Biomedical subjects

J Graham

Publications and source records attributed to J Graham.

At least 163 records · Page 9Linked to original sources

PubMed1991

Direct transcriptional regulation of the progesterone receptor by retinoic acid diminishes progestin responsiveness in the breast cancer cell line T-47D.

Retinoic acid (RA) treatment of T-47D human breast cancer cells results in a rapid decrease in the concentration of progesterone receptor (PR) mRNA which causes a slow loss of cellular PR protein (Clarke, C. L., Roman, S. D., Graham, J., Koga, M., Sutherland, R. L. (1990) J. Biol. Chem. 265, 12694-12700). The mechanisms involved are unknown and this study was undertaken to determine whether the decline in PR mRNA was due to transcriptional inhibition and to evaluate the functional consequences of the RA-mediated decrease in PR. The transcription rate of the PR gene was decreased by RA, and the effect was maximal 2-3 h after treatment. Cycloheximide cotreatment was unable to relieve the inhibitory effect of RA and PR transcription suggesting that the effect was not dependent on ongoing protein synthesis. There was no effect of RA on PR mRNA half-life at the times examined (0-6 h of RA treatment). To determine the functional consequence of PR down-regulation the progestin-responsive plasmid pMSG-CAT was expressed transiently in T-47D cells which were then exposed to RA for 24 h. RA-pretreated cells were then treated with the synthetic progestin ORG 2058 and the extent of progestin stimulation of chloramphenicol acetyltransferase (CAT) activity measured. ORG 2058 treatment resulted in an induction of CAT activity which was maximal at a progestin concentration of 1 nM. Interestingly, the ability of ORG 2058 to induce CAT activity was decreased in RA-pretreated cells. The diminished progestin responsiveness of RA-pretreated cells was confirmed in separate experiments which showed that the progestin inducibility of TGF-alpha mRNA was also decreased in cells treated with ORG 2058 following pretreatment with RA for 24 h. These data demonstrate that RA decreases PR mRNA concentrations by direct transcriptional inhibition, leading to decreased cellular PR concentrations. The decreased levels of PR result in impaired responsiveness to progestins and this suggests that RA derived from dietary vitamin A may have a role in modulating cellular sensitivity to progestins.

Breast Neoplasms↗

PubMed1991

Ten years of living with AIDS.

Everyone who has been involved in AIDS work over the past decade has lost a loved one to the disease. The crisis, unfortunately, is far from over; the loss of life will continue for many years. This tenth anniversary provides an opportunity both for reflection and for garnering strength for the tasks that lie ahead.

Acquired Immunodeficiency Syndrome↗

PubMed1990

A new, rapid, one-step method for the isolation of platelets from human blood.

We describe a new, rapid method for the isolation of platelets from human blood using a single centrifugation step through Nycodenz, an inert, nontoxic, nonionic medium. As judged by aggregation and nucleotide release studies, the platelets are recovered in high yield and in excellent functional condition.

Adenosine Diphosphate↗

PubMed1990

Evidence for a role of glycine in area tempestas for triggering convulsive seizures.

An epileptogenic region of the deep prepiriform cortex, area tempestas (AT), triggers convulsive seizures in response to the focal application of GABA antagonists, muscarinic agonists and excitatory amino acid agonists. In all cases, activation of N-methyl-D-aspartate (NMDA)-sensitive receptors in AT is required for triggering convulsions from this site. To determine whether glycine is involved in the activation of NMDA-sensitive receptors in AT, we evaluated the effects of 7-chlorokynurenic acid (7-CLKYN); kynurenic acid (KYN) and 3-amino-1-hydroxy-2-pyrrolidone (HA-966) on convulsions evoked by focal application of bicuculline methiodide (118 pmol) into AT. Significant anticonvulsant effects were obtained with 1.25 nmol of 7-CLKYN, 6.25 nmol of KYN and 60 nmol of HA-966 in AT. 7-CLKYN in AT also blocked the convulsant effects of carbachol (273 pmol) and kainic acid (117 pmol) injected into AT. When injected into the lateral ventricle, high doses (50-100 nmol) of 7-CLKYN were required in order to attenuate AT-evoked convulsions and these doses produced marked ataxia. In contrast, no ataxia was observed following 7-CLKYN application into AT at anticonvulsant doses. Our results implicate glycine antagonism as a mechanism for preventing convulsions triggered via NMDA receptor activation in AT and demonstrate that a different anatomical site of action is responsible for the motor impairment produced by glycine antagonism.

