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Biomedical subjects

L S Miller

Publications and source records attributed to L S Miller.

At least 19 recordsLinked to original sources
PubMed1992

Therapeutic advantage of high-affinity anticarcinoma radioimmunoconjugates.

The effect of the relative affinity (Ka) on the antitumor efficacy of monoclonal antibodies (MAbs) has been questioned. It has previously been shown in experimental models that the use of MAbs with higher relative Kas manifests itself in a higher percentage of injected dose of MAb bound to tumor. On the other hand, mathematical models have proposed that the use of higher affinity MAbs may be disadvantageous for antitumor effects, since higher Ka MAbs would bind more antigen and prevent penetration of MAb through tumor. To test this hypothesis, three MAbs reacting to the human pancarcinoma antigen TAG-72 were used as radioimmunoconjugates for therapeutic efficacy versus the LS-174T human colon carcinoma xenograft. MAbs B72.3, CC49, and CC83 have all been shown by depletion studies to react to the same molecule and to all react with overlapping epitopes. While the relative Ka of B72.3 is 2.5 x 10(9) M-1, the relative Kas of CC49 and CC83 are 16.2 and 27.7 x 10(9) M-1, respectively. Each MAb was radiolabeled with 131I, and each radioimmunoconjugate was assayed at five dose levels for therapeutic efficacy using the human xenograft model. The results of these studies demonstrate substantial therapeutic advantage of the higher affinity MAbs CC49 and CC83 versus B72.3 at every dose level. While 500 microCi of B72.3 were required to reduce tumor growth in only a minority of tumor-bearing animals, the use of the same amount or less of the radioimmunoconjugates of CC49 or CC83 resulted in strong antitumor effects in 80 to 100% of tumor-bearing animals. Thus, stronger antitumor effects were seen using as little as 2.5- to 3-fold less of the higher Ka immunoconjugates CC49 and CC83 as compared with B72.3. While we acknowledge the potential disadvantages of higher Ka MAbs in some situations, at least the experimental studies and model system described here show that a distinct therapeutic advantage exists with the use of higher affinity immunoconjugates.

Adenocarcinoma, Mucinous↗
PubMed1992

Help-seeking behavior and attitude of Chinese Americans regarding psychological problems.

Investigated the help-seeking behavior and attitude regarding psychological problems as mediated by mental health status, acculturation level, and sociodemographic characteristics in a community sample of Chinese Americans. Of the 128 respondents, 17 (13.3%) had consulted professional help for a nervous or emotional problem. Compared to the others, they reported significantly poorer mental health status (i.e., had more physical symptoms, had once come close to experiencing a "nervous breakdown," and had a relative who had been in treatment), and were more likely to be American-born. For those who had not previously sought help, attitude toward help seeking was examined. A positive attitude was mediated by superior English ability, being younger, married, and from a lower SES background. The findings suggested help-seeking behavior is primarily mediated by presence of need, whereas attitude reflected a general propensity. Acculturation was an important predictor of both behavior and attitude, with the less acculturated most in need of education about the utility of mental health service.

Acculturation↗
PubMed1992

Acetylator genotype-dependent N-acetylation of arylamines in vivo and in vitro by hepatic and extrahepatic organ cytosols of Syrian hamsters congenic at the polymorphic acetyltransferase locus.

Our laboratory recently reported the successful construction of homozygous rapid (Bio. 82.73/H-Patr) and homozygous slow (Bio. 82.73/H-Pat(s)) acetylator congenic Syrian hamsters. These hamsters are isogenic except for the polymorphic acetylator gene locus (Pat) and perhaps other closely linked loci. The purpose of the present investigation was to assess the expression of acetylator genotype both in vivo and in vitro in a variety of hepatic and extrahepatic organ cytosols. Levels of arylamine N-acetyl-transferase were generally high and in the relative order: liver greater than colon greater than kidney greater than pancreas greater than prostate, urinary bladder, and lung. However, an acetylator gene dose-response was clearly expressed in each tissue, with highest levels in homozygous Patr acetylators, intermediate levels in heterozygous Patr/Pat(s) acetylators, and lowest levels in homozygous Pat(s) acetylators. The magnitude of the acetylator genotype-dependent differences in N-acetyltransferase activity were substrate specific, wherein p-aminobenzoic acid showed the largest differences and p-aminophenol the smallest. The N-acetylation of p-aminobenzoic acid in vivo also reflected acetylator genotype in the congenic hamsters. These results further document the successful construction of rapid and slow acetylator congenic hamsters which should prove very valuable in future studies to assess the role of acetylator genotype in the toxicity and carcinogenicity of arylamine chemicals.

