Search PubMed⌕ Search

Biomedical subjects

L Harrison

Publications and source records attributed to L Harrison.

At least 55 records · Page 3Linked to original sources
PubMed1998

Prediction of MHC class II-binding peptides using an evolutionary algorithm and artificial neural network.

MOTIVATION: Prediction methods for identifying binding peptides could minimize the number of peptides required to be synthesized and assayed, and thereby facilitate the identification of potential T-cell epitopes. We developed a bioinformatic method for the prediction of peptide binding to MHC class II molecules. RESULTS: Experimental binding data and expert knowledge of anchor positions and binding motifs were combined with an evolutionary algorithm (EA) and an artificial neural network (ANN): binding data extraction --> peptide alignment --> ANN training and classification . This method, termed PERUN, was implemented for the prediction of peptides that bind to HLA-DR4(B1*0401). The respective positive predictive values of PERUN predictions of high-, moderate-, low- and zero-affinity binders were assessed as 0.8, 0.7, 0.5 and 0.8 by cross-validation, and 1.0, 0.8, 0.3 and 0.7 by experimental binding. This illustrates the synergy between experimentation and computer modeling, and its application to the identification of potential immunotherapeutic peptides. AVAILABILITY: Software and data are available from the authors upon request. CONTACT: vladimir@wehi.edu. au

Algorithms↗
PubMed1998

Gene therapy for malignant mesothelioma: a novel approach for an incurable cancer with increased incidence in Louisiana.

Malignant mesothelioma (MM) is a tumor of the pleura for which there is no satisfactory treatment. It is an almost universally fatal disease, regardless of the stage of the tumor at the time of diagnosis. Current treatment modalities include surgery, chemotherapy, and radiation therapy, although in some series none of these modalities is superior to no treatment at all. Because of the dismal prognosis for patients with MM, new modes of treatment are desperately needed. A promising area of research into the treatment of various malignancies is gene therapy. Recent studies have demonstrated the utility of exposing tumor cells to cells transduced to express the Herpes simplex virus gene for thymidine kinase (HSV-TK). By virtue of their expression of HSV-TK, the transduced cells are rendered susceptible to the antiviral drug, ganciclovir (GCV). Nearby untransduced tumor cells are killed by a so-called bystander effect. We are describing a Phase I clinical gene therapy trial for MM, which we are presently conducting at the Louisiana State University Medical Center of New Orleans. The purpose is to study the safety and to determine the maximal tolerated dose of an HSV-TK-transduced ovarian cancer cell line (PA1-STK cells) that is infused into the pleural cavities of patients. This infusion is followed by systemic administration of GCV. The hope is that administration of GCV will result in killing of both the transduced ovarian cancer cells as well as the nearby malignant cells.

Ganciclovir↗
PubMed1998

Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin.

BACKGROUND: Patients receiving long-term warfarin frequently develop asymptomatic excessive prolongation of their international normalized ratio (INR) results. The most appropriate management strategy in these patients is unknown. This prospective cohort study was designed to address whether 1 mg of oral vitamin K effectively reduces the INR value of such patients. METHODS: A prospective cohort study was performed in two tertiary care teaching hospitals, in which 62 patients receiving warfarin who had INR values between 4.5 and 10.0 received 1 mg of oral vitamin K. All patients had daily INR values and clinical assessments performed. RESULTS: The mean INR value at presentation was 5.79 (95% confidence interval (CI) 5.48 to 6.09, range 4.5 to 9.5). Sixteen hours after receiving the 1 mg of oral vitamin K, the mean INR was 2.86 (95% CI 2.50 to 3.23). On the second and third days after vitamin K, the mean INR values were 2.20 (1.93 to 2.47) and 2.14 (1.85 to 2.44), respectively. No adverse events or bleeding complications were observed. In three patients (6%) the INR value rose between the time of vitamin K administration and the next INR determination; two patients received a further 2 mg dose of subcutaneous vitamin K. CONCLUSIONS: In patients receiving warfarin who have asymptomatic excessive prolongations in their INR results, 1 mg of oral vitamin K reliably reduces the INR to the therapeutic range within 24 h. This therapy is more convenient, less expensive, and might be safer than parenteral vitamin K. Thus, it should be considered in all non-bleeding patients receiving warfarin, who present with INR results of 4.5 to 9.5.

