Biomedical subjects
Publications and source records attributed to D M Evans.
Pyridone-based peptidomimetic inhibitors of recombinant human Interleukin-1 beta-converting enzyme (ICE, caspase-1) with an aminomethylene ketone activating group in the P1' position are described. Several analogues with sub-nanomolar Ki's versus ICE and improved aqueous solubility are reported.
Ten wrists in eight children with severe destructive changes in the wrist due to juvenile chronic arthritis underwent distraction lengthening of the ulna between 1983 and 1996 in an attempt to restore wrist alignment, which had not been preserved by previous splinting. Eight wrists in six patients (four female and two male) were evaluated. The average age at the time of operation was 13.8 years (range, 12-15.5). The average follow-up period was 70 months (range, 12-152). The average ulna minus deformity was between 8 and 9 mm. It was found that ulnar lengthening can be done safely and the procedure seems to stabilize the carpus, is likely to improve appearance, may improve function and in the majority of cases does eliminate the use of an external splint. Results seem to be stable for at least 3 to 5 years.
Amiloride is an inhibitor of urokinase plasminogen activator (uPA), an essential component of the plasminogen/plasmin enzyme system. Inhibition of uPA prevents the conversion of plasminogen to tumor cell surface bound plasmin which is required for initiation of the metastatic process. MATB rat mammary cancer cells were introduced into the jugular venous system of 80 Fisher 344 female rats. Amiloride at high and low dosages was administered in the drinking water at the time of, prior to or several days following the tumor cell inoculation and continued daily for 10 days post inoculation. Control rats were maintained on water alone. The middle lobe of the right lung was examined microscopically for numbers of metastases. Suppression of metastases was significant at high amiloride dosages in all groups, and at low dosage when administered prior to inoculation. We conclude that amiloride suppresses induced metastases of rat mammary cancer, the effect being dose- and time-dependent.
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A case of osteoid osteoma in a young man is presented which evaded diagnosis for 9 years, and was eventually localized to the palmar aspect of the third carpometacarpal joint using the technique of registration bone scan to provide accurate localization. The lesion was removed with complete relief of pain.
Alcoholics with depressive symptoms score > or = 10 on the Beck Depression Inventory (A.T. Beck, C. H. Ward, M. Mendelson, J. Mock, & J. Erbaugh, 1961) received 8 individual sessions of cognitive-behavioral treatment for depression (CBT-D, n = 19) or a relaxation training control (RTC; n = 16) plus standard alcohol treatment. CBT-D patients had greater reductions in somatic depressive symptoms and depressed and anxious mood than RTC patients during treatment. Patients receiving CBT-D had a greater percentage of days abstinent but not greater overall abstinence or fewer drinks per day during the first 3-month follow-up. However, between the 3- and 6-month follow-ups, CBT-D patients had significantly better alcohol use outcomes on total abstinence (47% vs. 13%), percent days abstinent (90.5% vs. 68.3%), and drinks per day (0.46 vs. 5.71). Theoretical and clinical implications of using CBT-D in alcohol treatment are discussed.
Nitric oxide (NO), a mediator of cardiovascular homeostasis, neurotransmission, and immune function, has recently been found to have important effects in bone. Both constitutive and inducible forms of NO synthase are expressed by bone-derived cells, and cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon gamma (IFN-gamma), are potent stimulators of NO production. When combined with other cytokines, IFN-gamma markedly induces NO production, which suppresses osteoclast formation and activity of mature osteoclasts. This "superinduction" of NO is largely responsible for the selective inhibitory effect of IFN-gamma on cytokine-induced bone resorption. High concentrations of NO are also inhibitory for cells of the osteoblast lineage, and NO production appears to be partly responsible for the inhibitory effects of cytokines on osteoblast proliferation. At lower concentrations, however, NO has different effects. Moderate induction of NO potentiates bone resorption, and the constitutive production of NO at low concentrations promotes the proliferation of osteoblast-like cells and modulates osteoblast function. NO therefore appears to be an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage and represents one of the molecules produced by osteoblasts which directly regulate osteoclastic activity. Stimulation of NO production in bone by proinflammatory cytokines raises the possibility that NO may be involved as a mediator of bone disease in conditions associated with cytokine activation, such as rheumatoid arthritis, tumor associated osteolysis, and postmenopausal osteoporosis.
It has been suggested that bradykinin may play a role in stimulating cough in at least one pathological condition in humans. We have employed an animal model to investigate the possible role of this peptide in irritant-induced cough. The kinin antagonist Hoe 140 and codeine both produced dose-related inhibition of cough responses to inhalation of citric acid or bradykinin aerosols by conscious guinea pigs. The selective tissue kallikrein inhibitor CH694 inhibited cough caused by citric acid but not by bradykinin. Indomethacin pretreatment attenuated the responses to both stimuli as did phosphoramidon. It is concluded that cough produced by citric acid inhalation may be mediated, at least in part, by generation of kinins; secondary to this, a release of prostanoids also appears to participate in the response.
