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Biomedical subjects

C Powers

Publications and source records attributed to C Powers.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cerebral vessels express interleukin 1beta after focal cerebral ischemia.

Rapid and marked increased levels of expression of interleukin 1beta (IL-1beta) mRNA have been detected in animal models of cerebral ischemia. However, the protein production of IL-1beta and the cellular sources of IL-1beta are largely undefined after cerebral ischemia. In the present study, we have measured the cellular localization of IL-1beta protein in brain tissue from non-ischemic and ischemic mice using immunohistochemistry. Male C57B/6J (n=45) mice were subjected to middle cerebral artery (MCA) occlusion by a clot or a suture. The mice were sacrificed at time points spanning the period from 15 min to 24 h after onset of the MCA occlusion. Non-operated and sham-operated mice were used as control groups. A monoclonal anti-IL-1beta antibody was used to detect IL-1beta. In the non-operated and sham-operated mice, a few IL-1beta immunoreactive cells were detected scattered throughout both hemispheres. IL-1beta immunoreactive cells increased in the ischemic lesion as early as 15 min and peaked at 1 h to 2 h after MCA occlusion. IL-1beta immunoreactivity was detected in the cortex of the contralateral hemisphere 1 h after ischemia. By 24 h after onset of ischemia, IL-1beta immunoreactivity was mainly present adjacent to the ischemic lesion and in the non-ischemic cortex. IL-1beta immunoreactivity was found on endothelial cells and microglia. This study demonstrates an early bilateral expression of IL-1beta on endothelium after MCA occlusion in mice.

Animals↗
PubMed1998

Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB2.

The interleukin-2 CD28 response element (CD28RE) acts as a composite enhancer, in conjunction with a 3'-12-O-tetradecanoylphorbol-13-acetate response element (TRE)-like element, to confer CD28 receptor-dependent inducibility to the interleukin-2 promoter in T-cells. When inserted as a single copy upstream of a basal promoter, this composite enhancer, termed the CD28RE-TRE, is both highly active and CD28-inducible in transactivation assays. A multicomponent nuclear protein complex that binds the CD28RE-TRE was isolated by DNA affinity chromatography from nuclear extracts of mitogen- and CD28 receptor-costimulated human T-cells. Immunological and biochemical analyses of this complex reveal the presence of c-Rel, ATF-1, and CREB2 as major DNA-binding components. Coexpression of c-Rel in combination with ATF-1, CREB2, or ATF-1/CREB2 leads to synergistic transactivation of a CD28RE-TRE reporter plasmid in quiescent Jurkat T-cells. Furthermore, CD28-dependent transactivation of the CD28RE-TRE is specifically inhibited by cAMP response element-binding protein (CREB) dominant-negative expression vectors. Moreover, mutant promoter constructs in which the internal 5'-CD28RE and 3'-TRE-like sequences have been topologically positioned 180 degrees out of phase with one another show loss of mitogen- and CD28-dependent inducibility. Finally, the addition of the CREB-binding transcriptional coactivator p300 leads to a dramatic CREB-dependent increase in both mitogen- and CD28-mediated transactivation of the CD28RE-TRE. These findings demonstrate that full physiological responsiveness to CD28 receptor stimulation in T-cells is dependent on topologically linked sequences within the CD28RE-TRE composite enhancer and provide strong support of a direct role for the CREB family of transcription factors and p300/CREB-binding protein coactivator proteins in cytokine gene induction during T-cell activation.

Activating Transcription Factor 1↗
PubMed1998

Intrahepatic biliary enteric bypass provides effective palliation in selected patients with malignant obstruction at the hepatic duct confluence.

