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Biomedical subjects

J L Kelley

Publications and source records attributed to J L Kelley.

At least 19 recordsLinked to original sources
PubMed2000

Chemotherapy for malignant mixed Müllerian tumors of the ovary.

OBJECTIVE: The aim of this study was to review the chemotherapy experience at Magee-Womens Hospital for malignant mixed müllerian tumor (MMMT) of the ovary. Patients were treated with either paclitaxel/carboplatin (PC) outpatient chemotherapy or platinum/ifosfamide (PI) inpatient chemotherapy as first- or second-line therapy. METHODS: Thirteen patients diagnosed with MMMT of the ovary after complete surgical staging from 1990 to 1999 were studied retrospectively. Six patients received PC combination chemotherapy, of which 3 patients received PC as first-line treatment. The other 3 patients received PC as second-line therapy. Eight patients were treated with PI. Demographic data, pathology, cytoreductive surgery, treatment, and survival rates were reviewed. Complete clinical response (CR) was defined as the disappearance of all measurable disease or normalization of elevated CA 125 level after chemotherapy. Kaplan-Meier analysis was used for survival analysis. RESULTS: The median survival time of patients receiving PC was 19 months. One patient, after receiving PC as first-line treatment, demonstrated a CR and is free of disease beyond 33 months. The median survival time of patients managed with PI was 23 months. Three patients with suboptimal disease demonstrated CR after receiving PI. CONCLUSIONS: Optimal chemotherapy regimen for MMMT of ovary remains to be determined. Platinum-based chemotherapy in combination with ifosfamide or paclitaxel may be active against this rare malignancy.

Aged↗
PubMed2000

HIV risk behaviors in male substance abusers with and without antisocial personality disorder.

Antisocial personality disorder (ASP) is common in male substance abusers and may be associated with increased human immunodeficiency virus (HIV) risk behaviors. In this study, 91 male substance abusers were recruited from the community, and 42% met diagnostic criteria for ASP. Although ASP and non-ASP subjects demonstrated equivalent knowledge about HIV, subjects with ASP participated in more risky behaviors. On a lifetime measure of drug risk behaviors, ASP subjects reported higher rates of intravenous drug use (IVDU), frequency of needle-sharing, and number of equipment-sharing partners and lower rates of needle-cleaning. On a measure of past-month risk behaviors, ASP subjects reported higher rates of IVDU and lower rates of needle-cleaning. Subjects with ASP also reported greater participation in lifetime sexual risk behaviors, including number of sexual partners and frequency of anal sex. These findings suggest that clients entering substance abuse treatment programs should be screened for ASP, and clients identified with ASP should be provided risk-reduction interventions early in treatment.

Adult↗
PubMed2000

The molecular role of mast cells in atherosclerotic cardiovascular disease.

Human atherosclerosis has many characteristics of an inflammatory disorder. Recent data suggest that mast cells might be important in the pathogenesis of atherosclerotic disease. By secretion of pro-inflammatory cytokines, mast cells can assist in the recruitment of monocytes and lymphocytes into vascular tissue, thereby propagating the inflammatory response. Mast cell enzymes might activate pro-metalloproteinases, thereby destabilizing atheromatous plaques. Mast cells can facilitate foam cell formation by promoting cholesterol accumulation. However, mast cell tryptase could slow thrombus formation at sites of plaque rupture by interfering with coagulation. Therefore, mast cells can modulate coronary artery disease by both facilitatory and inhibitory pathways.

Arteriosclerosis↗
PubMed2000

Use of preoperative MR imaging in the management of endometrial carcinoma: cost analysis.

PURPOSE: To compare the cost of magnetic resonance (MR) imaging and its ability to direct the use of lymph node dissection with the cost and ability of conventional surgery for the staging of endometrial carcinoma. MATERIALS AND METHODS: Preoperative MR images of 25 patients who underwent hysterectomy for endometrial carcinoma were retrospectively evaluated. MR imaging results were compared with those of intraoperative gross dissection of the uterus and final histopathologic examination. Medicare reimbursements for two scenarios were compared in each patient. In the MR imaging scenario, the necessity for lymph node dissection was based on MR imaging results and histologic findings at biopsy. In the actual scenario, lymph node dissection was performed at the surgeon's discretion on the basis of findings at gross dissection of the uterus and histologic examination at biopsy. RESULTS: The cost of the MR imaging scenario, as defined by Medicare reimbursements, was 1% ($1, 265/$148,500) less than that of the actual scenario. In the MR imaging scenario, all patients who required lymph node dissection received it, and 86% of the lymph node dissections performed were necessary. In the actual scenario, one necessary lymph node dissection was not performed, and only 31% of the lymph node dissections performed were necessary. CONCLUSION: Staging with MR imaging has costs and accuracy similar to those of the current method of staging with intraoperative gross dissection of the uterus. In addition, MR imaging decreases the number of unnecessary lymph node dissections.