Animals↗

PubMed1990

Progesterone receptor regulation by retinoic acid in the human breast cancer cell line T-47D.

Data are presented which document the first known effect of retinoic acid on progesterone receptor (PR) gene expression. Treatment of T-47D human breast cancer cells with retinoic acid for 48 h resulted in a marked concentration-dependent decrease in the level of PR mRNA and immunoreactive protein which was similar to the known effect of progestins on these parameters. Retinoic acid, however, did not bind to PR, nor did it cause the previously demonstrated increase in PR molecular weight observed after progestin exposure. When T-47D cells were treated with retinoic acid for 6 h rather than 48 h, no reduction in the level of PR protein was noted at any retinoic acid concentration whereas the effects of retinoic acid on PR mRNA at 6 and 48 h were the same. Examination of the time course of the effects of retinoic acid revealed a rapid decrease in PR mRNA levels detectable 1 h after and maximal 6 h after treatment of T-47D cells with retinoic acid. These effects of retinoic acid contrasted with previously demonstrated progestin effects on PR mRNA which were not apparent until 3 h after and were not maximal until 12 h after treatment. As expected, the PR protein concentration was unaffected for at least 6 h but was maximally decreased 24-48 h after retinoic acid treatment. In summary, retinoic acid treatment of T-47D cells caused a decrease in the cellular PR concentration by decreasing levels of receptor mRNA and protein, suggesting that retinoic acid is capable of modulating sensitivity to progestins in human breast cancer cells.

Blotting, Northern↗

PubMed1990

Potent oral anticonvulsant action of CPP and CPPene in DBA/2 mice.

CPP (3-(2-carboxypiperazine-4-yl)-1-phosphonate), and its unsaturated analogue, CPPene (3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid), have potent anticonvulsant activity against sound-induced clonic seizures in DBA/2 mice. Following i.p. administration the protection is maximal at 1-2 h, and the ED50 values (mumol/kg) are: D(-)-CPPene, 1.54; D(-)-CPP, 2.75; D,L( +/- )-CPP, 4.36. Following oral administration the protection is maximal at 3-4 h and the ED50 (mumol/kg) values are: D(-)-CPPene, 40.19; D(-)-CPP, 65.80; D,L( +/- )-CPP, 108.1.

Acoustic Stimulation↗

PubMed1990

Treatment of intractable pruritus ani.

The majority of patients with idiopathic pruritus ani respond favorably to conservative treatment. Moreover, response to specific medical therapy is almost always favorable in certain dermatologic diseases such as psoriasis, mycotic dermatitis, and contact dermatitis. When surgery is performed for anorectal disorders such as hemorrhoids and fistulas, or potentially malignant entities such as extramammary Paget's disease, the accompanying pruritus ani invariably improves as well. Only patients with chronic intractable pruritus ani are included in the current study. Methylene blue (methylthionine chloride) 0.5 percent is injected intracutaneously on the anodermal and perianal skin. With one treatment, long-term cure has been observed.

Adult↗

PubMed1990

Treatment of 29 patients with bulky squamous cell carcinoma of the cervix with simultaneous cisplatin, 5-fluorouracil, and split-course hyperfractionated radiation therapy.

