Pyridazinodiazepines as a high-affinity, P2-P3 peptidomimetic class of interleukin-1 beta-converting enzyme inhibitor.
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Animals↗
Biomedical subjects
B E Miller
Publications and source records attributed to B E Miller.
Prognostic factors in adult granulosa cell tumor of the ovary.
BACKGROUND: The clinical course of adult granulosa cell tumor of the ovary is characterized by indolent growth tending toward late recurrence. A variety of clinical and pathologic parameters have previously been evaluated for prognostication with inconclusive results. METHODS: The clinical records and tumor sections of 70 patients with adult granulosa cell tumors of the ovary were reviewed. Patients with recurrent tumors (REC) (n = 19) were compared with patients who remained without disease (NED) (n = 51). RESULTS: Significant differences in stage and tumor size were noted between the two groups; however, after logistic regression analysis, only stage remained statistically significant. Pathologic evaluation revealed that Call-Exner bodies occurred more frequently in tumors of the NED patients. Cellular atypia and high mitotic rates were more frequent in the REC group; however, after logistic regression analysis, only atypia remained statistically significant. When early (< 10 years) and late recurring tumors (> 10 years) were compared, statistically significant differences were again noted: early recurring tumors had fewer Call-Exner bodies, higher mitotic rates, and higher degrees of atypia; late recurring tumors were similar to tumors in the NED patients. CONCLUSIONS: Tumor stage and, to a lesser extent, tumor size are the only clinical parameters of prognostic importance in adult granulosa cell tumors. Cellular atypia and, to lesser extents, mitotic rate and the absence of Call-Exner bodies are the only significant pathologic prognosticators. It is difficult to predict early recurrences and impossible to predict late recurrences using these clinical and pathologic parameters.
Adult↗
Suture conversion without the knots.
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Cost Savings↗
The endurance training on hormone and semen profiles in marathon runners.
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Humans↗
An approach to teaching ethical, legal, and psychosocial aspects of gynecologic oncology in a residency program.
An approach to teaching ethical, legal, and psychosocial issues in gynecologic oncology has been integrated into an obstetrics and gynecology residency program. Team-teaching is used, involving gynecologic oncology faculty members and a medical ethicist with experience teaching in the clinical setting of obstetrics and gynecology. The teaching takes place as part of ongoing teaching rounds in the division of gynecologic oncology. Articles from clinical journals are used to inform and stimulate discussion of clinical ethical, legal, and psychosocial issues. Integrating the teaching of ethical and legal aspects of gynecologic oncology into residency education is challenging, given the competing demands on the residents' time and the need for teaching to be clinically relevant. The program described in this article illustrates that such teaching can be carried out in a manner that covers main issues and has practical value for residents.
Curriculum↗
The inflammatory response to cardiopulmonary bypass.
The inflammatory response to cardiopulmonary bypass is the product of a complex interplay of humoral and cellular components. Contact activation cascades, the complement system, and cytokines comprise the humoral elements and interact in such a way as to propagate their own cascades and to activate the cellular elements. Neutrophils and endothelial cells are the cellular components and become involved after their "activation" by the humoral mediators. Neutrophil-endothelial cell adherence is the initial step of the cellular inflammatory response and is promoted by the expression of specific adhesion molecules on the surfaces of both of these cells leading to the emigration of neutrophils into the extravascular space where they release toxins that damage surrounding tissues. The resulting organ dysfunction produces the clinical picture referred to as the "postperfusion syndrome." Strategies to attenuate this response include the administration of corticosteroids, aprotinin, and anticytokine monoclonal antibodies, as well as various modifications of the bypass circuit. The existence of multiple pathways to trigger this inflammatory response hampers efforts at its attenuation and leaves much investigation to be done as the quest to understand the body's inflammatory response to cardiopulmonary bypass continues.
Adrenal Cortex Hormones↗
A comparison of the hemodynamic effects of amrinone and sodium nitroprusside in infants after cardiac surgery.
The phosphodiesterase inhibitor amrinone (AMR) increases cardiac output in children after cardiac surgery. In vitro, amrinone has both positive inotropic and vasodilatory effects. However the relative contribution of these effects to the increases in cardiac output observed clinically is unclear, and it has not been demonstrated that amrinone offers a hemodynamic advantage above that of pure vasodilators in infants. We compared the hemodynamic effects of AMR and sodium nitroprusside (SNP) in 10 infants after cardiac surgery. Cardiac index (CI) was measured by thermodilution after SNP administration, titrated to decrease mean blood pressure (MBP) by 20%, and then after a 1.5-mg/kg bolus dose of AMR. Each patient served as his or her own control. Preload, as measured by left atrial pressure and transesophageal echocardiography (in eight patients), was kept constant throughout the protocol. Both SNP and AMR caused significant decreases in MBP and systemic vascular resistance index (SVRI). However, only AMR resulted in a significant increase in CI. The ratio of fractional increase in CI to fractional absolute decrease in MBP was significantly greater for AMR than SNP, indicating greater efficacy for AMR in the treatment of low cardiac output syndrome and suggesting that, in infants after cardiac surgery, AMR has clinically relevant positive inotropic effects.
