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R Miller

Publications and source records attributed to R Miller.

At least 289 records · Page 16Linked to original sources
PubMed1997

Expressed sequences from conidial, mycelial, and sexual stages of Neurospora crassa.

In the Neurospora Genome Project at the University of New Mexico, expressed sequence tags (ESTs) corresponding to three stages of the life cycle of the filamentous fungus Neurospora crassa are being analyzed. The results of a pilot project to identify expressed genes and determine their patterns of expression are presented. 1,865 partial complementary DNA (cDNA) sequences for 1,409 clones were determined using single-pass sequencing. Contig analysis allowed the identification of 838 unique ESTs and 156 ESTs present in multiple cDNA clones. For about 34% of the sequences, highly or moderately significant matches to sequences (of known and unknown function) in the NCBI database were detected. Approximately 56% of the ESTs showed no similarity to previously identified genes. Among genes with assigned function, about 43.3% were involved in metabolism, 32.9% in protein synthesis and 8.4% in RNA synthesis. Fewer were involved in defense (6%), cell signalling (3.4%), cell structure (3.4%) and cell division (2.6%).

Amino Acid Sequence↗
PubMed1997

Integration of amino acid and carbon intermediary metabolism: studies with uniformly labeled tracers and mass isotopomer analysis.

The central pathways of metabolism include glycolysis and gluconeogenesis, fatty acid synthesis and beta-oxidation, the citric acid cycle and ureagenesis. Because these pathways intersect, changes in one pathway, due to inborn error or disease, affect pathways that may seem remote from the initial metabolic defect. These metabolic interrelationships also present difficulties for isotopic studies, because once carbon derived from isotopic tracers is introduced into metabolism it is extensively recycled. The use of multiple labeled (especially uniformly 13C-labeled ([U-13C]), metabolic tracers, in conjunction with mass isotopomer distribution analysis of mass and nuclear magnetic spectra, has enabled the development of methods that resolve some of these difficulties. Suitable choices of tracers and analytes allow the simultaneous measurement of multiple pathways and, importantly, their kinetic interrelationships. We illustrate three uses of the technique: (1) the unequivocal determination of trace fluxes; (2) the quantification of biosynthetic pathways: and (3) the dissection, in vivo, of the citric acid (Krebs) cycle. In each case, different combinations of [U-13C]tracer and metabolic end product have revealed metabolic phenomena that otherwise would remain unidentified. A particularly striking, and unexpected, observation that has emerged from recent studies using the technique, suggests that the key dehydrogenase reactions in the Krebs cycle may be reversible. Although this approach is of relatively recent development, it has already given a number of novel insights into the organization of the central metabolic pathways. It should provide a powerful method of investigating the metabolic impact of genetic disease and provide invaluable support of the assessment of new therapeutic interventions.

Amino Acids↗
PubMed1997

Ketotifen pharmacokinetics in children with atopic perennial asthma.

OBJECTIVE: Published pharmacokinetic data on ketotifen are sparse, although it is a commonly used prophylactic agent in various allergic disorders in adults and children. The aim of this study was to assess the steady-state pharmacokinetics of ketotifen in children with atopic perennial asthma who were participating in a clinical trial. METHOD: The NONMEM population approach with sparse sampling was utilized. The data set consisted of 239 samples from 48 children who were randomized to receive either 1 mg or 2 mg oral ketotifen daily. Patients underwent a clinical examination and had a blood sample taken at 2-week intervals for 12 weeks. The ketotifen concentrations were measured by RIA. RESULTS: A one-compartment model with first-order absorption was fit to the data. Volume was estimated at 394 l and clearance (CL) at 97.4 l.h-1 (3.6 l.h-1.kg-1). Weight or body surface area were the most influential covariates for explaining interindividual variability in CL. The 2-mg dose appeared to have a relative bio-availability of 85% of the 1-mg dose. CONCLUSION: Children have a faster clearance of ketotifen than adults and would therefore require a higher dose per kilogram body weight to give comparable steady-state levels.

Anti-Allergic Agents↗
PubMed1997

In vitro cultured human term cytotrophoblast: a model for normal primary epithelial cells demonstrating a spontaneous differentiation programme that requires EGF for extensive development of syncytium.

