Search PubMed⌕ Search

Biomedical subjects

A Russell

Publications and source records attributed to A Russell.

At least 73 records · Page 4Linked to original sources

Human phosphodiesterase 4A: characterization of full-length and truncated enzymes expressed in COS cells.

The type 4 phosphodiesterase (PDE) family comprises four enzymes (4A, 4B, 4C and 4D) that are characterized by their specificity for cAMP and selective inhibition by the anti-depressant drug rolipram (4-[3-(cyclopentoxyl)-4-methoxyphenyl]2-pyrrolidone). In common with other PDEs, they consist of a central conserved domain associated with catalytic activity in addition to two N-terminal upstream conserved regions (UCR1 and UCR2) that are unique to the type 4 enzymes. We have isolated a 2 kb cDNA encoding a full-length type 4A PDE{HSPDE4A4B[Bolger, Michaeli, Martins, St.John, Steiner, Rodgers, Riggs, Wigler and Ferguson (1993) Mol. Cell. Biol. 13, 6558-6571]} from a human frontal cortex cDNA library. Northern blot analysis showed that the major PDE4A mRNA of 4.5 kb was widely distributed in different human tissues. The recombinant PDE4A expressed in COS cells had a molecular mass of approx. 117 kDa as revealed by SDS/PAGE/Western blotting with a PDE4A-specific antibody and was specific for cAMP with a Km of 4.8 microM. The enzyme activity was potently inhibited by R-rolipram (IC50 204 nM) and showed a 2.7-fold stereoselectivity over the S enantiomer. Analysis of the kinetics of inhibition indicated that R-rolipram did not behave as a simple competitive inhibitor. Dixon replots suggested that there was more than one mode of interaction consistent with the detection in the enzyme of a high-affinity binding site for R-rolipram with a Kd of 2.3 nM. Truncation of the PDE4A enzyme by deletion mutagenesis showed that neither of the UCRs was required for catalytic activity and identified an approx. 71 kDa core enzyme with a K(m) for cAMP of 3.3 microM. In contrast with the full-length PDE4A, R-rolipram behaved as a simple competitive inhibitor of this form of the enzyme with decreased potency (IC50 1022 nM) and no stereoselectivity. In addition, no high-affinity rolipram-binding site was detected in the truncated enzyme, indicating that this interaction involves sequences upstream of the catalytic domain of the enzyme.

3',5'-Cyclic-AMP Phosphodiesterases↗

Molecular cloning and expression of a human phosphodiesterase 4C.

A cDNA coding for a human phosphodiesterase 4C (PDE4C2) was isolated from the mRNA prepared from the glioblastoma cell line, U87. The cDNA contained an ORF of 1818 bp corresponding to a 605 amino acid polypeptide. The sequence differed at the 5' end from the human PDE4C previously reported (Engels, P. et al, 1995 FEBs Letters 358, 305-310) indicating that it represents a novel splice variant of the human PDE4C gene. Evidence was also obtained for a third 5' splice variant. The PDE4C2 cDNA was transfected into both COS 1 cells and yeast cells, and shown to direct the expression of an 80 kD polypeptide by Western blotting using a PDE4C specific antiserum. The activity of cell lysates was typical of PDE4 being specific for cAMP and inhibitable by the selective inhibitor, rolipram. However, the Km for cAMP of the enzyme produced in COS cells was 0.6 microM compared to 2.6 microM for the yeast 4C activity. In addition the COS cell PDE4 activity was much more sensitive to R rolipram than the yeast PDE4 enzyme (IC50 of 23 nM compared to 1648 nM). This difference in rolipram sensitivity was associated with the detection of a high affinity [3H] R rolipram binding site on the COS cell 4C enzyme but not on the yeast expressed enzyme. The results indicate that the enzyme can adopt more than one active conformation, which are distinguished by their interaction with rolipram.

3',5'-Cyclic-AMP Phosphodiesterases↗

Extradural pneumatocele: an unusual cause of pulsatile tinnitus.