BACKGROUND: Palliating the effects of biliary obstruction is a major goal of therapy in patients with cancer at the hepatic duct confluence. This study was undertaken to evaluate the effectiveness of intrahepatic biliary-enteric bypass to either the segment III duct or the right sectoral hepatic ducts in patients with unresectable hilar cholangiocarcinoma or gallbladder carcinoma. METHODS: From December 1991 to October 1996, 55 consecutive bypass procedures were prospectively evaluated in patients with unresectable hilar cholangiocarcinoma or gallbladder cancer. Patients were divided into three groups based on the primary tumor and the type of bypass performed: group 1A, cholangiocarcinoma/segment III bypass (n = 20); group 1B, cholangiocarcinoma/right sectoral hepatic duct bypass (n = 14); group 2, gallbladder cancer/segment III bypass (n = 21). RESULTS: Mean hospital stay (14+/-2 days) and mean blood loss (629+/-84 mL) were similar among the three groups. Perioperative death occurred in 6 patients (11%): 0 in group 1A, 3 each in groups 1B and 2. All survivors had relief of jaundice and pruritus after bypass. Complications occurred in 25 patients (45%). Preoperative transhepatic biliary drainage, performed in 14 patients prior to referral, was associated with a higher incidence of contaminated bile, greater operative blood loss, and postoperative biliary leak that was less likely to resolve spontaneously. Median survival in patients with cholangiocarcinoma (groups 1A and 1B) was 52 weeks and was unaffected by the type of bypass performed. By contrast, median survival in patients with gallbladder cancer (group 3) was 20 weeks; all but 3 died within 32 weeks of surgery. In patients with cholangiocarcinoma, the 1-year bypass patency was 80% in group 1A (segment III bypass) and 60% in group 1B (right sectoral hepatic duct bypass). Overall, there were 9 late bypass failures (18%) requiring reintervention. CONCLUSIONS: Intrahepatic biliary-enteric bypass effectively relieves symptoms due to malignant hilar obstruction. In patients with cholangiocarcinoma, segment III bypass provides excellent palliation with relatively few late complications and can be performed with minimal morbidity and mortality. Bypass to the right sectoral hepatic ducts, on the other hand, is associated with significant procedure-related morbidity and mortality and more late complications. Patients with gallbladder cancer, because of their poor survival, are probably better palliated by percutaneous biliary stenting.

Anastomosis, Surgical↗
PubMed1998

Neuronal damage and plasticity identified by microtubule-associated protein 2, growth-associated protein 43, and cyclin D1 immunoreactivity after focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: An objective of therapeutic intervention after cerebral ischemia is to promote improved functional outcome. Improved outcome may be associated with a reduction of the volume of cerebral infarction and the promotion of cerebral plasticity. In the developing brain, neuronal growth is concomitant with expression of particular proteins, including microtubule-associated protein 2 (MAP-2), growth-associated protein 43 (GAP-43), and cyclin D1. In the present study we measured the expression of select proteins associated with neurite damage and plasticity (MAP-2 and GAP-43) as well as cell cycle (cyclin D1) after induction of focal cerebral ischemia in the rat. METHODS: Brains from rats (n=28) subjected to 2 hours of middle cerebral artery occlusion and 6 hours, 12 hours, and 2, 7, 14, 21, and 28 days (n=4 per time point) of reperfusion and control sham-operated (n=3) and normal (n=2) rats were processed by immunohistochemistry with antibodies raised against MAP-2, GAP-43, and cyclin D1. Double staining of these proteins for cellular colocalization was also performed. RESULTS: Loss of immunoreactivity of both MAP-2 and GAP-43 was observed in most damaged neurons in the ischemic core. In contrast, MAP-2, GAP-43, and cyclin D1 were selectively increased in morphologically intact or altered neurons localized to the ischemic core at an early stage (eg, 6 hours) of reperfusion and in the boundary zone to the ischemic core (penumbra) during longer reperfusion times. CONCLUSIONS: The selective expressions of the neuronal structural proteins (MAP-2 in dendrites and GAP-43 in axons) and the cyclin D1 cell cycle protein in neurons observed in the boundary zone to the ischemic core are suggestive of compensatory and repair mechanisms in ischemia-damaged neurons after transient focal cerebral ischemia.

Animals↗
PubMed1997

Granule cell apoptosis and protein expression in hippocampal dentate gyrus after forebrain ischemia in the rat.

We investigated the relationship between apoptosis and selective protein expression in brain from rats subjected to 8 (n=10) or 12 min (n=10) of forebrain ischemia and 48 h of reperfusion, and control sham operated (n=2) and normal (n=2). Coronal sections were processed for double staining with DNA fragmentation detection and immunohistochemical staining. In five of ten 8-min ischemic and three of ten 12-min ischemic animals, nearly all dead granule cells within the dentate gyrus exhibited apoptotic morphology. In the remaining animals, no granule cell death was evident. In the pyramidal regions (CA1/2), nearly all dead cells were necrotic with only scattered apoptotic cells present. The immunoreactive expression of wt-p53, p53-response proteins (WAF1, Bax and Gadd45), and a cell cycle protein (cyclin D) were detected and preferentially localized to nuclei of apoptotic granule cells, and were weakly expressed in nuclei of necrotic pyramidal CA1/2 cells. Thus, 48 h after 8 or 12 min of forebrain ischemia in the rat, most pyramidal cells and dentate granule cells undergo distinct cell death pathways of necrosis or apoptosis, respectively. In addition, the selective expression of proteins associated with DNA damage and cell cycle in apoptotic dentate granule cells suggests a role for these proteins in the induction of apoptosis.

