Med. Chem. 41, 6-9]. Although designed to inhibit Abeta42 production, 1 also effectively blocked Abeta40 formation. Various amino acid changes in 1 still resulted in inhibition of Abeta40 and Abeta42 production, suggesting relatively loose sequence specificity by gamma-secretase. The alcohol counterparts of selected difluoro ketones also lowered Abeta levels, indicating that the ketone carbonyl is not essential for activity and suggesting that these compounds inhibit an aspartyl protease. Selected compounds inhibited the aspartyl protease cathepsin D but not the cysteine protease calpain, corroborating previous suggestions that gamma-secretase is an aspartyl protease with some properties similar to those of cathepsin D. Also, since the gamma-secretase cleavage sites on APP are within the transmembrane region, we consider the hypothesis that this region binds to gamma-secretase as an alpha-helix and discuss the implications of this model for the mechanism of certain forms of hereditary AD.

Outcome of reoperation for carpal tunnel syndrome.

One hundred thirty-one patients with reoperation for carpal tunnel syndrome were followed for a mean of 11 years. Reoperation failed in 15 patients, necessitating a third operation. Satisfaction, symptom severity, and functional status scores were assessed with a standardized questionnaire in the other 116 patients. Patients with normal findings on preoperative nerve conduction studies, those who filed for compensation, and those who had pain in the distribution of the ulnar nerve had significantly worse results. Those with abnormal findings on nerve conduction studies who had not filed for compensation had the best symptom and function scores and satisfaction at latest follow-up examination; those with normal findings on nerve conduction studies who had filed for compensation had the poorest outcome. Although most patients were satisfied with the overall outcome, many reported residual symptoms; in addition to the 15 patients who required a third operation, 22 patients were dissatisfied with the final result.

The proliferative and synthetic response of isolated calvarial bone cells of rats to cyclic biaxial mechanical strain.

Isolated bone cells from the calvaria of newborn rats were grown in monolayer on polyurethane membranes in specially constructed culture chambers. These were subjected to cyclic biaxial mechanical strains of 0.02 per cent (200 microstrain), 0.04 per cent (400 microstrain), and 0.1 per cent (1000 microstrain) at a frequency of one hertz for periods ranging from fifteen minutes to seventy-two hours. DNA content, an index of proliferation, was significantly increased at a strain of 0.04 per cent applied for fifteen minutes and for twenty-four and forty-eight hours. DNA content was not increased at the other amplitudes of strain that were evaluated, nor was it increased after prolonged mechanical stimulation for forty-eight hours or longer. Synthesis of collagen, non-collagenous protein, and proteoglycan, as well as activity of alkaline phosphatase, all indicators of macromolecular synthesis, were significantly decreased at a strain of 0.04 per cent applied for fifteen minutes and for twenty-four, forty-eight, and seventy-two hours. Macromolecular synthesis was not affected by the other amplitudes of strain that were evaluated in this study. At a strain of 0.04 per cent, prostaglandin E2 content was significantly increased after five, fifteen, and thirty minutes of mechanical stimulation, whereas net cAMP content did not change significantly. This suggests that the described cellular events (increased proliferation and decreased macromolecular synthesis) that occur secondary to mechanical strain are mediated, at least in part, by prostaglandin E2.