Our objective is to heighten the awareness of the clinician to the unusual features of latrogenic, pulsatile, yet nonvascular tinnitus. We present the case of an elderly white male with pulsatile tinnitus immediately following microvascular trigeminal decompression. Computed tomography revealed an extradural air collection and mastoidal fistula. The patient noticed resolution of tinnius with digital pressure over the mastoidal operative site. Treatment included exposure of the aerocele with resection of the lateral wall, fistula obliteration with wax, and abdominal fat graft. The patient noted complete resolution of his tinnitus in the recovery room. The etiology of pulsatile tinnitus can be suspected based on history and can be confirmed with corroborative imaging techniques.

Case Reports↗

Sun exposure, sunscreen and their effects on epidermal Langerhans cells.

This study examined the effects of chronic and current sun exposure on the number of Langerhans cells in epidermal sheets of UV-exposed and unexposed skin of the arms and assessed the effect of sunscreens. Participants were enrolled in a skin cancer prevention trial and had been using sunscreen daily for the previous 3 years. There were significantly fewer Langerhans cells on the exposed (463 cells/mm2) than on the unexposed forearm (528 cells/mm2) (P = 0.0001). High sun exposure in the previous 2 weeks and a history of predominantly outdoor occupations were both associated with a reduced number of Langerhans cells, although age and other biological indicators of chronic exposure were not associated. Sunscreen use was protective against the effects of current but not chronic sun exposure, with a suggestion of a greater effect at higher levels of exposure. Unexpectedly, people with a past history of nonmelanoma skin cancer had more Langerhans cells in both the exposed and the unexposed skin. These results emphasize the need for continued public health education to protect the immune system from the damaging effects of UV radiation.

Adult↗

Cannabis use in a general psychiatric population.

It is known that there is an association between cannabis use and psychosis. Clinically we had thought that there were increasing numbers of patients admitted to hospital who were using cannabis and that this was affecting their illness. A study was therefore undertaken to determine the extent of cannabis use and its relationships over a one month period. The findings and their implications for junior doctors on-call are also discussed.

Adolescent↗

Clinical comparison of circular versus noncircular acquisition using technetium-99m myocardial perfusion SPECT imaging.

UNLABELLED: The optimal orbit for myocardial SPECT imaging has not yet been determined. In order to evaluate differences in image quality and reader interpretation between orbiting methods, 50 patients scheduled for routine stress/rest 99mTc-sestamibi imaging had both a circular and a noncircular study using an ADAC Vertex dual-head imaging system. METHODS: Each study was acquired using a 64 x 64 matrix, 64 stops at 25 sec per stop. Images were processed using a Butterworth filter with a frequency cutoff of 0.6 and an order of 5.0. Studies were interpreted by three experienced readers without knowledge of patient name or orbiting technique for normal and abnormal segments and overall image quality. RESULTS: There was no significant difference in the semi-quantitative assessment of either defect extent or reversibility or in the quantitative assessment of defect size between the two types of orbits. However, while all 50 noncircular studies were read as good or fair quality, 23 circular studies were read as fair or poor (p = < 0.0002). CONCLUSION: Qualitative and quantitative analysis revealed similar size and extent of perfusion defects using either circular or noncircular orbit, but images with the noncircular orbit were of significantly better image quality and may be preferable to a circular orbit with 99mTc-sestamibi.

Adrenergic beta-Agonists↗

The Dundee out-of-hours cooperative: preliminary outcomes for the first year of operation.

The Dundee out-of-hours cooperative (DDOC) was the first of its kind to be developed in a city in Scotland. In its first year of operation, the key features of the cooperative were that (a) two doctors could deal with the large majority of out-of-hours calls for a population of just under 100,000 patients, (b) only one third of calls required a home visit, (c) most calls were handled within a period of time acceptable to patients, (d) seven out of 10 patients rated the service equal to or better than previous services, and (e) there were extended opportunities for general practitioners (GPs) involved in the scheme to meet with other colleagues during out-of-hours work.

Family Practice↗

Cervical carcinoma and pregnancy. A national patterns of care study of the American College of Surgeons.