Normal human term cytotrophoblast cells prepared by trypsin-DNAse I digestion with and without secondary immunological purification with CD9 antibodies were investigated for the expression of morphological and genetic markers of proliferation and differentiation. After 24 h of culture, the cell preparations demonstrated spontaneous formation of microvilli and formation of small syncytial units as assessed by desmoplakin staining and FITC-dextran microinjection. EGF was required for mature syncytial formation. Compared to log-phase proliferating HeLa cells, uptake of [3H]thymidine incorporation was low and quickly decreased to negligible levels. Expression of the proto-oncogenes c-myc, c-fos, and c-jun and histone 2A decreased rapidly in the first 24 h of culture in both cell preparations, followed by an increase in expression of c-fos and junB over the next 3 days of culture. Proto-oncogene changes were similar in attached and suspension cells. Spontaneous increases in alpha hCG, pregnancy-specific beta(1)-glycoprotein and 3 beta-hydroxysteroid dehydrogenase (3 beta OHSD) occurred within 1 day in both cell preparations. EGF receptor blocking antibodies did not inhibit minor degrees of spontaneous syncytial formation nor inhibit spontaneous expression of alpha hCG or 3 beta OHSD mRNA, but did prevent extensive synctialization induced by EGF. The results demonstrate that term cytotrophoblast cells even in serum-free conditions or suspension culture rapidly commit to a non-proliferative differentiation program in culture which includes limited syncytialization and marked hormone mRNA expression. However, EGF is required for extensive syncytial development.

3-Hydroxysteroid Dehydrogenases↗
PubMed1997

A brief quality-of-life measure for ALS clinical trials based on a subset of items from the sickness impact profile. The Syntex-Synergen ALS/CNTF Study Group.

We previously demonstrated a significant relationship (P<0.0001) between maximum voluntary isometric contraction (MVC) plus pulmonary function scores (the Tufts Quantitative Neuromuscular Exam Combination Megascore (TQNE CM)), and the Sickness Impact Profile (SIP) in a cohort of 524 ALS patients. Because the 136-item SIP questionnaire can be difficult to administer in this population, we examined SIP subscales and clinically derived item sets in relation to the TQNE CM in an effort to define a briefer measure of quality of life for use in clinical trials. Two 'Mini-SIP' indices performed as well as the overall SIP in reflecting the impact of muscle weakness on ALS patients' quality of life: a combination of two SIP subscales ('SIP-33'), and a 19-item set of questions independently chosen by a panel of ALS specialists ('SIP/ALS-19'). Either index potentially could be useful in ALS clinical trials. The SIP/ALS-19 is currently being used in a National ALS data base, providing an opportunity to evaluate its utility prospectively against other QOL measures in ALS patients.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Behavioral effects of clozapine and dopamine receptor subtypes.

The atypical neuroleptic clozapine (CLZ) is an extremely effective antipsychotic that produces relatively few motoric side effects. However, CLZ displays limited antagonism at the dopamine (DA) D2 receptor, the receptor commonly thought to mediate the antipsychotic activity of neuroleptics. The mechanism of action behind the efficacy of CLZ remains to be determined. Miller, Wickens and Beninger [Progr. Neurobiol., 34, 143-184 (1990)] propose a "D1 hypothesis of antipsychotic action" that may explain the antipsychotic effects of CLZ. This hypothesis is built on the interactions between D2, cholinergic and D1 mechanisms in the striatum. These authors assert that although typical neuroleptics block D2 receptors, it is through an indirect action on D1 receptors that their antipsychotic action is manifest. The extra-pyramidal side effects produced by typical neuroleptics are hypothesized to be due to an indirect action on cholinergic receptors. It is argued that the anticholinergic properties of CLZ negate the D2 (motor side effects) action of CLZ, allowing CLZ to diminish psychotic symptoms through a direct action on D1 receptors. Thus, CLZ may function as a D1 receptor antagonist in behavioral paradigms. The current paper reviews and compares the behavioral profile of CLZ to those produced by D2- and D1-selective antagonists with specific reference to unconditioned and conditioned behaviors in order to more fully evaluate the "D1 hypothesis of CLZ action". Although the actions of CLZ remain unique, they do share some striking similarities with D1 receptor antagonists especially in tests of unconditioned behavior, possibly implicating the D1 receptor in the action of this antipsychotic drug.

Animals↗
PubMed1997

Patterns of health maintenance on Michigan equine operations.