Acetylation↗
PubMed1992

Acute esophageal hemorrhage from a vagal neurilemoma.

A man with known systemic neurofibromatosis developed an acute upper gastrointestinal hemorrhage while hospitalized after a neurosurgical procedure. Endoscopic evaluation showed a vascular lesion with an appearance consistent with a Dieulafoy-type lesion in the distal esophagus. Despite multiple endoscopic procedures with attempted coagulation of the bleeding lesion, the patient continued to have life-threatening hemorrhaging. At thoractomy, a tumor was found to arise from the vagus nerve at the site of bleeding. This tumor was resected and histologically determined to be a neurilemoma. Acute bleeding into the esophagus associated with this type of tumor has not been previously reported.

Cranial Nerve Neoplasms↗
PubMed1992

Time of day effects on a human force discrimination task.

Although numerous studies have demonstrated reliable relationships between various human performance measures and time of day, disagreement exists concerning the shape of these relationships and their dependence on task variables. Most perceptual-motor tasks emphasize responsiveness to exteroceptive stimuli. We used a multiple force-band discrimination task that requires responsiveness to both exteroceptive and proprioceptive information. Results for a response duration measure showed a quadratic time of day trend similar to previously reported performance tasks. Response latency to the force emission cue and number of correct inband force emissions showed cubic time of day trends not typically reported in the time of day and performance literature. These results have implications for time-of-day effects on real world perceptual performance.

Body Temperature↗
PubMed1992

Transnasal US of the esophagus: preliminary morphologic and function studies.

High-frequency catheter-based ultrasound (US) transducers can be inserted into the esophagus transnasally to evaluate esophageal wall structures. Studies were performed in two sheep esophagus specimens in vitro, in 17 healthy human subjects, and in 16 patients with esophageal abnormalities (eight with achalasia, four with scleroderma, three with esophageal carcinoma, and one with esophagitis). In the sheep specimens, endoluminal US delineated seven layers of the esophageal wall; these results correlated closely with histologic findings. Real-time US of the normal esophageal wall was performed during resting and swallowing. Muscles at the lower esophageal sphincter (LES) were shown to be thicker than muscles in the body of the esophagus. Thickening of the muscular layers at the LES in achalasia, dilated blood vessels within the submucosa in esophagitis, and fibrotic changes within the muscular layers in scleroderma were demonstrated. Extramural structures adjacent to the esophagus were also seen. These preliminary results suggest that transnasal esophageal US may become an important diagnostic tool in evaluation of the esophagus.

Adult↗
PubMed1992

The economic burden of mental illness.

Mental illness imposes a substantial burden on individuals and society. Using data from national surveys and a newly developed methodology for calculating costs, the authors estimate that in 1985 the total economic costs of mental illness were $103.7 billion. Of this total, direct treatment and support costs were $42.5 billion, or 11.5 percent of total personal health care spending for all illnesses. Morbidity costs--the value of reduced or lost productivity--amounted to $47.4 billion. Mortality costs--the lost value of productivity due to premature death resulting from mental illness--were estimated to be $9.3 billion, or 5.1 percent of total productivity losses for all deaths. Other related costs, including the cost of caregiver services, amounted to $4.5 billion.

Activities of Daily Living↗
PubMed1992

The morbid anatomy of congenital deficiency of the tibia and its relevance to treatment.

Two specimens obtained from a 5-month-old boy with bilateral type 1a congenital tibial deficiency were dissected to describe their morbid anatomy. Examination revealed a rigid equinovarus deformity, absence of a tibial remnant, an abnormal saddle-shaped talus, and several tarsal coalitions. Observation of the arterial pattern during surgery supported the previously reported finding that persistence of an immature arterial structure is inherent in this condition. Knowledge of potential structural anomalies is essential during the planning of an amputation or of a knee or an ankle reconstruction. Anatomic abnormalities may affect the design of soft-tissue flaps in an amputation and plantigrade positioning and foot biomechanics in reconstructive procedures.

Abnormalities, Multiple↗
PubMed1992

The relationship between reduction in periodontal inflammation and diabetes control: a report of 9 cases.