Administration, Oral↗
PubMed1997

Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy.

BACKGROUND: Loading doses of warfarin that are larger than those used for maintenance therapy are widely used in clinical practice, but they have never been prospectively evaluated. OBJECTIVE: To compare the effect of 5- and 10-mg loading doses of warfarin on laboratory markers of warfarin's anticoagulant effect. DESIGN: Randomized clinical trial. SETTING: Tertiary care teaching hospital. PATIENTS: 49 patients seen over a 5-month period with a target international normalized ratio (INR) of 2.0 to 3.0. INTERVENTION: Patients were randomly assigned to receive an initial dose of 5 or 10 mg of warfarin. Subsequent doses of warfarin were administered on the basis of dosing nomograms. MEASUREMENTS: INRs and levels of factors II, VII, IX, and X and protein C were measured daily for 5 days. RESULTS: 11 of 25 patients in the 10-mg group (44% [95% CI, 34% to 54%]) and 2 of 24 patients in the 5-mg group (8% [CI, 3% to 14%]) had INRs greater than 2.0 at 36 hours (P = 0.005), at which time the factor VII levels were 27% (CI, 18% to 36%) in the 10-mg group and 54% (CI, 43% to 65%) in the 5-mg group (P < 0.001). In contrast, factor II levels were 74% (CI, 67% to 81%) in the 10-mg group and 82% (CI, 73% to 93%) in the 5-mg group (P > 0.2). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) and no patients in the 5-mg group had INRs greater than 3.0. At 84 hours, 15 of 24 patients in the 10-mg group (63% [CI, 43% to 81%]) and 19 of 24 patients in the 5-mg group (79% [CI, 62% to 95%]) had INRs between 2.0 and 3.0. Four patients in the 10-mg group and 1 patient in the 5-mg group received vitamin K for excessive prolongation of the INR. CONCLUSIONS: A 5-mg loading dose of warfarin produces less excess anticoagulation than does a 10-mg loading dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hours of warfarin therapy.

Anticoagulants↗
PubMed1997

Lithium prevents ouabain-induced behavioral changes. Toward an animal model for manic depression.

Both mania and bipolar depression have been associated with decrements in the activity of the sodium and potassium-activated adenosine triphosphatase (Na,K-ATPase) membrane pump. Although the role of this observation in the pathophysiology of bipolar illness is unclear, it has been proposed that this defect could be central to the pathogenesis of the illness. In an effort to test this hypothesis, the authors examined the efficacy of lithium pretreatment in attenuating behavioral changes secondary to acute administration of a single intracerebroventricular (i.c.v.) dose of the Na,K-ATPase-inhibiting compound, ouabain, in the Sprague-Dawley rat. Ouabain (10(-3)M) significantly decreased motor activity in automated activity monitors. Lithium pretreatment for 7 d totally prevented this effect. These preliminary data suggest that i.c.v. ouabain administration in the rat may prove to be a viable animal model for bipolar illness.

Animals↗
PubMed1997

Promising survival with three-dimensional conformal radiation therapy for non-small cell lung cancer.