Amrinone↗
Functional maturity of the coagulation system in children: an evaluation using thrombelastography.
There are quantitative deficiencies in the coagulation system for at least the first 6 mo of life. Clinical experience, however, does not indicate an increased risk of excessive bleeding during surgical procedures. Thrombelastography, a test providing a functional evaluation of coagulation, was used to assess the hemostatic system of pediatric patients under 2 yr of age. Thrombelastographic data were obtained from 237 healthy pediatric patients less than 2 yr of age undergoing elective noncardiac surgery. Five groups were distinguished: under 30 days, 1-3 mo, 3-6 mo, 6-12 mo, and 12-24 mo. Thrombelastography revealed no defects in coagulation when these groups were compared to each other or to adults, indicating a functionally intact hemostatic process even in neonates. Indeed, children less than 12 mo of age were found to initiate and develop clot faster than adults, with the coagulation process slowing to adult rates after 1 yr of age. In addition to defining functional integrity, our data represents a set of pediatric control thrombelastographic values that have not been previously reported and that may become important in understanding coagulation changes that accompany disease states and surgery in pediatric patients.
Age Factors↗
The effect of endurance training on reproductive function in male runners. A 'volume threshold' hypothesis.
Investigations on reproductive function in male athletes are not as abundant in the literature as the research available on female athletes. The primary reason for this is the absence of an obvious clinical sign indicative of an alteration in reproductive function in male athletes. While alterations in the reproductive status of female athletes may be easily detected by the loss of menstrual regularity, a distinctive clinical sign reflective of reproductive dysfunction in the male is not apparent. In male runners, an effect of endurance training on reproductive function related to a specific 'volume threshold' of training is proposed. Data are supportive of this 'volume threshold' effect, provided careful and consistent definitions of volume of training are applied. In fact, if volume of training is carefully defined endurance-trained male runners exhibit a rather consistent range of subclinical modifications in the gonadal hormones and semen profile, and clinical (oligospermia) alterations in reproductive function. The precise mechanism responsible for these observed alterations remains unknown, although several peripheral and central mechanisms have been suggested. Clearly, more research is necessary to confirm, and to elucidate, the nature of the 'volume threshold' hypothesis in male runners.
Humans↗
Clinical, hematologic, and biochemical features of a syndrome in Bernese mountain dogs characterized by hepatocerebellar degeneration.
Seven related Bernese Mountain Dogs developed a syndrome Characterized by progressive cerebellar and hepatic disease. Clinically, stiffness in the hind limbs, mild incoordination, and a slight head tremor were first noticeable when pups were 4 to 6 weeks old. The condition progressed, causing pups to assume a wide-based stance. Other signs included head bobbing, spontaneous nystagmus, and, finally, paresis. Hematologic findings included leukocytosis with a left shift; normocytic, normochromic anemia; hypoproteinemia, low serum creatinine, and urea nitrogen concentrations; excessive fasting plasma ammonia concentration; and an increase in concentration of serum bile acids. Portal venography performed on 1 dog revealed a small liver and extensive extrahepatic varicosities. Necropsy revealed cerebellar hypoplasia, nodular liver, extensive abdominal varicosities, and ascites. Histologically, degeneration and depletion of Purkinje's cells and vacuolation, degeneration, and nodular regeneration of hepatic tissues were evident. Preliminary analysis of the pedigree was suggestive of an autosomal recessive pattern of inheritance.
Animals↗
Inhibition of mature IL-1 beta production in murine macrophages and a murine model of inflammation by WIN 67694, an inhibitor of IL-1 beta converting enzyme.
The proinflammatory cytokine IL-1 beta is synthesized by activated monocytes and macrophages as a 31-kDa, biologically inactive precursor that is proteolytically processed to the biologically active 17-kDa mature molecule by the IL-1 beta converting enzyme (ICE). WIN 67694, Z-Val-Ala-Asp-CH2O(CO)[2,6-(CI2)]Ph, is a potent, selective inhibitor of human ICE. In activated murine peritoneal macrophages, WIN 67694 inhibited the release of mature IL-1 beta with an IC50 of 1.8 microM without any effect on the release of IL-1 alpha, IL-6, or TNF-alpha. The effect was specific to mature IL-1 beta release; the ICE inhibitor did not effect IL-1 beta RNA levels or precursor protein synthesis. In vivo, WIN 67694 was also able to inhibit selectively the release of IL-1 beta in a dose-dependent manner in a subcutaneous tissue chamber implant model of inflammation. IL-1 beta levels in tissue chamber fluid were inhibited 35 and 55% at 10 and 100 mg/kg, respectively. IL-1 alpha, IL-6, and TNF-alpha levels were not affected. The ability to selectively inhibit mature IL-1 beta release in vivo with ICE inhibitors will allow for detailed studies of the role of IL-1 beta and ICE in inflammatory diseases.
