Biomedical subjects

J Lawrence Marsh

Publications and source records attributed to J Lawrence Marsh.

44 records · Page 3Linked to original sources

PubMed2002

A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila.

Huntington disease is caused by the expansion of a polyglutamine repeat in the Huntingtin protein (Htt) that leads to degeneration of neurons in the central nervous system and the appearance of visible aggregates within neurons. We have developed and tested suppressor polypeptides that bind mutant Htt and interfere with the process of aggregation in cell culture. In a Drosophila model, the most potent suppressor inhibits both adult lethality and photoreceptor neuron degeneration. The appearance of aggregates in photoreceptor neurons correlates strongly with the occurrence of pathology, and expression of suppressor polypeptides delays and limits the appearance of aggregates and protects photoreceptor neurons. These results suggest that targeting the protein interactions leading to aggregate formation may be beneficial for the design and development of therapeutic agents for Huntington disease.

Animals↗

PubMed2002

Interfragmentary surface area as an index of comminution energy: proof of concept in a bone fracture surrogate.

Fracture mechanics theory postulates a monotonic relationship between energy absorption and fracture surface generation. We hypothesized that this relationship was demonstrable to the point that, on a continuous scale, comminuted fractures created with disparate levels of energy delivery could be discriminated. Using a bone fracture surrogate in conjunction with digital image analysis of CT fracture data, we measured the surface area freed by controlled, discrete fracture simulations. Prior to these simulations, the reproducibility of the digital image analysis algorithm was validated with repeated measurements by two different operators. The parametric fracture series results showed a statistically significant difference in measured de novo surface area between four specimen groups, over a range of input energies from 1.4 x 10(10)-9.1 x 10(10)J/m(3) (or 12.5-80.2J/specimen). The results of this study provide confirmation that comminution severity can indeed be measured on a continuous scale, based on energy absorption (another clinically meaningful index).

Algorithms↗

PubMed2002

High-energy fractures of the tibial plateau. Knee function after longer follow-up.

BACKGROUND: Studies of the long-term outcomes of treatment of fractures of the tibial plateau have included wide mixtures of fracture types and mostly low-energy split and split-depression fractures. The long-term results of treatment of high-energy intra-articular proximal tibial fractures are unknown. The purpose of this study was to assess the function of the knee and the development of arthrosis at a minimum of five years after injury in a consecutive series of patients in whom a high-energy fracture of the tibial plateau had been treated with a uniform technique of external fixation. METHODS: Between July 1988 and December 1994, thirty patients with a total of thirty-one fractures of the tibial plateau were treated with a monolateral external fixator and limited internal fixation of the articular surface. Follow-up data on twenty-four knees in twenty-three patients were obtained at a mean of ninety-eight months. Twenty patients (twenty knees) returned specifically for the study, at which time they completed an Iowa Knee Score questionnaire and a Short Form-36 (SF-36) general health survey, a physical examination was performed, and weight-bearing radiographs were made. The results of the SF-36 evaluations for fourteen patients and the Knee Scores for twelve were compared with those obtained five years previously, at two to four years after the injury. RESULTS: After healing, no patient required a secondary reconstructive procedure. The range of motion of the knee averaged 3 degrees of extension to 120 degrees flexion, which was an average of 87% of the total arc of the contralateral knee. The average Iowa Knee Score was 90 points (range, 72 to 100 points). For twelve patients, the Iowa Knee Score previously recorded at two to four years averaged 92 points, as did the score at the time of the latest follow-up. Thirteen patients rated their outcome as excellent; six, as good; and three, as fair. Fifteen patients were working, and ten of them were performing strenuous labor. Radiographs showed no evidence of arthrosis in fourteen knees, grade-1 arthrosis in three, grade-2 in three, and grade-3 in two. Compared with the radiographic appearance two to four years after injury, there was no evidence of progression of arthrosis in eighteen knees and one grade of progression in four. The SF-36 subscale scores were similar to those of age-matched controls. The fourteen patients who had previous SF-36 scores had no deterioration of these scores. CONCLUSIONS: Patients with a high-energy fracture of the tibial plateau treated with external fixation have a good prognosis for satisfactory knee function in the second five years after injury. The knee joint cartilage appears to be tolerant of both the injury and mild-to-moderate residual articular displacement, which was associated with a low rate of severe arthrosis.

Adult↗

PubMed2001

Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer.

Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers. Activation of this pathway is caused by genetic mutations that stabilize the beta-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer factor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription factors (referred to collectively as LEF/TCFs) to activate transcription of target genes. Target genes such as MYC, CCND1, MMP7 and TCF7 (refs. 5-9) are normally expressed in colon tissue, so it has been proposed that abnormal expression levels or patterns imposed by beta-catenin/TCF complexes have a role in tumor progression. We report here that LEF1 is a new type of target gene ectopically activated in colon cancer. The pattern of this ectopic expression is unusual because it derives from selective activation of a promoter for a full-length LEF1 isoform that binds beta-catenin, but not a second, intronic promoter that drives expression of a dominant-negative isoform. beta-catenin/TCF complexes can activate the promoter for full-length LEF1, indicating that in cancer high levels of these complexes misregulate transcription to favor a positive feedback loop for Wnt signaling by inducing selective expression of full-length, beta-catenin-sensitive forms of LEF/TCFs.

