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M Miller

Publications and source records attributed to M Miller.

At least 559 records · Page 31Linked to original sources
PubMed1990

Pharmacology of pravadoline: a new analgesic agent.

Pravadoline is a new chemical entity with analgesic activity in humans. This report describes the pharmacology of pravadoline and compares the activity of pravadoline with that of two major classes of analgesics, the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Like the NSAIDs, pravadoline inhibited the synthesis of prostaglandins (PGs) in mouse brain both in vitro (IC50, 4.9 microM) and ex vivo (ED50, 20 mg/kg p.o.) and displayed antinociceptive activity in rodents subjected to a variety of chemical, thermal and mechanical nociceptive stimuli. Administration of pravadoline prevented the writhing response induced by i.p. administration of acetylcholine (ED50, 41 mg/kg p.o.) or PGE2 (ED50, 24 mg/kg p.o.) and prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees C (minimum effective dose, 100 mg/kg s.c.). In the rat, treatment with pravadoline prevented acetic acid-induced writhing (ED50, 15 mg/kg p.o.), brewer's yeast-induced hyperalgesia (Randall-Selitto test) (minimum effective dose, 1 mg/kg p.o.), the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50, 41 mg/kg p.o.) and bradykinin-induced head and forepaw flexion (ED50, 78 mg/kg, p.o.). The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg s.c.) and pravadoline did not bind to opioid receptors at concentrations up to 10 microM. However, like the opioid analgesics, pravadoline diminished the electrically induced twitch response of mouse vas deferens preparations, but, in contrast to opioids, this action of pravadoline was not attenuated by naloxone. The possibility is discussed that this effect of pravadoline upon isolated tissues may contribute to its antinociceptive activity. In contrast to NSAIDs, pravadoline was more potent ex vivo as an inhibitor of the formation of PGs in brain vs. stomach. In addition, pravadoline failed to produce gastrointestinal lesions when administered p.o. to rats or mice, and did not possess significant anti-inflammatory activity at antinociceptive doses. Also unlike NSAIDs, pravadoline inhibited rat gastrointestinal transit when administered at doses similar to those which were antinociceptive. The overall pharmacologic profile of pravadoline suggests that the compound may be capable of managing more diverse or more severe pain than is achieved by anti-inflammatory analgesics, without producing side effects commonly associated with either the opioid or the nonopioid analgesics.

Analgesics↗
PubMed1990

Access to hospital services in rural Minnesota.

A Minnesota Department of Health study on the financial condition of Minnesota's small, rural hospitals found that at least 12 hospitals were in precarious financial condition at the start of 1989, and many other hospitals were financially vulnerable. One-third or more of Minnesota's hospitals with fewer than 50 beds had negative net income in each year from 1984 to 1987. Using a standard of 30 minutes' maximum travel time for adequate access, the study revealed that about 19,000 Minnesotans in 14 counties currently have inadequate access to hospital services. Closing rural hospitals could leave additional Minnesotans without adequate access to hospital services. Given the financial condition of Minnesota's small, rural hospitals and the importance of maintaining access to hospital services in rural communities, the state may need to provide limited hospital subsidies to ensure access in geographically isolated areas.

Health Services Accessibility↗
PubMed1990

A fish oil diet preserves renal function in nephrotoxic serum nephritis.

