Biomedical subjects

M Lee

Publications and source records attributed to M Lee.

At least 19 recordsLinked to original sources

PubMed1992

Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for adults with acute myelogenous leukemia.

Modern induction chemotherapy produces 60% to 80% complete remissions in adults with newly diagnosed acute myelogenous leukemia. A major challenge is to eradicate subclinical disease in remission and prevent leukemic relapse. We analyzed the long-term results of high-dose cytarabine-anthracycline consolidation chemotherapy without maintenance treatment and examined the effect of major prognostic factors, including age, sex, history of preleukemia, and cytogenetics. Two hundred twenty-seven patients with newly diagnosed acute leukemia were enrolled on two sequential studies conducted from 1982 to 1991. One hundred fifty-one patients (67%) achieved a complete remission. One hundred twenty-three patients were eligible for high-dose cytarabine-based consolidation administered in two to three courses. After a median follow-up of 4.8 years, 40 patients remain alive, with 28 in continued remission. Median remission duration for all eligible patients is 12.8 months, and actuarial leukemia-free survival (LFS) at 5 years is 26% +/- 8%. Advanced age and male sex were negative prognostic indicators for LFS. For patients < or = 45 years of age, 5-year LFS was 35% +/- 13%, as compared with 18% +/- 11% for patients greater than age 45 (P = .03). Toxicity of consolidation chemotherapy included treatment-related death in nine patients and serious neurotoxicity in five. Our results show an improved LFS for younger patients treated with high-dose cytarabine-based consolidation. There was no apparent benefit for older patients compared with reported data with less intensive regimens.

Adult↗

PubMed1992

Catalytic properties of the human cytochrome P450 2E1 produced by cDNA expression in mammalian cells.

A full-length cDNA encoding human cytochrome P450 2E1 was expressed in mammalian cell lines using the vaccinia virus expression system. Immunoblot analysis showed that the expressed protein reacted with a polyclonal antibody against rat 2E1 and comigrated with P450 2E1 from human liver microsomes. P450 2E1 expressed in Hep G2 cells, a human cell line which contains both cytochrome b5 and NADPH:P450 oxidoreductase, was able to metabolize several known P450 2E1 substrates: N-nitrosodimethylamine (NDMA), N-nitrosomethylbenzylamine (NMBzA), p-nitrophenol, phenol, and acetaminophen. Apparent Km and Vmax values for NDMA demethylation were 22 microM and 173 pmol/min/mg microsomal protein, respectively. P450 2E1 expressed in TK-143 cells, which do not contain b5, displayed Km and Vmax values of 31 microM and 34 pmol/min/mg microsomal protein, respectively. Incorporation of purified rat liver b5 into TK-143 microsomes increased the Vmax 2.2-fold and decreased the Km to 22 microM. Addition of b5 to Hep G2 microsomes resulted in a 1.6-fold increase in Vmax, but showed no effect on the Km. P450 2E1 expressed in Hep G2 cells was shown to metabolize NMBzA with a Km of 47 microM and Vmax of 213 pmol/min/mg microsomal protein. Addition of b5 lowered the Km to 27 microM, but had no effect on Vmax. These results demonstrate conclusively that P450 2E1 is responsible for the low Km forms of NDMA demethylase and NMBzA debenzylase observed in liver microsomes and that these activities are affected by cytochrome b5.

Animals↗

PubMed1992

Photorefractive keratectomy for severe postkeratoplasty astigmatism.

We performed cylindric corneal ablations with the excimer laser on 12 patients to correct severe, disabling astigmatism after keratoplasty. In some patients, an additional ablation was performed to correct myopia. Patients were followed up for an average of eight months (range, six to 14 months). Uncorrected visual acuity improved in nine patients, and nine of the 12 patients had a decrease in refractive cylinder at last follow-up. The mean preoperative refractive cylinder was 7.0 +/- 3.6 diopters, which decreased to a mean of 3.1 +/- 2.6 diopters at one month (P = .0003) and 4.3 +/- 2.9 diopters at last follow-up (P = .03). Keratometric astigmatism decreased from 7.5 +/- 3.9 diopters preoperatively to 5.2 +/- 3.9 diopters at the last follow-up (P = .001). Mean spherical equivalent was reduced from -7.4 +/- 4.2 diopters preoperatively to -3.3 +/- 4.4 diopters postoperatively (P = .003). Postoperative corneal haze, when present, did not reduce visual acuity. Excimer laser superficial keratectomy thus appears to be safe when used for postkeratoplasty ametropia, although substantial regression may limit its effectiveness in some patients.