Animals↗
PubMed1997

Apoptosis and protein expression after focal cerebral ischemia in rat.

We used double staining histochemistry to investigate the relationship between apoptotic cell death and selective protein expression associated with DNA damage (p53, Bax, MDM2, Gadd45), DNA repair (PCNA) and cell cycle proteins (cyclin A, cyclin D, cdk2, cdk4) in rats (n = 6; control rats, n = 5) subjected to transient (2 h) middle cerebral artery occlusion (MCAo) and 46 h of reperfusion. Few apoptotic cells were detected in the non-ischemic hemisphere of control rats. In ischemic animals, scattered apoptotic cells were present in the ischemic core and clustered apoptotic cells were present and localized to the inner boundary zone of the ischemic core. Proteins were preferentially localized to the cellular cytoplasm of control rats and in the non-ischemic hemisphere of rats subjected to MCAo. However, after MCAo these proteins were expressed and were preferentially localized to nuclei within the ischemic lesion. DNA damage induced proteins (wt-p53 and p53-response proteins) were preferentially expressed within apoptotic cells after ischemia. DNA repair proteins and cell cycle proteins were preferentially expressed within morphologically intact cells and in reversibly damaged cells in the ischemic areas. The selective expression of proteins associated with DNA damage, DNA repair and cell cycle observed in morphologically intact cells, ischemic injured cells and apoptotic cells suggests a differential role for these proteins in cell survival and apoptosis after stroke.

Animals↗
PubMed1997

Late rectal sequelae following definitive radiation therapy for carcinoma of the uterine cervix: a dosimetric analysis.

PURPOSE: This study attempted to correlate patient, treatment, and dosimetric factors with the risk of late rectal sequelae in patients treated with radiation therapy (RT) for cervical carcinoma. METHODS AND MATERIALS: A total of 183 patients with cervical carcinoma (67 Stage I, 93 Stage II, and 23 Stage III) treated with definitive RT with a minimum of 2 years follow-up were evaluated. Treatment consisted of external beam pelvic RT (EBRT) followed by intracavitary RT (ICRT) consisting of one or two insertions. Complications were scored and analyzed as a function of 25 patient and treatment factors. Conventional total rectal doses were obtained by adding together the EBRT and ICRT rectal doses. To account for differences in dose rate between the ICRT and EBRT, and variations in EBRT fractionation schemes, biologically equivalent rectal doses (BED) were calculated using a linear quadratic model. In addition, the influence of the varying proportions of EBRT and ICRT rectal doses were evaluated. RESULTS: Twenty-eight patients (15.3%) developed late rectal sequelae (13 Grade 1, 3 Grade 2, and 12 Grade 3). Diabetes (p = 0.03), Point A dose (p = 0.04), and conventional EBRT dose (p = 0.03) were the most significant factors on multivariate analysis. Logistic regression analysis demonstrated a low risk (<10%) of late rectal sequelae below conventional and biological rectal doses of 75 Gy and 135 BED, respectively. The percentage of rectal dose delivered by the EBRT significantly influenced the dose-response relationship. A defined threshold percentage above which rectal sequelae were more common was identified over the range of doses evaluated. This threshold was 87% at a total rectal dose of 60 Gy and decreased to 60% at 80 Gy. CONCLUSION: Diabetes, Point A, and EBRT doses are the most significant factors associated with the risk of late rectal sequelae in patients treated with RT for cervical carcinoma. The percentage of rectal dose delivered by the EBRT significantly affects the conventional and biological dose-response relationship. This suggests that the volume of rectum irradiated is an important and independent parameter in the development of late rectal sequelae.

Adult↗
PubMed1997

Temporal profile of microglial response following transient (2 h) middle cerebral artery occlusion.

