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Biomedical subjects

S D Patterson

Publications and source records attributed to S D Patterson.

At least 37 records · Page 2Linked to original sources
PubMed2001

Ligamentous stabilizers against posterolateral rotatory instability of the elbow.

BACKGROUND: The lateral ulnar collateral ligament, the entire lateral collateral ligament complex, and the overlying extensor muscles have all been suggested as key stabilizers against posterolateral rotatory instability of the elbow. The purpose of this investigation was to determine whether either an intact radial collateral ligament alone or an intact lateral ulnar collateral ligament alone is sufficient to prevent posterolateral rotatory instability when the annular ligament is intact. METHODS: Sequential sectioning of the radial collateral and lateral ulnar collateral ligaments was performed in twelve fresh-frozen cadaveric upper extremities. At each stage of the sectioning protocol, a pivot shift test was performed with the arm in a vertical position. Passive elbow flexion was performed with the forearm maintained in either pronation or supination and the arm in the varus and valgus gravity-loaded orientations. An electromagnetic tracking device was used to quantify the internal-external rotation and varus-valgus angulation of the ulna with respect to the humerus. RESULTS: Compared with the intact elbow, no differences in the magnitude of internal-external rotation or maximum varus-valgus laxity of the ulna were detected with only the radial collateral or lateral ulnar collateral ligament intact (p > 0.05). However, once the entire lateral collateral ligament was transected, significant increases in internal-external rotation (p = 0.0007) and maximum varus-valgus laxity (p < 0.0001) were measured. None of the pivot shift tests had a clinically positive result until the entire lateral collateral ligament was sectioned. CONCLUSIONS: This study suggests that, when the annular ligament is intact, either the radial collateral ligament or the lateral ulnar collateral ligament can be transected without inducing posterolateral rotatory instability of the elbow.

Aged↗
PubMed2000

Case studies, practical issues and observations on population and individual bioequivalence.

The FDA has proposed replacing the 1992 average bioequivalence (ABE) with population and individual bioequivalence (PBE and IBE). This has led to considerable public discussion between regulatory, academic and industry experts. At the heart of the discussion has been the relatively modest amount of available data to examine the behaviour of the PBE and IBE criteria. A retrospective analysis of 22 data sets from 15 replicate cross-over bioequivalence studies has been conducted (n=12-74). AUC and C(max) parameters from these studies were analysed using ABE, PBE and IBE methods. Of the 22 data sets for AUC, 19 pass ABE, all pass PBE and 20 pass IBE. Of the three data sets that failed ABE, all passed PBE and one passed IBE. The results for C(max) are more variable. Of the 16 data sets where ABE is demonstrated, one data set failed both PBE and IBE. Of the six data sets that failed ABE, two passed both PBE and IBE, three passed PBE but not IBE and one failed all three criteria. There were five data sets that passed ABE and PBE but not IBE. Additional practical issues involving the behaviour of the new criteria and its expected impact on sample size for highly variable drug products will be presented. The characterization of key parameters and their interrelationships will also be discussed with particular emphasis on the subject by formulation term in the IBE criteria. It is concluded that more studies and simulations are desirable before full-scale implementation of PBE and IBE criteria.

Area Under Curve↗
PubMed2000

Cloning and characterization of the murine glucosamine-6-phosphate acetyltransferase EMeg32. Differential expression and intracellular membrane association.

N-Linked glycosylation is a post-translational modification occurring in many eukaryotic secreted and surface-bound proteins and has impact on diverse physiological and pathological processes. Similarly important is the generation of glycosylphosphatidylinositol linkers, which anchor membrane proteins to the cell. Both protein modifications depend on the central nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc). The enzymatic reactions leading to generation of nucleotide sugars are established, yet most of the respective genes still await cloning. We describe the characterization of such a gene, EMeg32, which we identified based on its differential expression in murine hematopoietic precursor cells. We further demonstrate regulated expression during embryogenesis. EMeg32 codes for a 184-amino acid protein exhibiting glucosamine-6-phosphate acetyltransferase activity. It thereby holds a key position in the pathway toward de novo UDP-GlcNAc synthesis. Surprisingly, the protein associates with the cytoplasmic side of various intracellular membranes, accumulates prior to mitosis, and copurifies with the cdc48 homolog p97/valosin-containing protein.