Fish oil diets preserve renal function in murine lupus, but we have found that these diets accelerate renal deterioration in renoprival nephropathy. In this study we examined the effects of dietary fish oil in accelerated nephrotoxic serum nephritis. For 1 month, 14 female rats were fed diets that differed only in fat composition, containing either menhaden (fish) oil or beef tallow (control). Rats were then preimmunized with rabbit IgG and, 5 days later, were injected with nephrotoxic serum. Glomerular filtration rate (GFR) was measured continuously in conscious animals by means of intraperitoneal 14C-labeled inulin minipumps. Fish oil-containing diets markedly attenuated the nephrotoxic serum-induced decline in GFR and the rise in proteinuria and significantly reduced glomerular prostaglandin E2 and thromboxane A2. The results of tests of renal histology showed no differences between the two groups. Five days after preimmunization, rats fed fish oil had more rabbit IgG remaining in their serum and had mounted less of an antibody response to the rabbit IgG. Fish oil diets also resulted in an attenuated disappearance of injected 14C-labeled rabbit IgG. In vitro, peritoneal macrophages from rats fed fish oil took up less rabbit IgG than macrophages from rats fed control diets. Thus the beneficial effects of a fish oil diet may result from defective immune surveillance and from alterations in eicosanoids.

Animals↗
PubMed1989

A formalin-inactivated whole SIV vaccine confers protection in macaques.

A vaccine against human immunodeficiency virus (HIV) would be highly effective in stopping the acquired immunodeficiency syndrome (AIDS) epidemic. A comprehensive evaluation of potential vaccine methodologies can be made by means of the simian model for AIDS, which takes advantage of the similarities in viral composition and disease potential between simian immunodeficiency virus (SIV) infection of rhesus macaques and HIV infection in humans. Immunization with a formalin-inactivated whole SIV vaccine potentiated with either alum and the Syntex adjuvant threonyl muramyl dipeptide (MDP) or MDP alone resulted in the protection of eight of nine rhesus monkeys challenged with ten animal-infectious doses of pathogenic virus. These results demonstrate that a whole virus vaccine is highly effective in inducing immune responses that can protect against lentivirus infection and AIDS-like disease.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution.

The structure of a complex between a peptide inhibitor with the sequence N-acetyl-Thr-Ile-Nle-psi[CH2-NH]-Nle-Gln-Arg.amide (Nle, norleucine) with chemically synthesized HIV-1 (human immunodeficiency virus 1) protease was determined at 2.3 A resolution (R factor of 0.176). Despite the symmetric nature of the unliganded enzyme, the asymmetric inhibitor lies in a single orientation and makes extensive interactions at the interface between the two subunits of the homodimeric protein. Compared with the unliganded enzyme, the protein molecule underwent substantial changes, particularly in an extended region corresponding to the "flaps" (residues 35 to 57 in each chain), where backbone movements as large as 7 A are observed.

Amino Acid Sequence↗
PubMed1989

Apolipoprotein B-100 Hopkins (arginine4019----tryptophan). A new apolipoprotein B-100 variant in a family with premature atherosclerosis and hyperapobetalipoproteinemia.

A 43-year-old woman with severe coronary artery disease and hyperapobetalipoproteinemia was heterozygous for an abnormal Msp I apolipoprotein B (APOB) gene fragment because of the absence of the MspI site around codon 4046 in exon 29 of the APOB gene. Using the polymerase chain reaction technique, 134 base pairs containing the mutant Msp I site were amplified, cloned, and sequenced. The mutation was a C to T transition, substituting tryptophan for arginine at amino acid position 4019 of the mature ApoB-100 protein. Seven relatives of the proband had the same mutation, which has been called "ApoB-100 Hopkins." Only three of seven relatives with the mutation had hyperapobetalipoproteinemia; one was borderline while two other relatives without the mutation had hyperapobetalipoproteinemia. Mutant low-density lipoprotein (LDL) was bound and degraded to a greater extent than normal LDL in cultured human fibroblasts. In conclusion, a new mutation, ApoB-100 Hopkins, was not linked to the hyperapobetalipoproteinemia phenotype, which also was segregating in this family. The increased affinity of this mutant LDL for the LDL receptor may be due to a specific effect of ApoB-100 Hopkins or to altered LDL size and composition.

Adult↗
PubMed1989

Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease.

