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Biomedical subjects

D C Richardson

Publications and source records attributed to D C Richardson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Interval breast cancers in the NHS Breast Screening Programme: does the current definition exclude too many?

OBJECTIVES: To examine the impact of the definition of interval breast cancers on interval cancer rates arising from the prevalent (first) screening round. DESIGN: Interval breast cancers arising from the prevalent (first) screening round at the Warwickshire, Solihull and Coventry Breast Screening Unit (17 April 1989 to 31 March 1992) were identified by comparison of data held at the unit with records at the West Midlands Cancer Intelligence Unit. Exclusion criteria used in National statistics were applied to this sample to quantify their impact on achieved interval cancer rates. The round lengths experienced by individual women at the unit were determined from the prevalent and incident invitation dates for 155 women with incident (re-screen) breast cancers detected in the second round. SETTING: Warwickshire, Solihull and Coventry Breast Screening Unit. SUBJECTS: 59,017 women screened between 17 April 1989 and 31 March 1992 with a negative screening result and 155 women with incident screen detected cancers. RESULTS: A total of 278 interval cancers were identified, giving an overall rate from the prevalent screening round of 47.1/10,000 women screened. Of these, 213 met the criteria used in the definition of interval cancers for National statistics and were termed "core" interval cancers. The overall "core" interval rate was 36.1/ 10,000 women screened, similar to interval cancer rates found in the north west of United Kingdom. Thus applying commonly used exclusion criteria produced a 23.4% reduction in the apparent interval cancer rate, with the largest decrease resulting from the exclusion of cancers arising at 36 months or more from the last screen. CONCLUSIONS: The exclusion criteria used in the definition of interval cancers have a significant impact on observed interval cancer rates. Of particular concern is the exclusion in the current National definitions of cancers arising at 36 months or more from the last screen, which may mask a problem with significant implications for the success of the NHSBSP.

Breast Neoplasms↗
PubMed1997

Improved osseointeraction of calcium phosphate-coated external fixation pins. Studies in calves.

We investigated osseointeraction of solution-precipitated calcium phosphate (SPCP)-coated transfixation pins used in external skeletal fixation of a calf stable fracture model. One group (SPCP) received centrally-threaded transfixation pins which had SPCP coating; the other group (control) received identical, but not coated, pins. Radiographs were obtained 1 and 40 days after surgery and examined for evidence of osteolysis. Bone phase 99mTc-MDP studies were performed 6 and 28 days after surgery. Calves were killed 40 days after surgery and mechanical tests performed. Dual-energy x-ray absorptiometry (DEXA) and histomorphometric analyses were done. A smaller proportion of SPCP pins (5/24) had evidence of discharge during the study compared with control pins (21/24). A smaller proportion of SPCP pins (4%) had radiographic evidence of osteolysis compared with control pins (42%). Uptake of 99mTc-MDP was similar for SPCP and control calves. Uptake was significantly greater in bone segments showing radiographic evidence of osteolysis than in bone segments not having osteolysis. Yield stress (MPa) for axial displacement was similar in the treatment groups. Bone mineral density was less in SPCP pins. Affinity index and interface histologic score were greater and osteoclastic index less in SPCP calves. Coating of transfixation pins with solution-precipitated calcium phosphate improved the osseointeraction of pin and bone during this 40-day study.

Absorptiometry, Photon↗
PubMed1996

Pharmacokinetic model for cefazolin distribution during total hip arthroplasty in dogs.