Acetyltransferases↗
PubMed2000

Identification and characterization of proSAAS, a granin-like neuroendocrine peptide precursor that inhibits prohormone processing.

Five novel peptides were identified in the brains of mice lacking active carboxypeptidase E, a neuropeptide-processing enzyme. These peptides are produced from a single precursor, termed proSAAS, which is present in human, mouse, and rat. ProSAAS mRNA is expressed primarily in brain and other neuroendocrine tissues (pituitary, adrenal, pancreas); within brain, the mRNA is broadly distributed among neurons. When expressed in AtT-20 cells, proSAAS is secreted via the regulated pathway and is also processed at paired-basic cleavage sites into smaller peptides. Overexpression of proSAAS in the AtT-20 cells substantially reduces the rate of processing of the endogenous prohormone proopiomelanocortin. Purified proSAAS inhibits prohormone convertase 1 activity with an IC(50) of 590 nM but does not inhibit prohormone convertase 2. Taken together, proSAAS may represent an endogenous inhibitor of prohormone convertase 1.

Adrenal Glands↗
PubMed2000

Simplification of complex peptide mixtures for proteomic analysis: reversible biotinylation of cysteinyl peptides.

A rapid means of identifying many components in an enriched mixture of proteins is enzymatic digestion of the entire protein fraction. This complex peptide mixture is then subjected to reversed-phase high performance liquid chromatography (HPLC) coupled on-line with a mass spectrometer capable of data-dependent ion selection for fragmentation (LC-tandem mass spectrometry; MS/MS). Thus, as many peptides as possible in the sample are fragmented to produce MS/MS spectra, which can then be searched against sequence databases. Ideally, one peptide from each protein in the mixture would be fragmented and identified. To this end, we employed an affinity selection method to capture cysteinyl peptides and thereby simplify the mixture. Both the captured cysteinyl and the noncysteinyl peptides are analyzed by LC-MS/MS, to increase the number of proteins identified. The method was tested on a limited set of standard proteins and applied to the analysis of a protein fraction obtained from isolated mitochondria treated with atractyloside. To further increase the number of different precursor ions selected for fragmentation, dynamic exclusion and ion selection from multiple narrow mass ranges of consecutive runs were employed.

Animals↗
PubMed2000

A simplified device for protein identification by microcapillary gradient liquid chromatography-tandem mass spectrometry.

A simplified device and procedure have been developed for microcapillary gradient liquid chromatography-tandem mass spectrometry (LC-MS/MS). This procedure has proved useful in identifying low level quantities of proteins from sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gel bands. Microelectrospray needles are packed with reversed-phase resin and function both as a high performance liquid chromatography (HPLC) column and a nanospray mass spectrometer tip when interfaced between an HPLC and ion trap mass spectrometer. Variable submicroliter flow rates are generated by flow splitting between the microelectrospray capillary and an HPLC system. A manual injector is used to inject a protein digest mixture that binds to the column and is then washed at a high flow rate (2 microL/min post split). Gradient elution of bound peptides was initiated by the injection of a filled loop of 70% v/v methanol (5 microL) concomitant with a reduction of flow rate (0.1 microL/min post split). This forms a diffusion-dependent gradient of variable length (typically 15-30 min in length) depending upon the final flow rate. Chromatographic separations of a standard solution digest demonstrate that this diffusion-dependent gradient provides reasonable separations such that multiple peptide identifications by MS/MS can be obtained. Application of this methodology to the analysis of several in-gel-digested gel-separated proteins is presented to demonstrate its utility.

Amino Acid Sequence↗
PubMed2000

PhRMA perspective on population and individual bioequivalence.