We have developed a series of novel, potent low molecular weight (4-600 Da) inhibitors of TK which were stable to cleavage by the enzyme and showed a high degree of selectivity for TK over several other serine proteases. Compound 7 (CH-2856) was found to reduce eosinophilia in a model of allergic inflammation. The effects observed in vivo provide further evidence for the involvement of TK and kinins in the pathophysiology of allergic diseases such as asthma.
The use of a single osteotomy combining both rotation and angulation is described, with a means of achieving the correct angle and direction of the osteotomy. Patients who have been treated by this method are presented.
We have developed an automated serial chromatographic technique for screening a library of compounds based upon their relative affinity for a target molecule. A "target" column containing the immobilized target molecule is set in tandem with a reversed-phase column. A combinatorial peptide library is injected onto the target column. The target-bound peptides are eluted from the first column and transferred automatically to the reversed-phase column. The target-specific peptide peaks from the reversed-phase column are identified and sequenced. Using a monoclonal antibody (3E-7) against beta-endorphin as a target, we selected a single peptide with sequence YGGFL from approximately 5800 peptides present in a combinatorial library. We demonstrated the applicability of the technology towards selection of peptides with predetermined affinity for bacterial lipopolysaccharide (LPS, endotoxin). We expect that this technology will have broad applications for high throughout screening of chemical libraries or natural product extracts.
Based on a tetrapeptide fragment [Pro387-Ser390] of HK we have developed a series of potent low molecular weight (5-600 Da) inhibitors of PK which are stable to the enzyme. These inhibitors show good selectivity for PK versus tissue kallikrein, thrombin and plasmin. Such inhibitors will help define the role of PK and kinins in human physiology and pathophysiology. They may also find clinical use in the treatment of diseases where kinins are important mediators.
The identification of a lead ligand from a library of compounds for a specific target requires both a selection process and a method to assess relative affinities. Using a tandem-column chromatographic technique, we have developed a novel and rapid method for determination of relative affinities for ligands binding to a specific target molecule. We demonstrate, using known ligands for the lipid A region of lipopolysaccharide, that the relative affinities of these ligands can be determined and may be used to characterize the competitive interaction between ligands for the same target. The method can be adapted toward screening of soluble libraries of peptides and small molecules and those ligands exhibiting a desired affinity can be rapidly selected for further characterization/development.
A review of the world literature regarding carcinoma of ectopic breast tissue along with the addition of one case is reported. A total of 90 cases of carcinoma of ectopic breast tissue were found, 64 of which occurred in the axilla. The combined survival beyond the 4-year post-treatment period was 9.4%. No survival advantage was found for radical or modified radical mastectomy over that of local excision combined with axillary dissection or radiation. The addition of radiation therapy to either type of mastectomy provided no additional benefit. The correct preoperative diagnosis was rarely made. Outcome was reported in 42 cases; 28 survived longer than 1 year, with 12 recurrences at the time of reporting, and 6 were alive with no evidence of disease at 4 years or longer. Improved prognosis requires diagnostic suspicion and early biopsy of unidentified lesions of the axilla or embryonic milk line.
A 21-year-old man is reported in whom flap tissue was required to reconstruct the face and nose following burns. The whole of both forearms were used as radial forearm flaps for both cheeks, both lower eyelids, the right upper eyelid, upper and lower lips and chin. A Tagliacozzi arm flap and a dorsalis pedis flap were used for the nose. The ears were resurfaced using grafted skin along the line of the superficial temporal arteries. No thinning of the flaps was required and some facial muscle attachments to the forearm deep fascia led to more recovery of facial movement than might be expected with a flap reconstruction.
A new incision is described for the correction of radial club hand. By the use of a bilobed flap, redundant skin is transferred from the ulnar side of the wrist to the radial side, where there is tension as the wrist becomes straight. The flap has been shown to be safe and effective in six consecutive cases, and access to the wrist and surrounding soft tissue structures is excellent.
OBJECTIVE: Social learning theory models of alcohol use have assumed an increasingly influential role in recent years. Despite their growing popularity, research on social learning theory models has focused almost exclusively on establishing the independent links among particular aspects of theory and indices of alcohol use and abuse. In response to the need for research that incorporates multiple aspects of theory into a testable framework, this article endeavored to replicate and extend the Copper et al. study in a college sample (Cooper, Russell and George, J. Abnorm. Psychol. Vol. 97, pp. 218-230, 1988). METHOD: Subjects were 157 college student volunteers from a large midwestern university. Standard hierarchical multiple regression analyses were used to examine both the simultaneous and incremental contributions of self-efficacy judgments, alcohol expectancies and coping responses to dependent measures of alcohol use and alcohol-related problem behaviors. RESULTS: Collectively, 22% of the variance in subjects' self-reported use of alcohol and greater than 50% of the variance in subjects' endorsement of alcohol-related problems was explained. Despite considerable overlap among the constructs measured, analyses also demonstrated that each variable accounted for significant and unique variance in the prediction of the criteria. CONCLUSIONS: These results provide considerable support for the application of social learning theory principles to the drinking practices of collegiate youth. In particular, the salience of social learning theory constructs as relevant risk factors was highlighted, as lower self-efficacy judgments, positive alcohol expectancies and reliance avoidant, emotion-focused coping strategies were significantly associated with increased alcohol consumption levels and greater endorsement of alcohol-related problem behaviors.