Data from two 12 month prospective monitoring programs that followed management, economics and animal health from randomly-sampled equine operations in Michigan were used to determine patterns of health maintenance. Health maintenance measures were grouped, and average uses per year were computed for the most-common measures reported: respiratory, Potomac Horse Fever, neurological and multiple-system vaccinations, deworming, and general farrier work. Factors examined for potential association with health maintenance measure use were numbers of equids and horse-days on the operation, average age of equids, disease prevention management procedures, and operation and individual equine activities. The most-common vaccinations reported were respiratory vaccines (administered an average of 0.9 times per equid per year, of which 61% were for rhinopneumonitis). Multiple-system, Potomac Horse Fever and neurological vaccines were given on average 0.9, 0.9 and 0.7 times per equid per year, respectively. Deworming treatments were administered approximately 2.7 times per equid per year, of which 64% were ivermectin. Overall farrier work was reported 3.3 times per equid per year, trimming was done 2.9 times and shoeing was done 1.5 times per equid per year. In general, operations with active equids engaged in training, breeding or showing showed increased use of health maintenance measures. Overall use of health maintenance measures in the Michigan equine operations monitored did not appear to reach recommended levels, because many operations reported no use of these measures. However, on operations where health maintenance measures were reported, operators were using these measures at or near recommended levels.

Aging↗
PubMed1997

The Michigan equine monitoring system. II. Frequencies and impact of selected health problems.

A prospective study was designed to document the frequencies of equine health problems in the state of Michigan, USA. A total of 2469 horses from a random sample of 138 equine operations were monitored in the study in two 12-month periods: 1992-1993 and 1993-1994. All the major breeds of horses in the state were proportionately represented in the sample. Using weighted annual incidence densities as measures of disease frequencies, the 10 most frequently observed groups of health problems were (from most to least frequent) leg lameness, dermatological problems, respiratory problems, hoof and foot problems, reproductive problems, systemic problems, colic, whole body lameness, neurological problems and gastrointestinal problems (other than colic). This ranking of the top 10 health problems was different from the ranking provided by equine owners/operators at the beginning of the study. Overall, very low specific mortality rates were observed in the study. However, the conditions that were associated with mortality resulted in fairly high case fatalities. The five specific illnesses that most commonly resulted in fatalities were (from greatest to least case fatality risk) systemic problems, colic, gastrointestinal problems (other than colic), neurological problems, and foot and hoof problems. Impact of disease was evaluated in terms of average duration of a case and days lost for performance. Neurological problems, lameness and dermatological problems had the longest duration per case. Neurological problems, lameness, respiratory problems and gastrointestinal problems (other than colic) had the longest average days lost per case.

Animals↗
PubMed1997

Risk factors for colic in the Michigan (USA) equine population.

A population-based prospective epidemiological study was conducted to assess risk factors for equine colic. A stratified sample of 3925 equids in 138 randomly selected equine farms in the state of Michigan was monitored in two 12-month rounds of data collection. Incidence densities were used to describe the rate of development of colic in the study population. Mortality rates, case fatality rates and survival rates were used to describe the severity of colic on the study population. Multivariable logistic regressions with random effects (grouped according to farm) were used to identify risk factors associated with occurrence of colic. A total of 3175 equids from 132 farms from the starting population of 3925 equids in 138 farms was used in the multivariable analysis. There were 77 cases of colic reported during the study period in 62 animals. Of these animals, 54 (87%) had one case, 5 (8%) had two cases, 2 (3%) had three cases, and 1 (2%) had seven cases. Of the cases reported, 49 (64%) were non-specific diagnoses, 13 (17%) impaction/acute intestinal obstruction colics, 7 (9%) spasmodic colics, 4 (5%) sand colics, 2 (3%) gas colics, 1 (1%) verminous mesenteric arteritis, and 1 (1%) enteritis due to ingestion of moldy grain. The annual incidence density of colic in the study was 3.5 cases per 100 equid-years. The surgical treatment risk was 17% (13/77). The overall mortality risk due to colic was 0.5 deaths per 100 equids, and the case fatality risk was 13% (10/77). The case fatality risk for cases treated surgically was 31% (4/13), while the case fatality risk for non-surgical colics was 10% (7/69). Risk factors associated with significantly increased likelihood of developing colic were foaling during the study, deworming during the study, increased age, and participation in showing activities. Geldings and equids provided group drinking water from sources other than tanks, buckets and automatic waterers were significantly associated with reduced risk of colic.

Animals↗
PubMed1997

The association of serum nonesterified fatty acids and cholesterol, management and feeding practices with peripartum disease in dairy cows.