The Food and Drug Administration (FDA) issued a second-draft guidance in August 1999 on the subject of in vivo bioequivalence, which is based on the concepts of individual and population bioequivalence (IBE and PBE, respectively). The intention of this guidance is to replace the 1992 guidance that requires that in vivo bioequivalence be demonstrated by average bioequivalence (ABE). Although the concepts of population and individual bioequivalence are intuitively reasonable, a detailed review of the literature has not uncovered clinical evidence to justify the additional burden to the innovator and generic companies as well as the consumer that the new guidelines would impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in bioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technical aspects of the statistical approach are reasonably sound. However, PhRMA believes that important operational issues remain that need to be resolved before any changes to current practice are implemented. PhRMA believes that the ideals of prescribability and switchability are intuitively reasonable, but it is uncertain of the extent to which the proposed guidance can achieve these goals. It is not clear whether the attainment of such goals is necessary in the evaluation of bioequivalence given the role this plays in drug development, and the lack of clinical evidence argues against a pressing need to change current practice. PhRMA is concerned that the trade-off offered by the aggregate criteria may ultimately represent more harm than good to the public interest. PhRMA recommends more rigorous evaluation of methods based on two-way crossover designs before moving to methods that require more complex designs. One such method is identified herein and contains procedures for estimating prescribability and switchability. The possibility of a phase-in or trial period to collect replicate crossover data to further evaluate IBE and PBE and possibly allow market access based on these criteria as they are being evaluated has been proposed. PhRMA believes this is unprecedented and will offer little additional information beyond that which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the sensitivity of various procedures to represent the data patterns as created within the simulation. Operating characteristics by which proposed criteria can be adequately judged have not yet been defined. The limitations of ABE for highly variable drugs and narrow therapeutic drugs are well appreciated and may be addressed by means other than a wholesale change in the current criteria.

Humans↗
PubMed2000

Proteomics: the industrialization of protein chemistry.

Establishing a proteomics platform in the industrial setting initially required implementation of a series of robotic systems to allow a high-throughput approach to analysis and identification of differences observed on 2-D electrophoresis gels. Now, a simpler alternative approach employing chromatography-based systems is emerging for identification of many components of complex mixtures, which can also provide quantitative comparisons through the use of a new labeling methodology.

Automation↗
PubMed2000

Mass spectrometric identification of proteins released from mitochondria undergoing permeability transition.

Mitochondrial membrane permeabilization is a rate-limiting step of cell death. This process is, at least in part, mediated by opening of the permeability transition pore complex (PTPC) Several soluble proteins from the mitochondrial intermembrane space and matrix are involved in the activation of catabolic hydrolases including caspases and nucleases. We therefore investigated the composition of a mixture of proteins released from purified mitochondria upon PTPC opening. This mixture was subjected to a novel proteomics/mass spectrometric approach designed to identify a maximum of peptides. Peptides from a total of 79 known proteins or genes were identified. In addition, 21 matches with expressed sequence tags (EST) were obtained. Among the known proteins, several may have indirect or direct pro-apoptotic properties. Thus endozepine, a ligand of the peripheral benzodiazepin receptor (whose occupation may facilitate mitochondrial membrane permeabilization), was found among the released proteins. Several proteins involved in protein import were also released, namely the so-called X-linked deafness dystonia protein (DDP) and the glucose regulated protein 75 (grb75), meaning that protein import may become irreversibly disrupted in mitochondria of apoptotic cells. In addition, a number of catabolic enzymes are detected: arginase 1 (which degrades arginine), sulfite oxidase (which degrades sulfur amino acids), and epoxide hydrolase. Although the functional impact of each of these proteins on apoptosis remains elusive, the present data bank of mitochondrial proteins released upon PTPC opening should help further elucidation of the death process.

Amino Acid Sequence↗
PubMed2000

Dorsal perilunate dislocations and fracture-dislocations: questionnaire, clinical, and radiographic evaluation.