Adult↗
PubMed1997

6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents.

A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H- purine (80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure--activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.

Aggression↗
PubMed1997

Inhibition of uridine phosphorylase. Synthesis and structure-activity relationships of aryl-substituted 1-((2-hydroxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil.

Structure-activity relationship studies on a series of 1-((2-hydroxyethoxy)methyl)-5-(3-(substituted-phenoxy)benzyl)uracils as inhibitors of murine liver uridine phosphorylase have led to compounds with IC50s as low as 1.4 nM. The two most potent compounds, 10j (3-cyanophenoxy) and 11f (3-chlorophenoxy) were tested in vivo for effects on steady-state concentrations of circulating uridine in mice and rats. Both compounds were substantially more efficacious than BAU (5-benzylacyclouridine) both in vitro and in vivo.

Animals↗
PubMed1997

A trial of outpatient paclitaxel and carboplatin for advanced, recurrent, and histologic high-risk endometrial carcinoma: preliminary report.

The purpose of this study was to evaluate the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin in patients with endometrial cancer known to be resistant to standard therapy. Subjects were taken from three groups: (1) recurrent or persistent disease following surgery and/or radiation, (2) advanced disease at diagnosis, and (3) high-risk histology. The combination of carboplatin (pharmacologically dosed at an area under the concentration-time curve of 5) and paclitaxel (135 to 175 mg/m2 over 3 hours) was given intravenously every 4 weeks for eight courses. Data about response, overall and progression-free survival, and toxicity were collected. Response and toxicity were evaluated by physical examinations, x-ray films, and blood tests. Twenty patients have participated to date, including eight considered evaluable for response. Due to limited follow-up, survival and progression-free intervals are not yet assessable. Of patients with measurable disease, five of eight (63%) have had significant reduction in the size of evaluable tumor masses, constituting a partial response. Although two patients had clinical and radiographic complete responses, occult disease was found at surgery. There were no complete responders. Fifteen patients had grade 3 or 4 hematologic toxicity, but none had neutropenic fever or hospitalization for sepsis. One patient was taken off study for grade 3 neuropathy. There was one possible treatment-related death. In this preliminary report, this combination is active against tumors of the endometrium, with acceptable levels of toxicity. Further follow-up will be required to determine the duration of response and whether progression-free and overall survival are influenced by treatment with these drugs.

Adult↗
PubMed1996

Receptor binding and internalization of a water-soluble (1-->3)-beta-D-glucan biologic response modifier in two monocyte/macrophage cell lines.

Glucan phosphate, a water-soluble, chemically defined (1-->3)-beta-D-glucan biologic response modifier, has been reported to exert antisepsis activity and accelerate wound healing. In this study we describe the specific binding of glucan phosphate to human and murine monocyte/macrophage cell lines, U937 and J774A.1, respectively. At 37 degrees C, equilibrium binding was rapidly achieved, i.e., within 1 min. In U937 cells, binding occurred with an affinity (Kd) of 37 microM and a Bmax of 65 x 106 binding sites/cell at 37 degrees C. In J774A.1 cells, glucan phosphate bound with an affinity (Kd) of 24 microM and a Bmax of 53 x 106 binding sites/cell at 37 degrees C. In both cases there was insignificant nonspecific binding. We further demonstrated that bound glucan phosphate cannot be displaced by a 50-fold excess of unlabeled ligand, suggesting internalization of glucan phosphate. Transmission electron microscopy showed significantly increased cytoplasmic vacuolization and significantly decreased mitotic activity in glucan phosphate-treated U937 cells compared with that in untreated cells. Pullulan, a random coil alpha-(1-->4)-(1-->6)-linked glucose polymer that served as a control, did not compete for the same binding site as glucan phosphate in either cell line, indicating the specificity of the binding site for (1-->3)-beta-D-glucans. We conclude that water-soluble pharmaceutical grade (1-->3)-beta-D-glucan phosphate specifically binds to and is internalized by U937 and J774A.1 cells.