The rational design of drugs that can inhibit the action of viral proteases depends on obtaining accurate structures of these enzymes. The crystal structure of chemically synthesized HIV-1 protease has been determined at 2.8 angstrom resolution (R factor of 0.184) with the use of a model based on the Rous sarcoma virus protease structure. In this enzymatically active protein, the cysteines were replaced by alpha-amino-n-butyric acid, a nongenetically coded amino acid. This structure, in which all 99 amino acids were located, differs in several important details from that reported previously by others. The interface between the identical subunits forming the active protease dimer is composed of four well-ordered beta strands from both the amino and carboxyl termini and residues 86 to 94 have a helical conformation. The observed arrangement of the dimer interface suggests possible designs for dimerization inhibitors.

Amino Acid Sequence↗
PubMed1989

Molecular modeling of the HIV-1 protease and its substrate binding site.

The human immunodeficiency virus (HIV-1) encodes a protease that is essential for viral replication and is a member of the aspartic protease family. The recently determined three-dimensional structure of the related protease from Rous sarcoma virus has been used to model the smaller HIV-1 dimer. The active site has been analyzed by comparison to the structure of the aspartic protease, rhizopuspepsin, complexed with a peptide inhibitor. The HIV-1 protease is predicted to interact with seven residues of the protein substrate. This information can be used to design protease inhibitors and possible antiviral drugs.

Amino Acid Sequence↗
PubMed1989

Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites.

STUDY OBJECTIVE: To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents. DESIGN: In-vitro toxicity assay on lymphocytes. SETTING: Clinics for adverse drug reactions in an adult and pediatric tertiary care center. PATIENTS: Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the clinic for assessment of adverse drug reactions to sulfonamide agents. Thirty-one patients had clinical histories consistent with a diagnosis of hypersensitivity reaction, whereas 45 patients had clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction. INTERVENTIONS: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole. MEASUREMENTS AND MAIN RESULTS: The lymphocytes from patients with a history of hypersensitivity reactions showed markedly increased toxicity across a tenfold-concentration toxicity-concentration curve compared with those from controls and patients with a history of nonhypersensitivity reactions. These differences were highly significant (P less than 0.01). No difference was found between the toxicity shown by the lymphocytes from controls and that shown by the lymphocytes from patients with a history of nonhypersensitivity reactions. CONCLUSIONS: Metabolic differences in the production and detoxification of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to these agents. These results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating these reactions. Sulfonamide hydroxylamines are useful in the diagnosis and study of the pathogenesis of hypersensitivity reactions to sulfonamide agents.

Adult↗
PubMed1989

Crystal structure of a retroviral protease proves relationship to aspartic protease family.

Retroviral gag, pol and env gene products are translated as precursor polyproteins, which are cleaved by virus-encoded proteases to produce the mature proteins found in virions. On the basis of the conserved Asp-Thr/Ser-Gly sequence at the putative protease active sites, and other biochemical evidence, retroviral proteases have been predicted to be in the family of pepsin-like aspartic proteases. It has been suggested that aspartic proteases evolved from a smaller, dimeric ancestral protein, and a recent model of the human immunodeficiency virus (HIV) protease postulated that a symmetric dimer of this enzyme is equivalent to a pepsin-like aspartic protease. We have now determined the crystal structure of Rous sarcoma virus (RSV) protease at 3-A resolution and find it is dimeric and has a structure similar to aspartic proteases. This structure should provide a useful basis for the modelling of the structures of other retroviral proteases, such as that of HIV, and also for the rational design of protease inhibitors as potential antiviral drugs.

Amino Acid Sequence↗
PubMed1989

CT demonstration of the appendix in asymptomatic adults.

We prospectively examined 103 consecutive adults (67 women, 36 men; mean age: 58.7 years) referred for abdominal and pelvic computed tomography (CT) in whom there was no history of right lower quadrant symptoms or appendectomy. Contiguous 5-mm CT images through the pericecal region were obtained in each subject, once routine scanning was completed. Three radiologists reviewed all CT images and reached a consensus on appendiceal visualization and the quantity of intraperitoneal fat. Statistical methods were applied to the collected data to seek significant associations between a visualized appendix and the following factors: patient age, sex, intraperitoneal fat grade, and the presence of oral contrast in the cecal lumen. The appendix was definitely visualized in only 45 of the 103 patients (43.7%). Analysis of variance revealed no statistically significant correlation between a CT-demonstrated appendix and the four variables examined. The clinical implications of these findings are discussed.