Twenty-two consecutive patients (23 wrists) underwent open reduction internal fixation of dorsal perilunate dislocations and fracture-dislocations through combined dorsal and volar approaches. One of 5 experienced wrist surgeons performed these procedures within an average of 3 days of injury (range, 0-26 days) and intercarpal fixation was kept within the proximal carpal row. Motion was instituted an average of 10 weeks (range, 5-16 weeks) after injury. All patients were males. The average age at the time of injury was 32 years (range, 16-60 years). The average follow-up period was 37 months (range, 13-65 months). Average flexion-extension motion arc and grip strength in the injured wrist were 57% and 73%, respectively, compared with the contralateral wrist. The scapholunate angle increased and the revised carpal height ratio decreased over time, which was statistically significant for both measurements. Three patients (3 wrists) required wrist arthrodesis and a fourth patient had an immediate scaphoid excision and 4-corner arthrodesis secondary to an irreparable scaphoid fracture. One patient required a proximal row carpectomy to treat septic arthritis. Nine of the remaining 18 wrists had radiographic evidence of arthritis, most often at the capitolunate or scaphocapitate articulations. Short form-36 mental summary scores were significantly greater than age- and gender-matched US population values; physical summary scores were significantly less. The disabilities of arm, shoulder, and hand evaluation, Mayo wrist score, and patient-rated wrist evaluation all reflected loss of function. Seventy-three percent of all patients had returned to full duties in their usual occupations and a total of 82% were employed.

Adolescent↗
PubMed2000

Early excision of heterotopic bone in the forearm.

Five patients undergoing early excision of heterotopic bone in the forearm with radiation therapy and indomethacin were reviewed. Inciting causes of heterotopic ossification included distal biceps tendon repairs, ulna fractures, and a fracture of the radius and ulna. Preoperative forearm rotation arc averaged 17 degrees. Excision was performed at an average of 4 months after injury. Patients were administered 500 to 1,000 cGy of radiation after surgery and received indomethacin for 6 weeks. At an average of 37 months after surgery the forearm rotation arc averaged 136 degrees. All patients had resumed normal activities and had no radiographic recurrence of heterotopic bone or other treatment complications. In the past excision of heterotopic ossification after more than 12 months has been advocated to prevent recurrence. The results of this study suggest that early excision with radiation therapy and indomethacin is a viable option in treating and preventing recurrent heterotopic ossification in the forearm.

Adult↗
PubMed2000

Surgical approaches to the elbow.

The recent explosion of interest in the elbow and the need for better surgical approaches, has produced numerous new approaches and the modification of other approaches, the result of which is a much shorter but more useful list of surgical approaches. Surgeons who perform a large number of elbow procedures have found that these approaches permit them to perform the majority of elbow procedures with only one skin incision, usually a straight posterior midline incision. Knowledge of the deep intermuscular and internervous intervals allows the surgeon to expose the elbow circumferentially through one skin incision. This approach has been associated with fewer wound complications and has allowed immediate active motion of the elbow.

Elbow↗
PubMed2000

The effectiveness of turnbuckle splinting for elbow contractures.

We have treated 22 patients with an elbow contracture using a static progressive turnbuckle splint for a mean of 4.5 +/- 1.8 months. All had failed to improve with supervised physiotherapy and splinting. The mean range of flexion before splintage was from 32 +/- 10 degrees to 108 +/- 19 degrees and afterwards from 26 + 10 (p = 0.02) to 127 +/- 12 degrees (p = 0.0001). A total of 11 patients gained a 'functional arc of movement,' defined as at least 30 degrees to 130 degrees. In eight patients movement improved with turnbuckle splinting, but the functional arc was not achieved. Six of these were satisfied and did not wish to proceed with surgical treatment and two had release of the elbow contracture. In three patients movement did not improve with the use of the turnbuckle splint and one subsequently had surgical treatment. Our findings have shown that turnbuckle splinting is a safe and effective treatment which should be considered in patients whose established elbow contractures have failed to respond to conventional physiotherapy.

Adolescent↗
PubMed2000

Functional outcome of semiconstrained total elbow arthroplasty.