Colonic Neoplasms↗

PubMedDate not supplied

Evidence-based assessment of acute pain in older adults: current nursing practices and perceived barriers.

OBJECTIVES: To report data on current nurse practice behaviors related to evidence-based assessment of acute pain in older adults, perceived stage of adoption of pain assessment practices, and perceptions of barriers to optimal assessment in this population. METHODS: Medical records from 709 older adult patients hospitalized with hip fractures from 12 acute care settings were abstracted for nurse assessment practices during the first 72 hours after admission. Questionnaires sent to nurses on study units regarding perceived stage of adoption and barriers to assessment in older adults. RESULTS: Data revealed several areas in which pain assessment practices were not optimal. Pain was not routinely assessed every 4 hours, and pain location was assessed even less frequently. Pain behaviors were assessed more in patients with a diagnosis of dementia compared to those without dementia, but the frequency of pain behavior assessments was low. Pain was not routinely assessed within 60 minutes of administering an analgesic. Nurses reported not using optimal pain assessment practices even when they were aware of and persuaded that those practices were desirable. In addition, nurses reported that difficulty communicating with patients created the greatest challenge in managing pain. CONCLUSIONS: Our data suggest that pain is not being assessed and reassessed in a manner that is consistent with current practice recommendations in older adult patients with pathologic processes that highly suggest the presence of acute pain.

Aged↗

PubMedDate not supplied

Kinematic and contact stress analysis of posterior malleolus fractures of the ankle.

OBJECTIVE: To determine if there are measurable dynamic contact stress aberrations and kinematic abnormalities (instability) that have not been observed in conventional static loading studies of posterior malleolar ankle fractures. DESIGN: Cadaveric fracture model. SETTING: Biomechanics laboratory. INTERVENTION: Seven fresh cadaveric specimens were fixed in an unconstrained testing apparatus and loaded to one body weight. The ankle was moved from 25 degrees of plantarflexion to 15 degrees of dorsiflexion. The model included the intact ankle and four fracture simulations (50% fracture without internal fixation, 2 mm gap and step malreductions, and anatomically fixed). MAIN OUTCOME MEASURE: Motion at the ankle was monitored with an electromagnetic tracking device, and intra-articular contact stresses were measured using a real-time stress sensor. RESULTS: There were no kinematic abnormalities suggestive of tibiotalar subluxation in any of the fracture simulations. There was no increase in peak contact stress in any of the fracture models compared with the unfractured model. However, there was a shift in the location of the contact stresses to a more anterior and medial location following the fracture. When summed over the range of motion, these areas of cartilage bore significantly higher cumulative contact stresses relative to the nonfracture situation. CONCLUSIONS: We found no talar subluxation and no increase in contact stresses near the articular incongruity, making it unlikely that these factors explain the increased incidence of arthrosis after trimalleolar fractures (OTA/AO classification 44 B3 fractures). Rather, we found that the joint remaining bears increased stress and that the center of stress shifts anteriorly, loading cartilage that normally sees little load.

Ankle Joint↗

PubMedDate not supplied

Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease.

Although posttraumatic osteoarthritis (OA) is a common and important entity in orthopedic practice, no data presently exist regarding its prevalence or its relative burden of disease. A population-based estimate was formulated, based on one large institution's experience in terms of its fraction of patients with OA presenting to lower-extremity adult reconstructive clinics with OA of posttraumatic origin. The relative proportion of these patients undergoing total joint replacement provided a basis for extrapolating institutional experience with posttraumatic OA to a populationwide estimate because the numbers of lower-extremity total joint arthroplasty procedures performed were reliably tabulated both within the institution and populationwide. By this methodology, approximately 12% of the overall prevalence of symptomatic OA is attributable to posttraumatic OA of the hip, knee, or ankle. This corresponds to approximately 5.6 million individuals in the United States being affected by posttraumatic OA sufficiently severe to have caused them to present for care by an orthopedic lower-extremity adult reconstructive surgeon. Further, based on the relative prevalence of OA versus rheumatoid arthritis, and their relative impacts as assessed by the SF-36 (Short-Form 36) lower-extremity physical composite scores, about 85.5% of the societal costs of arthritis are attributable to OA. The corresponding aggregate financial burden specifically of posttraumatic OA is Dollars 3.06 billion annually, or approximately 0.15% of the total U.S. health care direct cost outlay.

Adult↗

PubMedDate not supplied

Articular fractures.

Although injuries to articular cartilage may lead to radiographic osteoarthritis, pain, and decreased joint function, the actual effects of such injury and of its treatment on joint function are not completely understood. The mechanisms of repair after impact loading are different from those after frank disruption by fracture of the articular cartilage, but basic and clinical research both indicate that the resultant articular surface is prone to degeneration. The sensitivity of a joint to resultant incongruity varies considerably, depending on the thickness and modulus of the articular cartilage and the geometry of the joint. Also, factors other than articular congruity play a substantial role in determining outcomes after treatment. For these reasons, defining a single threshold for articular displacement that correlates with outcomes in all joints is not practical. Some articular fractures injure cartilage so severely that the joint will degenerate even with an accurate articular reduction. Also, radiographic evidence of osteoarthritis does not necessarily correlate with poor function. More reliable measurement techniques are needed to accurately assess how treatment affects arthritis, and factors other than articular congruity are needed to predict posttraumatic arthritis.

Animals↗