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Biomedical subjects

M Miller

Publications and source records attributed to M Miller.

At least 397 records · Page 22Linked to original sources
PubMed1995

Phase II study of all-trans-retinoic acid and alpha-interferon in patients with advanced non-small cell lung cancer.

Between April 1993 and June 1994, 29 patients (pts) with unresectable, locally advanced, or metastatic non-small cell lung cancer were treated with a combination of p.o. trans-retinoic acid (TRA), 150 mg/m2/day, in three divided doses and s.c. IFN-alpha, 3 x 10(6) units/day. The age range was 41-80 years (median, 63 years). The Eastern Cooperative Oncology Group performance status was 0-1 (24 pts) and 2 (5 pts). Pts had advanced disease, refractory to conventional therapy (5 stage IIIB and 24 stage IV). Twenty-one pts had adenocarcinoma, six had squamous cell carcinoma, and two had large cell carcinoma. Only 3 pts completed 8 weeks of treatment, requiring neither interruption nor dose modification. Fatigue occurred in 88% of pts. A syndrome complex consisting of dry oral and nasal mucosa, recurrent sinus infections, and epistaxis occurred in 64% of pts. Grade II/III dermatitis was seen in 52%. Severe scrotal dermatitis was seen in 7 pts (47% of 15 males). Hypertriglyceridemia was moderate/severe in 11 pts, and 3 pts required gemfibrozil for levels up to 1660 mg/dl. Hematological toxicity was not encountered, and none of the pts had leukocytosis. One pt died with complications of myocardial infarction while on TRA/IFN-alpha. Twenty-five pts had more than 2 weeks of treatment and are evaluable for response; two pts died early with complications of cancer, and two pts declined to continue after only 3 and 5 days of treatment. Final assessment of response was by accepted clinical and radiological criteria at 8 weeks. There have been four objective responses: complete response, 2 (18+ and 17 months) and partial response, 2 (7 and 14 months). Responses were observed in all histologies. Combined differentiation treatment with TRA/IFN-alpha has modest but objective activity in non-small cell lung cancer. Toxicity is considerable. Additional studies to elucidate the biological basis of TRA/IFN-alpha and to define prognostic parameters predicting response are needed.

Adenocarcinoma↗
PubMed1994

RNA expression of complement regulatory proteins in human brain tumors.

The expression of complement regulatory proteins (CRP) on the surface of neoplastic cells has been proposed as a mechanism by which these cells evade immune surveillance. We have examined the RNA expression of the genes that encode 5 kinds of CRP in various human brain tumors to determine whether CRP expression might play a role in the malignant progression of these tumors. The benign and atypical meningiomas, and the astrocytomas showed high expression of SP-40,40, low expression of CD59, and barely detectable expression of CD46, CD55 and S-protein. The benign and atypical menigiomas showed significantly greater expression of SP-40,40 at the RNA level when compared to malignant meningiomas. This study describes the mRNA expression of meningiomas, astrocytomas, tumor cell lines and normal human tissues.

Antigens, CD↗
PubMed1994

High molecular weight kininogen binds to Mac-1 on neutrophils by its heavy chain (domain 3) and its light chain (domain 5).

