Biomedical subjects
R L Williams
Publications and source records attributed to R L Williams.
Biodegradation of hyaluronic acid derivatives by hyaluronidase.
Hyaluronic acid (salt) (HA) has been chemically modified as a biomaterial for medical applications such as controlled drug release matrices, nerve guides and wound dressings. A series of HA derivatives, which include different ester types and different degrees of esterification, have been used to investigate the stability of these materials in testicular hyaluronidase. Gel permeation chromatography and capillary viscometer have been employed to determine the size of the molecules, the former used for the water insoluble derivatives that dissolve in dimethyl sulphoxide, the latter for the water soluble samples. The preliminary experimental results indicated that the molecular weight of fully esterified hyaluronic acid (both ethyl and benzyl esters) did not decrease after treatment in the enzyme for 7 and 14 days while the water soluble partially esterified HA were degraded by the enzyme producing a sharp reduction of viscosity within minutes. These observations tend to suggest that the carboxylic groups in the beta-glucoronic acid unit are the activation centre of this enzyme and the total blockage of these groups can restrict the cleavage of beta (1-->4) glycoside bonds by this enzyme.
Bioequivalence: performance of several measures of extent of absorption.
The determination of the area under the concentration-time curve (AUC) is the method most commonly used by regulatory agencies to assess extent of drug absorption after single-dose administration of oral products. Using simulations, several approaches toward measuring the actual area, in whole or part, were tested. In addition, the performance of the peak concentration (Cmax), usually taken as a measure of the rate of absorption was assessed evaluating extent. Model scenarios for drugs with typical mean characteristics and statistical distributions were investigated. Using different kinetic models of disposition, the time course of the drug concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and Cmax. However, being also sensitive to rate, Cmax as a measure of extent is of limited potential.
Bioequivalence: performance of several measures of rate of absorption.
The highest point of the plasma concentration-time profile, Cmax, is currently used by regulatory agencies to assess the rate of drug absorption after single dose administration of oral products. It is, however, quite insensitive, and a number of new measures of rate have been proposed. Using simulations, several approaches toward measuring rate were tested. A set of model scenarios for drugs with typical mean characteristics and statistical distributions was investigated. Using different kinetic models of disposition, the time course of the concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of rate were evaluated by simulating crossover design clinical trials and then determining the probability of declaring bioequivalence as a function of differences in rates of absorption between test and reference formulations. All of the rate measures tested showed a degree of insensitivity to changes in rate and no universally superior measure was found. Indeed, the main conclusion is that the choice of a measure should be based on simulations of the particular situation in a bioequivalence trials.
Strategies for the isolation and characterization of bovine embryonic stem cells.
The practical application of advanced breeding technologies and genetic manipulation of domestic animals is dependent on the efficient and routine isolation of embryonic stem (ES) cell lines from these species. ES cell lines of proven totipotency have thus far been isolated only from the mouse. Murine ES cells can be identified by a number of criteria including morphology and characteristics in culture, the presence of specific markers, differentiative capacity and contribution to chimaeras. Reported cell lines derived from ruminant preimplantation embryos do not stably exhibit these characteristics. As demonstrated for the mouse, primordial germ cells may provide an alternative source for pluripotential cell lines. The isolation, culture and preliminary characterization of bovine primordial germ cell-derived (PGCd) cells are described in this paper. The PGCd cells are capable of differentiation in vitro and display murine ES cell markers including alkaline phosphatase. With farm animals, long generation intervals and small numbers of offspring make it important to develop techniques for evaluating chimaeric embryos in vitro before embarking on expensive in vivo programmes. A method for labelling putative pluripotential cells with a fluorochrome marker to follow the fate of such cells was developed. Labelled PGCd cells were injected into blastocysts and the chimaeric embryos were monitored in vitro. Preliminary results demonstrate that the labelled PGCd cells incorporate preferentially within the inner cell mass of the host blastocyst.(ABSTRACT TRUNCATED AT 250 WORDS)
Regulatory aspects of modifications to innovator bronchodilator metered dose inhalers and development of generic substitutes.
