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Biomedical subjects

M A Miller

Publications and source records attributed to M A Miller.

At least 289 records · Page 16Linked to original sources
PubMed1993

Role of polymorphic and monomorphic human arylamine N-acetyltransferases in determining sulfamethoxazole metabolism.

Sulfonamides are associated with a variety of adverse reactions, some of which have been linked with the classical acetylator phenotypes. Although the slow acetylator phenotype has been identified as a risk factor for hypersensitivity reactions to sulfamethoxazole (SMX), the disposition of this compound appears not to be affected by the acetylation polymorphism in vivo in humans. We therefore investigated the acetylation of SMX by monomorphic (NAT1) and polymorphic (NAT2) arylamine N-acetyltransferases in humans with the objective of determining their role in the metabolism of SMX. SMX was acetylated by both NAT1 and NAT2. Km values determined in hepatic cytosol for NAT1- and NAT2-mediated acetylation of SMX were 1.2 mM and approximately 5 mM, respectively, at an acetyl coenzyme A concentration of 100 microM. Mononuclear leukocytes, which contain only NAT1, had a Km value of 1.2 mM. Km values determined with recombinant NAT1 and NAT2 proteins expressed in Escherichia coli were 1.5 mM and approximately 15 mM, respectively. The higher affinity of NAT1 for SMX indicates that acetylation by this enzyme will predominate at therapeutic plasma concentrations, in agreement with the observed in vivo monomorphic acetylation of SMX. NAT1 may be the primary determinant of SMX systemic metabolic clearance. However, in the hepatocyte NAT2 variation may be an important competitive pathway which influences the extent of oxidative metabolism of SMX to its reactive hydroxylamine metabolite. Therefore, variation in both monomorphic and polymorphic N-acetyltransferases may play a role in determining susceptibility to sulfamethoxazole toxicity.

Acetylation↗
PubMed1993

Extra-hypothalamic vasopressin neurons coexpress galanin messenger RNA as shown by double in situ hybridization histochemistry.

Vasopressin (VP) neurons in the bed nucleus of the stria terminalis (BNST) and medial amygdala (AMe) exhibit sexual dimorphism and steroid dependency. VP neurons in the supraoptic nucleus and paraventricular nucleus have been shown to coexpress other transmitters including galanin (GAL). However, little is known about what other neurotransmitters may be colocalized with VP in the BNST and AMe. Here, we have used radio-labeled and digoxigenin-labeled cRNA probes to perform double in situ hybridization histochemistry for VP and GAL in the BNST and AMe of intact, adult male rats. We provide evidence that in the basal state, the majority of VP-synthesizing cells in the BNST and AMe of the adult male rat also express galanin mRNA. Likewise, the majority of GAL-expressing neurons in these regions also contain VP mRNA. These findings give further evidence for the similarity of the BNST and AMe and provide a rationale for studies investigating the role of GAL in functions involving extrahypothalamic VP pathways.

Amygdala↗
PubMed1993

Osseous implant for studies of biomaterials using an in vivo electrochemical transducer.

The in vitro and in vivo electrochemical behavior of commercially pure titanium (cp Ti) was characterized using a specialized osseous implant in conjunction with electrochemical impedance spectroscopy (EIS) measurement techniques. Studies performed in vitro were used to verify the operation of the transducer and develop methods of deconvoluting EIS data. This method was subsequently used to describe an electrochemical equivalent circuit model of the surface oxide and electrical double-layer capacitance of cp Ti in the endogenous electrolyte found in the medullary compartment of a baboon tibia. Kinetic profiles of the double-layer capacitance and the polarization resistance were constructed from multiple in vitro and in vivo EIS measurements performed over 60 min at 0 V (reference Ag/AgCI) conditioning potential. The profiles demonstrated that the growth of surface oxides was biphasic, with rapid decrease in the double-layer capacitance occurring within 20 min and reaching steady-state conditions at approximately 40 min. These data suggested that a passive, stable biofilm formed on the cp Ti surface in vivo and in vitro.

Animals↗
PubMed1993

Alterations in cell membrane permeability by the lentivirus lytic peptide (LLP-1) of HIV-1 transmembrane protein.

Previously we reported that synthetic peptide homologs of an amphipathic region (designated the lentivirus lytic peptide, or LLP-1) near the carboxy terminus of HIV-1 transmembrane protein (TM) were toxic for both prokaryotic and eukaryotic cells when added exogenously to cell cultures. We postulated that these peptides may exert their toxic effects in much the same manner as natural cytolytic peptides such as magainins, cecropins, and melittin by forming pores through cellular membranes. Here we show the results of 51Cr-release assays and membrane flux measurements of peptide treated cells that support our hypothesis. We have also tested a limited panel of LLP-1 peptide analogs in these assays and found that relatively minor alterations in peptide charge or amphipathicity in the parent HIV LLP-1 sequence resulted in total loss of membrane perturbative properties. These results demonstrate that the peptide homolog of HIV-1 LLP-1 can indeed perturb membranes by forming pores of defined size in cytoplasmic membranes. Furthermore, the analog studies described here reveal that the amphipathy and high positive charge of this protein segment are required for the membrane perturbative properties.