Attempting to improve local disease control in bulky (greater than 8 cm) primary or recurrent pelvic tumors, 29 patients with squamous cell carcinoma of the cervix (stage II, 4; III, 10; IV, 6; recurrent, 9) were treated with concomitant chemotherapy and split-course hyperfractionated radiation therapy between April 1983 and August 1988. Cisplatin (CDDP) and 5-fluorouracil (5-FU) have been shown to be radiation enhancers; furthermore, CDDP, radiation therapy, and continuous-infusion 5-FU have elicited high local response rates in head and neck squamous cell carcinoma. A pilot study of cyclical week on/week off CDDP, continuous-infusion 5-FU, and hyperfractionated radiation therapy was developed. Radiation was administered at 116 cGy twice daily, Days 1-5, every other week for a median dose of 4600 cGy to a pelvic field, with paraaortic extension if indicated. Concomitant chemotherapy included CDDP 60 mg/m2 IV Day 1 and 5-FU 600 mg/m2 IV continuous infusion for 96 hr following CDDP infusion. Patients received a median of four cycles of combined treatment, and intracavitary or interstitial brachytherapy followed in 21 patients. Local pelvic response was achieved in 29 of 29 (100%): complete response (CR) in 19 of 29 (66%), partial response (PR) in 10 of 29 (34%). Among CR patients 10 of 19 (53%) were without evidence of disease at a mean follow-up of 29 (range 12-76) months. Five-year actuarial disease-free survival among complete responders was 65%. Of the 10 CR patients 2 failed in the pelvis, for a local control rate of 17/19 (89%). Chemotherapy-related and acute radiation morbidity was minimal but 2 patients required surgical correction of radiation injury. Aggressive combination of split-course hyperfractionated radiation therapy with radiation enhancers resulted in promising local control of bulky pelvic tumor, with an acceptable complication rate, in this otherwise very poor prognostic group of patients.

Adult↗

PubMed1990

Prophylaxis of aphakic cystoid macular edema without corticosteroids. A paired-comparison, placebo-controlled double-masked study.

Prior investigations have reported that topical nonsteroidal anti-inflammatory drug (NSAID) therapy prevents the development of postoperative angiographic signs of angiographic cystoid macular edema (CME). However, these studies include concurrent use of corticosteroids. The current study reports therapeutic efficacy for ketorolac ophthalmic solution (an NSAID) in the prophylaxis of angiographic aphakic CME (ACME) after cataract surgery without concurrent corticosteroids for the first time. Fifty patients with bilateral cataracts were enrolled in this placebo-controlled, paired-comparison, double-masked study. Eleven patients had evidence of angiographic ACME on postoperative day 40. Two of these patients demonstrated bilateral ACME, one patient had ACME in the NSAID-treated eye, and eight patients demonstrated ACME in the placebo-treated eye. This is a statistically significant difference favoring drug treatment. The signs of anterior ocular inflammation were greater in the eyes with ACME. This study suggests prophylactic treatment of ACME may be possible without the risks of concurrent corticosteroid toxicity. In addition, a higher incidence of ACME in black patients (22%) is observed in this study than has been recognized previously.

Adult↗

PubMed1990

Underwater orthodontics.

A report is presented of a scuba diver who was unable to dive using a normal commercial mouthpiece due to wearing a fixed orthodontic appliance. The situation was resolved with the provision of a customized mouthpiece of simple design and manufacture.

Adolescent↗

PubMed1990

Muscle injuries.

Muscle is a very active metabolic tissue and is frequently injured in sport. The injury heals predominantly by scar tissue which leaves a persistent abnormality within the muscle. Prompt treatment and appropriate rehabilitation can minimize the degree of muscle damage and reduce the incidence of later complications.

Athletic Injuries↗

PubMed1990

Antibiotic prophylaxis and tourniquet inflation in total knee arthroplasty.

