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Biomedical subjects

J Brady

Publications and source records attributed to J Brady.

At least 91 records · Page 5Linked to original sources
PubMed1986

Cyclosporine pharmacokinetic profiles in liver, heart, and kidney transplant patients as determined by high-performance liquid chromatography.

Cs pharmacokinetic profiles using HPLC have aided in predicting necessary dosage alterations for specific groups of transplant patients. Additional information has been gained by HPLC profiles in nontransplant subjects who are healthy or have a stable disease state. The clinician now knows that liver disease not only impairs Cs elimination but may also have a pronounced effect upon drug absorption. While the cardiac failure patient may have reversible inhibition of Cs clearance, other factors may affect the distribution of the drug to lower dosage requirements. Impaired renal function is not an impediment to Cs elimination, but malabsorption similar to that observed in liver and bone marrow transplant patients may still occasionally complicate therapy. Pharmacokinetic information on Cs must be integrated into the complex care plan of a transplant patient to optimally utilize and monitor this pharmacologic agent.

Adult↗
PubMed1985

Interaction between two transcriptional control sequences required for tumor-antigen-mediated simian virus 40 late gene expression.

Transcriptional control signals required for tumor (T)-antigen trans-activation of the simian virus 40 (SV40) late promoter include T-antigen binding sites I and II and the SV40 72-base-pair (bp) repeats. We have used in vivo competition studies to examine how these signals function in relationship to one another. In vivo competition with recombinant plasmids containing the entire SV40 late regulatory region and promoter sequences [map position (mp) 5171-272] results in quantitative removal of limiting trans-acting factor(s) required for late gene expression in COS-1 cells. Deletion of either the T-antigen binding sites (mp 5171-5243) or the 72-bp tandem repeat (mp 128-272) from the competitor plasmid results in markedly less efficient binding of the trans-acting factor, as judged by the loss of competition. Cotransfection of two separate plasmids, one containing the T-antigen binding sites I and II and the other containing the 72-bp repeats, fails to compete for the trans-acting factors. Insertion of increasing lengths of DNA sequences between the T-antigen binding sites and the enhancer sequences also dramatically reduces the efficiency of competition. These results suggest that efficient binding of trans-acting factors requires the presence, in cis, of at least two SV40 regulatory domains. Our studies further suggest that the distance separating these two transcriptional signals is important.

Animals↗
PubMed1985

Structure of proteins with single-site mutations: a minimum perturbation approach.

A large number of mutant proteins with single amino acid substitutions are now being produced. The ability to predict the structural changes expected from such mutations would aid greatly in the efficient utilization of the mutagenic techniques and in the interpretation of the changes in stability and function that result. A minimum perturbation approach is suggested as a first step in such structural predictions and is tested by application to a recently isolated variant of the hemagglutinin glycoprotein. The agreement between the predicted structure and that inferred from the x-ray refinement is encouraging and provides support for the proposed modeling procedure.

Hemagglutinin Glycoproteins, Influenza Virus↗
PubMed1985

trans Activation of the simian virus 40 late transcription unit by T-antigen.

We have investigated the role of simian virus 40 (SV40) T-antigen in the induction of late gene expression independent of its function in amplifying templates through DNA replication. Northern blot and S1 nuclease analyses showed that stimulation occurred at the transcriptional level. At least two template elements, the T-antigen-binding sites and the 72-base-pair repeats, appeared to be important for this induction. Using template mutants, we demonstrated that deletions within T-antigen-binding site II decreased T-antigen-mediated late gene expression approximately 10- to 20-fold. In addition, multiple point mutations within a single retained copy of the SV40 72-base-pair repeat decreased T-antigen-mediated late gene expression. Using in vivo competition studies, we demonstrated that competitor DNA fragments containing the SV40 control region (nucleotides 5171 through 272) quantitatively decreased SV40 late gene expression in COS-1 cells. In contrast, competition with a plasmid containing SV40 nucleotides 1 through 294 (which removes all of T-antigen-binding site I and half of site II) was much less efficient. Finally, we demonstrated that in vivo competition experiments employing competitor fragments distal to the T-antigen-binding sites within the late template region (SV40 nucleotides 180 through 2533) resulted in superinduction of late gene expression in COS-1 cells. This finding suggests that negative factors such as repressors or attenuators may modulate late SV40 gene expression before induction. Our results are consistent with a model in which induction of late gene expression involves an interaction of the SV40 origin region with DNA-binding proteins, one of which may be T-antigen. Activation of the SV40 late transcription unit may involve induction of the SV40 enhancer or removal of a repressor-like protein or both.

Animals↗
PubMed1985

Reductions in coverage for mental and nervous illness in the Federal Employees Health Benefits Program, 1980-1984.