We measured the time-dependent morphological changes of microglial cells reacting to ischemic cell damage after transient (2 h) middle cerebral artery occlusion in the rat by means of lectin histochemistry with the B4-isolectin from Griffonia simplicifolia as well as immunohistochemistry with monoclonal antibodies directed against monocyte/microphage (ED1) and major histocompatibility complex (MHC) class II (OX-6) antigens. As early as 1 h after onset of reperfusion, microglia were absent in the severely neuronal damaged preoptic area. However, ameboid-like microglia were evident in an adjacent area containing scattered shrunken neurons. Rod, round and ameboid-like microglia were present in the ischemic lesion between 2 to 10 h of reperfusion. Round and ameboid cells became predominant in the ischemic core lesion and were mingled with highly ramified microglia to the boundary at 22 h of reperfusion. Highly ramified microglia were found in an adjacent area containing morphologically intact neurons. Round and ameboid cells were localized to the inner boundary of the ischemic lesion surrounding the infarct zone at 46 of reperfusion. Round and ameboid cells were present throughout the entire ischemic lesion in the infarct zone from 70-166 h of reperfusion. A marked increase in number and in intensity of highly ramified microglial cells were present in the outer boundary of the lesion during this period. In addition, a significant increase in both ED1- and OX-6-immunoreactive cells in the ischemic region was detected after 10 h of reperfusion and persisted up to 166 h of reperfusion. These data demonstrate that microglia exhibit a time dependent change in morphology after reperfusion and that the severity of injury may be reflected in the state of microglial activation.

Animals↗
PubMed1997

Congenital cervicovaginal aplasia with septate uterus and functioning endometrium.

A 14-year-old adolescent girl presented with primary amenorrhea and uncontrolled pelvic pain. Evaluation using pelvic sonogram, magnetic resonance imaging, and laparoscopy confirmed the diagnosis of cervicovaginal aplasia with functioning endometrium and a vaginal fistulous tract. At age 19 years, hysterectomy and vaginoplasty allowed the patient to be free of pain and to have normal sexual function.

Adolescent↗
PubMed1997

Immunoreactivity of cyclin D1/cdk4 in neurons and oligodendrocytes after focal cerebral ischemia in rat.

We investigated the expression of cyclin D1 and its kinase, cdk4, after induction of focal cerebral ischemia in the rat. Brain from rats (n = 6) subjected to 2 hours of transient middle cerebral artery occlusion and 46 hours of reperfusion, and control sham-operated (n = 3) and normal (n = 2) rats were processed for dual label immunohistochemical study for cellular identification of the expression of these cell cycle proteins. Antibodies raised against microtubule-associated protein 2 and neuronal specific enolase for neurons, glial fibrillary acidic protein for astrocytes, myelin basic protein for oligodendrocytes and lectin histochemical study with the B4-isolectin for microglia were used for cell type identification. Double staining for DNA fragmentation detection (TUNEL) and expression of cyclin D1 and cdk4 also was performed. Cyclin D1 and cdk4 were selectively expressed in morphologically intact or altered neurons and oligodendrocytes localized to the ischemic tissue. Apoptotic cells were not immunoreactive to cyclin D1 and cdk4 at 46 hours after 2 hours of middle cerebral artery occlusion. The selective expression of cell cycle proteins observed in nonapoptotic ischemic postmitotic neurons and oligodendrocytes suggests a role for these proteins in cell survival after transient focal cerebral ischemia.

Animals↗
PubMed1997

Race and clinical outcome in breast cancer in a series with long-term follow-up evaluation.

PURPOSE: To compare the outcome of African American (AA) and Caucasian (C) breast cancer patients who had equivalent disease extent and were similarly treated. PATIENTS AND METHODS: We compared prognostic characteristics, treatment, and outcome of 1,037 C and 481 AA breast cancer patients treated with mastectomy between 1946 and 1987. The median follow-up duration was 15.6 years. RESULTS: During the study period, there was a successive increase in the percent of patients who presented with early breast cancer. Between 1980 and 1987, 35.1% AA versus 47.6% C patients had < or = 2-cm tumors and 50.0% AA versus 61.9% C patients were node-negative, while between 1946 and 1959, 27.7% AA and 31.3% C had < or = 2-cm tumors and 41.5% AA versus 40.4% C patients were node-negative. The treatments were similar during the study period. The 20-year disease-free survival (DFS) rate of AA compared with C patients with node-negative < or = 2-cm, 2.1- to 4-cm, and greater than 4-cm tumors and of patients with one to three and > or = four positive nodes was not significantly different. Equal-size tumors had similar proportion of positive axillary nodes in AA compared with C patients. The DFS for AA patients compared with C patients was similar in the periods 1946 to 1959, 1960 to 1969, and 1970 to 1979, but was lower between 1980 and 1987 (P = .02). In multivariable analysis, race was not a significant variable. CONCLUSION: In this large group of uniformly treated breast cancer patients, race was not an independent factor that influenced outcome. The racial differences seen between 1980 and 1987 are likely because of a larger percent of greater than 2-cm and node-positive tumors in AA patients. Education and access to early diagnosis should reduce or eliminate the racial differences seen.