OBJECTIVES: To compare cefazolin pharmacokinetics in serum and concentrations in tissues during total hip arthroplasty in dogs with and without hip dysplasia, and to calculate the optimal dosage of cefazolin for prophylactic use during total hip arthroplasty. ANIMALS: 10 dogs with hip dysplasia and 3 clinically normal dogs. PROCEDURE: Blood samples and tissue specimens from the coxofemoral joint capsule, acetabulum, and femur were obtained during unilateral total hip arthroplasty. Cefazolin concentrations in serum and tissue specimen supernatant were determined, using high-performance liquid chromatography, for use in pharmacokinetic analysis. Mathematical simulation of serum cefazolin concentration was used to to predict the optimal dose. RESULTS: Mean pharmacokinetic constants (SEM) were 0.146 (0.013) min-1 for alpha, 4.47 min for t1/2 alpha 0.015 (0.004) min-1 for beta, 46.83 min for t1/2 beta. Significant different was not detected for cefazolin distribution and elimination between dogs with and without hip dysplasia. Additional, significant difference was not observed in pharmacokinetic parameters describing distribution and elimination between the first and second doses of cefazolin. The predicted optimal dosage regimen was 8 mg/kg of body weight, i.v. every hour or mg/kg, i.v. every 2 hours. CLINICAL RELEVANCE: For prophylactic i.v. treatment during total hip arthroplasty, use of cefazolin at a dosage of 8 mg/kg every hour or 22 mg/kg every 2 hours should maintain serum cefazolin concentrations at least 10x the minimum inhibitory concentration for 3 to 4 hours.

Acetabulum↗
PubMed1996

Puzzle pieces defined: locating common packing units in tertiary protein contacts.

Puzzle pieces are defined as small packing units which make up the unique tertiary interactions in proteins. Anti-parallel and perpendicular helix-helix contacts were broken down into basic puzzle-piece pairs in order to study the traits of such contacts: their limited geometry, preferred residue involvement, residue conformation and other common constraints. These traits can then be used for continued comparison of other protein structures, improving models of and designing proteins de novo and, in time, predicting 3D structure from primary sequence. Results from a small (100 proteins) database of anti-parallel helix-helix contacts and from preliminary work on a large database (600 proteins) of perpendicular helix-helix contacts are presented.

Amino Acid Sequence↗
PubMed1996

Association of periodontal disease and histologic lesions in multiple organs from 45 dogs.

Forty-five mixed breed dogs were evaluated for the presence and extent of periodontal disease. Histopathology was performed on samples of lung, myocardium, liver, kidney, tonsil, spleen, submandibular lymph node and tracheobronchial lymph node. Mitral valves were evaluated grossly. Statistical analysis was used to determine if there was a relationship between the extent of periodontal disease and histopathologic changes in the tissues examined. In the forty-five dogs studied, an association was found between periodontal disease and histopathologic changes in kidney, myocardium (papillary muscle), and liver.

Animals↗
PubMed1995

The response of cancellous and cortical canine bone to hydroxylapatite-coated and uncoated titanium rods.

Because of the recent trend in total hip arthroplasty to achieve direct contact of the endoprosthesis with cortical bone, comparison of bone apposition from cortical bone and cancellous bone was performed. The response of cortical and cancellous bone to hydroxylapatite was also compared. Implants in cortical bone demonstrated a higher interface shear strength and more bone apposition than those in cancellous bone over all time periods tested. Hydroxylapatite coating increased the interfacial shear and bone apposition in cortical bone at all time periods and in both the 3- and 6-week cancellous bone models. The potential effect of stress shielding (and subsequent bone resorption) by femoral stems ingrown with cortical bone is discussed.

Animals↗
PubMed1995

The Alacoil: a very tight, antiparallel coiled-coil of helices.