Adolescent↗
PubMed1989

Occult polymicrobial endocarditis with Haemophilus parainfluenzae in intravenous drug abusers.

PURPOSE AND PATIENTS AND METHODS: Fewer than 8 percent of intravenous drug abusers are found to have polymicrobial endocarditis. We report on cases of occult polymicrobial infective endocarditis with Haemophilus parainfluenzae in 10 intravenous drug abusers. Clinical and laboratory data on all 10 patients were obtained from hospital charts, and information on illicit drug use methods was given by five patients. Blood cultures were performed, as well as susceptibility testing to antibiotics. Subsequent molecular epidemiologic studies were performed on selected Staphylococcus aureus and H. parainfluenzae strains. Phage typing of S. aureus and biotyping of H. parainfluenzae strains were also done. RESULTS: Results of the initial blood cultures were positive on the second to fifth days (mean, 2.6 days), demonstrating a gram-positive pathogen in nine patients and Bacteroides asaccharolyticus in one. Significantly, in each case, H. parainfluenzae alone was subsequently identified from additional blood cultures, with a mean delay of 20.4 days (range, five to 57 days) to the isolation of this organism. Epidemiologic data indicated that our cases did not represent a point-source outbreak. Antibiotic therapy uniformly failed until an agent active against H. parainfluenzae was added. The constellation of clinical, microbiologic, and epidemiologic findings was similar, and permitted prospective diagnosis and therapy in three patients. Despite the absence of S. aureus bacteremia in four, all 10 patients had right-sided endocarditis with septic pulmonary emboli. Five patients had initial blood cultures that were positive for two facultative gram-positive cocci (S. aureus and commensal oral streptococcal species). CONCLUSION: Our findings suggest that polymicrobial endocarditis with H. parainfluenzae in intravenous drug abusers is a distinct clinical syndrome, and should be considered in all patients if the response to appropriate antibiotics is atypical or if pulmonary emboli continue with therapy.

Adult↗
PubMed1989

Radiotherapy planning for simulation of prostate cancer: computerized tomographic scanning vs. conventional radiographic localization.

A computerized tomographic localization protocol for prostate cancer treatment planning is described. In 23 patients, this new method is compared to localization using conventional orthogonal radiographic simulation with contrast media in the rectum, bladder, and urethra. Advantages of the CT localization protocol include enhanced ability to delineate the tumor extension, particularly for superior, lateral, anterior, and posterior spread. Accurate CT localization of the inferior border of the target volume has also been demonstrated to be feasible, thereby avoiding the need for invasive urethral, bladder, and rectal manipulations.

Aged↗
PubMed1989

Visual outcome after surgical removal of craniopharyngiomas.

Thirty patients with craniopharyngiomas were examined preoperatively and immediately postoperatively to determine their level of visual impairment and the extent of visual recovery. Twenty-two patients also were examined during extended follow-up. Twelve of these patients were younger than 18 years of age and 18 were older than 18 years of age at the time of diagnosis. Visual acuity was reduced in 42% of eyes preoperatively. One week postoperatively, visual acuity was reduced in only 23% of eyes. Color vision was a more sensitive indicator of afferent system damage, being abnormal at presentation in 71% of patients. Visual field defects were typically bitemporal hemianopsias, but 20% of patients with evidence of optic neuropathy had no definite visual field deficit preoperatively. Postoperatively, 48% of patients had normal visual fields. There was no long-term improvement in visual acuity or field performance for patients with deficits present after the first postoperative month during an average 2.8 years of follow-up.

Adolescent↗