Regulatory requirements for modifications to an approved innovator metered dose inhaler (pressurized MDI; USP nomenclature: inhalation aerosol) and for development of a new generic product are discussed. Although many of the requirements apply generally to MDI's, they are discussed with specific reference to albuterol. Changes to the container and closure system may impact on the dosimetry of the redesigned product, as well as upon toxicologic and chemistry, manufacturing and controls (CMC) concerns. Changes to the formulation, including the use of alternate propellants, may raise issues requiring both clinical and in vivo performance evaluation. In view of the level of interest of a number of firms in approval requirements for generic Albuterol Inhalation Aerosol products, the article discusses in considerable detail the CMC and bioequivalence requirements for a generic product. Similarities in the CMC requirements for innovator and generic products are evident. Three comparative in vivo bioequivalence tests, particle size distribution, spray pattern and plume geometry, and unit spray content, established by the Division of Bioequivalence are discussed. Similarities and differences in the in vivo requirements for innovator and generic products are evident. Differences are the result of U.S. statute, which requires safety and efficacy testing for a product approved under a new drug application (NDA), but documentation of bioequivalence for a product approved under an abbreviated new drug application (ANDA). The advantages and disadvantages of three pharmacodynamic study designs which have potential usefulness for documentation of in vivo bioequivalence are discussed.
Biomechanical analysis of a new external fixation system and its clinical significance.
The present study was conducted to analyze the biomechanical properties of a new external fixation system. Each frame was tested in compression, tension, and four-point bending and compared under similar conditions with the performance of the standard configurations of the Orthofix, Hoffmann, and AO models. With the new model we are able to create frames of variable rigidity, both higher and lower than that of the commercially available models. It was also possible to change the rigidity of the new frame as the fracture healed without losing the stability of the fracture. This study demonstrated that the new design, with its simplicity, versatility, and modularity, has sound biomechanical properties and these compare well with the clinical success that the model has achieved during trials.
Outbreaks of syphilis in rural Texas towns, 1991-1992.
Between 1986 and 1990, rates of primary and secondary syphilis increased 134% in rural counties in the South. Reasons for the increases are speculative. During the 14 months ending in October 1992, outbreaks in four eastern Texas counties provided an opportunity to characterize syphilis in rural Texas. We reviewed records for 118 patients and 339 sex partners. Three outbreaks were concentrated in neighborhoods where crack cocaine dealers conducted business and exchange of sex for drugs or money was common; the fourth outbreak involved out-of-town prostitutes who visited undocumented alien workers. Among the 118 syphilis cases, 15 (13%) were primary, 35 (30%) were secondary. Most patients were black (105, 89%); the male-female ratio was 1:1. One woman gave birth to an infant with congenital syphilis. Almost half of the sex partners were infected. HIV pretest counseling was completed for only 55 patients (47%), and only 23 (19%) were tested for the human immunodeficiency virus. These four rural outbreaks of syphilis associated with crack cocaine and the exchange of sex for drugs or money mirror recent urban syphilis outbreaks. Patients in these rural syphilis outbreaks are at risk for HIV infection, but HIV testing has not been emphasized by public health workers.
Office laboratory procedures, economics of practice, patient and parent education, and urinary tract infection.
This review highlights recent advances in four major areas that are relevant to office practice: office laboratory procedures, economics of practice, adolescent risk-taking behavior in terms of sexually transmitted diseases, and urinary tract infections. Who should be screened for diseases and where these screening tests should be done are addressed, keeping the practicing pediatrician in mind. Next we review current office economics, including whether professional courtesy should be continued, how our practices are going to be increasingly influenced by guidelines developed by the American Academy of Pediatrics, the Clinical Laboratory Improvement Amendments, and the new Clinton Health Plan if it survives Congress, and finally how all of these issues will affect our expected income in the years ahead. As pediatricians strive to retain adolescent patients in their practices, they will need to find appropriate ways of counseling these patients concerning risk behaviors that could result in sexually transmitted diseases or HIV infections. Should we leave the comfortable confines of our offices to participate in these counseling programs for adolescents, and are there lessons from existing successful International Health Programs that we can use? Finally, urinary tract infections (UTIs) continue to be a common cause of childhood infections with possible serious long-term sequelae. Can we do a better job of diagnosing UTIs, has improved treatment become available, and is prevention of recurrences possible? Once the diagnosis has been made, how can we best evaluate these children with UTIs for underlying urologic abnormalities? It is our hope that the practicing pediatrician will be better prepared to face these issues having read this review.