The established correlation between diabetes and periodontal diseases and the increasing prevalence of Type II diabetes in the general population indicate that dental practitioners will probably treat an increasing number of diabetic patients. Despite the fact that there is little scientific evidence to support the concept, it has been generally accepted that treatment for periodontal disease in diabetic patients may reduce insulin requirements and improve metabolic balance. However, to date no one has evaluated the effects of periodontal therapy on the metabolic state of the poorly-controlled diabetic patient. The purpose of this pilot study was to evaluate the effect of controlling gingival inflammation on blood glucose levels as determined by glycosylation of hemoglobin and albumin.

Blood Glucose↗
PubMed1991

Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate.

177Lutetium (177Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here the first use of a 177Lu-labeled immunoconjugate, 177Lu-CC49, in an experimental therapy model for human carcinoma. 177Lu-CC49 was shown to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Overt toxicity was observed with the administration of approximately 500 microCi of 177Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 microCi of 177Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 microCi of 177Lu-CC49 (250 microCi/week for 3 consecutive weeks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm3) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, 177Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the 177Lu-CC49 versus that of the 177Lu-control MAb. The merits and limitations of the use of 177Lu-labeled immunoconjugates (in particular, 177Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.

Adenocarcinoma, Mucinous↗
PubMed1991

Evaluating cognitive impairment in depression with the Luria-Nebraska Neuropsychological Battery: severity correlates and comparisons with nonpsychiatric controls.

Depressed patients often complain of memory and attentional difficulties, and some research suggests an increased incidence of neuropsychological impairment in depression. Yet, many prior studies contain methodological problems, including the following: (1) inclusion of medicated patients, (2) small sample sizes, and (3) tests with unknown psychometric properties. We administered the Luria-Nebraska Neuropsychological Battery (LNNB) to 28 unmedicated inpatients who met Research Diagnostic Criteria for major depression. Twenty of the 28 patients were given additional cognitive measures (e.g., Wechsler Adult Intelligence Scale-Revised, Benton Tests). The depressed patients performed similarly to an age- and education-matched nonpsychiatric reference sample. When data for a subset of the most severely depressed patients were analyzed separately, these patients too were found to perform similarly to matched controls. There were no relationships between Hamilton rating scale measures of depression severity and any cognitive measures among the depressed patients. The results suggest that cognitive functioning in depressed patients does not differ significantly from that in carefully matched controls and is independent of symptom severity.

Adult↗
PubMed1991

Zollinger-Ellison syndrome: prospective assessment of abdominal US in the localization of gastrinomas.

The ability of abdominal ultrasound (US) to help localize gastrinomas was prospectively studied in 79 patients with Zollinger-Ellison syndrome. The results were assessed by means of laparotomy, autopsy, or percutaneous liver biopsy. For hepatic gastrinoma, US had a sensitivity of 63% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 89%. US was slightly less sensitive for detecting gastrinoma in the liver than were computed tomography (CT) (66%) and selective angiography (78%). For detection of extrahepatic gastrinoma, US had a sensitivity of 30%, a specificity of 94%, a positive predictive value of 100%, and a negative predictive value of 25%. US enabled detection of tumor in eight cases not detected with CT and in four not detected with angiography. Specificity for extrahepatic gastrinoma was similar for all three modalities (89%-95%). CT and US were equally effective for the detection of extrahepatic gastrinoma, and angiography was significantly more effective than both US and CT (P less than .01). The authors conclude that US, although of low sensitivity, remains useful as the initial imaging modality in patients with Zollinger-Ellison syndrome.

Abdomen↗
PubMed1991

Clinical factors that may confound the assessment of drug efficacy.

The development of new chemical classes of psychotherapeutic drugs offers the potential for new patterns of drug efficacy as well as decreases in side effects. However, the determination of drug efficacy can be confounded by sample selection and outcome determination factors. The ability of selected clinical factors of both types to affect the outcome of antipsychotic drug trials is reviewed. Suggestions for future clinical drug trials are made.

Clinical Trials as Topic↗
PubMed1991

Polymorphic and monomorphic expression of arylamine carcinogen N-acetyltransferase isozymes in tumor target organ cytosols of Syrian hamsters congenic at the polymorphic acetyltransferase locus.