High molecular weight kininogen (HK) binds specifically, saturably, and reversibly to neutrophils and also reciprocally inhibits the binding of fibrinogen to neutrophils. Since fibrinogen binds to the leukocyte integrin CD11b/18 (Mac-1, alpha M beta 2), we investigated whether HK bound to Mac-1 and whether the binding site was similar to that for factor X. We also examined whether one or both chains of cleaved HK (HKa) were involved. Two monoclonal antibodies, 2B5 (0.29 microM) to HK heavy chain domains 2 (D2) and 3 (D3), and C11C1 (0.26 microM) to HK light chain domain 5 (D5), inhibited by 99 and 93% the binding, respectively, of 125I-HK (8.3 nM) to neutrophils. To minimize steric hindrance, we further demonstrated that the Fab' fragments of 2B5 and C11C1 were able to inhibit the binding of this ligand to virtually the same extent as the intact antibody, indicating that, as in binding of HK to platelets and endothelial cells, both chains are involved. To directly demonstrate the involvement of each chain, we showed that the reduced alkylated light chain derived from HK and low molecular weight kininogen, which contains the same heavy chain as HK, each markedly inhibited the binding of HK to neutrophils. We localized the domain responsible for the binding in each chain by showing that recombinant D3 and D5 decreased the binding of HK to neutrophils. To define the receptor for HK, we employed three monoclonal antibodies to Mac-1: OKM1 and OKM10 to epitopes on the alpha M subunit and IB4 to an epitope on the beta 2 chain. OKM1, which can inhibit fibrinogen binding to neutrophils, inhibited HK binding by 79%, whereas the other antibodies inhibited HK binding less than 25%. Coagulation factor X also binds to Mac-1 on monocytes at a similar site to C3bi. Synthetic peptides which define noncontiguous surface loops in factor X that interact with Mac-1, failed to inhibit 125I-HK binding to neutrophils. We conclude that HK binds, via domains on its heavy chain, D3, and light chain, D5, to Mac-1 on the neutrophil surface, and HK occupies a site overlapping with fibrinogen and different from factor X.

Amino Acid Sequence↗
PubMed1994

Hemochromatosis, multiorgan hemosiderosis, and coronary artery disease.

OBJECTIVE: To examine the prevalence of coronary artery disease (CAD) in autopsies of patients with iron-overload syndromes. DESIGN: Retrospective autopsy study of CAD in cases of hemochromatosis and multiorgan hemosiderosis. SETTING: Registry of nearly 48,000 autopsies performed at The Johns Hopkins Hospital between 1889 and 1992. SUBJECTS: One hundred twenty-three subjects were studied. In a 2:1 control-case ratio, 82 controls matched by age, race, and sex were compared with 41 cases with iron overload. MAIN OUTCOME MEASURE: Severity of CAD. RESULTS: Pathological description of the coronary arteries were recorded as advanced or severe in 12% of iron-overload cases (n = 41) (mean age, 57.6 +/- 13.2 years) compared with 38% of controls (n = 82) (mean age, 57.0 +/- 13.8 years) (P = .01). The prevalence of three-vessel disease assessed by postmortem coronary arteriography was 11.1% in iron-overload cases (n = 18) (mean age, 61.7 +/- 12.2 years) compared with 33.3% in controls (n = 36) (mean age, 61.1 +/- 12.5 years) (P = .04). The odds ratio of CAD with iron overload was 0.18 (95% confidence interval, 0.04 to 0.73). CONCLUSIONS: Iron overload resulting from hemochromatosis or multiorgan hemosiderosis is not associated with an increased prevalence of CAD.

Adult↗
PubMed1994

Association of a cellular myosin II with anionic phospholipids and the neuronal plasma membrane.

Myosin II has been observed in close proximity to the neuronal plasma membrane, suggesting the possibility that at least one isoform of neuronal myosin II may be capable of direct association. Here, we demonstrate that a significant fraction (> 30%, saturable around 90%) of brain myosin II, but not myosins from skeletal or cardiac muscle, can bind to lipid vesicles composed of the anionic phospholipid L-alpha-phosphatidyl-L-serine but not with vesicles made from the neutral phospholipid L-alpha-phosphatidylcholine. Binding to lipid vesicles made from L-alpha-phosphatidyl-L-serine is enhanced in the presence of millimolar amounts of free calcium. ATPase activity remains unimpaired after vesicle association. Myosin II was also shown to remain in tight association with purified plasma membranes, even after depletion of actin. The above observations suggest that mechanisms involving membrane-bound myosin II are required to facilitate metazoan cell motility.

Animals↗
PubMed1994

Self-monitoring of blood glucose in overweight type 2 diabetic patients.

