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L Harrison

Publications and source records attributed to L Harrison.

At least 19 recordsLinked to original sources

A randomized trial comparing 5-mg and 10-mg warfarin loading doses.

BACKGROUND: Warfarin sodium therapy is usually initiated with a loading dose to reduce the time required to elevate the international normalized ratio (INR). Warfarin loading doses are associated with early overanticoagulation and the development of a potential hypercoagulable state; they also may not hasten achieving an INR value between 2.0 and 3.0. This study was designed to prospectively confirm our observation that a 5-mg warfarin sodium loading dose is as effective as a 10-mg loading dose in achieving a therapeutic INR for 2 consecutive days on days 3 and 4 or 4 and 5 of therapy. METHODS: Fifty-three patients initiating warfarin therapy with a target INR of 2.0 to 3.0 were randomly allocated to receive an initial dose of 5 or 10 mg of warfarin. Subsequent doses were based on dosing algorithms. The INR was measured daily for 5 days. The primary end point of the study was the proportion of patients whose INR values were between 2.0 and 3.0 on 2 consecutive daily determinations on days 3, 4, or 5 of the study and whose INR did not exceed 3.0 at any point during the study. RESULTS: Five (24%) of 21 patients in the 10-mg group and 21 (66%) of 32 patients in the 5-mg group achieved the primary end point (relative risk 2.22, 95% confidence interval 1.30-3.70 [P < .003]). A trend toward less overanticoagulation was seen in the 5-mg warfarin group. CONCLUSION: A 10-mg loading dose of warfarin is unlikely to be more effective than a 5-mg loading dose in achieving an INR of 2.0 to 3.0 by day 4 or 5 of therapy.

Aged

Radiographic grading for knee osteoarthritis. A revised scheme that relates to alignment and deformity.

OBJECTIVE: To develop a radiographic grading scheme for osteoarthritis of the knee that would relate to arthritic progression and deformity. METHODS: The scheme of Scott, et al was revised to include new fields of Tibial Erosion and Subluxation; the fields of Tibial Osteophytes and Sclerosis were removed. The worst affected compartment only was scored on frontal Standardized Knee Images, which were used to define knee alignment variables. RESULTS: The interreader reliability (kappa = 0.92) and correlation for total scores (r = 0.94) were both excellent (p < 0.001). Individual field scores and total knee scores both correlated well with most limb alignment variables, especially the hip-knee-ankle angle (r = 0.77, p < 0.001). CONCLUSION: These findings encourage further evaluations for outcome measurement, diagnostic sensitivity, and sensitivity to define arthritic change over time.

Arthroscopy

Tsetse thrombin inhibitor: bloodmeal-induced expression of an anticoagulant in salivary glands and gut tissue of Glossina morsitans morsitans.

The tsetse thrombin inhibitor, a potent and specific low molecular mass (3,530 Da) anticoagulant peptide, was purified previously from salivary gland extracts of Glossina morsitans morsitans (Diptera: Glossinidae). A 303-bp coding sequence corresponding to the inhibitor has now been isolated from a tsetse salivary gland cDNA library by using degenerate oligonucleotide probes. The full-length cDNA contains a 26-bp untranslated segment at its 5' end, followed by a 63-bp sequence corresponding to a putative secretory signal peptide. A 96-bp segment codes for the mature tsetse thrombin inhibitor, whose predicted molecular weight matches that of the purified native protein. Based on its lack of homology to any previously described family of molecules, the tsetse thrombin inhibitor appears to represent a unique class of naturally occurring protease inhibitors. Recombinant tsetse thrombin inhibitor expressed in Escherichia coli and the chemically synthesized peptide are both substantially less active than the purified native protein, suggesting that posttranslational modification(s) may be necessary for optimal inhibitory activity. The tsetse thrombin inhibitor gene, which is present as a single copy in the tsetse genome, is expressed at high levels in salivary glands and midguts of adult tsetse flies, suggesting a possible role for the anticoagulant in both feeding and processing of the bloodmeal.