Amino Acid Sequence↗
Cathepsin D from Alzheimer's-diseased and normal brains.
An acid protease activity from human brain was found to cleave a fluorogenic peptide substrate encompassing the amino terminus of Alzheimer's amyloid-beta peptide (A beta). The protease was isolated and determined to be cathepsin D based on chromatographic, immunological, and enzymatic data. Analysis of the cleavage sites indicated that cathepsin D hydrolyzed the methionine--aspartate bond generating the in vivo amino terminus of A beta. These data suggested that cathepsin D could be involved in amyloidogenic processing of the amyloid precursor protein. Consequently, cathepsin D from both Alzheimer's-diseased and control brains was compared to determine whether there were any differences which could account for an increase in A beta production in Alzheimer's disease. No differences were detected in isoform composition or tissue content of cathepsin D as measured by 2-D IEF-SDS-PAGE. Enzymological characterization of brain cathepsin D demonstrated that it could undergo a previously undescribed pH-dependent reversible activation. However, that activation appeared identical for both AD and normal brain enzymes. These data demonstrate that concentration, isoform distribution, and several enzymological characteristics of cathepsin D are not distinguishable between AD and normal brain. The pH dependence of cathepsin D activity suggests, however, that its intracellular localization may be important in considering the potential role of cathepsin D in Alzheimer's disease.
Aged↗
Inflammatory cytokines workshop.
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Animals↗
Successful application of the Norwood procedure for infants without hypoplastic left heart syndrome.
Although the first-stage Norwood procedure mostly has been used for hypoplastic left heart syndrome, there are other anomalies in which the Norwood procedure can be applied. Since 1991, 18 newborns without hypoplastic left heart syndrome underwent a first-stage Norwood procedure. All had a hypoplastic aortic annulus, ascending aorta, and transverse aorta. Ten had normally related great arteries: aortic atresia or aortic stenosis with inadequate left ventricle in 4, mitral atresia or stenosis in 4, and interrupted aortic arch in 2. The 8 others had double-outlet right ventricle with mitral atresia or complete transposition with a hypoplastic right ventricle. Age ranged from 2 to 77 days (median, 6 days) and weight from 2.4 to 4.4 kg (mean, 3.0 kg). The patients with interrupted aortic arch simultaneously underwent primary repair of the interruption. There were 17 hospital survivors (94%). There have been no late deaths in follow-up from 4 to 30 months (mean, 15.5 months). Thirteen children have had subsequent creation of a bidirectional Glenn shunt with takedown of the original systemic to pulmonary shunt. The 2 with interrupted aortic arch underwent a Rastelli-type biventricular repair. These results show that the Norwood procedure can be applied to infants without hypoplastic left heart syndrome who have hypoplastic aortas and excessive pulmonary blood flow with very low mortality and excellent palliation.
Aorta↗
Association of Chlamydia trachomatis immunoglobulin gamma titers with dystrophic peritoneal calcification, psammoma bodies, adhesions, and hydrosalpinges.
OBJECTIVE: To correlate Chlamydia trachomatis immunoglobulin gamma (IgG) titers with psammoma bodies, dystrophic peritoneal calcification, degree of calcification, adhesions, and hydrosalpinges. DESIGN: This is a prospective single-blinded histologic analysis of tissue and retrospective analysis of historical laboratory and clinical variables. SETTING: Tertiary hospital and private practice patient charts. PATIENTS: Sixty consecutive patients with C. trachomatis IgG titers reported on the coding sheets of a previous study for endometriosis. MAIN OUTCOME MEASURES: The histologic slides were reviewed in a blinded fashion for calcification. Previously used data sheets were reviewed for C. trachomatis IgG titers. Historical data, adhesion scores, hystrosalpingogram findings, and laparoscopic findings were obtained from charts. RESULTS: Dystrophic calcification, psammoma bodies, moderate-to-severe dystrophic calcification and hydrosalpinges were associated with positive C. trachomatis IgG titers. CONCLUSION: This study suggests relationship of C. trachomatis with dystrophic calcification, psammoma bodies, adhesions, and hydrosalpinges. This relationship suggests that C. trachomatis IgG titers can be used as a marker to help determine those infertility patients who might best benefit from hysterosalpingogram or laparoscopy and in clinical studies of endometriosis, infertility, pain, or ovarian cancer. However, there is no current data to suggest a need for therapy on the basis of a positive C. trachomatis IgG titer or of dystrophic peritoneal calcification.