Self-monitoring of blood glucose (SBGM) is widely recommended for both type 1 and type 2 diabetic patients despite the lack of evidence of benefit in glucose control or as an aid in weight loss in type 2 subjects. This study tested the hypothesis that combined use of SMBG and dietary carbohydrate (CHO) counting, using the blood monitoring results to shape dietary CHO quotas, is beneficial in managing type 2 diabetes. Twenty-three overweight (body mass index, BMI 27.5-44 kg/m2) patients aged 40-75 participated in a 28-week behavioral weight control program. Baseline hemoglobin HbA1c ranged between 9.5% and 13.5% (normal range 5.5%-7.7%). Subjects were matched for weight, sex, and HbA1c and assigned to small (4-8 participants) groups which met weekly for 12 weeks and then monthly for 16 weeks. After 8 weeks, the groups were randomized either to continue the behavioral program or to have SMBG and dietary CHO counting. Glucose monitoring was performed 6 times daily (pre- and 2 h postprandially) for the first month, focusing on the meal increment and correlating this to dietary CHO intake. Weight loss was identical in both groups during the year of follow-up. The HbA1c level showed a progressive decline in experimental subjects (P < 0.05), whereas there was no improvement in control subjects.

Adult↗
PubMed1994

Drug discrimination using a Pavlovian conditional discrimination paradigm in pigeons.

Three pigeons were studied using a discriminated autoshaping procedure in which the presence or absence of methadone served as a conditional stimulus signalling which of two key light CSs would be followed by grain access. Drug sessions alternated randomly with no-drug sessions. Methadone (2.0 mg/kg) was administered prior to drug sessions in which a black vertical line on a white background served as CS+ and a diffuse white keylight served as CS- (reversed for bird 681). Saline or no injection was administered prior to no-drug sessions and the CS+/CS- contingencies were reversed. Discriminated performances emerged in which over 80% of the responding occurred to the appropriate stimulus. Stimulus control by methadone was assessed by presenting a range of methadone doses during 10-trial extinction sessions. A graded dose-effect curve was produced with low doses of methadone controlling saline-appropriate responding and higher doses controlling drug-appropriate responding. A range of doses of morphine, cocaine, and pentobarbital were also tested. Morphine produced methadone-appropriate responding while cocaine and pentobarbital did not.

Animals↗
PubMed1994

Predicting the risk of abrupt vessel closure after angioplasty in an individual patient.

OBJECTIVES: We proposed to examine the relation between angiographic morphologic characteristics and abrupt closure after coronary angioplasty and to develop an empirically based risk stratification system. BACKGROUND: Certain lesion morphologic characteristics are associated with higher rates of abrupt closure after coronary angioplasty. Previous approaches have been limited by relatively small sample sizes and an inability to combine multiple characteristics to predict risk in an individual patient. METHODS: Lesion morphology was determined for 779 lesions in 658 patients undergoing an elective first angioplasty. Abrupt closure occurred in 63 lesions (8.1%). Variables associated with abrupt closure were identified by univariate and stepwise multiple logistic regression analysis, and internal validity was assessed by use of bootstrapping. An empirically based scoring system was developed by assigning different weights to each predictive characteristic and was then validated. RESULTS: Almost all lesion characteristics previously labeled "adverse" were associated with an increased risk of abrupt closure, but only total occlusion, location at a branch point, increasing lesion length, evidence for thrombus and right coronary artery location were statistically significant independent predictors. Despite the large sample size, the study was underpowered to detect even a 50% increase in risk with many characteristics. Using a scoring system, we assigned each lesion a specific risk of abrupt closure. The distribution of risk was broad, with 20% of patients having < or = 2.5% risk and 25% having > 10% risk. Internal validation techniques revealed that when 10% of patients were randomly eliminated from the sample in multiple iterations, the risk estimates varied, again pointing to the need for a larger sample. CONCLUSIONS: Empirically based weighting of lesion characteristics could quantify the risk of abrupt closure for individual patients, but a very large sample will be required to understand the interplay of complex lesion characteristics in altering expected outcomes.

Aged↗
PubMed1994

Fetal cocaine exposure and neonatal bilirubinemia.