A prospective study was conducted to determine the relationship of serum nonesterified fatty acids (NEFA) and cholesterol concentrations and herd management practices to the occurrence of metritis, mastitis and retained placenta in Holstein cows in Michigan. Serum samples were collected once prepartum and once postpartum from 257 cows. Animals were under observation for disease occurrence from the date of calving until 3 months postpartum. Metabolic variables used were (1) prepartum only; (2) postpartum only; (3) the NEFA/cholesterol ratio for both pre- and postpartum samples. Management variables included maternity management, feed management, and factors such as season and parity. Multivariable logistic models with random-effect terms to account for the herd effect were used for data analysis. Results showed that: (1) metabolic events associated with energy insufficiency-increased fat mobilization and serum lipoprotein metabolism-were related to increased risk of metritis and retained placenta; (2) higher energy consumption during the last weeks of the dry period might reduce disease risk at parturition; (3) serum NEFA and cholesterol concentrations have potential as indicators of disease risk in dairy cows.

Animal Feed↗
PubMed1997

Asymmetric angioneurotic edema associated with thrombolysis for acute stroke.

We present a case of acute asymmetric angioneurotic edema associated with the use of recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke. rtPA was administered for an acute ischemic stroke in accordance with the recently reported National Institute of Neurological Disorders and Stroke protocol, after which marked asymmetric angioedema requiring upper-airway control developed. Although atypical and anaphylactoid reactions have been reported with the use of rtPA for acute myocardial infarction, to our knowledge this is the first case report of asymmetric angioedema associated with the use of rtPA for acute ischemic stroke.

Acute Disease↗
PubMed1997

Dose-response relationships for the antipsychotic effects and Parkinsonian side-effects of typical neuroleptic drugs: practical and theoretical implications.

1. From a review of published literature it is concluded that the minimum dose of a neuroleptic drug (NLD) required to alleviate psychosis is very similar to that producing minimal parkinsonian side effects (PSE). This conclusion is reached both from group comparisons and individual comparisons of dose/response relations (DRR) for the two effects. 2. A lower dose of NLD is usually sufficient to prevent relapse in well stabilized patients than is needed to check an active psychotic state. 3. Anticholinergic agents used to reduce side effects of typical NLD can retard the therapeutic process during neuroleptic treatment of acute psychosis. Although it is not fully established that this is a central interaction, it is consistent with the idea that minimal side effects are a necessary condition for therapeutic effectiveness with typical antipsychotic drugs. 4. In relapse-free maintenance of psychosis-prone patients, tolerance occurs to PSE. Thus few patients need experience prolonged side effects during maintenance treatment with neuroleptics. 5. The evidence reviewed is discussed with respect to a previous hypothesis of the supposedly "indirect" action of typical neuroleptic drugs in therapy for psychosis. The evidence is consistent with the idea of a close causal relation between minimal PSE of these drugs, and their therapeutic effectiveness in the acute stage of treatment.

Antipsychotic Agents↗
PubMed1997

The effects of perceived stigma and psychological over-control on the behavioural problems of children with epilepsy.

This pilot study finds that parents who think that their child will be stigmatized and who perceive that epilepsy limits their child, report higher levels of four child behavioural problems than reported by other parents of children with epilepsy. Those children with epilepsy who report that their parents use an over-controlling psychological approach to parenting report higher levels of four behavioural problems than those children with epilepsy who do not report over-controlling behaviour from their parents. The effects of simple partial seizures and of seizure severity on children's behavioural problems are completely mediated by perceived stigma, perceived limitations, and perceived parenting. Seizure frequency, absence seizures, and treatment with ethosuximide have direct effects on three children's behavioural problems; the effects of these medical variables are generally unaffected by control for parent's and children's perceptions.

Adolescent↗
PubMed1997

Development of monoclonal antibodies to the malondialdehyde-deoxyguanosine adduct, pyrimidopurinone.

Malondialdehyde (MDA), an endogenous product of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in bacterial and mammalian cells and carcinogenic in rats. In order to determine whether MDA-modified bases are formed in nucleic acids in vivo, sensitive immunoassays to detect MDA-DNA and MDA-RNA adducts are being developed in our laboratory. Murine monoclonal antibodies reactive with the MDA-deoxyguanosine adduct 3-beta-D-erythro-pentofuranosylpyrimido[1,2-alpha]purin-10(3H)-one (M1G-R) were prepared and characterized. Several MDA-modified nucleosides and deoxynucleosides and structural analogs were synthesized and characterized and were compared as competitive inhibitors in enzyme-linked immunosorbent assays (ELISAs). Less than 5 fmol of M1G in MDA-modified DNA was detected in a direct ELISA, and antibody binding to the modified DNA was competitively inhibited by free M1G-dR. DNA from Salmonella typhimurium treated with concentrations of MDA that induce reversion to histidine prototrophy was enzymatically digested, and M1G-dR was quantitated by competitive ELISA. Over a range of MDA concentrations from 10 to 40 mM, the level of M1G residues in bacterial DNA increased from 0.2 to 2.5/10(6) base pairs.