After nearly 15 years of nondiscriminatory coverage, the largest plan in the Federal Employees Health Benefits Program cut its coverage of care for mental illness disproportionately to coverage for other health care in 1981 and 1982. "Catastrophic" coverage for inpatient mental illness care was introduced by many of the plans in 1984. The authors review the reductions in coverage from economic and clinical perspectives, highlighting the impact of the disparity between the coverage for mental illness and other medical conditions. The model of catastrophic protection for treatment of mental illness set forth in the Federal Employees Health Benefits Program does not bode well for the patient and family who must cope with such a financial contingency.

Blue Cross Blue Shield Insurance Plans↗
PubMed1985

Utilization and coverage of mental health services in health maintenance organizations.

Health maintenance organizations (HMOs) generally have very limited coverage of mental health care and have been charged with shortchanging chronic patients in the interests of economy. The authors analyzed 1979-1980 coverage and utilization data from 53 federally qualified HMOs. They found that while coverage is limited and very similar across the spectrum of HMOs, utilization rates vary greatly and do not correlate with extent of coverage. They suggest that management decisions may be critical in determining access to and use of mental health benefits in HMOs.

Ambulatory Care↗
PubMed1985

Intraperitoneal recombinant alpha 2-interferon for 'salvage' immunotherapy in persistent epithelial ovarian cancer.

Fourteen patients with epithelial ovarian cancer were treated with intraperitoneal (i.p.) administration of alpha-recombinant interferon (rIFN-alpha 2) after documentation of persistent disease at second-look laparotomy and combination chemotherapy. After therapy, 11 patients had a surgical re-evaluation which confirmed 4 complete responses (36%), 1 partial response (9%), and disease progression in 6 (55%). Five of 7 patients (71%) with minimal residual disease (MRD, i.e. less than 5 mm) had a surgically-documented response, whereas there was none in the 4 patients whose tumors were greater than or equal to 5 mm. Fever greater than or equal to 38 degrees C was seen in 58%, greater than or equal to 39.0 degrees C in 18%; nausea and vomiting in 37%, and abdominal pain in 22%. There was no consistent alteration in peripheral WBC's during treatment, while i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer (NK) lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood NK values showed considerable variability. Pharmacokinetic studies showed i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. I.p. rIFN-alpha 2 may act by increasing concentrations of drug and augmenting regional host cells in patients with MRD ovarian cancer.

Adult↗
PubMed1985

Intraperitoneal recombinant alpha-interferon for "salvage" immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study.

Fourteen patients with persistent epithelial ovarian cancer documented at second look laparotomy after combination chemotherapy were treated with 146 cycles of alpha-recombinant interferon (rIFN-alpha 2) administered i.p. The initial dose was 5 X 10(6) units which was escalated weekly to 50 X 10(6) units over 4 weeks and then continued weekly for a total of 16 weeks. Eleven patients underwent surgical reevaluation after therapy which confirmed four pathological complete responses (36%), one partial response (9%), and disease progression in six patients (55%). Five of seven patients (71%) with residual tumor less than 5 mm had a surgically documented response, whereas there was no response in the four patients whose tumors were greater than or equal to 5 mm. Three patients were evaluable for clinical response only: one patient who refused surgery had a complete clinical response with total resolution of ascites; one had stable disease; and one had disease progression. Fever greater than or equal to 38 degrees C was seen in 58%, fever greater than or equal to 39.0 degrees C was seen in 18%, vomiting in 37%, abdominal pain was reported in 22%, and one patient had infectious peritonitis. Peripheral white blood cell counts and i.p. washings were obtained pretreatment and on days 1, 3, and 7 after treatment. While there was no consistent alteration in peripheral white blood cell counts, the numbers of i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood natural killer lymphocyte cytotoxicity values showed considerable variability. Pharmacokinetic studies show that i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. rIFN-alpha 2 i.p. may act by increasing concentrations of drug and augmenting regional host cells in patients with minimal residual ovarian cancer.

Adult↗
PubMed1984

Stimulation of simian virus 40 late gene expression by simian virus 40 tumor antigen.

The early simian virus 40 (SV40) gene product, large tumor (T) antigen, is responsible for the initiation of viral DNA replication and the autoregulation of early gene expression through direct protein-DNA interactions. We investigated the role of T antigen in late viral gene expression, independent of its function in amplifying templates through DNA replication. SV40 DNA was transfected into BSC-1 and COS-1 cells and cultured in the presence of inhibitors of DNA replication. Electrophoretic immunoblot analysis indicated that both the onset and the extent of SV40 late gene expression is increased in COS-1 cells, which constitutively express SV40 T antigen. Blot hybridization analysis of poly(A)-selected RNA demonstrated that the level of synthesis of the major late structural protein VP-1 in COS-1 cells was due to increased transcription. Similar results were obtained when plasmids that contain the SV40 late gene but lack both the origin for viral DNA replication and the early gene coding region were transfected onto COS-1 cells. Using lines of SV40-transformed monkey kidney cells that express altered T antigens, we found that enhanced expression of the late gene product is correlated with the ability of T antigen to bind SV40 DNA. These results indicate that large T antigen plays a role in the stimulation of late viral gene expression.

