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Biomedical subjects

K R Brown

Publications and source records attributed to K R Brown.

At least 19 recordsLinked to original sources
PubMed2000

A 3'-5' exonuclease in human leukemia cells: implications for resistance to 1-beta -D-arabinofuranosylcytosine and 9-beta -D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate.

A 3'-5' exonuclease that excises the nucleotide analogs 1-beta-d-arabinofuranosylcytosine monophosphate and 9-beta-d-arabinofuranosyl-2-fluoroadenine 5'-monophosphate incorporated at 3' ends of DNA was purified from the nuclei of: 1) primary human chronic lymphocytic leukemia cells, 2) primary and established human acute myeloblastic leukemia cells, and 3) lymphocytes obtained from healthy individuals. The activity of this nuclear exonuclease (exoN) is elevated approximately 6-fold in 1-beta-d-arabinofuranosylcytosine-resistant leukemia cells as compared with drug-sensitive cells, and it differs between two healthy individuals and among three leukemia patients. exoN is a 46-kDa monomer, requires 50 mm KCl and 1 mm magnesium for optimal activity, and shows a preference for single-stranded over duplex DNA. Its physical and enzymatic properties indicate that exoN is a previously uncharacterized enzyme whose activity may confer resistance to clinical nucleoside analogs in leukemia cells.

Antimetabolites, Antineoplastic↗
PubMed2000

Defects in nuclear and cytoskeletal morphology and mitochondrial localization in spermatozoa of mice lacking nectin-2, a component of cell-cell adherens junctions.

Nectin-2 is a cell adhesion molecule encoded by a member of the poliovirus receptor gene family. This family consists of human, monkey, rat, and murine genes that are members of the immunoglobulin gene superfamily. Nectin-2 is a component of cell-cell adherens junctions and interacts with l-afadin, an F-actin-binding protein. Disruption of both alleles of the murine nectin-2 gene resulted in morphologically aberrant spermatozoa with defects in nuclear and cytoskeletal morphology and mitochondrial localization. Homozygous null males are sterile, while homozygous null females, as well as heterozygous males and females, are fertile. The production by nectin-2(-/-) mice of normal numbers of spermatozoa containing wild-type levels of DNA suggests that Nectin-2 functions at a late stage of germ cell development. Consistent with such a role, Nectin-2 is expressed in the testes only during the later stages of spermatogenesis. The structural defects observed in spermatozoa of nectin-2(-/-) mice suggest a role for this protein in organization and reorganization of the cytoskeleton during spermiogenesis.

Animals↗
PubMed1999

Techniques for improving ear definition in microtia reconstruction.

Surgeons involved in microtia repair recognize the difficulty in creating a natural appearing ear. One key to successful reconstruction is to provide sufficient relief between the helix, scaphoid fossa and antihelix to create the illusion of thin skin overlying thin cartilage. Problems such as thick skin, hair-bearing skin and poor-quality cartilage serve to frustrate the surgeons attempt to achieve the desired result. Surgical techniques to improve cartilaginous framework definition in microtia repair are discussed.

Cartilage↗
PubMed1998

Osteoinduction using bone morphogenic protein in irradiated tissue.

OBJECTIVE: To prove the efficacy of bone morphogenic protein as an osteoinductive agent in irradiated tissue. DESIGN: Prospective randomized controlled trial designed to test the effectiveness of recombinant bone morphogenic protein 2 (rBMP-2) combined with solid hydroxyapatite disks in an irradiated tissue bed. SUBJECTS: Eighteen adult, male, white New Zealand rabbits weighing 3.0 to 3.5 kg. INTERVENTION: The rabbits were randomly divided, with 9 receiving radiation treatment and 9 receiving no radiation treatment. Each animal underwent implantation of 2 hydroxyapatite disks onto the snout at 9 weeks following radiation treatment. One disk was impregnated with rBMP-2 and the other with buffer only. The animals were killed at 3, 6, or 20 weeks after implantation for analysis. RESULTS: Histological analysis demonstrated that rBMP-2 was equally effective as an osteoinductive agent in the irradiated and nonirradiated tissue. We also found significantly increased new bone formation in the rBMP-2 group vs the buffer group. CONCLUSIONS: This study supports the potential clinical utility of rBMP-2 and solid hydroxyapatite in irradiated tissue beds. These findings have interesting implications for patients with head and neck cancer who have undergone radiation therapy and need bony reconstruction.