Acrolein↗
PubMed1997

Nonlinear mixed effects modeling of single dose and multiple dose data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam.

PURPOSE: NONMEM was applied to single dose and multiple dose bioavailability data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam to acquire additional information from the data which are not easily obtainable by traditional means. METHODS: The objective function value (OBJ) and diagnostic plots were used as measures of goodness of fit of the model to the data. A change in the OBJ value of 7.9 was necessary to show statistical significance (p < 0.005) between two models when the two models differed by 1 parameter. RESULTS: A two-compartment linear model with first-order absorption and elimination best describes the data. Including a lag time, two different rates of absorption (KAIR and KACR), and bioavailability for the CR relative to the IR dosage form significantly improved the fit of the model to the data. Cigarette smoking was associated with a 100% increase in clearance of alprazolam as compared to non-smokers. The higher residual variability observed in this study, where interoccasion variability (IOV) was not initially modeled, could be explained to a large extent by the presence of significant interoccasion variability (IOV). CONCLUSIONS: Since alprazolam has been suggested to be mainly metabolized by the CYP3A4 isozyme in humans, it appears that tobacco could be an inducer of CYP3A4 and/or alprazolam may be metabolized by other isozyme(s) (specifically, CYP1A1/1A2) that are induced by cigarette smoke. The population pharmacokinetic model approach combined with exploratory graphical data analysis is capable of identifying important covariates from well-controlled "data rich" Phase I studies early in drug development.

Adult↗
PubMed1997

GnRH perikarya in medial basal hypothalamus of pubertal female rhesus macaque are ensheathed with glia.

A previous study in our laboratory revealed that the cell bodies of gonadotropin releasing hormone (GnRH) neurons in the preoptic area (POA) of early to midpubertal female rhesus monkeys were extensively invested with thick glial processes. Because the medial basal hypothalamus (MBH) plays a critical role in the control of pulsatile and cyclic gonadotropin release in the primate, we have now focused on the ultrastructural milieu of GnRH neurons of this region in the same sample of monkeys. The ensheathment of the perikarya of GnRH neurons in the MBH with such glial processes was more pronounced than in the POA. Whereas the mean proportion of the cell membrane covered by these glia was 57% in the POA, it was 72% in the MBH. In addition, the cell bodies of GnRH neurons in the MBH of the pubertal monkey (unlike those in the POA) were less well innervated than were those in the adult cycling monkey, further highlighting differences between these brain regions. Differences in the anatomical milieu of the MBH between immature monkeys, in which GnRH release is still relatively quiescent, and adult cycling monkeys are consistent with the hypothesis that GnRH neurons within the MBH are under particular constraint in the immature animals. The functional significance of these observations must, however, await further studies.

Animals↗
PubMed1997

Characterization of additional casein kinase I sites in the C-terminal "tail" region of chicken and rat neurofilament-M.

In previous studies we have identified Ser502, Ser528, and Ser534 as target sites in chicken neurofilament middle molecular mass protein (NF-M) for casein kinase I (CKI) in vitro and have shown that these sites are also phosphorylated in vivo. We now make use of a combination of molecular biological and protein chemical techniques to show that two additional in vivo phosphorylation sites in chicken NF-M, Ser464 and Ser471, can also be phosphorylated by CKI in vitro. These two sites are conserved in higher vertebrate NF-M molecules, and recombinant protein constructs containing the homologous rat NF-M peptides can be phosphorylated by CKI in vitro, suggesting that phosphorylation of these sites is conserved at least in higher vertebrates. The two new sites are adjacent to a conserved peptide sequence (VEEIIEET-V) found once in higher vertebrate NF-M molecules and twice in lamprey NF-180. Variants of this sequence are also found in neurofilament low and high molecular mass proteins (NF-L and NF-H) and alpha-internexin, and in mammalian NF-L are known to be associated with in vivo phosphorylation sites. We speculate that CKI phosphorylation in general, and these sites in particular, may be important in neurofilament function.

Amino Acid Sequence↗