Adult↗

PubMed1992

Pharmacokinetic properties of recombinant factor VIII compared with a monoclonally purified concentrate (Hemofil M). The Recombinate Study Group.

A recombinant FVIII preparation, Recombinate, was compared with a high-purity plasma-derived concentrate, Hemofil M, in 47 hemophilia A patients in a cross-over evaluation of pharmacokinetic properties. The recombinant material showed a significantly lower clearance, volume of distribution, and higher in vivo recovery, but a similar half-life to the plasma-based product. In a comparison with reported data from other standard concentrates, the recombinant preparation exhibited potentially better pharmacokinetic properties in that its clearance was slower and its half-life was longer. We conclude that the recombinant DNA method of preparation does not adversely affect the biological and pharmacological characteristics of the factor VIII molecule.

Adolescent↗

PubMed1992

Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids.

Cerebral deposition of the beta-amyloid peptide (A beta) is an invariant feature of Alzheimer's disease. Since the original isolation and characterization of A beta (ref. 1) and the subsequent cloning of its precursor protein, no direct evidence for the actual production of discrete A beta has been reported. Here we investigate whether A beta is present in human biological fluids using antibodies specific for an epitope within A beta that spans the site of normal constitutive cleavage. These antibodies were used to construct a sandwich-type enzyme-linked immunosorbent assay that detects A beta in cerebrospinal fluid, plasma and conditioned medium of human mixed-brain cells grown in vitro (see also ref. 14). By affinity chromatography, we have purified and sequenced A beta and a novel A beta fragment from human cerebrospinal fluid and conditioned medium of human mixed-brain cell cultures. These findings demonstrate that A beta is produced and released both in vivo and in vitro. These observations offer new opportunities for developing diagnostic tests for Alzheimer's disease and therapeutic strategies aimed at reducing the cerebral deposition of A beta.

Alzheimer Disease↗

PubMed1992

Introduction of hydroxyl-bearing amino acids causes bathochromic spectral shifts in rhodopsin. Amino acid substitutions responsible for red-green color pigment spectral tuning.

Comparisons of the deduced amino acid sequences of eight primate photopigment genes led to the proposal that three amino acid substitutions produce the approximately 1,000 cm-1 difference in the absorption maxima of human red and green pigments (Neitz, M., Neitz, J., and Jacobs, G.H. (1991) Science 252, 971-974). We tested this proposal by mutating these three residues in rhodopsin and evaluating the effects on spectral properties. Nonpolar residues normally present in rhodopsin and in the green pigment were substituted by hydroxyl-bearing residues normally present in the red pigment. Two of these substitutions (Phe-261 to Tyr or Ala-269 to Thr) caused significant red shifts in the absorption maxima of the resulting mutant pigments. A third substitution (Ala-164 to Ser) caused only a slight effect. Combinations of substitutions caused additive shifts in absorption maxima. A double mutant (Phe-261 to Tyr/Ala-269 to Thr) displayed an absorption maximum that was red-shifted by 775 cm-1. Wavelength modulation in the visual pigments responsible for red-green color vision is likely to be governed by retinal-protein interactions involving primarily these two amino acid residues. Furthermore, interactions of hydroxyl-bearing amino acids with the chromophore may be a general mechanism of the opsin shift in visual pigments.

Amino Acid Sequence↗

PubMed1992

Multifocal corneal topographic changes with excimer laser photorefractive keratectomy.

Excimer laser photorefractive keratectomy can flatten the central cornea, thereby eliminating myopic refractive errors; in older patients, however, presbyopia limits satisfaction. Computer-assisted topographic analysis of corneas after refractive surgery indicates that a minority of patients achieve a multifocal lens effect, such that they maintain reasonable acuity over a range of defocus. We have purposefully attempted to create a multifocal refractive effect and have analyzed the subsequent topographies quantitatively to determine if multifocality was achieved. In corneas not operated on and plastic hemispheres, a fairly small range of corneal powers is observed; the range of powers is increased after a monofocal ablation. After multifocal ablations, a greater spread of surface powers is observed, often with a bimodal distribution, indicative of an apparent multifocal effect. These observations suggest that in some patients undergoing photorefractive keratectomy for myopia, it may be possible to reduce symptoms of presbyopia, although a decrease in image contrast or monocular diplopia may complicate this approach.