A number of human epidemiological investigations suggest a relationship between acetylator phenotype and the incidence and/or severity of tumors caused by exposure to arylamine carcinogens. Conclusions drawn from these investigations can be compromised by a variety of environmental and other genetic factors. To eliminate variability in these other factors, our laboratory recently completed construction of homozygous rapid (Bio. 82.73/H-Patr), heterozygous intermediate (Bio. 82.73/H-Patr/Pat(s)) and homozygous slow (Bio. 82.73/H-Pat(s)) acetylator congenic hamsters. The purpose of the present study was to assess the utility of this congenic hamster model for investigations into the relationship between acetylator genotype and arylamine carcinogenesis. We report the expression of acetylator genotype-dependent (polymorphic) and acetylator genotype-independent (monomorphic) N-acetyltransferase isozymes in hepatic cytosols. The hepatic polymorphic N-acetyltransferase isozyme isolated from the congenic hamsters expressed clearly acetylator-genotype dependent (Patr greater than Patr/Pat(s) greater than Pat(s)) N-acetylation towards p-aminobenzoic acid, 4-aminobiphenyl, 2-aminofluorene, p-aminophenol, 1-aminopyrene, 5-aminosalicylic acid, beta-naphthylamine, 3,4-dichloroaniline, 3,2'-dimethyl-4-aminobiphenyl and p-phenetidine. Acetylator genotype-dependent N-acetylation for a number of arylamines also was observed in liver, colon, kidney and urinary bladder cytosols derived from the congenic hamster lines, including arylamines highly carcinogenic to hamster colon and urinary bladders. It is concluded that the congenic hamster model will be useful in studies to delineate the role of acetylator genotype in the incidence or severity of arylamine tumors.

Animals↗
PubMed1990

Purification of hepatic polymorphic arylamine N-acetyltransferase from homozygous rapid acetylator inbred hamster: identity with polymorphic N-hydroxyarylamine-O-acetyltransferase.

The polymorphic acetyltransferase isozyme expressed in homozygous rapid acetylator inbred hamster liver cytosol was purified over 2000-fold by sequential Q-Sepharose fast-flow anion-exchange chromatography, Sephacryl S-200 high-resolution size-exclusion chromatography, Mono Q anion-exchange fast-protein liquid chromatography, and preparative polyacrylamide gel electrophoresis. The isozyme migrated as a single homogeneous monomer following both preparative and sodium dodecyl sulfate-polyacrylamide electrophoresis. The molecular weight was estimated at 34,170 following elution via size-exclusion chromatography and 35,467 following migration via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The homogeneous polymorphic acetyltransferase exhibited a broad substrate specificity; it catalyzed the acetyl coenzyme A-dependent N-acetylation of p-aminobenzoic acid, carbocyclic arylamine carcinogens such as 2-aminofluorene, 4-aminobiphenyl and beta-naphthylamine, and heterocyclic arylamine carcinogens such as 2-aminodipyrido[1,2-a:3'2'd]imidazole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole. It also readily catalyzed the acetyl coenzyme A-dependent metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene to DNA adducts but not the metabolic activation (via intramolecular, N,O-acetyltransfer) of N-hydroxy-2-acetylaminofluorene or N-hydroxy-4-acetylaminobiphenyl to DNA adducts. Conversely, the partially purified monomorphic acetyltransferase isozyme from the same hamsters readily catalyzed the metabolic activation of N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl, and rates of metabolic activation of these substrates did not differ between homozygous rapid and slow acetylator liver, intestine, kidney, and lung cytosols. Heat inactivation rates for the purified polymorphic acetyltransferase isozyme were first order and indistinguishable for the acetyl coenzyme A-dependent N-acetylation and O-acetylation activities. The results strongly suggest the expression of a single polymorphic acetyltransferase product of the hamster polymorphic acetyltransferase gene that catalyzes both acetyl coenzyme A-dependent N-acetylation and O-acetylation of arylamine and N-hydroxyarylamine carcinogens but not the metabolic activation of N-hydroxy-N-acetylarylamines (arylhydroxamic acids) via intramolecular N,O-acetyltransfer. Consequently, acetylator genotype-dependent metabolic activation of N-hydroxyarylamines to a DNA adduct in hamster is catalyzed by direct O-acetylation of the hydroxyl group and not via sequential N-acetylation followed by N,O-acetyltransfer.

Acetyltransferases↗