The Alacoil is an antiparallel (rather than the usual parallel) coiled-coil of alpha-helices with Ala or another small residue in every seventh position, allowing a very close spacing of the helices (7.5-8.5 A between local helix axes), often over four or five helical turns. It occurs in two distinct types that differ by which position of the heptad repeat is occupied by Ala and by whether the closest points on the backbone of the two helices are aligned or are offset by half a turn. The aligned, or ROP, type has Ala in position "d" of the heptad repeat, which occupies the "tip-to-tip" side of the helix contact where the C alpha-C beta bonds point toward each other. The more common offset, or ferritin, type of Alacoli has Ala in position "a" of the heptad repeat (where the C alpha-C beta bonds lie back-to-back, on the "knuckle-touch" side of the helix contact), and the backbones of the two helices are offset vertically by half a turn. In both forms, successive layers of contact have the Ala first on one and then on the other helix. The Alacoil structure has much in common with the coiled-coils of fibrous proteins or leucine zippers: both are alpha-helical coiled-coils, with a critical amino acid repeated every seven residues (the Leu or the Ala) and a secondary contact position in between. However, Leu zippers are between aligned, parallel helices (often identical, in dimers), whereas Alacoils are between antiparallel helices, usually offset, and much closer together. The Alacoil, then, could be considered as an "Ala anti-zipper." Leu zippers have a classic "knobs-into-holes" packing of the Leu side chain into a diamond of four residues on the opposite helix; for Alacoils, the helices are so close together that the Ala methyl group must choose one side of the diamond and pack inside a triangle of residues on the other helix. We have used the ferritin-type Alacoil as the basis for the de novo design of a 66-residue, coiled helix hairpin called "Alacoilin." Its sequence is: cmSPDQWDKE AAQYDAHAQE FEKKSHRNng TPEADQYRHM ASQY QAMAQK LKAIANQLKK Gsetcr (with "a" heptad positions underlined and nonhelical parts in lowercase), which we will produce and test for both stability and uniqueness of structure.

Alanine↗
PubMed1995

An algorithm for smoothly tessellating beta-sheet structures in proteins.

An algorithm is presented for tiling the surface of beta-sheet structures, smoothed both along the strands and perpendicular to them. The algorithm is intended for creating graphical representations of beta structure within the three-dimensional context of proteins. This article presents sufficient detail to allow a programmer with some knowledge of protein structure to implement the tiling algorithm. Several examples of its use are illustrated.

Algorithms↗
PubMed1994

Betadoublet: de novo design, synthesis, and characterization of a beta-sandwich protein.

How an amino acid sequence encodes the information necessary for a protein to adopt a unique tertiary structure remains unresolved. We are addressing this problem by designing "from scratch" protein molecules that will adopt predetermined three-dimensional structures. Based on this strategy, two identical four-stranded beta-sheets were designed to dimerize and form a beta-sandwich protein, called betadoublet. A synthetic gene encoding half the beta-sandwich protein was expressed in Escherichia coli, and the protein was purified to homogeneity. Biophysical characterization of betadoublet in aqueous solution demonstrated that the disulfide formed between the two sheets and that the dimer was a compact unaggregated globular protein, consisting predominantly of beta-sheet and stable to thermal denaturation. It has some backbone amide protons whose exchange is slow enough to be measured by NMR but binds more of the dye 1-anilinonaphthalene-8-sulfonate than a well-folded protein.

Amino Acid Sequence↗
PubMed1994

Sculpting proteins interactively: continual energy minimization embedded in a graphical modeling system.

We describe a new paradigm for modeling proteins in interactive computer graphics systems--continual maintenance of a physically valid representation, combined with direct user control and visualization. This is achieved by a fast algorithm for energy minimization, capable of real-time performance on all atoms of a small protein, plus graphically specified user tugs. The modeling system, called Sculpt, rigidly constrains bond lengths, bond angles, and planar groups (similar to existing interactive modeling programs), while it applies elastic restraints to minimize the potential energy due to torsions, hydrogen bonds, and van der Waals and electrostatic interactions (similar to existing batch minimization programs), and user-specified springs. The graphical interface can show bad and/or favorable contacts, and individual energy terms can be turned on or off to determine their effects and interactions. Sculpt finds a local minimum of the total energy that satisfies all the constraints using an augmented Lagrange-multiplier method; calculation time increases only linearly with the number of atoms because the matrix of constraint gradients is sparse and banded. On a 100-MHz MIPS R4000 processor (Silicon Graphics Indigo), Sculpt achieves 11 updates per second on a 20-residue fragment and 2 updates per second on an 80-residue protein, using all atoms except non-H-bonding hydrogens, and without electrostatic interactions. Applications of Sculpt are described: to reverse the direction of bundle packing in a designed 4-helix bundle protein, to fold up a 2-stranded beta-ribbon into an approximate beta-barrel, and to design the sequence and conformation of a 30-residue peptide that mimics one partner of a protein subunit interaction. Computer models that are both interactive and physically realistic (within the limitations of a given force field) have 2 significant advantages: (1) they make feasible the modeling of very large changes (such as needed for de novo design), and (2) they help the user understand how different energy terms interact to stabilize a given conformation. The Sculpt paradigm combines many of the best features of interactive graphical modeling, energy minimization, and actual physical models, and we propose it as an especially productive way to use current and future increases in computer speed.