Amino Acid Sequence↗
PubMed1993

Enzymatic and immunohistochemical evaluation of tyrosine phosphorylation in breast cancer specimens.

Using a synthetic peptide substrate, tyrosine protein kinase (TPK) activity was measured in 21 tumors from patients with histologically confirmed breast cancer and in five normal breast tissues from patients undergoing reduction mammoplasty. In 20 of 21 cancer specimens, tumor was available to assess phosphotyrosine (PT) immunohistochemically. Breast cancer specimens possessed significantly more TPK activity than normal breast tissues (Cancer = 43.9 +/- 3.1 pm/mg protein/min, [Mean +/- S.E.M.]; Normal = 3.4 +/- 0.9, p < 0.001). TPK activity was higher in the clinically more aggressive infiltrating ductal cancers compared to the less aggressive intraductal cancers (Infiltrating = 55.9 +/- 5.8; Intraductal = 17.2 +/- 3.4, p < 0.01). TPK activity in tumors with both infiltrating and intraductal histology was intermediate (34.0 +/- 7.2). Significant correlation existed between membrane TPK enzymatic activity and PT expression by immunohistochemistry. There was no relationship between estrogen or progesterone receptor status and TPK activity or PT; however, TPK activity from node negative breast cancer tissue was significantly less than from node positive specimens (p < 0.01). We conclude that breast cancer specimens possess elevated amounts of TPK which correlate with PT expression, and that increased tyrosine phosphorylation appears to correlate with the biologic aggressiveness of the malignant tumor.

Breast↗
PubMed1993

Eosinophilic granuloma of the hand.

The first reported case of eosinophilic granuloma of the hand is presented. A slowly expanding lesion of the right third metacarpal shaft was treated by biopsy and curettage. Histological examination confirmed the presence of eosinophilic granuloma. A bone scan showed that it was a solitary lesion. There has been no evidence of recurrence of the lesion during follow-up. Eosinophilic granuloma is a rare disease of the mononuclear phagocyte system, representing one of the clinical manifestations of Langerhans-cell histiocytosis. The lesions are usually associated with the skull, femur, mandible and ribs; this condition has not been previously reported in the hand.

Adult↗
PubMed1993

Identification of a calmodulin-binding and inhibitory peptide domain in the HIV-1 transmembrane glycoprotein.

A number of studies suggest a critical role of the HIV-1 envelope glycoprotein in cytopathogenesis, but the detailed mechanisms of cell injury remain to be defined. HIV-1 envelope proteins associate with the host cell membrane, and studies have demonstrated that HIV perturbs membrane structure and function. We describe here a structurally conserved region of the HIV-1 transmembrane protein (TM) that displays functional properties of target regions of proteins that interact directly with calcium-saturated calmodulin as part of cellular response cascades. The synthetic peptide homolog encompassing the carboxyl terminus (amino acid residues 828-855) of HIV-1 TM protein (LLP-1) is shown in standard in vitro assays to bind efficiently to purified calmodulin (CaM) and to inhibit in vitro CaM-mediated stimulation of phosphodiesterase activity. This suggests that this peptide homolog binds to CaM at affinities similar to those reported for a reference CaM-binding peptide. In addition, the CaM-dependent process of phospholipid synthesis can be inhibited in cell cultures by exogenous addition of the LLP-1. Finally, we have shown that the full-length TM protein binds CaM, whereas a truncated TM protein lacking the LLP-1 segment does not bind CaM. These results suggest a novel mechanism of viral cytopathogenesis mediated by the interaction of HIV-1 TM protein with cellular CaM, that could lead to an uncoupling of critical cellular signal transduction pathways.

Amino Acid Sequence↗
PubMed1993

Comparison of antimicrobial susceptibility, beta-lactamase production, plasmid analysis and serum bactericidal activity in Edwardsiella tarda, E. ictaluri and E. hoshinae.

Antimicrobial susceptibility profiles of clinical and environmental isolates of Edwardsiella demonstrate that the three species are susceptible to beta-lactam antibiotics. All strains were susceptible to two quinolones tested and to gentamicin and doxycycline. E. tarda and E. hoshinae were resistant to clindamycin, whereas E. ictaluri was moderately susceptible. beta-Lactamase was produced by all strains of E. tarda, but not by E. hoshinae or E. ictaluri. A 54-kb plasmid was detected in six of 13 E. hoshinae strains. Five of the 10 E. tarda isolates studied gave an identical plasmid pattern of four plasmids ranging in size from 76-kb to 5.0-kb. One strain exhibited a 54-kb plasmid; four strains did not contain plasmid DNA. All E. ictaluri isolates contained a 5.7-kb and a 4.9-kb plasmid. E. tarda and E. ictaluri strains were resistant to human serum 20%; 12 of 13 strains of E. hoshinae were also serum resistant. Serum resistance may play an important part in the pathogenicity of these species.

