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B Miller

Publications and source records attributed to B Miller.

At least 109 records · Page 6Linked to original sources
PubMed1998

Novel cyclic compounds as potent phosphodiesterase 4 inhibitors.

The synthesis and biological activity of a novel series of 2, 2-disubstituted indan-1,3-dione-based PDE4 inhibitors are described. This structurally unique class of PDE4 inhibitors is markedly different from the known PDE4 inhibitors such as RP 73401 (2) and CDP 840 (3). Structure-activity relationship (SAR) studies led to the identification of inhibitors with nanomolar potency and oral activity in a murine endotoxemia model for TNF-alpha inhibition. Unlike other classical PDE4 inhibitors, several analogues were found to be nonemetic in a canine emesis model at intravenous doses of up to 3 mg/kg.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I.

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the 'rolipram-like' 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-alpha levels in LPS challenged mice (mouse endotoxemia model) are also reported.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action.

Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Brx, that contains a region of identity to the oncogenic Rho-guanine nucleotide exchange (Rho-GEF) protein Lbc, and a unique region capable of binding to nuclear hormone receptors, including the ER. Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium. Brx bound specifically to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogen-responsive reporter revealed that Brx augmented gene activation by the ER in an element-specific and ligand-dependent manner. Moreover, activation of ER by Brx could be specifically inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Brx represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors.

A Kinase Anchor Proteins↗
PubMed1998

High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype.

OBJECTIVE: To evaluate cerebrospinal fluid (CSF) levels of amyloid beta protein ending at amino acid 42 (Abeta42) and tau as markers for Alzheimer disease (AD) and to determine whether clinical variables influence these levels. DESIGN: Cohort study. SETTING: Six academic research centers with expertise in dementia. SUBJECTS: Eighty-two patients with probable AD, including 24 with very mild dementia (Mini-Mental State Examination score >23/30) (AD group); 60 cognitively normal elderly control subjects (NC group); and 74 subjects with neurological disorders, including dementia (ND group). MAIN OUTCOME MEASURES: Levels of Abeta42 and tau were compared among AD, NC, and ND groups. Relationships of age, sex, Mini-Mental State Examination score, and apolipoprotein E (Apo E) genotype with these levels were examined using multiple linear regression. Classification tree models were developed to optimize distinguishing AD from NC groups. RESULTS: Levels of Abeta42 were significantly lower, and levels of tau were significantly higher, in the AD group than in the NC or ND group. In the AD group, Abeta42 level was inversely associated with Apo E epsilon4 allele dose and weakly related to Mini-Mental State Examination score; tau level was associated with male sex and 1 Apo E epsilon4 allele. Classification tree analysis, comparing the AD and NC subjects, was 90% sensitive and 80% specific. With specificity set at greater than 90%, the tree was 77% sensitive for AD. This tree classified 26 of 74 members of the ND group as having AD. They had diagnoses difficult to distinguish from AD clinically and a high Apo E epsilon4 allele frequency. Markers in CSF were used to correctly classify 12 of 13 patients who later underwent autopsy, including 1 with AD not diagnosed clinically. CONCLUSIONS: Levels of CSF Abeta42 decrease and levels of CSF tau increase in AD. Apolipoprotein E epsilon4 had a dose-dependent relationship with CSF levels of Abeta42, but not tau. Other covariates influenced CSF markers minimally. Combined analysis of CSF Abeta42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging. In subjects in the ND group with an AD CSF profile, autopsy follow-up will be required to decide whether CSF results are false positive, or whether AD is a primary or concomitant cause of dementia.

Adult↗
PubMed1998

The apolipoprotein E epsilon4 allele is not a significant risk factor for frontotemporal dementia.

Frontotemporal dementia (FTD) is the most common early-onset non-Alzheimer's dementia (non-AD). Although the role of the epsilon4 allele of apolipoprotein E (ApoE) has been well established in AD, studies of ApoE allele distribution in patients with FTD have produced variable results. We studied 33 rigorously diagnosed FTD patients, including several who were pathologically confirmed, and compared the frequency of the epsilon4 allele in patients with FTD with the frequency in those with early-onset AD (EOAD), in those with late-onset AD (LOAD), and in non-demented elderly controls. The frequency of ApoE epsilon4 was 21% in patients with FTD, significantly less than the ApoE epsilon4 frequency in those patients with EOAD (38%) and those with LOAD (40%), but not significantly different from the ApoE epsilon4 frequency in elderly controls (13%).