BACKGROUND: The objective of the present study was to review the results of primary total elbow arthroplasty with use of the Coonrad-Morrey prosthesis. Two hypotheses were tested: (1) the results in patients with inflammatory arthritis would be superior to those in patients with a traumatic or posttraumatic condition, and (2) the isometric extensor torque after total elbow arthroplasty would be significantly less than that of the contralateral elbow. METHODS: Forty-seven consecutive patients (fifty-one elbows) had the operation performed by one of three surgeons between November 1, 1989, and June 30, 1996. Thirty-six surviving patients (thirty-nine elbows) were available for follow-up. The mean duration (and standard deviation) of follow-up was 50 +/- 11 months (range, twenty-four to ninety-seven months). The mean age at the time of the operation was 64 +/- 11 years (range, twenty-seven to eighty-seven years). Eighteen patients (twenty-one elbows) had inflammatory arthritis. Eighteen patients (eighteen elbows) had an acute fracture or posttraumatic condition (posttraumatic osteoarthritis in eight, an acute fracture of the humerus in seven, nonunion of the distal aspect of the humerus in two, and primary osteoarthritis in one). The patients were evaluated with use of questionnaires (the Mayo elbow performance index, the Short Form-36 [SF-36], and the Disabilities of the Arm, Shoulder and Hand [DASH] Questionnaire); clinical examination by an orthopaedic surgeon who was not involved with the pre-operative, operative, postoperative, or follow-up care; radiographs; and elbow strength-testing with an isokinetic dynamometer. RESULTS: The mean score (and standard deviation) on the Mayo elbow performance index for the group that had inflammatory arthritis (90 +/- 11 points) was significantly higher than that for the group with a traumatic or posttraumatic condition (78 +/- 18 points) at the time of the latest follow-up (p < 0.05). In both groups, the mean extensor torque of the involved elbow was significantly less than that of the contralateral elbow (p < 0.05). No significant difference between the groups was found with respect to the flexion-extension arc of motion. Ten elbows (26 percent) had ulnar nerve dysfunction (a transient deficit in six and a permanent deficit in four); nine (23 percent), an intraoperative fracture (of the humeral diaphysis in four, of the ulnar diaphysis in four, and of the olecranon in one); three (8 percent), a periprosthetic infection; three, a triceps disruption; and one (3 percent), a revision because of a fracture of the ulnar component. There were no other revisions. Of the thirty-four elbows with complete radiographic follow-up, twenty-three had no change in the bone-cement interface. Progressive radiolucency was noted around the ulnar prosthesis in eight elbows, around the humeral prosthesis in one elbow, and around both components in two elbows. CONCLUSIONS: Patients who had a total elbow arthroplasty with use of a semiconstrained Coonrad-Morrey prosthesis were generally satisfied; the mean level of patient satisfaction was 9.2 of a possible 10 points for those who had inflammatory arthritis and 8.6 points for those who had a fracture or posttraumatic condition. The rates of complications involving the ulnar nerve, intraoperative fracture, triceps disruption, deep infection, and periprosthetic radiolucency are of concern.

Aged↗
PubMed1999

Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea.

Affinity chromatography, employing the extracellular domain of the Sea receptor, was used to enrich Sea-binding proteins from chicken serum. One isolated protein bound both a Sea-immunoglobulin fusion protein and an antisera raised against murine macrophage stimulating protein. Amino-terminal sequencing of the dual-reactive protein yielded sequences which were identical to the predicted alpha and beta subunits of chicken macrophage stimulating protein. The partially purified chicken macrophage stimulating protein caused autophosphorylation of the Sea receptor. Previous work showed that recombinant expression of fully activatible human or mouse macrophage stimulating protein required a specific Cys to Ala substitution (Wahl, R. C., Costigan, V. J., Batac, J. P., Chen, K., Cam, L., Courchesne, P. L., Patterson, S. D. Zhang, K., and Pacifici, R. E. (1997) J. Biol. Chem. 272, 1-4). Therefore, we expressed both the wild type and the specific Cys to Ala form of chicken macrophage stimulating protein as recombinant proteins. After proteolytic activation, only conditioned media from COS cells transfected with the C665A chicken macrophage stimulating protein, but not from wild type chicken macrophage-stimulating protein, or control vector, was detected by the Sea-immunoglobulin fusion protein in Western blotting experiments. Conditioned media containing the C665A chicken macrophage-stimulating protein readily caused Sea phosphorylation, while conditioned media containing the wild type chicken macrophage-stimulating protein was only effective at inducing receptor phosphorylation at high concentrations. In addition to receptor phosphorylation, the C665A chicken macrophage-stimulating protein induced phosphorylation of Shc, Erk1, and Erk 2. We conclude that macrophage-stimulating protein is a ligand of the Sea receptor protein-tyrosine kinase.

Animals↗