Animals↗
PubMed1984

Simian virus 40 major late promoter: an upstream DNA sequence required for efficient in vitro transcription.

We have previously identified an 11-base DNA sequence, 5'-G-G-T-A-C-C-T-A-A-C-C-3' (simian virus 40 [SV40] map position 294 to 304), which is important in the control of SV40 late RNA expression in vitro and in vivo (Brady et al., Cell 31:625-633, 1982). We report here the identification of another domain of the SV40 late promoter. A series of mutants with deletions extending from SV40 map position 0 to 300 was prepared by nuclease BAL 31 treatment. The cloned templates were then analyzed for efficiency and accuracy of late SV40 RNA expression in the Manley in vitro transcription system. Our studies showed that, in addition to the promoter domain near map position 300, there are essential DNA sequences between nucleotide positions 74 and 95 that are required for efficient expression of late SV40 RNA. Included in this SV40 DNA sequence were two of the six GGGCGG SV40 repeat sequences and an 11-nucleotide segment which showed strong homology with the upstream sequences required for the efficient in vitro and in vivo expression of the histone H2A gene. This upstream promoter sequence supported transcription with the same efficiency even when it was moved 72 nucleotides closer to the major late cap site. In vitro promoter competition analysis demonstrated that the upstream promoter sequence, independent of the 294 to 304 promoter element, is capable of binding polymerase-transcription factors required for SV40 late gene transcription. Finally, we show that DNA sequences which control the specificity of RNA initiation at nucleotide 325 lie downstream of map position 294.

Base Sequence↗
PubMed1984

Nitrendipine: effects on vascular responses and myocardial binding.

We have further defined the binding characteristics of [3H]nitrendipine to myocardial microsomal membranes of cats, dogs, rats, and rabbits and to canine coronary vasculature (1.5-3.0 mm OD), and we have studied nitrendipine's effect on contractile responses in isolated feline cardiac muscle and canine coronary arteries. [3H]nitrendipine binding is rapid, saturable, and reversible in all four species and in all of these tissues. Feline myocardium has a single binding site with a dissociation constant (KD) of 1.94 nM. Canine myocardium may have two classes of binding sites, with the high-affinity site having a KD of 0.17 nM. Nitrendipine depresses contractility in isolated feline cardiac muscle and canine coronary arteries in a dose-dependent manner [half-maximal dose (ED50) 0.20 microM in isolated feline cardiac muscle and 1.6-6.3 nM for potential dependent contractile responses in isolated canine coronary arteries] and severely blunts the contractile response to increases in extracellular calcium concentration in isolated feline papillary muscles. In contrast to verapamil and D 600, nitrendipine does not prevent the treppe phenomenon. In isolated feline cardiac muscle and large canine coronary arteries, the minimal nitrendipine concentration required for specific binding and for depression of contractile responses is similar. However, only in large canine coronary arteries is the ED50 for nifedipine's depression of contractility similar to the KD for [3H]nitrendipine binding in the respective tissue.

Animals↗
PubMed1984

Internal resorption complicating orthodontic tooth movement.

A case report is presented of an orthodontic patient who suffered internal resorption and a consequent 'pink spot' affecting a maxillary central incisor. Its management is outlined. The aetiology and possible cellular events responsible are discussed.

Adult↗
PubMed1983

Differences in myocardial alpha- and beta-adrenergic receptor numbers in different species.

In the present study, we tested the hypotheses that 1) different species have different myocardial adrenergic receptor numbers and 2) selected "slow-channel" calcium antagonists compete with alpha-adrenergic antagonists for binding to varying degrees in different species. The data obtained in the present study demonstrate that there is a markedly decreased number of alpha 1-adrenergic and increased number of beta-adrenergic receptors in canine compared with rabbit and rat myocardium. The differences in adrenergic receptor numbers exist without major differences in alpha 1-adrenergic receptor affinity in the species studied. There was no significant difference in left ventricular or plasma catecholamine content between the rat and dog. Selected slow-channel calcium antagonists compete for alpha 1-adrenergic receptor binding in rabbit, rat, and canine myocardium. However, only in rabbit myocardium does verapamil antagonize alpha 1-adrenergic receptor binding at moderate concentrations, whereas verapamil in canine and rat myocardium and 1) 600 in all three species antagonize alpha 1-adrenergic receptor binding only at relatively high concentrations. Nifedipine, a dihydropyridine-type slow-channel calcium antagonist, had no effect on prazosin binding to rat, rabbit, and dog myocardial membranes.

Animals↗