Effects on Navajo birthrate from loss of the intrauterine device.
The concerns of relatively powerless groups may not be adequately addressed by health-care decisions based on market forces and on considerations of the general population. Calculations of the number of Navajo women at risk of unintended pregnancy suggest that several hundred such pregnancies would have occurred as a result of the withdrawal of intrauterine devices from the United States' market. Analysis of birthrate data confirms this estimate: approximately four to five percent of Navajo births in 1988 may have been due to this market withdrawal. Available data are limited in their ability to assess impacts on small groups of health-policy decisions made for the population as a whole. A mechanism for surveilling such effects needs to be established to protect the interests of such groups, particularly when they have restricted alternatives.
Use of assisted reading to improve reading rate, word accuracy, and comprehension with ESL Spanish-speaking students.
The present experiment examined the effectiveness of an assisted reading program on reading rates and comprehension of three Spanish-speaking students learning English. The effects of assisted reading on reading rate, word accuracy, and comprehension were examined using a multiple-baseline design across individuals. Increases in words read correctly per minute with repeated readings of the passage and on new passages, decreases in errors per minute, and increases in comprehension were noted.
TQM--fad or reality?
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Hypertonic saline/dextran versus lactated Ringer's treatment for hemorrhage in dehydrated swine.
To determine the efficacy of low-volume resuscitation in dehydrated subjects, 7.5% hypertonic saline/6% dextran 70 (HSD) and lactated Ringer's (LR) treatments were compared in conscious pigs dehydrated for 48 hr prior to a 37% blood volume hemorrhage. Pigs randomized to treatment were resuscitated with equivalent sodium loads of either HSD (4 ml/kg) or LR (33.3 ml/kg) following the 60-min hemorrhage. Dehydration resulted in a 7-8% body weight loss. Mortality through 180 min of recovery was 1/13 (7.7%) for HSD, 1/11 (9.1%) for LR, and 4/8 (50%) for a group of dehydrated and untreated controls (DC). HSD and LR solutions elicited similar heart rate, cardiac output, arterial pressure, and oxygen transport responses in the recovery period following hemorrhage and resuscitation. HSD was as effective as LR in expanding plasma volume in dehydrated hemorrhaged pigs. Serum chemistries provided no evidence for a sustained systemic toxicity from HSD treatment. These findings support low-volume HSD resuscitation of hemorrhagic shock in moderately dehydrated subjects.
Origin of the right subclavian artery from the right pulmonary artery in a newborn with complete transposition of the great arteries.
The clinical and angiographic features of a newborn with differential cyanosis between the right arm and the rest of the body are described. The embryology of the vascular anomalies and the hemodynamic mechanisms are discussed.
A key informant "tree" as a tool for community oriented primary care. The Cleveland COPC Group.
OBJECTIVE: Although community oriented primary care (COPC) is conceptually appealing, lack of practical methodology has limited its application. To implement the initial portions of COPC, most practitioners need to have available inexpensive, quick methods of doing community assessment. Use of community members identified as key informants is one method for conducting the qualitative portion of a community assessment. A key informant "tree" was developed at an inner city health center to analyze its costs, benefits, and limitations as a tool for COPC. METHODS: Using a semi-structured format, 14 of 24 key informants were interviewed using open-ended, closed-ended, and rating questions. An analysis was conducted of the costs of this approach and of the responses received. RESULTS: Planning and implementation of the tree took 6 hours of physician time and 8 hours of nonphysician time. Useful data was obtained from each of the different types of questions, although it appeared best suited to open-ended questions. Response bias was an important problem. The key informant approach appeared most useful with informal community leaders. CONCLUSIONS: With appropriate recognition of the potential biases, key informant trees appear to be a practical and clinically useful tool for the subjective portion of the community assessment component of COPC.