Animals↗
PubMed1995

1-(Fluorobenzyl)-4-amino-1H-1,2,3-triazolo[4,5-c]pyridines: synthesis and anticonvulsant activity.

A series of (fluorobenzyl)triazolo[4,5-c]pyridines was synthesized and tested for activity against maximal electroshock-induced seizures in rodents. The most promising compound, 14 (BW 534U87), which is a carbon-nitrogen isoster of a purine anticonvulsant, has a profile in rodents that suggests 14 will be free of emesis and useful in the treatment of seizure disorders for which phenytoin is presently indicated.

Animals↗
PubMed1995

Inhibition of uridine phosphorylase: synthesis and structure-activity relationships of aryl-substituted 5-benzyluracils and 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils.

A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesized and tested for inhibition of murine liver uridine phosphorylase (UrdPase). Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine-induced anemia in animal models. We prepared a series of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a good inhibitor of UrdPase (IC50 of 0.46 microM), to develop a compound with enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substituted 5-benzyluracils found several 5-(3-alkoxybenzyl) analogues of 5-benzyluracil with enhanced potency. The acyclovir side chain, the (2-hydroxyethoxy)methyl group, was substituted on the more potent aryl-substituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC50s of 0.047 and 0.027 microM, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in rats. Plasma uridine levels were elevated 3-9-fold by compound levels that ranged from 8 to 50 microM.

Animals↗
PubMed1995

Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine.

Analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine (1) containing isosteric replacements of the imidazole ring atoms were synthesized and tested for anticonvulsant activity. The pyrrolo[2,3-d]-, pyrazolo[3,4-d]-, and triazolo[4,5-d]pyrimidines were less active than 1 against maximal electroshock-induced seizures (MES) in rats when given po. The differences in anti-MES activity for these analogues was not explained by differences in pKa or lipophilicity. However, the four classes of heterocycles have distinctly different calculated electrostatic isopotential maps, which may be related to optimum anticonvulsant activity.

Animals↗
PubMed1995

8-Amino-3-benzyl-1,2,4-triazolo[4,3-a]pyrazines. Synthesis and anticonvulsant activity.

Eleven substituted 8-amino-3-benzyl-1,2,4-triazolo[4,3-a] pyrazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures (MES) in rats. The compounds were prepared in four stages from the phenylacetonitriles. I. The intermediate (2,2,2-triethoxyethyl)benzenes III were condensed with 2-chloro-3-hydrazinopyrazine (IV) to provide the 3-benzyl-8-chloro-1,2,4-triazolo[4,3-a]pyrazines V. The latter were converted to the 8-amine targets VI with methylamine or ammonia. Several compounds exhibited potent activity against MES; the 3-(2-fluorobenzyl)-8-(methylamino) and 3-(2,6-difluorobenzyl)-8-(methylamino)congeners (4 and 12) exhibited the best anticonvulsant activity with oral ED50S of 3 mg/kg. The 1,2,4-triazolo[4,3-a]pyrazine ring system serves as a bioisostere of the purine ring for anticonvulsant activity; however, these agents exhibit less propensity to cause emesis.

Animals↗
PubMed1995

[[(Guaninylalkyl)phosphinico]methyl]phosphonic acids. Multisubstrate analogue inhibitors of human erythrocyte purine nucleoside phosphorylase.

A series of [[(guaninylalkyl)phosphinico]methyl]phosphonic acids, 2, was synthesized and tested as inhibitors of human erythrocyte purine nucleoside phosphorylase (PNPase). The target (phosphinicomethyl)phosphonic acids 2 were synthesized in six or seven steps from alkenylphosphonates 4. The latter were converted to the intermediate alkylmesylates 9 in a series of steps that included (1) conversion of the diethyl phosphonates 4 to the (phosphinoylmethyl)-phosphonates 7 and (2) conversion of the terminal double bond of [(alkenylphosphinoyl)methyl]-phosphonates 7 to the alkylmesylates 9. The pure 9-isomers 2 were obtained by alkylation of 2-amino-6-(2-methoxyethoxy)-9H-purine with alkylmesylates 9 followed by hydrolysis of the protecting groups with concentrated hydrochloric acid and ion exchange chromatography to give 2 as hydrated ammonium salts. The most potent inhibitor of human erythrocyte PNPase, [[[5-(2-amino-1,6-dihydro-6-oxo-9H-purin-9- yl)pentyl]phosphinico]methyl]phosphonic acid (2b), was a multisubstrate analogue inhibitor with a Ki' of 3.1 nM. Optimum PNPase inhibitory activity required the presence of zinc ions in the assay medium. These potent inhibitors of PNPase exhibited only weak activity against human leukemic T-cells in vitro.