To assess the effect of fetal exposure to cocaine on neonatal serum bilirubin values, we compared 17 infants whose cocaine exposure was confirmed by urine toxicology studies, with no evidence of other drug exposure by history or urinalysis, with 31 sequentially born healthy term infants without evidence of maternal drug use. The mean (+/- SD) bilirubin concentration in control infants was 110 +/- 32 mumol/L (6.5 +/- 1.9 mg/dl) at 30.5 +/- 5.4 hours of age, compared with 55 +/- 26 mumol/L (3.2 +/- 1.5 mg/dl) at 30.8 +/- 5.3 hours in cocaine-exposed infants (p < 0.001). We also compared the abilities of cocaine and clofibrate, a known inducer of bilirubin uridine diphosphate-glucuronosyl transferase (BGT), to induce drug and bilirubin metabolizing pathways in young male Sprague-Dawley rats. Animals received drugs or saline solution for 7 days, and livers were assayed for cytochrome P-450, peroxisomal beta-oxidase, delta 5-3-ketosteroid isomerase (KSI), glutathione-S-transferase (GST), and BGT. Cocaine was a weak inducer of GST but a strong inducer of KSI, a member of the GST family of enzymes that is closely associated with bilirubin transport (ligandin) in liver, and a moderately strong inducer of BGT. Neither drug increased cytochrome P-450 levels, and only clofibrate induced peroxisomal beta-oxidase. We conclude that cocaine appears to induce bilirubin metabolizing pathways, resulting in a lower risk of neonatal hyperbilirubinemia.

Animals↗
PubMed1994

Treatment of orbital capillary haemangioma with interferon.

BACKGROUND: Capillary haemangiomas are vascular tumours of childhood characterised by proliferative and involutional phases and affecting 1% to 2% of newborns. Recently, recombinant interferons have been used in the treatment of life and sight threatening complications of these tumours. METHODS: The history, results of examination, investigations, management and outcome of two patients with sight-threatening orbital capillary haemangiomas treated with recombinant interferon alpha-2a and 2b respectively were reviewed. RESULTS: Orbital and systemic lesions displayed good response to interferons. Side effects noted were transient pyrexia and elevated serum aminotransferase levels. Disturbed liver function test results occurred in one case and normalised with temporary cessation of therapy. CONCLUSIONS: The interferons are a useful alternative treatment of orbital capillary haemangioma in selected cases.

Female↗
PubMed1994

Autism in thalidomide embryopathy: a population study.

Of a population of 100 Swedish thalidomide embryopathy cases, at least four met full criteria for DSM-III-R autistic disorder and ICD-10 childhood autism. Thalidomide embryopathy of the kind encountered in these cases affects fetal development early in pregnancy, probably on days 20 to 24 after conception. It is argued that the possible association of thalidomide embryopathy with autism may shed some light on the issue of which neural circuitries may be involved in autism pathogenesis.

Adult↗
PubMed1994

Ventricular septal defect in an infant chimpanzee (Pan troglodytes).

During clinical examinations and imaging studies of a prematurely born chimpanzee, a heart murmur, tachypnea, dyspnea, and disturbances of blood flow were observed. At necropsy, cardiomegaly, ventricular hypertrophy, and septal defects confirmed the presence of congenital VSD.

Animals↗
PubMed1994

Pharmacokinetics of fluconazole in cerebrospinal fluid and serum of rabbits: validation of an animal model used to measure drug concentrations in cerebrospinal fluid.