PURPOSE: Local failure is a major obstacle to the cure of locally advanced non small-cell lung cancer. Three-dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially representing an enhancement of the therapeutic ratio of radiation therapy for lung cancer. We performed this analysis of 45 non-small cell lung cancer patients treated with 3-DCRT alone, to evaluate the ability of computer derived lung dose volume histograms to predict serious pulmonary toxicity, to assess the feasibility of this approach, and to examine the resulting survival. METHODS: There were 28 males (62%) and 17 females (38%). The median age was 65 (range: 38-82). Tumor stage was Stage I/II in 13%, IIIa in 42%, and IIIb in 44%. The histology was squamous in 44%, adenocarcinoma in 36%, and other non-small cell histologies in the others. Only 47% of patients. had combined favorable prognostic factors (i.e. KPS < or = 80, and < or = 5% wt. loss). The median dose of radiation to gross disease was 70.2 Gy (range: 52.2-72 Gy) delivered in fractions of 1.8 Gy, 5 days per week. RESULTS: Seven patients did not complete 3-DCRT due to disease progression outside the port. Follow-up data are mature: the median follow up of the 6 survivors is 43.5 months (35-59). Thoracic progression occurred in 46%. Median survival (all 45 patients.) is 15.7 months and survival is 32% at 2 years and 12% at 59 months. Pulmonary toxicity > or = grade 3 occurred in 9% of patients. Dose volume histograms were available in 31 patients and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% (3/8) of patients with > 30% of lung volume receiving > or = 25 Gy, versus 4% (1/23) of patients with < or = 30% lung receiving > or = 25 Gy (P = 0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (4/14) of patients with a predicted pulmonary normal tissue complication probability of 12% or higher versus 0% (0/17) in patients with a predicted probability of less than 12% (P = 0.03). CONCLUSIONS: Despite adverse prognostic criteria median survival is encouraging and may be higher than some combined modality approaches. Dose volume histogram parameters may be useful to determine the maximum dose for individual patients and thereby permit avoidance of toxicity.

Adult↗
PubMed1997

Intoxicated ED patients: a 5-year follow-up of morbidity and mortality.

STUDY OBJECTIVES: To determine the rates of alcohol-related morbidity and mortality in a cohort of intoxicated ED patients 5 years after presentation and to compare them with those of non-intoxicated ED patients. METHODS: The study group comprised 150 consecutive ED patients who presented with intoxication (blood alcohol level higher than 100 mg/dL) in June 1986 and 50 control patients matched for age, sex, ED arrival time, and date. The setting was an urban university hospital ED. Morbidity and mortality over a 5-year follow-up period were measured using hospital ED and admission records from all state Level I trauma centers and computerized statewide databases. RESULTS: The 5-year mortality rate among alcohol-intoxicated patients was 2.4 times that of the comparison group (95% confidence interval, .3 to 18.9). The 5-year death rate among intoxicated patients aged 40 to 69 years was especially high (19%). Thirty-seven percent of the intoxicated patients made at least one alcohol-related ED revisit during the follow-up period, compared with 6% of the comparison group (P < .001). Intoxicated patients were more likely to revisit EDs because of suicidal behavior or domestic violence (P = .001). Admission to an alcohol detoxification unit during the follow-up period occurred in 24% of the intoxicated patients, compared with 10% of the sober controls (P = .03). At least one arrest for drunk driving occurred in 47% of the intoxicated group; the rate was lower, but still substantial, in the comparison group (20%, P < .001). CONCLUSION: A single alcohol-related ED visit is an important predictor of continued problem drinking, alcohol-impaired driving and, possibly, premature death.

Adolescent↗
PubMed1997

Comparison of the promoters of the mouse (APEX) and human (APE) apurinic endonuclease genes.

We investigated the minimal promoter of APEX, which encodes mouse apurinic DNA repair endonuclease. A 1.85-kb fragment with APEX upstream sequences and approximately 290 bp of the transcribed region linked to a chloramphenicol acetyltransferase (CAT) reporter gene was assayed by transient transfection in NIH-3T3 cells. The minimal APEX promoter was comprised of approximately 190 bp of upstream and approximately 170 bp of transcribed DNA (exon 1 and most of intron 1). This approximately 360-bp region contains two CCAAT boxes and other consensus protein binding sites, but no TATA box. Deletion of the 5'-most CCAAT box decreased activity approximately 5-fold. The second CCAAT box (situated in exon 1) may play an independent role in APEX expression. Transcription start sites have been identified downstream of the second CCAAT box, and DNase I footprinting demonstrated NIH-3T3 nuclear proteins binding this region, including an Spl site located between the CCAAT boxes. Electrophoretic mobility-shift assays indicated binding by purified Sp1. Mouse proteins did not bind three myc-like (USF) sites in the APEX promoter, in contrast to the APE promoter. The APEX and APE promoter had similar activity in Hela cells, but in mouse cells, the murine promoter had approximately 5-fold higher activity than did the human promoter. Both the APEX and APE promoters exhibited bidirectional activity in their cognate cells.