Amino Acid Sequence

The treatment of malignant mesothelioma with a gene modified cancer cell line: a phase I study.

Malignant mesothelioma is a tumor of the pleura for which there is no satisfactory treatment. It is almost universally fatal, 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 malignant mesothelioma, a new mode of treatment is 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). and nearby tumor cells are killed by a phenomenon termed the bystander effect. In this protocol we propose a Phase I trial to study the safety and determine the maximal tolerated dose of an HSV-tk-transduced ovarian cancer cell line (PA1-STK cells) infused into the pleural cavities of patients with malignant pleural mesothelioma, followed by systemic administration of ganciclovir. The hope is that administration of ganciclovir will result in killing of the HSV-tk transduced ovarian cancer cells as well as the nearby malignant mesothelioma cells. This is a standard dose-escalation protocol.

Clinical Protocols

Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin.

BACKGROUND: Low-molecular-weight (LMW) heparins are safe and effective for out-of-hospital treatment of acute deep-vein thrombosis (DVT) in a clinical trial setting. We examined the efficacy, safety, and feasibility of home treatment with LMW heparin of consecutive eligible patients with acute DVT in a routine care setting. In addition, we report our experience with patient compliance, acceptance, and satisfaction. METHODS: We performed a prospective cohort study of consecutive patients presenting to 2 thromboembolism clinics in a large Ontario city. Eligible patients were treated with LMW heparin for a minimum of 5 days and with long-term warfarin sodium. Outcomes included the incidences of bleeding and recurrence of DVT and pulmonary embolism and patient satisfaction as determined by a questionnaire. RESULTS: One hundred thirteen patients with objectively confirmed DVT underwent screening; 89 patients were treated at home with LMW heparin. During the study, 1 patient died of a combination of pulmonary embolism and major bleeding, another patient required admission to the hospital for bleeding, and 5 patients with active malignant disease had recurrent DVT. Of the patients who completed the satisfaction questionnaire, 75 (91%) of 82 were pleased with home treatment; 44 (70%) of 63 felt comfortable self-injecting the LMW heparin; and 71 (92%) of 77 were satisfied with the support and instruction they received during the outpatient treatment. CONCLUSIONS: Outpatient treatment of DVT with LMW heparin is safe, effective, and feasible for most patients and is associated with a high degree of patient satisfaction.

Adult

Diagnosis of porcine cysticercosis: a comparative study of serological tests for detection of circulating antibody and viable parasites.

Epidemiological studies of porcine cysticercosis require identification of pigs harbouring viable Taenia solium cysticerci and estimates of the degree of exposure to the parasite in the pig population destined for human consumption. Identification of infected pigs with viable larvae is achieved through detection of their secretory products. However, detectable levels of circulating antibody may also be present in the absence of viable larvae. In this study, both types of tests have been evaluated in groups of pigs experimentally infected with T. solium. Detection of viable cysticerci was achieved using a monoclonal antibody-based (HP10) antigen capture assay. HP10 epitope-bearing antigens have now been demonstrated in T. solium and T. crassiceps cyst fluid and excretion/secretions. Serum antibodies were measured in ELISA assays using two parasite preparations as antigens; T. solium cyst fluid and T. crassiceps cyst fluid antigens bearing the HP10 epitope. Low-background values were obtained with sera from non-infected animals in all the assays used. In heavily infected pigs, both antigens and antibodies were detected at least 29 days and up to 200 days post-infection (pi), while in lightly infected pigs antigen and antibodies were first observed between 61-97 days pi. Thus, the levels of the serum antigen and antibody varied with the intensity of the infection.

Animals

Relationship between peptide selectivities of human transporters associated with antigen processing and HLA class I molecules.