BACKGROUND: The American College of Surgeons conducted a national patient care and evaluation study of invasive cervical carcinoma in pregnant patients. METHODS: Invasive cervical carcinoma was diagnosed in 161 patients who were pregnant at the time of diagnosis. A long term study of 78 patients diagnosed in 1984 was compared with a short term study of 83 patients diagnosed in 1990. RESULTS: The mean age of the patients was 31.8 years. Clinical stages were: IA (29%); IB (54%); IIA (6%); IIB (4%); IIIA (0%); IIIB (3%); IV (1%; AND IVB 3%). Thirty-one percent of patient were diagnosed in the first trimester, 34% in the second, and 35% in the third. A tumor size of 4 cm or larger in diameter was found in 36% of the patients diagnosed in the first trimester, 40% of the patients diagnosed in the second, and 38% of the patients diagnosed in the third. Patients were treated with surgery alone (86), radiotherapy alone (30), or with combination therapy (45). The overall 5-year survival rate for patients diagnosed in 1984 was 82%. In this group, the 5-year survival rate for patients diagnosed in the first trimester was 94.6%, in the second, 76.9%, and in the third, 68.9%. Comparing the two time periods, surgical therapy was performed more often by gynecologic oncologists in 1990 (69% vs. 42%), and a greater percentage of patients were diagnosed with a tumor size of 4 cm or larger in diameter (43% vs. 26%) as well as with stage IIB-IVB disease (15% vs. 6.7%). CONCLUSIONS: The prognosis of pregnant patients with invasive cervical carcinoma is similar to that for nonpregnant patients. The significant number of patients diagnosed in the second and third trimesters and the frequent finding of large tumors in all trimesters emphasize the need for patient education and early prenatal evaluation, including cervical cytology and biopsy of any clinically abnormal cervix.

Adult↗

Final results of a phase II chemoradiation protocol for locally advanced cervical cancer: RTOG 85-15.

BACKGROUND: The lack of improved cure rates for advanced cervical cancer after three decades of megavoltage radiotherapy (RT) has prompted continued efforts in improved treatment delivery. Concurrent chemoradiation (CR) is one of the several avenues being explored to improve these results. METHODS: Sixty women with advanced cervical cancer (30 patients with unfavorable Stage IIB and 30 patients with Stages III and IVA) were treated with CR comprising of a combination of external and intracavitary RT delivering between 7000 to 7500 cGy total to point A and 5890 to 6015 cGy to point B along with one cycle of 5-FU and mitomycin C and a second cycle of 5-FU and cis-platinum. RESULTS: Grade 3 and 4 RT-related toxicities were 15 and 3%, respectively. Chemotherapy-related Grade 3 and 4 toxicities were 9 and 2%, respectively. The 5-year survival for unfavorable Stage IIB patients was 48%; for Stages III and IVA it was 39%. CONCLUSIONS: The toxicity of this particular CR regimen was acceptable and suggests that further qualitative and quantitative intensification of chemoradiation may be attempted. Retrospective comparisons with PCS studies and previous RTOG studies 79-20 and 80-05 suggest that this particular chemoradiation regimen may offer a modest survival advantage over RT alone for Stages III and IVA disease. A CR regimen with higher doses of radiotherapy and a greater number of active chemotherapeutic agents may yet result in acceptable toxicity and further improve cure rates in advanced and poor prognostic featured cervical cancer.

Adolescent↗

The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4.