3T3 Cells↗
PubMed1997

Managing risk in the city: the role of welfare professionals in managing risks arising from vulnerable individuals in cities.

Modern cities depend on individualism and the process of contracting. Contracts between individuals contribute to stability and order in cities. However, this is challenged by risks and uncertainties especially those relating to vulnerable individuals who are unable or unwilling to enter into contractual relations. This paper focuses on the role of caring professions and the impact of new strategies for managing risks related to vulnerable adults and children, especially the shift from managing risk in institutions to managing risk in the community. This paper is based on research funded through the ESRC Risk and Human Behaviour Programme.

Adult↗
PubMed1997

Regulation of eukaryotic abasic endonucleases and their role in genetic stability.

Abasic (AP) sites in DNA arise from spontaneous reactions or the action of DNA glycosylases and represent a loss of genetic information. The AP sites can be mutagenic or cytotoxic, and their repair is initiated by class II AP endonucleases, which incise immediately 5' to AP sites. The main enzyme of S. cerevisiae. Apn1, provides cellular resistance to oxidants (e.g., H2O2) or alkylating agents, and limits the spontaneous mutation rate. AP endonucleases from other species can replace Apn1 function in yeast to different extents. We studied the main human enzyme, Ape, with respect to its incision specificity in vitro and the expression of the APE gene in vivo. The results suggest that Ape evolved to act preferentially on AP sites compared to deoxyribose fragments located at oxidative strand breaks and that the incision modes of Ape and Apn1 may be fundamentally different. We also defined the functional APE promoter, and showed that APE expression is transiently downregulated during the regeneration of epidermis after wounding. This latter effect may lead to a window of vulnerability for DNA damage and perhaps mutagenesis during the healing of epidermal and other wounds. Such unexpected effects on the expression of DNA repair enzymes need to be taken into account in analyzing the susceptibility of different tissues to carcinogens.

DNA Damage↗
PubMed1997

Ethnic differences in substance use and alcohol-use-related mortality among first generation migrants to England and Wales.

Epidemiological studies among migrant ethnic groups are potentially important as a way to provide insight into the relative importance of genetic, cultural, and socioeconomic factors in the etiology of substance use disorders. This paper summarizes prior United Kingdom studies of the prevalence of substance-use-associated problems in different ethnic groups before analyzing trends in recent mortality data by country of birth. On this evidence, rates of alcohol-related mortality may be marginally higher for those born in the Caribbean than for the native British, but are substantially raised for those born in Ireland and the Indian subcontinent. There is some indication that rates for the Caribbean and possibly the Irish groups have risen more rapidly than for the national population over a 12-year period. These differences in mortality rates seem to have arisen for complex reasons.

Adolescent↗
PubMed1997

Introduction--the validity of self-reported drug use: improving the accuracy of survey estimates.

Measuring levels and patterns of illicit drug use, their correlates, and related behaviors requires the use of self-report methods. However, the validity of self-reported data on sensitive and highly stigmatized behaviors such as drug use has been questioned. The goal of this monograph is to review current and cutting-edge research on the validity of self-reported drug use and to describe methodological advances designed to reduce total error in estimates of drug use and quantify sources of nonsampling error. This monograph reviews a number of studies that use some presumably more accurate measure of drug use to validate self-reported use. In addition, evolving methods to improve a wide variety of procedures used in survey designs are explored, including computer-assisted interviewing, predictors of response propensity, measurement error models, and improved prevalence estimation techniques. Experimental manipulations of various survey conditions and situational factors also show promise in improving the validity of drug prevalence estimates in self-report surveys.