Actuarial Analysis↗
PubMed1996

Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer.

BACKGROUND: Angiogenesis (the formation of new blood vessels) is necessary for tumor growth and metastasis. PURPOSE: We investigated whether angiogenesis as measured by microvessel count (MVC) predicts clinical outcome in a series of patients with axillary lymph node-negative breast cancer who received no adjuvant therapy and who were followed for a long period of time. Our long-term goal is to identify those patients who may or may not need adjuvant chemotherapy. METHODS: Pathologic archival material and clinical information were analyzed for 167 patients treated with mastectomy from 1941 through 1987; none received adjuvant treatment. The median follow-up time among living patients was 15.4 years (range, 2.6-35.8 years). Ninety-six (58%) patients had a tumor size of 2 cm or less, 52 (31%) had tumors of 2.1-3 cm, and 19 (11%) had tumors of larger than 3 cm. Paraffin-embedded tissue sections were stained for expression of CD34 antigen on microvessel-associated endothelial cells by use of a monoclonal anti-CD34 antibody. Vascularity was defined as the number of microvessels (average of the three highest counts) per high-power microscopic field (400 x magnification) in the area of highest vascular density. A high vascular count was defined as 15 or more microvessels per field. Actuarial survival curves were calculated according to the Kaplan-Meier method and comparisons were made with the logrank test. The Cox proportional hazards model was used for multivariate analysis. All P values were based on two-sided testing. RESULTS: The 20-year disease-free survival (DFS) for the 167 node-negative patients treated with mastectomy and no adjuvant therapy was 74.8% (95% confidence interval [CI] = 64.7%-82.0%). The 20-year DFS was 93.1% (95% CI = 79.9%-97.7%) if the MVC was low versus 68.9% (95% CI = 56.8%-78.0%) if the MVC was high (P = .018). This difference was maintained irrespective of tumor size: for tumor size of 2 cm or less (93.3% [95% CI = 75.3%-98.3%] versus versus 67.8% [95% CI = 50.1%-80.3%]) and for tumor size of larger than 2 cm (92.3% [95% CI = 56.6%-98.9%] versus 70.9% [95% CI = 54.6%-81.6%]). However, the likelihood of a high MVC was greater with large tumors (P = .05). The proportions of tumors with low and high MVC were 33% and 67%, respectively, if the tumor size was 2 cm or less, and 20% and 80%, respectively, if tumor size was larger than 2 cm. There was no significant difference in the 20-year DFS as a function of tumor grade (P = .2). After combining patients with tumors of nuclear grades 2 and 3 compared with those of nuclear grade 1, the 20-year DFS was 93.9% (95% CI = 77.2%-98.4%) for low MVC versus 66.9% (95% CI = 52.2%-78.0%) for high MVC (P = .02). In a multivariate analysis that included the variables tumor size, age, nuclear grade, estrogen receptor status, and MVC, only MVC appeared to be an independent prognostic indicator (P = .04). CONCLUSIONS: Angiogenesis as measured by MVC is a reliable independent prognostic marker of long-term survival in patients with node-negative breast cancer. The prognostic usefulness of this marker is maintained after more than 15 years of follow-up. A low MVC identifies a subgroup of patients with DFS of 92% or more, independent of tumor size or grade.

Adult↗
PubMed1996

Modulation of JunD.AP-1 DNA binding activity by AP-1-associated factor 1 (AF-1).