Animals↗
PubMed1998

Changes in the use profile of Mectizan: 1987-1997.

The usually conservative approach of Merck & Co. to drug development became even more so in the Mectizan (ivermectin, MSD) programme because of adverse experiences following 'extra-label' use in Collie dogs and the discovery of a low threshold for acute neurotoxicity in CF-1 mice. Although a very cautious approach and rapid development programme ensued, Merck remained conservative and excluded children under the age of 5 years, pregnant women, and mother who were nursing children under the age of 3 months from treatment. A subsequent, more relaxed set of standards was based on vast human clinical experience, inadvertent use in hundreds of pregnant women without ill-effect, and new laboratory information indicating that the presence of a protective blood-brain barrier protein component (P-glycoprotein) helped to stop Mectizan from crossing the placenta and from crossing the blood-brain barrier in most animal species, including humans. This has allowed more groups to be included in Mectizan treatments: pregnant women living in areas where the risk of loss of sight because of onchocerciasis is very high; and women who are nursing children as young as 1 week of age. Mass distribution of the drug continues to be largely under community control and the likelihood of serious adverse experiences related to finding a human population with unusually low levels of P-glycoprotein (or no P-glycoprotein) seems remote.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Mutagenesis of the Mn2+-binding site of manganese peroxidase affects oxidation of Mn2+ by both compound I and compound II.

The present study investigates whether compound I and compound II of manganese peroxidase from the white-rot fungus Phanerochaete chrysosporium utilize the same Mn-binding site for catalysis. Manganese peroxidase was expressed from its cDNA in Escherichia coli and refolded from inclusion bodies to yield fully active enzyme. Three mutants of the enzyme were generated by site-directed mutagenesis. Each of the three amino acid residues proposed to be involved in Mn2+ binding, E35, D179, and E39, was mutated. The acidic side chains of E35 and E39 were shortened by one carbon to the acidic group D, and the acidic side chain of D179 was shortened by one carbon to the alkyl group A. These mutants, E35D, D179A, and E39D, were used to determine whether Mn2+ reacts at the same site with both compound I and compound II of manganese peroxidase and to determine whether phenolic substrates for the enzyme react at this site. Our results conclusively demonstrate that E35 and D179 residues are involved not only in Mn2+ binding but also in electron transfer from Mn2+ to the enzyme for both compound I and compound II. In contrast, E39 is not critically important to either process. None of the three residues is involved in reactions with phenolic substrates or with H2O2.

Basidiomycota↗
PubMed1997

Negligible prevalence of antibodies against Trypanosoma cruzi among blood donors in the southeastern United States.

Trypanosoma cruzi, a hemoflagellate, causes Chagas' disease and is endemic throughout Latin America. Increasing Latin American immigration to the United States has enhanced concern about transmission of Chagas' disease by infected donor blood. The insect vector and parasites also have been found in the southeastern United States. Autochthonous infection of several species of wild and domesticated mammals suggests that the general human population also may be at risk. To assess the prevalence of antibodies to T cruzi in humans, randomly selected donor blood was screened. Initial screening was performed by indirect hemagglutination (1:4 initial serum dilution) and at least one of three different enzyme immunoassays. All samples testing positive by at least one screening method were tested by radioimmunoprecipitation and indirect immunofluorescence supplemental methods, which were used for confirmation and calculation of specificity. Of the 6,013 serum samples evaluated, 85 tested positive by one screening method. Only 10 of the samples tested positive by more than one method. The percentages of positive screening tests are 0.05% by indirect hemagglutination and 0.06%, 0.91%, 3.97% by Abbott Laboratories (Abbott Park, Ill), Gull (Gull Laboratories, Salt Lake City, Utah), and Polychaco (Polychaco S.A.I.C., Buenos Aires, Argentina) enzyme immunoassays, respectively. All samples were negative by radioimmunoprecipitation and indirect immunofluorescence. These results suggest that although parasite and vector are found in the southeastern United States and both infect mammals, the risk of natural infection to humans in this region seems to be negligible. There was variation in positivity among different screening methods. The highest percentage of positive results was with the enzyme immunoassay, in which the binding of serum antibodies to antigens is amplified by enzymatic reactions.