Adult↗
PubMed1998

Evaluation of the safety and immunogenicity of a new, heat-treated human rabies immune globulin using a sham, post-exposure prophylaxis of rabies.

A double-blind, controlled, randomized trial was conducted to evaluate the safety and immunogenicity of a new human rabies immune globulin (HTRIG). This product, manufactured by Pasteur Merieux Connaught, PMC, has undergone a heat-treatment step (10 h at 60 degrees C) and removal of mercurothiolate. The corresponding unheated product available from the same manufacturer (human rabies immune globulin, HRIG, IMOGAM RABIES[spr2]) was used for comparison. These two rabies immune globulins (RIGs) were administered either alone or in association with the human diploid cell rabies vaccine (HDCV, IMOVAX[spr2] RABIES, PMC) according to a standard, post-exposure rabies prophylaxis schedule. Sixty-four healthy adults were randomly assigned to four groups of 16 to receive either HRIG/placebo, HTRIG/placebo, HRIG/HDCV or HTRIG/HDCV. RIG was administered at the recommended dose of 20 IU/kg by three intramuscular (i.m.) injections in the gluteus. HDCV or placebo was given on day (D) 0, D3, D7, D14, and D28 into the deltoid by the intramuscular (i.m.) route. Any local reaction from D0 to D3 at the immune globulin injection site, and any systemic reaction from D0 to D42, were monitored by subject diaries. Rabies-neutralizing serum antibody levels were assessed by the rapid fluorescent focus inhibition test (RFFIT) before treatment and on D3, D7, D14, D28, D35, and D42. No serious adverse reactions and, in particular, no allergic-type reactions were reported. The safety profiles of HTRIG and HRIG were similar, except that complaints of pain, or tenderness at the injection site were half as common in the HTRIG group. Most of the local reactions were mild or moderate. After the administration of HTRIG/placebo or HRIG/placebo, 60% of subjects had detectable rabies antibodies levels, but by D42 all titres were below the seroprotective level (i.e. below 0.5 IU/ml). In the groups HTRIG/HDCV and HRIG/HDCV, the antibody titres rose markedly from D7, and reached a maximum value of 19 IU/ml (95% CI, 11 to 38 IU/ml) and 31 IU/ml (95% CI, 20 to 48 IU/ml), respectively, on day 14. All subjects who received RIG and vaccine maintained a protective antibody level from D14 to D42. No significant difference in immunogenicity results between these two groups (HTRIG/HDCV and HRIG/HDCV) was observed, and no interference of immune globulin with vaccine was reported. The safety and immunogenicity profiles of PMC HTRIG appear comparable with the current reference product. The heat-treatment step will enhance the safety by further reducing the probability of virus transmission through immune globulin treatment. The low levels of rabies antibodies obtained by intramuscular administration of either PMC HTRIG or of PMC HRIG support the recommendations that call for local infiltration of wounds with RIG.

Adolescent↗
PubMed1998

Evaluation of the in vitro micronucleus test as an alternative to the in vitro chromosomal aberration assay: position of the GUM Working Group on the in vitro micronucleus test. Gesellschaft für Umwelt-Mutations-forschung.