Animals↗

PubMed1992

Bone excrescence at the medial base of the distal phalanx of the first toe: normal variant, reactive change, or neoplasia?

In a review of 157 anteroposterior (AP) foot radiographs in 117 adult and pediatric patients, we observed a medial excrescence on the plantar aspect of the terminal phalanx of the hallux in 88.5% of the feet. Histologic analysis documented the presence of reactive bone. The bony outgrowth appears after closure of the adjacent physeal plate and is rarely symptomatic. Its high prevalence indirectly implies that it is not specific to any particular type of foot. Although certain types of foot may contribute to its development, we believe that repetitive forces occurring during ambulation induce this reactive bone formation.

Adipose Tissue↗

PubMed1992

Immunoglobulin replacement in patients with chronic lymphocytic leukemia (CLL): kinetics of immunoglobulin metabolism.

Fifteen patients with low-grade B-cell tumours were given 3-weekly infusions for 1 year of intravenous immunoglobulin (IVIg) at a dose of 0.4 g/kg. Serial measurements of serum IgG levels were made; analysis of eight samples taken at intervals after the end of the last (17th) infusion showed that the half-life of IgG in such patients was no shorter than in normal individuals. To look at the average rates of catabolism of IgG during the year serum IgG was measured at four time points (pre, post, day 7, and day 21) after the 5th, 8th, 13th, and 17th infusions; these data showed that there were no changes in catabolism. Finally, there was a significant correlation (P less than 0.005) between the pretreatment serum IgG level and the increase to the mean trough level achieved after the fifth and subsequent infusions (in each individual). These data suggest that the catabolic rate of IgG is normal in patients with low-grade B-cell tumours and that it is not altered by regular IVIg infusions once a steady state is reached. Significant correlation of the increment of serum IgG with the endogenous synthesis level supports the theory that the IgG half-life is proportional to the IgG level at any given time.

Agammaglobulinemia↗

PubMed1992

Nonessential role of leukotrienes as mediators of acute gastric mucosal injury induced by aspirin in rats.

The present study was designed to determine the role of leukotrienes in aspirin-induced acute gastric mucosal injury in rats. We examined the effects of aspirin, indomethacin, and sodium salicylate on gastric mucosal injury, and on eicosanoid synthesis and content. Aspirin, indomethacin, and acidified salicylate caused significant mucosal injury, while salicylate at pH 7 did not induce significant injury. Aspirin and indomethacin significantly reduced mucosal prostaglandin synthesis and content. No significant changes in mucosal leukotriene C4 synthesis and content were observed. There were no correlations between changes in mucosal leukotriene B4 synthesis and the extent of mucosal injury. We also evaluated the effects of MK-571 (a leukotriene D4 receptor antagonist) and MK-886 (a leukotriene biosynthesis inhibitor) on aspirin-induced gastric mucosal injury. Neither MK-571 nor MK-886 could reduce the mucosal lesions induced by aspirin. These findings suggest that leukotrienes are not involved in aspirin-induced acute gastric mucosal injury in rats.

Acute Disease↗

PubMed1992

Tissue antioxidant status in streptozotocin-induced diabetes in rats. Effects of dietary manganese deficiency.

Interactions between manganese (Mn) deficiency and streptozotocin (STZ)-diabetes with respect to tissue antioxidant status were investigated in male, Sprague-Dawley rats. All rats were fed either a Mn-deficient (1 ppm) or a Mn-sufficient (45 ppm) diet for 8 wk. Diabetes was then induced by tail-vein injection of STZ (60 mg/kg body weight), after which the rats were kept for an additional 4 or 8 wk. The control groups comprised rats not injected with STZ and fed either Mn-deficient or Mn-sufficient diets for a total of 12 wk. The Mn-deficient diet decreased the activities of manganese superoxide dismutase (MnSOD) in kidney and heart, and of copper-zinc superoxide dismutase (CuZnSOD) in kidney, in the non-diabetic animals. In the diabetic rats, the Mn-deficient diet induced more pronounced decreases in activities of these same enzymes, and also increased liver MnSOD activity. Plasma and hepatic vitamin E levels increased progressively with the duration of diabetes, independent of dietary Mn intake. Lipid peroxidation, as measured by H2O2-induced production of thiobarbituric acid reactive substances in erythrocytes, also increased, concomitant with decreased liver and kidney glutathione (GSH) levels. These findings demonstrate for the first time and interactive effective between Mn deficiency and STZ-diabetes, resulting in amplification of tissue antioxidant changes seen with either Mn deficiency or STZ-diabetes alone. This effect of Mn deprivation in experimental diabetes suggests a physiological role for Mn as an antioxidant nutrient.