Amino Acid Sequence↗
PubMed1994

The tyrosine corner: a feature of most Greek key beta-barrel proteins.

The Tyr corner is a conformation in which a tyrosine (residue "Y") near the beginning or end of an antiparallel beta-strand makes an H bond from its side-chain OH group to the backbone NH and/or CO of residue Y - 3, Y - 4, or Y - 5 in the nearby connection. The most common "classic" case is a delta 4 Tyr corner (more than 40 examples listed), in which the H bond is to residue Y - 4 and the Tyr chi 1 is near -60 degrees. Y - 2 is almost always a glycine, whose left-handed beta or very extended beta conformation helps the backbone curve around the Tyr ring. Residue Y - 3 is in polyproline II conformation (often Pro), and residue Y - 5 is usually a hydrophobic (often Leu) that packs next to the Tyr ring. The consensus sequence, then, is LxPGxY, where the first x (the H-bonding position) is hydrophilic. Residues Y and Y - 2 both form narrow pairs of beta-sheet H-bonds with the neighboring strand. delta 5 Tyr corners have a 1-residue insertion between the Gly and Tyr, forming a beta-bulge. One protein family has a delta 4 corner formed by a His rather than a Tyr, and several examples use Trp in place of Tyr. For almost all these cases, the protein or domain is a Greek key beta-barrel structure, the Tyr corner ends a Greek key connection, and it is well-conserved in related proteins. Most low-twist Greek key beta-barrels have 1 Tyr corner. "Reverse" delta 4 Tyr corners (H bonded to Y + 4) and other variants are described, all less common and less conserved. It seems likely that the more classic Tyr corners (delta 4, delta 5, and delta 3 Tyr, Trp, or His) contribute to the stability of a Greek key connection over a hairpin connection, and also that they may aid in the process of folding up Greek key structures.

Amino Acid Sequence↗
PubMed1993

Intra-arterial cisplatin with or without radiation in limb-sparing for canine osteosarcoma.

METHODS: Forty-nine dogs with spontaneously occurring osteosarcoma underwent limb-sparing surgery after preoperative therapy consisting of intra-arterial cisplatin alone or intra-arterial cisplatin in combination with doses of radiation from 20-40 Gy in 10 fractions. All resections were marginal, and the defect was repaired with a cortical allograft. RESULTS: Local tumor control was strongly influenced by the percent necrosis in the excised specimen. Overall, the estimated 1-year local recurrence rate was approximately 32% (by life-table estimate). Dogs with less than 75% necrosis had an estimated 1-year recurrence rate of 65%; those with greater than 75% necrosis had an estimated 1-year recurrence rate of 15% (P = 0.004, by log-rank test). Local recurrence was influenced by the radiation dose. Dogs receiving 28 Gy or less had an estimated 50% 1-year recurrence rate, and those receiving 32 Gy or more had an estimated 8% 1-year recurrence rate (P = 0.03, by log-rank test). Normal host bone more frequently became necrotic at doses of 36 Gy or more. CONCLUSIONS: Intra-arterial cisplatin in combination with moderate doses of radiation (32 Gy) can achieve a high percent tumor necrosis while maintaining host bone viability. Survival was limited by distant metastasis but was lengthened by treatment compared with some earlier findings.

Amputation, Surgical↗
PubMed1992

The kinemage: a tool for scientific communication.

A "kinemage" (kinetic image) is a scientific illustration presented as an interactive computer display. Operations on the displayed kinemage respond within a fraction of a second: the entire image can be rotated in real time, parts of the display can be turned on or off, points can be identified by selecting them, and the change between different forms can be animated. A kinemage is prepared and specified by the author(s) of a journal article, in order to better communicate ideas that depend on three-dimensional information. The kinemages are distributed as plain text files of commented display lists and accompanying explanations. They are viewed and explored in an open-ended way by the reader using a simple graphics program, such as the one described here (called MAGE), which presently runs on Macintosh computers. A utility (called PREKIN) helps authors prepare the kinemages. Kinemages are being implemented under the auspices of the Innovative Technology Fund.