Computers↗
PubMed1997

The validity of self-reported drug use in survey research: an overview and critique of research methods.

Since illicit drug use is by definition illegal, the tasks of measuring incidence and prevalence and charting the course of the epidemic have fallen to survey researchers over the past 30 years. Although survey methods have obvious advantages over indirect measures such as arrests, seizures, and treatment admissions, they are frequently criticized because the rely on valid self-reporting of sensitive and highly stigmatized behavior. Validation studies conducted before the mid-1980s involving known samples of drug users or urinalysis techniques suggested that drug use was fairly accurately reported in self-report surveys. However, more recent validation studies conducted with criminal justice and former treatment clients using improved urinalysis techniques and hair analyses demonstrate that self-report methods miss a lot of recent drug use. A review of the research literature suggests that neither self-reports nor bioassays are wholly accurate, and both have inherent problems. However, because self-report measures are necessary to understand the complexity of causal and correlational attributes of drug abuse, it is necessary to determine what can be done to improve valid self-reporting. This chapter examines the research literature on validation studies to provide an overview of what is known about the accuracy of self-reported drug use.

Health Surveys↗
PubMed1997

Co-activation of the hamstrings and quadriceps during the lunge exercise.

The anterior lunge exercise is a closed chain kinetic exercise that has been developed to improve the function of the lower limb and to strengthen the hamstrings and quadriceps, simultaneously. In this study, a three-dimensional biomechanical analysis of this exercise was conducted in order to understand the mechanics of this rehabilitation activity. Experimental conditions were recorded using an active optoelectronic kinematic data capture system (OPTOTRAK), two force plates (AMTI) and electromyography (EMG). Data were collected from healthy male subjects while performing several lunges. When the distance between the toe of the rear leg and the heel of the front leg (lunging distance) was maximum, a large net flexion moment was predicted in the front leg in the extented position. This moment was reversed to a large net extension moment in the flexed position. A large increase in the net extension moment in the rear leg was also predicted as the front knee was bent from 5 degrees to 90 degrees of flexion. These data suggest that quadriceps and hamstring muscles co-contraction occur during a maximum lunge in the front leg when it is in the flexed position.

Biomechanical Phenomena↗
PubMed1997

Knee kinematics in-vivo of kneeling in deep flexion examined by bi-planar radiographs.

Squatting and kneeling are important daily activities for Middle and Far East cultures that require positioning the knee in deep flexion. In these activities, the limb becomes fully flexed with a knee flexion angle reaching between 150 and 160 degrees and the heel reaching the posterior surface of the upper thigh. Existing knee prostheses do not allow a full return to normal activities for this large population since they are limited to achieving knee flexion of about 120 degrees. Also, there is very limited information on knee kinematics and/or forces in the range beyond 120 degrees. The purpose of this study is to describe the kinematics of normal knees in-vivo, assessed in deep flexion, using bi-planar radiographs. A-P and lateral views were obtained from 5 healthy subjects during three sequential positions of kneeling. In the 1st position, the subject knelt with the knees fully flexed (deep flexion between 150 degrees and 160 degrees) and torso upright. In the 2nd position, the subject bowed forward to an intermediate position (about 120 degrees of knee flexion). In the 3rd position, the subject bowed further until his/her head touched the floor, supporting the upper torso with hands and attaining a knee flexion of about 90 degrees. The results show that past 135 degrees of knee flexion, the patella was found to clear the femoral groove and was in contact only with the condyles. The results also show that the classical femoral "roll back" does not appear to occur in deep flexion. It seems that the lateral femoral condyle rolls over the postero medial aspect of the lateral tibial plateau while contact of the medial femoral condyle occurs more anteriorly, but still in the posterior aspect of the medial tibial plateau. This asymmetric rolling motion implies an element of internal tibial rotation. Furthermore, the tibia was found to articulate with the femur at the most proximal points of the condyles in deep flexion. These data on the kinematics and contact characteristics of the tibio-femoral joint must be considered in any approach to design for a Deep Flexion Knee Implant.

Biomechanical Phenomena↗