Animals↗

PubMed1992

Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis.

The effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on inflammation, tissue damage, and production of inflammatory mediators in rabbit formalin-immune complex colitis were examined. Treatment of rabbits with intravenous administration of IL-1ra before and periodically throughout the first 43 hours after the induction of colitis (total 7 doses) suppressed inflammation and tissue damage in a dose-related manner. Maximum inhibition of inflammatory index (from 3.0 +/- 0.3 to 0.8 +/- 0.3, P less than 0.001), edema (from 2.3 +/- 0.2 to 0.6 +/- 0.2, P less than 0.001), percent of mucosal necrosis (from 44% +/- 7% to 7% +/- 3%, P less than 0.02) and myeloperoxidase (MPO) activity (from 4.9 +/- 1.0 U/g to 1.0 +/- 0.3 U/g, P less than 0.001) occurred with the dose of 5 mg/kg. Colonic prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, measured in rectal dialysates by specific radioimmunoassays, was also dose dependently suppressed (from 1124 +/- 319 pg/mL to 190 +/- 75 pg/mL, P less than 0.001 and 568 +/- 192 pg/mL to 92 +/- 51 pg/mL, P less than 0.001, respectively, at 5 mg/kg). In contrast, colonic IL-1 alpha tissue levels measured by a specific radioimmunoassay after tissue extraction were similar in all groups. When only two doses of IL-1ra, 10 minutes before and 3 hours after the induction of colitis were given, there was no longer an inhibitory effect on inflammation or production of inflammatory mediators. However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1 alpha levels were unchanged compared with vehicle-treated animals. These studies show the ability of human recombinant IL-1 receptor antagonist to suppress the proinflammatory activity of IL-1 produced in the colon during the induction and progression of rabbit immune complex colitis.

Animals↗

PubMed1992

Importance of gastric acid in gastric ulcer formation in rabbits with antibody-induced prostaglandin deficiency.

The role of gastric acid in the development of gastroduodenal ulcers in prostaglandin-deficient conditions is unclear. In the current study, the effect of the proton pump inhibitor omeprazole on the formation of gastric ulcers was examined in a previously validated rabbit model of antibody-induced prostaglandin deficiency. Intragastric administration of 20 mg/kg omeprazole every 12 hours caused a profound suppression of gastric acidity (i.e., pH above 5 continuously). This same dose of omeprazole significantly reduced gastric ulcer formation induced by passive immunization with 6-keto-prostaglandin F1 alpha antibodies. It is concluded from these observations that gastric acid plays a critical role in the formation of gastric ulcers in rabbits with antibody-induced prostaglandin deficiency.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Sinonasal small cell neoplasm developing after radiation therapy for retinoblastoma: an immunohistologic, ultrastructural, and cytogenetic study.

Patients with retinoblastoma have an increased risk of developing second primary tumors. Only a few examples of sinonasal small cell neoplasms developing after radiation therapy for retinoblastoma have been reported. We report one such case that developed 18 years after treatment for retinoblastoma. Histologic examination revealed a small, blue, round cell tumor without rosettes or cytoplasmic glycogen. Immunohistochemically, the tumor cells were positive for neuron-specific enolase, synaptophysin, and S-100 protein, but negative for epithelial and mesenchymal markers, suggesting that this was a primitive neuroectodermal tumor. Cytogenetic studies of this tumor failed to reveal the chromosome 13 abnormality typical of retinoblastoma and the t(11:22) translocation typical of the group of peripheral neuroepitheliomas.

Adult↗

PubMed1992

Statistical analysis of the effect of cadmium and zinc on hamster teratogenesis.