1. The novel tri-aryl ethane CDP840, is a potent and selective inhibitor of cyclic AMP phosphodiesterase type 4 (PDE 4) extracted from tissues or recombinant PDE 4 isoforms expressed in yeast (IC50S: 4-45 nM). CDP840 is stereo-selective since its S enantiomer (CT 1731) is 10-50 times less active against all forms of PDE 4 tested while both enantiomers are inactive (IC50S: > 100 microM) against PDE types 1, 2, 3 and 5. 2. Oral administration of CDP840 caused a dose-dependent reduction of interleukin-5 (IL-5)-induced pleural eosinophilia in rats (ED50 = 0.03 mg kg-1). The eosinophils in pleural exudates from CDP840-treated animals contained higher levels of eosinophil peroxidase (EPO) than cells from control animals, suggesting a stabilizing effect on eosinophil degranulation. CDP840 was approximately equi-active with the steroid dexamethasone in this model and was 10-100 times more potent than the known PDE 4-selective inhibitors rolipram and RP73401. The activity of CDP840 was not influenced by adrenalectomy, beta-sympathomimetics or beta-sympatholytics. 3. Antigen-induced pulmonary eosinophilia in sensitized guinea-pigs was reduced dose-dependently by CDP840 (0.01-1 mg kg-1, i.p.) and intracellular EPO levels were significantly higher. CDP840 was more potent in these activities than CT1731 or rolipram and comparable in potency to RP73401. 4. Rolipram or CDP840 were less active than dexamethasone in preventing neutrophil accumulation, or exudate formation in carrageenan-induced pleurisy in rats and thus do not exhibit general anti-inflammatory activity. 5. In sensitized guinea-pigs, aerosols of the antigen ovalbumin caused a dose-dependent bronchoconstriction demonstrated by an increase in pulmonary inflation pressure. Administration of CDP840 (0.001-1.0 mg kg-1, i.p.), 1 h before antigen challenge, resulted in dose-dependent reduction in response to antigen. This activity was not due to bronchodilatation since higher doses of CDP840 (3 mg kg-1) did not significantly change the bronchoconstrictor response to histamine. Rolipram was approximately 10 times less active than CDP840 in preventing antigen-induced bronchoconstriction. 6. These results confirm the observations that selective PDE 4 inhibitors reduce antigen-induced bronchoconstriction and pulmonary eosinophilic inflammation. CDP840 is more potent than rolipram in inhibiting native or recombinant PDE 4. Unlike the recently described potent PDE 4 inhibitor RP73401, CDP840 is more active than rolipram in the rat IL-5 model following oral administration. The novel series of tri-aryl ethanes, of which CDP840 is the lead compound, could be the basis of an orally active prophylactic treatment for human asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗

The expression of parathyroid hormone and parathyroid hormone-related protein in developing rat parathyroid glands.

Secretion of parathyroid hormone-related protein (PTHrP) by sheep fetal parathyroid glands is reported to be an important factor in the maintenance of a placental calcium pump. The aim of the present study was to determine whether the developing rat parathyroid glands express PTHrP or parathyroid hormone (PTH), or both. Hybridisation histochemistry was used to detect transcription of PTHrP and PTH in serial paraffin sections through the 12.5- and 13.5-day rat embryo parathyroid anlage, as well as in sections through the 17.5-day embryonic and adult parathyroid glands. Results show strong expression of PTH in the 13.5-day embryonic parathyroid anlage, as well as in the parathyroid gland of the 17.5-day embryo and adult. Transcription of the PTHrP gene was not detected. The more sensitive technique of reverse transcription PCR was then performed. The pharyngeal region of 11.5-, 12.5- and 13.5-day rat embryos was dissected out and, at each stage, RNA was extracted from these tissues, as well as pooled tissues from the rest of the embryo. RNA that had been extracted from adult thyroid/parathyroid tissue was also tested. After reverse transcription, the resulting cDNAs were amplified by PCR (50 cycles) using specific PTH and PTHrP primers. The results show an abundance of PTH mRNA, specific to the pharyngeal region of the 13.5-day embryo, as well as to adult thyroid/parathyroid tissue. PTHrP expression was detected at very low levels in both parathyroid and extraparathyroid tissues. The presence of immunoreactive PTHrP and immunoreactive PTH in the pharyngeal region and rest of the body of 12.5- and 13.5-day rat embryos was assessed by specific RIAs. Whilst immunoreactive PTHrP was not detected in any of the tissues assayed, immunoreactive PTH was detected only in the pharyngeal region of the 13.5-day embryo. This confirms the results obtained from the gene expression studies. We conclude then that, in the developing rat embryo, PTH rather than PTHrP is more likely to play a role in calcium regulation. This is in contrast with the reported situation in the sheep, and suggests that fundamental species differences in fetal calcium regulation exist in mammals.

Aging↗

Hysterectomy in invasive cervical cancer: a national patterns of care study of the American College of Surgeons.