Animals↗
PubMed1995

Industry perspective on clinical trial issues for combination vaccines.

The development and production of vaccines remains complicated, largely because of the complexity of the vaccines, which are virtually always manufactured in a biological system; the nature of most vaccines precludes the use of the detailed chemical analysis that is possible for simple chemical entities. Therefore, approval and release of vaccines is dependent upon careful view of the manufacturing processes, the analytical data that are available, and data from clinical trials of consistency lots. The makeup of consistency lots from combinations, the purpose and utility of such lots, and the timing of their production depend not only on the maturity of the manufacturing process but also upon mutual agreement between the sponsor and the regulators. Consistency of application of regulations and precedent are important in the sponsor's ability to carry out successful development programs. The science of adjuvants is still in its infancy, but opportunities for it to mature are legion. Aluminum salts remain the mainstay of contemporary adjuvants but will no doubt be supplanted in the near future. The ethics of doing efficacy studies in infants who could be protected by safe and well-tolerated vaccines must be debated openly. Closely related to efficacy studies are the use of surrogates, which should be developed, recognized, and utilized. Finally, the potential utility of M-M-R IIV was shown by studies of the individual attenuated virus components in vaccines.

Adjuvants, Immunologic↗
PubMed1994

New challenges in quality control and licensure. Regulation.

The Children's Vaccine Initiative (CVI) will result in profound changes in immunization practice. Before the CVI is fully developed, it will present numerous challenges to regulatory practice that will require new applications of existing ideas and innovative solutions to practical issues, especially in combining existing vaccines.

Child Welfare↗
PubMed1993

Recombinant erythropoietin overdose.

Deliberate self-administration of recombinant human erythropoietin (rHuEpo) in a patient without anemia has never been documented. The case of a 62-year-old man who worked in an allied health care field and surreptitiously injected the drug, causing his hematocrit to increase to a dangerously high level is presented. Resultant complications of the misuse of erythropoietin in this patient included worsening hypertension, exacerbation of chronic lung disease and development of new onset angina. Medical management consisted of endotracheal intubation with mechanical ventilation, intravenous hydration, and serial phlebotomy. The unusual possibility of erythropoietin abuse must be added to the differential diagnosis with a patient with unexplained polycythemia. This case highlights the potential abuse of biological growth factors that may mask medical conditions.

Angina Pectoris↗
PubMed1992

Concentrations of copper, zinc and lead in the Sydney rock oyster, Saccostrea commercialis (Iredale and Roughley) from the Georges River, New South Wales.

Copper, zinc and lead were analysed from samples of non-commercially grown Sydney rock oysters collected from the Georges River estuary in spring 1987. The results, when compared with previous data from 1975, indicated a marked increase in the concentration of copper (up to 40%) and zinc (up to 300%). For several sites, the recommended (National Health and Medical Research Council) levels for copper and zinc (70 micrograms g-1 and 1000 micrograms g-1 respectively) were exceeded. There appears to be a decrease in the concentration of lead since 1975. The gradient of increasing copper and zinc concentrations with increasing distance upstream from the mouth of the estuary reported in 1975 could not be statistically validated. A significant correlation was found between copper and zinc loadings in the oysters. It was noted that data collected in 1975 were based on commercially grown oysters. The use of commercially grown oysters, rather than indigenous oysters, to examine interaction of contaminant load and distance upstream, is complicated as commercial oysters are moved within the estuary and between estuaries to maximise growth potential.

Animals↗
PubMed1991

Blunt trauma-induced pacemaker failure.

A 54-year-old man with an artificial pacemaker sustained blunt trauma to his chest when he was struck with a baseball bat. Within 15 minutes after the injury, the patient experienced cardiovascular collapse. His pacemaker failed, and he required insertion of a temporary transvenous pacemaker. At surgery, the defect was traced to failure of the pulse generator, a rare cause of pacemaker failure. Emergency department evaluation should include prompt and continuous ECG monitoring, an overpenetrated chest radiograph, and telemetry evaluation after discharge.

Cardiac Pacing, Artificial↗
PubMed1990

The regulation of biological products.