Efficiency of presentation of a peptide epitope by a MHC class I molecule depends on two parameters: its binding to the MHC molecule and its generation by intracellular Ag processing. In contrast to the former parameter, the mechanisms underlying peptide selection in Ag processing are poorly understood. Peptide translocation by the TAP transporter is required for presentation of most epitopes and may modulate peptide supply to MHC class I molecules. To study the role of human TAP for peptide presentation by individual HLA class I molecules, we generated artificial neural networks capable of predicting the affinity of TAP for random sequence 9-mer peptides. Using neural network-based predictions of TAP affinity, we found that peptides eluted from three different HLA class I molecules had higher TAP affinities than control peptides with equal binding affinities for the same HLA class I molecules, suggesting that human TAP may contribute to epitope selection. In simulated TAP binding experiments with 408 HLA class I binding peptides, HLA class I molecules differed significantly with respect to TAP affinities of their ligands. As a result, some class I molecules, especially HLA-B27, may be particularly efficient in presentation of cytosolic peptides with low concentrations, while most class I molecules may predominantly present abundant cytosolic peptides.

ATP-Binding Cassette Transporters

Multiply damaged sites in DNA: interactions with Escherichia coli endonucleases III and VIII.

Bursts of free radicals produced by ionization of water in close vicinity to DNA can produce clusters of opposed DNA lesions and these are termed multiply damaged sites (MDS). How MDS are processed by the Escherichia coli DNA glycosylases, endonuclease (endo) III and endo VIII, which recognize oxidized pyrimidines, is the subject of this study. Oligonucleotide substrates were constructed containing a site of pyrimidine damage or an abasic (AP) site in close proximity to a single nucleotide gap, which simulates a free radical-induced single-strand break. The gap was placed in the opposite strand 1, 3 or 6 nt 5' or 3' of the AP site or base lesion. Endos III and VIII were able to cleave an AP site in the MDS, no matter what the position of the opposed strand break, although cleavage at position one 5' or 3' was reduced compared with cleavage at positions three or six 5' or 3'. Neither endo III nor endo VIII was able to remove the base lesion when the gap was positioned 1 nt 5' or 3' in the opposite strand. Cleavage of the modified pyrimidine by endo III increased as the distance increased between the base lesion and the opposed strand break. With endo VIII, however, DNA breakage at the site of the base lesion was equivalent to or less when the gap was positioned 6 nt 3' of the lesion than when the gap was 3 nt 3' of the lesion. Gel mobility shift analysis of the binding of endo VIII to an oligonucleotide containing a reduced AP (rAP) site in close opposition to a single nucleotide gap correlated with cleavage of MDS substrates by endo VIII. If the strand break in the MDS was replaced by an oxidized purine, 7,8-dihydro-8-oxoguanine (8-oxoG), neither endo VIII cleavage nor binding were perturbed. These data show that processing of oxidized pyrimidines by endos III and VIII was strongly influenced by the position and type of lesion in the opposite strand, which could have a significant effect on the biological outcome of the MDS lesion.

Base Sequence

"When you carry condoms all the boys think you want it": negotiating competing discourses about safe sex.

With the advent of HIV, sexual health campaigns and formal sex education in schools have worked to instil the concept of safe sex into the collective minds of Australia's youth. However the concept in its present guise is a fairly limited one. We argue in this paper that the predominant emphasis in education programmes on safe sex as condom use may be counter-productive for some young heterosexuals for two reasons. First, this strategy is male-focused and may not extrapolate well to young women who face special risks around pregnancy and rigid societal gender norms which govern sexual behaviour. Second, health promotion strategies aimed at young heterosexuals are based on an assumption of rational decision-making in sexual encounters and obscure the non-rational nature of arousal and desire, and the unequal power relations that exist between young men and women engaging in sex. Five hundred and twelve senior rural students participated in the study which included group discussions about sexuality and survey items which focused on the meanings of safe sex and the accessibility and use of condoms. The results showed that though most students identified condoms with safe sex, many were ambivalent about using them. Reasons given related to problems of negotiation, difficulties of access, and the risks which condoms gave no protection from, such as a sullied reputation. Perhaps, partly because of this, some students were looking to less secure methods of protection such as informal history-taking and monogamy. It is argued that successful sexual health promotion strategies must address the broad spectrum of concerns facing young men and women when they become sexually active and that consideration be given to the social context in which young people conduct their sexual lives.

Adolescent

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

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

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

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

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

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

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

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