BACKGROUND: As the use of Papanicolaou cytologic screening became widespread in the United States of America, there was a shift toward diagnosis of earlier clinical stages in patients with carcinoma of the cervix. This increase in early stage disease has also resulted in increased use of surgery as the primary treatment. Thus, it seems appropriate to investigate the role of hysterectomy in the modern treatment of patients with invasive carcinoma of the cervix, including survival rates and the role of the gynecologic oncologist. STUDY DESIGN: Approximately 1,800 hospitals were sent invitations to submit data on a standard collection form designed by a multidisciplinary committee of specialists. Cancer registrars at 703 hospitals submitted anonymous data on 11,721 patients with carcinoma of the cervix who were diagnosed or treated, or both, in 1984 and 1990. RESULTS: There were 6,570 (56.1 percent) women who had major operations. An operation with curative intent, either total hysterectomy (TAH) or radical type II or III hysterectomy with pelvic node dissection PND (RHPND), was carried out in 5,105 (43.6 percent) women, constituting 38.9 percent of the patients in 1984, and 48.2 percent of the patients in 1990. Overall (both years), 66.5 percent of patients had squamous cell carcinomas and 21.1 percent had adenocarcinomas. The type of operation performed was judged appropriate in 95.6 percent of the patients who underwent RHPND, but in only 80.0 percent of the patients who underwent TAH. Gynecologic oncologists performed 46.8 percent of the hysterectomies in 1984, and 63.8 percent in 1990. Recurrence and long-term survival data are available for the 1984 patients; five-year survival rates for women who underwent TAH (n = 1,013) and RHPND (n = 1,279) were 89 and 85 percent, respectively. A RHPND with negative nodes resulted in a 90 percent five-year survival rate (n = 916) as compared to 70 percent in those with positive nodes (n = 194). CONCLUSIONS: The use of hysterectomy as definitive therapy increased markedly from 1984 to 1990 and was associated with low complication and high five-year survival rates. Gynecologic oncologists now perform the majority of hysterectomies for this type of carcinoma, with general gynecologists playing a lesser role than in the earlier study year. Guidelines should be developed for the use of TAH in patients with invasive carcinoma of the cervix.

Adenocarcinoma↗

Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas.

BACKGROUND: Epidemiologic evidence of associations between the high intake of fat and low intake of dietary fiber, beta carotene, and other dietary constituents and the risk of colorectal neoplasia has been inconsistent and has not provided a sufficient basis for recommendations concerning the dietary prevention of large-bowel cancer in humans. PURPOSE: We conducted a clinical trial to assess the effects on the incidence of adenomas of reducing dietary fat to 25% of total calories and supplementing the diet with 25 g of wheat bran daily and a capsule of beta carotene (20 mg daily). METHODS: We performed a randomized, partially double-blinded, placebo-controlled factorial trial in which half the patients were assigned to each intervention, resulting in seven intervention groups and one control group. Eligibility criteria included histologic confirmation of at least one colorectal adenoma and confidence expressed by the colonoscopist that all polyps had been removed. Dietary changes were individually initiated and monitored by dietitians and research nurses. At surveillance colonoscopy, the size and location of all polyps were recorded, and their histology was later centrally reviewed. Among 424 patients who were randomly assigned in the trial, 13 were found to be ineligible upon histologic review. Among the remaining 411, complete outcome data were collected from 390 at 24 months and from 306 at 48 months. All P values are from two-sided tests of statistical significance. RESULTS: There was no statistically significant prevention of total new adenomas with any of the interventions. We found a statistically non-significant reduced risk of large adenomas (> or = 10 mm) with the low-fat intervention: At 24 months, the odds ratio (OR) adjusted for potential confounders = 0.4 and 95% confidence interval (CI) = 0.1-1.1; at 48 months, OR = 0.3 and 95% CI = 0.1-1.0. Less and statistically nonsignificant reductions in the risk of large adenomas were found with wheat bran: At 24 months, OR = 0.8 and 95% CI = 0.3-2.2; at 48 months, OR = 0.8 and 95% CI = 0.3-2.5. Patients on the combined intervention of low fat and added wheat bran had zero large adenomas at both 24 and 48 months, a statistically significant finding (P = .03). CONCLUSIONS: Because only small numbers of patients were studied, our finding that the combination of fat reduction and a supplement of wheat bran reduced the incidence of large adenomas in this randomized, controlled trial must be treated with caution. The results do suggest, however, that these interventions may reduce the transition from smaller to larger adenomas, a step that may critically define those adenomas most likely to progress to malignancy.

Adenoma↗

Patterns of care for invasive cervical cancer. Results of a national survey of 1984 and 1990.