Anti-Bacterial Agents↗
PubMed1993

Review of the clinical efficacy of theophylline in the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality. Therapeutic options are few and are often limited in efficacy. Theophylline is one option, but its use appears to have recently reached a threshold point of deemphasis. Given the consequences of further diminishing the available treatment of COPD, a reappraisal of theophylline's role is imperative. This report reviews the clinical efficacy of theophylline in managing patients with COPD. Special consideration is given to theophylline's effects on pulmonary function (i.e., bronchodilation, exercise capacity, and gas exchange), dyspnea, mucociliary clearance, respiratory muscle performance, cardiovascular function, and neuroinspiratory drive. Despite the lack of standardization in study design and methodology among the studies evaluating theophylline, the conflicting results, and the questions that remain to be answered, evidence indicates that theophylline can provide meaningful therapeutic benefit to patients with COPD. In addition, several studies in patients with COPD have shown that theophylline and inhaled beta-agonists interact in an additive fashion, and the combination therapy results in additional objective and subjective improvement over that achieved by either preparation alone.

Animals↗
PubMed1993

Allergic bronchopulmonary mycosis caused by Pseudallescheria boydii.

Two cases of allergic bronchopulmonary pseudallescheriosis (ABPP) are described. These are the first cases of this allergic bronchopulmonary mycosis (ABPM) reported in which the clinical and serologic criteria are described. The first case was in a patient with mild asthma, and it resolved spontaneously after expectoration of a mucous plug. The second was in a patient with recurrent allergic bronchopulmonary aspergillosis with an exacerbation of ABPM caused by Pseudallescheria boydii. The total serum IgE, IgG, and IgE antibodies against P. boydii and the clinical picture well define ABPP. This diagnosis may be important to recognize in order to prevent a progression of the patient's lung disease.

Adult↗
PubMed1993

A method for simultaneous detection of multiple mRNAs using digoxigenin and radioisotopic cRNA probes.

We present a simple, reliable method for simultaneous detection of two distinct mRNAs within the same tissue sample by double in situ hybridization histochemistry. Sections are hybridized with a cocktail of radiolabeled and digoxigenin-labeled cRNA probes. The digoxigenin-labeled probe is detected with an alkaline phosphatase (AP)-dependent chromogen reaction and then the radiolabeled probe is detected by conventional autoradiography. The sensitivities of the two detection methods are comparable and demonstrate the feasibility of using double in situ hybridization histochemistry to investigate the co-localization and co-regulation of mRNAs that are expressed at relatively low levels.

Animals↗
PubMed1993

Pharmacokinetic and galactopoietic response to recombinant variants of bovine growth hormone.

Two studies were designed to examine the pharmacokinetic and galactopoietic potency of three molecular variants of recombinant-derived bovine GH (rbGH): [Met1, Leu127]-bGH, [Ala1, Val127]-bGH and [Ala1, Val127, His133]-bGH. Histidine substitution for arginine at residue 133 of rbGH was shown to impart thrombin resistance. In a Latin square design, nine lactating Holstein cows received a 25 mg rbGH bolus infusion via the jugular vein followed by frequent blood sampling over the next 12 h. The serum GH concentration data were found to fit a two-compartment open model. Neither primary nor secondary kinetic parameter estimates differed significantly (P > 0.05) among the three rbGH variants. Thus, the disposition of GH concentration at time t was described by the equation C(t) = (1295.5 micrograms/l) (e-(0.11/min)(t)) + (317.3 micrograms/l)(e-(0.03/min)(t)). Overall averages were: area under the curve = 27.1 mg.min per l, clearance = 0.15 litres/min per 100 kg and volume of distribution of the central compartment = 2.59 litres/100 kg. The t 1/2 for the two compartments averaged 8.2 and 29.1 min. In the second study, 36 lactating Holstein cows received i.m. injections of one of four oil-based formulation treatments: control vehicle or 500 mg of one of the three rbGH variants every 14 days for 42 days. Average and maximum serum GH concentrations and area under the curve estimates were increased by approximately 3-6 micrograms/l, 5-15 micrograms/l and 40-90 micrograms.day per 1 respectively. Ala1, Val127 rbGH treatments elicited greater blood GH concentrations than [Met1, Leu127]-bGH when administered in an oil-based formulation. Blood GH responses did not directly translate into milk response differences, possibly due to differences in biopotency or receptor availability. Thrombin resistance resulting from substitution of histidine at position 127 of rbGH did not affect blood GH pharmacokinetic parameters or milk response over other rbGH variants.

Animals↗
PubMed1993

Choline levels in human peritoneal dialysate.

The average free choline level was determined to be 14 mumol/L in peritoneal dialysates and 22 mumol/L in the plasma of 30 patients on continuous ambulatory peritoneal dialysis (CAPD). Daily choline loss via dialysate averaged 129 mumol with 32 mumol choline lost per dwell. Daily choline loss via the dialysate was positively correlated with plasma choline concentrations. Choline levels in dialysate during CAPD exceed plasma levels of choline 9 mumol/L in healthy individuals.

Choline↗