Twins: double pleasure or double trouble?
The birth of twins can be an exciting and challenging experience for a family. However, circumstances unique to the relationship between the twin and the family and the relationship between the twins themselves may exacerbate existing problems or create new ones. Parents are often overwhelmed by the amount of time and work involved in caring for the twins, and other siblings may feel excluded from the family. Twins themselves may have difficulties with processes such as individuation and bonding with other family members. With supportive anticipatory guidance, physicians can help parents and siblings of newborn twins adjust to the special circumstances that the birth of twins can bring.
Crystal structure of Myxococcus xanthus nucleoside diphosphate kinase and its interaction with a nucleotide substrate at 2.0 A resolution.
The X-ray crystallographic structure of nucleoside diphosphate (NDP) kinase from Myxococcus xanthus has been determined using multiple isomorphous replacement techniques and refined at 2.0 A resolution to a crystallographic R-factor of 0.17. This is the first report of the structure of an enzymatically active NDP kinase and of the enzyme with a bound nucleotide. The structure has been determined in P4(3)2(1)2 and I222 crystal forms. The enzyme monomer consists of a four-stranded antiparallel beta-sheet. The surfaces of the sheet are partially covered with five helical segments. There are two protein molecules in the asymmetric unit of the tetragonal crystal form. They form a dimer with an extensive interface in which 1092 A2 per monomer is buried. The majority of the contact area in the dimer interface is between hydrophobic or aromatic residues. Two dimers are related by a crystallographic 2-fold axis to yield a tetramer. This tetramer is also present in the orthorhombic crystals; however, in this case, the 222 symmetry is entirely crystallographic. Upon tetramer formation, an additional 473 A2 of solvent-accessible surface area from each monomer becomes buried. The interface between dimers in the tetramer is stabilized by salt bridges. Equilibrium sedimentation studies are consistent with the enzyme being a tetramer in solution. The structure of a complex of adenosine diphosphate (ADP) with the enzyme was determined and reveals that most of the nucleotide interactions with the protein are with the pyrophosphate and ribose groups, while the base has no hydrogen bonds with the protein and interacts only by stacking with the side chain of Phe59. The Mg2+ interacts with the pyrophosphate of the ADP and via a solvent molecule with the side chain of the conserved Asp120 residue. The mode of interaction with the nucleotide is novel, with the nucleotide binding at the side of the beta-sheet. The structures of the nucleotide in crystals grown in the presence or absence of Mg2+ are essentially identical. In addition, the phosphotransfer reaction from adenosine triphosphate (ATP) to the enzyme can occur without Mg2+. This suggests that only the second step of the reaction in which the enzyme transfers the phosphate to a nucleoside diphosphate acceptor is significantly catalyzed by the metal.
A revised structure for fucoidan may explain some of its biological activities.
Fucoidan from Fucus vesiculosus inhibits human sperm-zona pellucida binding and blocks the zona pellucida-induced acrosome reaction in human sperm. Fucoidan also potently inhibits selectin-mediated adhesion of leukocytes to vascular endothelium. To understand the molecular basis for fucoidan's inhibition of specific cell adhesion events, we have investigated the structure of this fucan using definitive methods of carbohydrate structural analysis. We report the revised average structure for fucoidan. [formula: see text] This average structure differs from the previous model for fucoidan in two respects. First, the core region of the fucan is composed primarily of a polymer of alpha 1-3-linked fucose with sulfate groups substituted at the 4 position on some of the fucose residues. Secondly, fucose is also attached to this polymer to form branch points, one for every 2-3 fucose residues within the chain. This revised average structure is consistent with previous studies suggesting a branched random coil as the best model for this polysaccharide. The proposed model is also a closer structural analogue of the sulfated carbohydrate ligands that bind to selectins. This information should be useful for determining whether a relationship exists between selectin-mediated adhesion of leukocytes and human sperm-egg binding.