AP-1-associated factor 1 (AF-1), is a novel protein complex that dramatically enhances the assembly of JunD-containing dimers onto AP-1 consensus sites. We describe the partial purification of AF-1 from nuclear extracts of the T-cell line MLA 144 by ionic, hydrophobic and gel filtration chromatography. AF-1 is a DNA-binding protein composed of low molecular mass polypeptides of 7-17 kDa that exists in solution as a 34-kDa complex. JunD interactions with DNA are accelerated in the presence of AF-1 through the formation of a true tri-molecular complex with JunD dimers and DNA that assembles much more rapidly on DNA than JunD alone. DNA binding analysis of AF-1 interaction with JunD.AP-1 and DNA shows that AF-1 increases the DNA binding affinity of JunD for AP-1 sites over 100-fold. DNA cleavage footprint analysis of isolated AF-1.JunD DNA complexes shows that the ternary complex makes nearly twice as many contacts with DNA than JunD dimers alone. AF-1 interacts readily, but differentially with Jun homodimers and Jun.Fos heterodimers. These findings distinguish AF-1 as a significant protein-specific modulator of AP-1.JunD in T-cells.

Biopolymers↗
PubMed1996

Breast preservation in stage I and II carcinoma of the breast. The University of Chicago experience.

BACKGROUND: Although breast conservation has received increased acceptance, there are still unresolved issues regarding local treatment techniques, such as the extent of surgery, in relation to the final margins of excision and the use of tumor bed boost radiation. The goal of this study was to determine the local control and breast preservation with particular emphasis on the importance of the final microscopic margins in patients receiving tumor bed boost therapy. METHODS: The authors analyzed 869 cases of Stage I and II breast carcinoma in 852 women who were treated with breast-conserving surgery and radiation therapy between 1984 and 1994. The median follow-up was 43 months. Final microscopic margins were negative in 762 (88%), microscopically positive in 82 (9%), and unknown in 25 (3%) of the patients. Negative margins were defined as no tumor cells at the surgical margin. The patients were treated with external beam radiation therapy to the entire breast to a median dose of 46 Gray (Gy). A boost to the tumor bed was delivered to 863 (99%) of the patients. The median tumor bed dose was 60 Gy. A multivariate analysis of factors impacting on the local control and overall survival was performed. Variables introduced into the model included size, age, lymph node status, microscopic margins, nuclear grade, histologic grade, and estrogen and progesterone receptor status. RESULTS: The actuarial 5-year local control rate was 97%. The median time to local failure was 32 months (range, 14-69 months). In multivariate analysis, the only significant factor affecting local control was the status of margins. In patients receiving boost radiation to the excision site, the local control rate at 5 years was 98% and 89%, respectively, if the margins were negative or positive (P < 0.01). This resulted in 5-year actuarial breast preservation rates of 98% and 92% (P = 0.03). In the patients in whom the margins of excision were microscopically positive, the local control rate was 91% if the total dose to the tumor bed was > 60 Gy compared with 76% for a dose < or = 60 Gy (P = 0.05). The 5-year actuarial overall survival rate was 89%. Approximately 94% of the women considered their cosmetic outcome good to excellent. CONCLUSIONS: By obtaining microscopically negative margins and using tumor bed boost therapy, excellent local control, breast preservation, and cosmesis can be achieved. In patients with microscopically positive margins, an acceptable local control rate can be achieved if a tumor bed boost is given.

Adult↗
PubMed1996

Louisiana health and nutrition survey.

The objective of this project was to conduct a survey to estimate the current prevalence of high-risk dietary, occupational, and other lifestyle factors in subgroups of the Louisiana population by age, sex, race, and geographic region. A probability sample of adult Louisiana residents was selected using a 3-stage cluster design identical to that used in the Louisiana Behavioral Risk Factor Surveillance System. The reduced version of the Health Habits and History Questionnaire developed by Block et al at the National Cancer Institute was administered by telephone. The survey results are presented and discussed.

Adolescent↗
PubMed1995

Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.

N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.

Administration, Oral↗
PubMed1995

Supernumerary ovary with an endometrioma and osseous metaplasia: a case report.

A 32-year-old-woman with a history of endometriosis and chronic pelvic pain had left-sided pain and ultrasonographic documentation of a left pelvic complex cyst approximately 5 cm in diameter. Laparotomy revealed a left retroperitoneal cystic mass adjacent to the iliopsoas muscle and overlying the major pelvic vessels. The mass was dissected and excised. Histopathologic study revealed endometrioma and osseous metaplasia in a supernumerary ovary.

Adult↗