Binding, Competitive↗
PubMed1995

Serous psammocarcinoma of the ovary in an adolescent female.

A rare form of epithelial ovarian carcinoma in an adolescent female is reported. Serous psammocarcinoma is a type of ovarian cancer that is characterized by extensive psammoma body formation and has not been reported in this age group. Histopathologically, this tumor exhibits stromal invasion, vascular invasion, epithelial cells with low to moderate nuclear atypia, nests of solid epithelial cells less than 15 cells in diameter, and psammoma bodies that involve at least 75% of papillae or nests of cells. The patient underwent optimal surgical debulking and nine courses of adjuvant chemotherapy with carboplatinum and cyclophosphamide and is currently disease free. The prognosis for this type of ovarian cancer is unclear, but it appears to be better than other forms of epithelial ovarian cancer.

Adolescent↗
PubMed1995

A survey of blood transfusion practices of gynecologic oncologists.

OBJECTIVE: To survey the attitudes of gynecologic oncologists about indications for blood transfusion, and compare them to current recommendations about transfusion practice. METHODS: With the permission of the Society of Gynecologic Oncologists (SGO), a study questionnaire was mailed to 548 members and candidates in their directory. The questions asked about transfusion threshold before chemotherapy, following ovarian debulking, and after endometriosis surgery. Indications for transfusion were assessed using a qualitative/quantitative scale. Responses were analyzed with respect to years of SGO membership and practice setting using the chi 2 test and analysis of variance. Results were compared to the 1992 guidelines for transfusion of the American College of Physicians (ACP). RESULTS: Two hundred eighty-five forms were returned (52% of total). Fifty-one percent of respondents were in full-time academic positions; 36% were in private practice. Sixty-one percent were full SGO members, and 35% were candidates. The average prechemotherapy transfusion threshold (TT) was a hemoglobin concentration (hgb) of 7.9 +/- 0.7 g/dl (g). At that level the mean transfusion was 1.9 +/- 0.5 units of packed red blood cells (U). For the ovarian debulking scenario, the mean postoperative TT was 8.1 +/- 0.8 g with a mean transfusion of 1.9 +/- 0.4 U. For the endometriosis case, the mean TT was 7.0 +/- 0.8 g, with a mean transfusion of 1.9 +/- 0.5 U. Analysis showed no difference in practice based on years of SGO membership or practice setting. CONCLUSION: A majority of the gynecologic oncologists surveyed offers transfusion at levels of anemia similar to ACP recommendations, but frequently transfuse more units than recommended. A substantial minority does not follow the guidelines at all.

Blood Transfusion↗
PubMed1995

Double contrast upper gastrointestinal barium examination with biopsy versus endoscopy with biopsy in dyspeptic patients.

RATIONALE AND OBJECTIVES: The financial restrictions of the managed care environment require reconsideration of the barium upper gastrointestinal examination as a diagnostic tool for gastritis patients. However, a greater sensitivity and specificity for gastritis is needed. A prospective study was performed comparing barium examinations with gastric biopsies to endoscopy with biopsy. METHODS: Forty adult patients underwent upper gastrointestinal barium examination with gastric biopsies obtained under fluoroscopy through a nasogastric tube. Twenty-seven patients gave consent for subsequent endoscopy with biopsy. Both sets of biopsies were compared, as were the interpretations of the radiographs and visual appearances. RESULTS: For barium examinations with gastric biopsies, sensitivity for gastritis was 94% and specificity was 100%, using endoscopic biopsies as the gold standard. CONCLUSIONS: In addition to endoscopy with biopsy, the upper gastrointestinal barium examination with biopsy is another option of sufficient sensitivity and specificity for consideration by clinicians in their workup of patients with gastritis.

Adult↗