The purpose of regulations for biological products is the same as that for any other medicinal or related products: the protection of recipients of the products. The entry into the age of molecular biology with its attendant development and manufacturing technology has placed new demands on regulatory agencies and related industry personnel. While the general goals of regulations remain the same, the scientific bases by which biological products must be reviewed and registered vary from those traditionally used for drugs or even older vaccines produced by conventional methods of growth, harvesting and purification. New regulations must be developed which take into account the new science involved in molecular biology and recombinant technology; new definitions must be provided and widely understood. The regulation of biologic products on an international basis is complicated by issues such as national interests superceding individual patient needs, bureaucracies being driven primarily by regulation and secondarily by science, industry expecting priority treatment for innovative products while having to absorb costs related to lost regulatory review time, and agencies or industry relying upon outdated regulations and/or archaic tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotechnology↗
PubMed1990

Norfloxacin versus trimethoprim-sulfamethoxazole in the treatment of urinary tract infections.

In a controlled, randomized trial of 133 patients with proven urinary tract infections (UTIs), significantly more pathogens were found to be susceptible to norfloxacin than to trimethoprim-sulfamethoxazole (TMP-SMZ) (p less than 0.01). Among patients with pathogens susceptible to both drugs, more of those treated with norfloxacin were cured or improved (p = 0.06). When at least one patient variable, i.e., prior history of therapy, was corrected for, this difference became significant (p = 0.03). Norfloxacin eradicated 11 of 13 infections due to Pseudomonas aeruginosa and 6 of 7 due to enterococci. Five patients treated with norfloxacin and two treated with TMP-SMZ had relapses within 6 weeks. Significantly fewer adverse experiences occurred in patients receiving norfloxacin (p less than 0.01).

Adult↗
PubMed1990

Ivermectin--clinical trials and treatment schedules in onchocerciasis.

Initial clinical trials with ivermectin were performed in patients with both roundworm infestation and onchocerciasis. Obvious clinical safety allowed for rapid progression through 5-30-50-100-150-200 mcg/kg in infected patients. Initial studies showed some effect at 50 mcg/kg; subsequent double-blind controlled studies, either with placebo or diethylcarbamazine (DEC), confirmed the efficacy of ivermectin as well as further defining its safety profile. Absence of adverse eye findings or serious systemic reactions justified the further open trials. Studies of patients treated at 6, 12, or 18 month intervals showed a long lasting effect of ivermectin in reducing skin microfilaria counts. Phase III studies confirmed safety and efficacy and further refined the dose to 150 mcg/kg every 12 months. Large trials in Liberia and other countries in West Africa, and subsequently under Onchocerciasis Control Program (OCP), included approximately 120,000 persons carefully followed during which few patients with serious adverse experiences were reported. These extensive field trials confirmed the relative safety allowing for broad distribution of ivermectin in programs not able to provide physician monitoring.

Animals↗
PubMed1989

The role of cytochrome c4 in bacterial respiration. Cellular location and selective removal from membranes.

The cellular location of cytochrome c4 in Pseudomonas stutzeri and Azotobacter vinelandii was investigated by the production of spheroplasts. Soluble cytochrome c4 was found to be located in the periplasm in both organisms. The remaining cytochrome c4 was membrane-bound. The orientation of this membrane-bound cytochrome c4 fraction was investigated by proteolysis of the cytochrome on intact spheroplasts. In P. stutzeri, 78% of the membrane-bound cytochrome c4 could be proteolysed, whilst 82% of the spheroplasts remained intact, suggesting that the membrane-bound cytochrome c4 is on the periplasmic face of the membrane in this organism. Cytochrome c4 was not susceptible to proteolysis on A. vinelandii spheroplasts, in spite of being digestible in the purified state. Cytochrome c5 was shown to have a similar cellular distribution to cytochrome c4. Selective removal of cytochrome c4 from membranes of P. stutzeri was accomplished by the use of sodium iodide and propan-2-ol, with the retention of most of the ascorbate-TMPD (NNN'N'-tetramethylbenzene-1,4-diamine) oxidase activity associated with the membrane. Sodium iodide removed most of the cytochrome c4 from A. vinelandii membranes with retention of 62% of the ascorbate-TMPD oxidase activity. Cytochrome c4 could be returned to the washed membranes, but with no recovery of this enzyme activity. We conclude that cytochrome c4 is not involved in the ascorbate-TMPD oxidase activity associated with the membranes of these two organisms.

Azotobacter↗