In order to license a pharmaceutical or chemical, a compound has to be tested for several genotoxicity endpoints, including the induction of chromosomal aberrations in vitro. A working group within the GUM has evaluated published data on the in vitro micronucleus test with the aim of judging its suitability as a replacement for the in vitro chromosomal aberration test. After strict rejection criteria were applied, a database including 96 publications and 34 compounds was obtained. For 30 of these compounds, data on both tests were available. For 24 of the 30, concordant results in both test systems were obtained (80% correlation). The discordant results in 6 compounds can be explained by a known or suspected aneugenic potential of these compounds. Considering that cell types and test protocols were extremely heterogeneous, this correlation is rather encouraging. Comparison of the different protocols, and experience established within the working group yielded several recommendations for the routine use of the in vitro micronucleus test. Although many cell lines are suitable, those most often used in genotoxicity testing (e.g. CHL, CHO, V79, human lymphocytes, L5178Y mouse lymphoma cells) are recommended. Cytochalasin B may be used in the case of human lymphocytes; however, the possibility of its interaction with aneugenic test compounds should be considered. For continuously dividing cell lines, cytochalasin B is not recommended by the working group. Although, there seems to be flexibility in the choice of treatment and sampling times, the average generation time of the chosen cell line of choice should be taken into account when determining sampling time, and treatment of cells for at least one cell cycle duration is recommended. The use of appropriate cytotoxicity tests is strongly recommended. Although studies on some parameters of the test protocol may be useful, the introduction of the in vitro micronucleus test into genotoxicity testing and guidelines should not be delayed. Even in its present state, the in vitro micronucleus is a reliable genotoxicity test. Compared with the chromosomal aberration test, it detects aneugens more reliably, it is faster and easier to perform, and it has more statistical power and the possibility of automation.

Animals↗
PubMed1998

A community outbreak of Salmonella berta associated with a soft cheese product.

In September 1994, a complaint was registered at a public health unit concerning a cheese product. In addition, public health laboratories in Ontario reported an increase in the number of isolates of Salmonella berta from patients with diarrhoeal illness. A clinical, environmental and laboratory investigation was initiated to determine the nature of this outbreak. Isolates of Salmonella berta were compared using large fragment genomic fingerprinting by pulsed-field gel electrophoresis (PFGE). By late October, 82 clinical cases had been identified including 35 confirmed, 44 suspected and 3 secondary. The investigation linked illness to consumption of an unpasteurized soft cheese product produced on a farm and sold at farmers' markets. Subtyping results of patient, cheese and chicken isolates were indistinguishable, suggesting that the cheese was contaminated by chicken carcasses during production. The outbreak illustrates the potential role of uninspected home-based food producers and of cross-contamination in the transmission of foodborne bacterial pathogens.

Adolescent↗
PubMed1998

Tuberculosis control in a changing health care system: model contract specifications for managed care organizations.

Increasingly, patients with tuberculosis are receiving clinical care in managed care organizations as a result of enrollment in Medicaid or Medicare, or coverage under privately purchased insurance policies or employee benefit plans. This represents a change from the system that has been in place for decades, where the clinical care and public health functions concerning treatment and control of tuberculosis occurred primarily in local health departments. The separation of individual patient care from the public health aspects of tuberculosis control has created challenges for managed care administrators, medical providers, and public health officials. To assist in the integration of the goals of managed care and public health with respect to the prevention and control of tuberculosis, we developed a set of model contract specifications for use by purchasers of managed care and by managed care organizations concerning the management of patients with tuberculosis and other related public health issues. These specifications can assist health officials in continuing their leadership roles by ensuring that managed care contracts address public health needs.

Contract Services↗
PubMed1998

Tolerance of N-chlorotaurine, an endogenous antimicrobial agent, in the rabbit and human eye--a phase I clinical study.

N-chlorotaurine (NCT), an essential weak oxidative N-chloro compound produced by stimulated human leukocytes, shows bactericidal, fungicidal, virucidal and vermicidal efficacy. A double-blind, randomized and placebo controlled study was done to evaluate the tolerance of the aqueous NCT solution by application to rabbit and human conjunctiva. In six rabbits treated with 1% and 3% NCT regimen for nine days no ocular and behaviour changes could be observed. In a pilot study with two volunteers, treatment with 2.8% NCT for five days caused a self-limited conjunctival injection of one subject, while 1% NCT was well tolerated. Subsequently, eight healthy volunteers participated in a phase I clinical study. One percent NCT was applied for five days and was well tolerated by all subjects except for minimal eye burning after the application. Because of these positive results, usage of the antimicrobial agent NCT in ophthalmology is suggested.

Adult↗
PubMed1998

A model of the cost-effectiveness of directly observed therapy for treatment of tuberculosis.