Maternal smoking is correlated with lower average birth weights and an increase in malformations in some studies. Increased maternal cadmium levels and reduction of zinc levels in certain tissues from fetuses of women who smoke suggest a biological association during pregnancy. Zinc has a protective effect on hamster teratogenesis caused by cadmium. To determine whether this protective effect is additive or synergistic (interactive), pregnant golden Syrian hamsters were injected (iv) on Day 8 of gestation with a test solution based on maternal body weight (0.5 ml per 100 g). Five doses were given: 2 mg/kg zinc chloride, 2 mg/kg cadmium chloride, 3 mg/kg cadmium chloride, 2 mg/kg zinc chloride plus 2 mg/kg cadmium chloride, and 2 mg/kg zinc chloride plus 3 mg/kg cadmium chloride. Fifty dams were randomly placed into one of the groups, for a total of 10 pregnant dams in each group. Twenty other dams were randomly placed into untreated or saline control groups. Fetuses were recovered on Day 15 and weighed, crown-rump length was measured, and fetuses were examined for viability and external malformations. Resorptions were noted. Statistical analyses included one- and two-way nested ANOVA, and logistic regression adjusted for litter effect. Zinc's protective effect on acute cadmium embryonic/fetal toxicity and teratogenicity was confirmed. The protective effect was of the same magnitude relative to the dose-dependent effect of the cadmium exposure, indicating that the effect was statistically additive and not synergistic. This suggests that the effect depends on competition of the two elements at some common binding site(s).

Abnormalities, Drug-Induced↗

PubMed1992

Assessing the use of medications in the elderly: methods and initial experience in the Cardiovascular Health Study. The Cardiovascular Health Study Collaborative Research Group.

The Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary heart disease and stroke, recruited 5201 community-dwelling adults aged 65 years or older. To assess the prevalence of medication use at baseline, we used the method of medication inventory and transcribed information about drug names and doses from prescription bottles. Using a specially-written computer program, persons without a knowledge of drug nomenclature coded 10,511 (89%) of the 11,846 medicines entered. We compared the results of the medication inventory and answers to questions on specific medications for reliability and validity. The use of beta-blockers and beta-agonists assessed by the method of medication inventory, but not by the method of directed recall, was associated with a significant effect on mean heart rate. Among 5197 participants with medication data, 76.1% were taking at least one medicine, and the mean number of drugs per person was 2.28. Among those with a reported history of high blood pressure, participants with cardiovascular disease (CVD) were more likely to be treated, and they were more likely to be taking beta-blockers and calcium-channel blockers than those without CVD. Daily aspirin use was also more common among those with CVD (30.5% of women and 43.2% of men) than among those without CVD (14.0% of women and 14.0% of men). The prevalence of post-menopausal estrogen use differed significantly among the four clinical centers (range = 5.5%-22.5% of women). We conclude that this method of assessing medications was easy to use and provided estimates of exposure to drugs that may affect risk of cardiovascular disease.

Aged↗

PubMed1992

Fatal disseminated infection with human herpesvirus-6.

A 13-month-old immunocompetent girl had fever, rash, and multisystem disease, and she eventually died of cardiac failure. Autopsy revealed intracellular viral inclusions of the herpesvirus group, with results of in situ hybridization positive for human herpesvirus-6. This is apparently the first case of fatal disseminated herpesvirus-6 infection.

Exanthema Subitum↗

PubMed1992

Corneal wound healing after excimer laser ablation. Effects of nitrogen gas blower.

PURPOSE: To examine the effects of blowing nitrogen gas over the cornea during photorefractive keratectomy. METHODS: Excimer laser ablations for myopia were performed on rabbit corneas with or without the blowing of nitrogen across the surface of the cornea. All eyes underwent a 5-diopter myopic ablation; in 8 eyes, a ring was used to blow nitrogen gas across the cornea, and, in 8 eyes, the same ring was used, but no nitrogen gas was blown. RESULTS: Epithelial healing occurred more rapidly in the eyes that were not treated with the gas (3.8 +/- 1.3 days) than in the gas-treated group (6.1 +/- 0.8 days; P = 0.0025). Corneal haze was greater in the group treated with gas. Results of histologic examination showed the ablated area to have a smoother surface when nitrogen was not blown across the cornea surface. CONCLUSION: Superficial corneal deturgescence produced by the nitrogen gas appears to result in a rougher surface immediately postoperatively with undesirable effects on surface healing, but further studies will be necessary to determine the applicability of these results to humans.

Animals↗