Twenty-four patients receiving total knee arthroplasty (TKA) were randomized into one of three groups based on tourniquet inflation one, two, or five minutes after administration 1 g cefazolin. Simultaneous serum, soft-tissue, and bone samples were obtained at regular intervals during surgery. All soft-tissue and bone samples were corrected for cefazolin content. The percentage of cefazolin penetration into soft tissue and bone was calculated using the area under the concentration time curve. Adequate cefazolin concentrations for soft tissue and bone were defined as greater than or equal to 4 x minimum inhibitory concentration90 (MIC90 = 1 microgram/ml) of cefazolin to Staphylococcus aureus and coagulase-negative staphylococci. Patients were similar in age, actual body weight, creatinine clearance, and length of tourniquet inflation. The median percentage of cefazolin penetration into soft tissue and bone for the five-, two-, and one-minute groups was 14.5% and 4.6%, 6.7% and 3.0%, and 5.9% and 4.6%, respectively; the percentage of penetration into soft tissue between the five- and one-minute groups was statistically significant. A higher percentage of patients achieved the desired cefazolin concentration (greater than or equal to 4 micrograms/g) if a five-minute interval was selected. The five-minute group achieved the highest mean ratios of concentration to MIC compared with the two- and one-minute groups, although the differences were not statistically significant. The standard 1 g of cefazolin with a five-minute interval between administration and tourniquet inflation resulted in adequate mean soft-tissue and bone concentrations for prophylaxis during TKA with a tourniquet time less than two hours. Additional doses are not warranted after tourniquet release.

Aged↗

PubMed1989

Whole-abdomen radiation therapy in ovarian carcinoma: its role as a salvage therapeutic modality.

A significant proportion of patients with epithelial ovarian carcinoma eventually fail after initial responses to chemotherapy. Further treatment with chemotherapy consisting of either the same combination or second-line regimens has been ineffective in producing durable responses. Thus, between June 1983 and June 1987, thirty patients with epithelial ovarian carcinoma who failed one or more chemotherapeutic regimens were treated with whole-abdominopelvic-cavity radiation therapy. Prior to the radiation the amount of residual disease after debulking was noted to be microscopic in 16 patients and macroscopic in 14 patients. Radiation was delivered with an open-field technique that extended from the domes of the diaphragm to the obturator foramina. Doses of 2500 cGy were planned to the whole abdomen, with a boost of another 2500 cGy to the pelvic and or paraaortic nodes when indicated. Higher doses were delivered to the areas of gross disease in the pelvis. Only 2 patients were unable to complete the planned therapy. Another 26% of the patients required interruption of the therapy secondary to hematologic toxicity but eventually completed the treatment. With an overall median follow-up of 14 months, 56% of the patients remain alive. Two-year actuarial survival and recurrence-free survival rates are 47 and 32%, respectively. The survival and recurrence-free survival rates for the group with microscopic residual disease--61 and 33%, respectively--are better than those for the patients with macroscopic residual disease--36 and 18%. The abdominopelvic cavity was the first site of failure in all but one of the 17 patients who have failed. In spite of the higher doses, pelvic failure alone or as a component occurred in 54% of the patients. Small bowel obstruction necessitating surgical intervention as a complication of therapy was seen in 13% of the patients.

Abdomen↗

PubMed1989

Long term pathological sequelae of neonatal endotracheal intubation.

In neonates, acquired subglottic stenosis (SGS) is the most serious long term complication of endotracheal intubation. In this case report, we describe the pathological changes in the larynx of a child who died two years after successful treatment, involving corrective surgery, for neonatally acquired SGS. Stenosis, due to dense fibrous connective tissue, was still present at death. However, there was evidence that there had been growth of the laryngeal cartilages. Disruption of the laryngeal cartilages was present anteriorly due to the antecedent surgery but major cricoid cartilage injury secondary to intubation was not seen. The crico-arytenoid joints demonstrated ankylosis and to this was attributed the abnormal quality of voice noted in the child at follow-up. The pathological changes are considered in relation to the pathology of endotracheal intubation and pathogenesis of acquired subglottic stenosis.

Humans↗

PubMed1989

Volumetric growth of the major brain divisions in fetal Macaca nemestrina.