Complete concentration-time data describing the pharmacokinetics of fluconazole in the cerebrospinal fluid (CSF) following a single dose are not available for humans or animals. We studied the pharmacokinetics of fluconazole with an indwelling intracisternal needle as described by R.G. Dacey and M.A. Sande (Antimicrob. Agents Chemother. 6:437-441, 1974). To determine whether the presence of an intracisternal needle alters pharmacokinetics in the CSF, we validated this model with uninfected rabbits by measuring pharmacokinetic constants following direct intracisternal and intravenous administration of fluconazole. Following direct injection, there was no alteration of elimination rates in the CSF with increasing sample number or time. Following intravenous administration, the penetration and kinetic constants were the same in individual animals from which multiple CSF samples were obtained as in a composite subject constructed by pooling virgin samples from different animals. The presence of the intracisternal needle did not alter CSF chemistry or leukocyte counts, and erythrocyte contamination was < 0.001%. While drug concentrations were measured by a microbiological assay, we also compared the sensitivity and reproducibility of a high-performance liquid chromatography (HPLC) assay with those of the microbiological assay. Following a single intravenous dose, the maximum concentration of the drug in serum, the time to maximum concentration of the drug in serum, the terminal elimination half-life in the CSF, and the percent penetration by fluconazole were 6.12 micrograms/ml, 1 h, 9.0 h, and 84.3%, respectively. We conclude that the sampling of CSF via an indwelling needle does not alter fluconazole pharmacokinetics, cause inflammation, or alter chemical parameters; that the microbiological assay is at least equivalent in sensitivity and reproducibility to the HPLC assay; and that robust parameters describing the pharmacokinetics of fluconazole are possible with this model.

Animals↗
PubMed1994

The effect of three serum basic proteins on the mass of lipids in normal and hyperapoB fibroblasts.

We studied whether serum basic proteins (BPs) produce abnormal changes in the mass of cellular lipids in fibroblasts from patients with hyperapobetalipoproteinemia (hyperapoB) and if inhibition or stimulation of protein kinase C affects these processes. In normal cells, BP I increased the mean mass of triglycerides about twofold, whereas there was significantly less stimulation in hyperapoB cells (P < .005). The increase in the mass of cell cholesteryl esters seen in normal cells with BP I was also significantly reduced in hyperapoB cells (P < .005). In contrast, BP II abnormally stimulated the mass of cell cholesteryl esters sixfold in hyperapoB cells (P < .005). BP I also stimulated the mass of total phospholipids about twofold in normal cells, an effect that was reduced by about one third in hyperapoB cells (P = .08). No abnormality was found in hyperapoB cells with BP III. H-7, an inhibitor of protein kinase C, decreased the effects of BP I and BP II in normal and hyperapoB cells. C:8, an analogue of diacylglycerol, activated protein kinase C and stimulated triglyceride formation in normal (fourfold) and hyperapoB (fivefold) cells in the absence of BP I. When added with C:8, BP I further increased triglyceride production 1.5-fold in normal cells but not in hyperapoB cells. Two cellular abnormalities in lipid metabolism in hyperapoB fibroblasts were found, one with BP I, another with BP II. Protein kinase C activity was not deficient in hyperapoB cells, and the defect(s) may occur at another, perhaps earlier, step in the pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Abnormal coagulation profile in brain tumor patients during surgery.

Neurosurgical patients are at high risk for the development of thrombosis and thromboembolism. We compared the perioperative clotting factor and coagulation parameters of 20 patients undergoing elective craniotomy for brain tumors to those of 20 patients undergoing elective abdominal surgery. We also measured the levels of plasma arginine vasopressin to determine if changes in this hormone might be associated with changes in clotting factors, activated partial thromboplastin times, or bleeding times. The results demonstrated a significant reduction in partial thromboplastin times and bleeding times in the neurosurgery group, which began at the initiation of surgery and lasted to the end of the study (12 h postoperatively). Elevations in factor assays and plasma arginine vasopressin occurred in both groups during surgery, but there were no differences between the neurosurgical and abdominal surgical patients, except with Factor IX levels, which were elevated only in the neurosurgical patients. Serum osmolality and hemoglobin levels were significantly higher in the neurosurgical cohort. These results suggest that there are hemostatic differences between neurosurgical patients with brain tumors and abdominal surgery patients that cannot be explained solely by elevations in plasma arginine vasopressin or the clotting factors measured; these differences may be the consequence of perioperative variables such as dehydration and hyperosmolality.

Adult↗