A hypothetical cohort of 25,000 TB patients and their contacts were followed for a 10-year period; rates of treatment default, infectiousness following partial treatment, relapse, hospitalization, and development of drug-resistant TB were included. The average cost per case cured was $16,846 with 15% of patients starting DOT, $17,323 with 100% starting DOT, and $20,106 with none starting DOT. The incremental cost per additional case cured was $24,064 when all patients, started treatment on DOT, indicating that outpatient DOT provides a cost-effective method of improving health outcomes for TB patients and their contacts while controlling direct costs.

Adult↗
PubMed1998

Dynamically determined contractile states of airway smooth muscle.

The contractile state of maximally activated bovine airway smooth muscle is altered during imposed tidal stretches that simulate the action of breathing. When the amplitude of imposed tidal stretch is very small (0.25% of muscle optimal length), the steady-state value of the muscle force, F, approximates the isometric force, the muscle stiffness, E, is large, and the muscle hysteresivity, eta, is small. When the amplitude is increased beyond 1%, however, F and E promptly decrease and eta promptly increases. The provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, is slightly greater than 2%. By contrast, the stretch amplitude expected during quiet breathing at rest is 4%. Therefore, the isometric force generating capacity of airway smooth muscle may not be applicable to the force generated in normal physiologic circumstances, even during maximal bronchial provocation.

Animals↗
PubMed1998

Midlife cardiovascular risk factors, ApoE, and cognitive decline in elderly male twins.

OBJECTIVE: To investigate the combined effect of the apolipoprotein E epsilon4 (ApoE*4) allele and midlife cardiovascular risk factors on cognitive decline. METHODS: Data are from the National Heart, Lung, and Blood Institute Twin Study-a longitudinal cardiovascular epidemiologic study of World War II male veteran twins currently in its 27th year of follow-up. Subjects were assessed for cardiovascular risk factors, including BP and glucose levels, at mean ages 48, 58, and 63 years. Participants in the current study are 410 individual twin subjects for whom cognitive function was measured twice, at ages 63 and 73 years. Ten-year change scores in performance on neuropsychological test examinations were adjusted for age, education, baseline score, and incident cardiovascular disease. RESULTS: For the sample as a whole, we observed a significant decline (p < 0.01) in cognitive performance over the 10 years of follow-up. ApoE*4 carriers with midlife hyperglycemia experienced the greatest decline in performance, which was also greater than expected from the separate effects combined. Midlife hypertension and ApoE*4, were each associated with excess decline in performance on tests of psychomotor speed. Their joint effect, however, was not greater than expected from the separate effects combined. CONCLUSIONS: ApoE*4 and midlife cardiovascular risk factors may have a synergistic effect on decline in cognitive function. This effect may be due to greater vascular or degenerative damage among subjects with ApoE*4.

Aged↗
PubMed1998

Tuberculosis.

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Antitubercular Agents↗
PubMed1998

Lack of effect of prophylactic gentamicin treatment on intraocular and extraocular fluid cultures after pars plana vitrectomy.

BACKGROUND AND OBJECTIVE: To analyze the effect of preoperative prophylatic 0.3% gentamicin sulfate eyedrops on intraocular and extraocular fluid cultures after pars plana vitrectomy. PATIENTS AND METHODS: Forty consecutive patients undergoing pars plana vitrectomy were randomly assigned to receive either 0.3% gentamicin eyedrops or placebo preoperatively. Fluids from the vitreous cavity and from the conjunctival sac were collected for bacteriologic studies. RESULTS: Positive cultures from extraocular fluids were obtained in 30.4% of the gentamicin group and 35.3% of the placebo group (P = .75). Furthermore, 1 (3%) of 40 cultures of intraocular fluid and 13 (33%) of 40 cultures of extraocular fluid were positive. Culture growth positivity was not influenced by the patients' age, by diabetes, or by the duration of the operation. CONCLUSIONS: Prophylactic gentamicin treatment by the method applied in this study is not effective on reducing growth positivity. Contaminated extraocular fluid may play an important role in the pathogenesis of bacterial endophthalmitis following pars plana vitrectomy.

Administration, Topical↗