Communication↗
PubMed1992

The role of nutrition in canine hip dysplasia.

The role of nutrition in canine hip dysplasia is a multifactorial as the disease itself. Large and giant breeds primarily are at risk for the disease. Rate of growth, feeding methods, feed consumption, specific nutrients, and electrolyte balances within the diet have all been shown to influence hip dysplasia. Known nutritional risk factors are rapid weight gain and excessive calcium supplementation. Nutritional factors with less secure roles in their influence on the disease process are vitamin C, protein, and carbohydrates. There exists a need to identify further and control the various nutritional factors in the diet that influence canine hip dysplasia.

Animal Nutritional Physiological Phenomena↗
PubMed1992

Looking at proteins: representations, folding, packing, and design. Biophysical Society National Lecture, 1992.

Looking at proteins is an active process of interpretation and selection, emphasizing some features and deleting others. Multiple representations are needed, for such purposes as showing motions or conveying both the chain connectivity and the three-dimensional shape simultaneously. In studying and comparing protein structures, ideas are suggested about the determinants of tertiary structure and of folding (e.g., that Greek key beta barrels may fold up two strands at a time). The design and synthesis of new proteins "from scratch" provides a route toward the experimental testing of such ideas. It has also been a fruitful new perspective from which to look at structures, requiring such things as statistics on very narrowly defined structural categories and explicit attention to "negative design" criteria that actively block unwanted alternatives (e.g., reverse topology of a helix bundle, or edge-to-edge aggregation of beta sheets). Recently, the field of protein design has produced a rather unexpected general result: apparently we do indeed know enough to successfully design proteins that fold into approximately correct structures, but not enough to design unique, native-like structures. The degree of order varies considerably, but even the best designed material shows multiple conformations by NMR, more similar to a "molten globule" folding intermediate than to a well ordered native tertiary structure. In response to this conclusion, we are now working on systems that test useful questions with approximate structures (such as determining which factors most influence the choice of helix-bundle topology) and also analyzing how natural proteins achieve unique core conformations (e.g., for side chains on the interior side of a beta sheet, illustrated in the kinemages).

Amino Acid Sequence↗
PubMed1991

Ischemic necrosis of cartilage in spontaneous and experimental lesions of osteochondrosis.

This study was designed to examine the association of spontaneous lesions of osteochondrosis with vascular supply to epiphyseal cartilage, and to determine whether similar lesions could be experimentally reproduced by selective interruption of cartilage canal blood supply. The vascular supply to the articular-epiphyseal cartilage complex of the distal end of the femur was studied in 27 microfil- or barium-injected and cleared specimens and 24 serially sectioned microangiographic specimens from 27 clinically normal female swine (3.6 to 71.0 kg). Blood vessels supplying the articular-epiphyseal cartilage complex were consistently restricted to the epiphyseal region and the number of vessels decreased as the pigs increased in weight (p less than 0.001). Spontaneous lesions of osteochondrosis (i.e., cartilage necrosis) were initially seen in the first areas of epiphyseal cartilage to become avascular and were associated with necrotic blood vessels. The number and size of foci of necrotic cartilage increased as the pigs increased in weight (p less than 0.001). Blood supply to epiphyseal cartilage from cartilage canal vessels was surgically interrupted in a highly vascular area of the medial femoral condyle in eight additional 23-kg female swine. This procedure resulted in necrosis of blood vessels within cartilage canals followed by necrosis of surrounding cartilage, lesions that appeared to be identical to early spontaneous lesions of osteochondrosis. These results suggest that the viability of epiphyseal cartilage in the articular-epiphyseal cartilage complex is highly dependent on an adequate blood supply from cartilage canal vessels, and strongly implicates a defect in blood supply in the pathogenesis of osteochondrosis.

Animals↗