BACKGROUND: The American College of Surgeons conducted a national patient care and evaluation study of invasive cervical cancer to measure any changes in patterns of care for the years 1984 and 1990. METHODS: Hospitals with cancer programs were invited to submit data on up to 25 consecutive patients with newly diagnosed invasive cervical cancer for each of the two study years. Data were obtained from 684 hospitals on 5904 patients diagnosed in 1984 and from 700 hospitals on 5817 patients diagnosed in 1990. A long term study of patients diagnosed in 1984 was compared with a short term study of patients diagnosed in 1990. Survival data were described only for patients diagnosed in 1984. RESULTS: Of a total of 11,721 patients, 59.4% were diagnosed and treated at the reporting institution in 1984 and 54.8% in 1990. The remaining patients were referred for treatment after diagnosis elsewhere. The diagnosis was established by cervical biopsy for 69.8% of patients, by conization alone for 9.3%, and by both procedures for 11.8%. The histopathologic diagnoses were squamous cell carcinoma (79.8%), adenocarcinoma (15.8%), and other (4.4%). The stage distributions were as follows: IA, 15.9%; IB, 36.8%; IIA, 8.2%; IIB, 15.5%; IIIA, 2.5%; IIIB, 13.3%; IVA, 2.6%; and IVB, 5.2%. The stage was listed as unknown for 20.3% of patients. Patients were treated with surgery alone (29.2%), radiation alone (40.7%), chemotherapy alone (0.7%), or combination therapy (21.5%), and 7.9% received no treatment at the reporting institution. The overall survival for patients diagnosed in 1984 was 68.3%. Survival by stage in this group was as follows: IA, 93.7%; IB, 80.0%; IIA, 67.2%; IIB, 64.7%; III, 37.9%; and IV, 11.3%. CONCLUSIONS: These data indicate that invasive cervical cancer is highly curable when diagnosed early. During the 5-year period, stage distributions were similar, the use of extended hysterectomy increased, and gynecologic oncologists were more often the primary surgeons. The use of radiation alone decreased.

Adult↗

Late injury of cancer therapy on the female reproductive tract.

The purpose of this article is to review the late effects of cancer therapy on the female reproductive tract. The anatomic sites detailed are the vulva, vagina, cervix, uterus, fallopian tubes, and ovaries. The available pathophysiology is discussed. Clinical syndromes are presented. Tolerance doses of irradiation for late effects are rarely presented in the literature and are reviewed where available. Management strategies for surgical, radiotherapeutic, and chemotherapeutic late effects are discussed. Endpoints for evaluation of therapeutic late effects have been formulated utilizing the symptoms, objective, management, and analytic (SOMA) format. Late effects on the female reproductive tract from cancer therapy should be recognized and managed appropriately. A grading system for these effects is presented. Endpoints for late effects and tolls for the evaluation need to be further developed.

Dose-Response Relationship, Drug↗

Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes.

Three mouse homologues of the Drosophila homeotic gene Caudal (Cad) have been described. They are currently designated Cdx-1, Cdx-2, and Cdx-4. Cdx-1 and 2 are both strongly expressed in the adult mid- and hindgut, while Cdx-1 and 4 have been shown to be activated in the embryonic primitive streak. Using a polyclonal antibody against a fusion protein containing the amino terminal 109 amino acids of murine Cdx-2, we here describe the topographical location of the gene product from early cleavage to 12.5 days of embryonic development. Cdx-2 expression begins at 3.5 days and is confined to the trophectoderm, being absent from the inner cell mass. Subsequently, staining is located in the extra-embryonic ectoderm adjacent to the epiblast, but sparing the more superficially placed polar, as well as the mural trophoblastic cells. Continuing expression in the fetal membranes involves the chorion, the allantoic bud, and, at even later stages, the spongiotrophoblast. From 8.5 days, Cdx-2 begins to be expressed in embryonic tissues, principally (unlike Cdx-1) in the posterior part of the gut from its earliest formation, as well as in the tail bud and in the caudal part of the neural tube. Cdx-2 is, therefore, transcribed well before any other membrane of the Cad homologue group and of the related Hox-C group; its expression in the extra-embryonic membranes and in the hindgut reflects the phylogenetic relationship between the cloaca and the chorio-allantois and suggests the possibility that homeobox genes may be involved in placental development and/or patterning.

Animals↗