Brains from 22 age-dated fetal Macaca nemestrina were embedded in celloidin and prepared for histological serial sections. A computer-based morphometric system was used to digitize contours of neural structures and to calculate their areas and volumes. Shrinkage of the brain sections was corrected by a multiplication factor relating pre-processed brain volume to the computer-calculated volume of the processed brain. Volume growth of the telencephalon, mesencephalon and pons-medulla was linear over the fetal period of 60 days postconception to near-term at 166 days postconception. Volume growth of the total brain, diencephalon and cerebellum, was curvilinear with respect to age, with slower growth initially and faster growth in the later stages of gestation. Total brain and body grew with an almost 1:1 relation during the fetal period. The proportionate growth of the brain was largely accounted for by telencephalic growth. The other brain divisions all showed different growth rates in relation to growth of the body.

Animals↗

PubMed1988

Quantitative assessment of postsurgical breakdown of the blood-aqueous barrier following administration of 0.5% ketorolac tromethamine solution. A double-masked, paired comparison with vehicle-placebo solution study.

Preoperative and serial postoperative anterior chamber fluorophotometry were performed after oral administration of fluorescein sodium in patients undergoing extracapsular cataract extraction and posterior chamber intraocular lens insertion. The administration of topical 0.5% ketorolac tromethamine solution before and after surgery markedly decreased the breakdown of the blood-aqueous barrier compared with vehicle-placebo solution administration at each time period, as measured by fluorophotometry. Corticosteroids were not given to any patients throughout the duration of the study. These fluorophotometric results correlated well with slit-lamp observations of postoperative ocular inflammation. Both ketorolac and vehicle were well tolerated by patients. No effects on intraocular pressure were seen with ketorolac administration. This study suggests that ketorolac ophthalmic solution is effective and safe as a nonsteroidal anti-inflammatory agent for topical use following cataract surgery and intraocular lens implantation.

Adult↗

PubMed1988

Cochlear implants in children: physiological considerations.

Cochlear implants now play a standard role in the management of adults with acquired profound sensorineural deafness. Their role in children is more controversial. However, as demonstrated by a 1979 report on childhood deafness in the European Communities, there is no reason for complacency in the present management of profoundly deaf children. Transtympanic electrocochleography has been used as a method of estimating neural survival in deafened adults being assessed for the U.C.H./R.N.I.D. single channel extracochlear implant and also in a parallel group of profoundly deaf children referred by a paediatric hearing assessment clinic. In adults the effectiveness of electrocochleography in judging neural survival was monitored by electrical stimulation of the cochlea and found to be significantly effective. This result was extrapolated to the paediatric group to estimate the proportion of congenitally deaf children who might benefit from a cochlear implant. It is suggested that in a programme designed to implant such children at 2 years of age, techniques should be chosen that neither damage the cochlea nor the middle ear sound conducting mechanism.

Adult↗

PubMed1988

Results of treatment of non seminomatous germ cell tumours; 122 consecutive cases in the West of Scotland, 1981-1985.

Between January 1981 and December 1985, 122 patients with non-seminomatous germ cell tumours (NSGT) were seen at a regional referral centre. Of these, a total of 98 patients received chemotherapy for metastatic disease. Treatment was given within collaborative EORTC Urology group studies, all of which involved cis-platin-containing schedules. Ninety patients had tumours of testicular origin, and their 2 year actuarial survival rate is 91%; 8 had tumours of extragonadal origin and their 2 year actuarial survival is 25%. Patients with testicular tumours were subdivided by volume of metastatic disease using the recommendations of the Testicular Cancer Subgroup of the MRC Urological Cancer Working Party and survival was significantly worse in the group with very large volume metastatic disease (VLVM, 57%) compared with the groups with large volume metastases (LVM, 100%) and small volume metastases (SVM, 98%). There were 31 patients with Stage I disease at presentation; of these 6 were treated by prophylactic abdominal radiotherapy and 25 were managed by a policy of surveillance only. Seven of these Stage I patients (23%) relapsed with metastatic disease (median 8 months); all have been successfully treated with chemotherapy. These data confirm that the majority of patients now presenting with metastatic NSGCT are curable with chemotherapy, but that a small proportion with very large volume metastases or extragonadal tumours require alternative chemotherapy schedules.

Antineoplastic Combined Chemotherapy Protocols↗