Body Fluids↗
Enhanced metastatic ability of TNF-alpha-treated malignant melanoma cells is reduced by intercellular adhesion molecule-1 (ICAM-1, CD54) antisense oligonucleotides.
Treating human malignant melanoma cells with tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma (IFN-gamma) causes a dose- and time-dependent increase in surface expression of ICAM-1. Increased ICAM-1 expression corresponds to greater binding of human leukocyte functional antigen-1 (CD11a/CD18)-expressing peripheral blood mononuclear cells (PBMC) to C8161 monolayers, suggesting that cytokine-treated melanoma cells would be more metastatic due to PBMC-tumor cell emboli. The purpose of this study was: (1) to test whether TNF-alpha-treated human melanoma cells are indeed more metastatic than untreated C8161 and (2) to determine whether ICAM-1 plays a role in metastasis of C8161. When surface ICAM-1 expression is upregulated, formation of lung metastases in nude mice increases 1.5- to 4-fold (P < 0.05) for human melanoma cell lines C8161, MeWo, and A375. Treatment of C8161 with ICAM-1 phosphorothioate antisense oligonucleotides using cationic lipids results in > 90% inhibition of ICAM-1 surface expression as determined by ELISA and flow cytometry. Antisense ICAM-1-treated cells form 41-64% fewer metastases than sham-treated cells. Metastasis does not increase when antisense-treated melanoma cells are exposed to TNF-alpha. However, treatment of C8161 with antisense 5-lipoxygenase (5-LO) oligonucleotides inhibits metastases 39% in Lipofectin-treated cells, but does not inhibit TNF-alpha-induced upregulation of experimental metastases. Similar experiments were performed to measure PBMC adhesion to antisense oligonucleotide-treated C8161 cells; however, TNF-alpha-inducible increase in adhesion was unaffected by ICAM-1 or 5-LO antisense oligonucleotides. These results demonstrate that ICAM-1 is involved in melanoma metastasis, but probably not at the step of PBMC adhesion to C8161 cells.
Animals↗
Quantification of skeletal alkaline phosphatase in osteoporotic serum by wheat germ agglutinin precipitation, heat inactivation, and a two-site immunoradiometric assay.
Three methods for quantifying skeletal alkaline phosphatase (ALP; EC 3.1.3.1) activity/immunoactivity in serum--heat inactivation, wheat germ agglutinin (WGA) precipitation, and an immunoradiometric assay--were tested for recovery and specificity and applied to 81 sera collected from 14 postmenopausal osteoporotic subjects. The heat-inactivation and WGA precipitation assays showed relative recoveries of 91-100% and 16-32%, respectively, for skeletal ALP with complete specificity (no cross-reactivity with hepatic or intestinal ALP); the IRMA showed a relative recovery of 86-100% and 11-14% cross-reactivity with hepatic ALP. There was a closer correlation between the heat-inactivation assay and IRMA (r = 0.833) than between the WGA precipitation assay and IRMA (r = 0.673) or between the heat-inactivation and WGA-precipitation assays (r = 0.568). The WGA precipitation assay failed to detect skeletal ALP in three serum samples that contained significant amounts as determined by the heat-inactivation assay and the IRMA.
Alkaline Phosphatase↗
Glutamate receptor gene expression in spinal cord of arthritic rats.
Injury to peripheral tissue leads to hyperalgesia that appears to be partly mediated by functional changes at the level of the spinal cord. Glutamate receptors are thought to play a role in acute and short-term (minutes to hours) spinal cord nociceptive responses and may be involved in prolonged or chronic pain (hours to days). We used in situ hybridization to examine AMPA/kainate (GluR1, GluR2, and GluR3) and NMDA (NR1) receptor gene expression in spinal cord following induction of prolonged inflammation by a unilateral intraarticular injection of lipopolysaccharide (LPS; 10 micrograms) into the hindpaw. In control rats, GluR1 expression was prominent throughout the layers of the gray matter of the spinal cord. Microscopic examination revealed labeling of neuronal cell somata in all major nuclei. GluR2 was abundant in substantia gelatinosa and motor nuclei; emulsion-dipped sections exhibited intense labeling over densely packed neurons in the superficial laminae of dorsal horn and individual motoneurons of ventral horn. GluR3 and NR1 were expressed at low levels throughout spinal cord gray matter. One day after LPS injection, when joint swelling was maximal, GluR1 expression was bilaterally decreased by 25% in the substantia gelatinosa at the level of the lumbar cord. In contrast, no significant change was apparent in GluR2, GluR3, or NR1 expression in any nucleus of the cord. At 72 hr after injection, when joint diameter approached control values, all four transcripts were expressed at near control levels. These findings provide evidence for a specific decrease in GluR1 expression in the cord in response to joint inflammation.
Animals↗