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R Gregory

Publications and source records attributed to R Gregory.

At least 55 records · Page 3Linked to original sources
PubMed1999

A chimeric type 2 adenovirus vector with a type 17 fiber enhances gene transfer to human airway epithelia.

In studies of the genetic disease cystic fibrosis, recombinant adenovirus type 2 (Ad2) and Ad5 are being investigated as vectors to transfer cystic fibrosis transmembrane conductance regulator cDNA to airway epithelia. However, earlier work has shown that human airway epithelia are resistant to infection by Ad2 and Ad5. Therefore, we examined the efficiency of other adenovirus serotypes at infecting airway epithelia. We found that several serotypes of adenoviruses, in particular, wild-type Ad17, infected a greater number of cells than wild-type Ad2. The increased efficiency of wild-type Ad17 could be explained by increased fiber-dependent binding to the epithelia. Therefore, we constructed a chimeric virus, Ad2(17f)/betaGal-2, which is identical to Ad2/betaGal-2 with the exception of having the fiber protein of Ad17 replace Ad2 fiber. This vector retained the increased binding and efficiency of gene transfer to well-differentiated human airway epithelia. These data suggest that inclusion of Ad17 fiber into adenovirus vectors may improve the outlook for gene delivery to human airway epithelia.

Adenoviridae↗
PubMed1999

Parental allele-specific chromatin configuration in a boundary-imprinting-control element upstream of the mouse H19 gene.

The mouse H19 gene is expressed from the maternal chromosome exclusively. A 2-kb region at 2 to 4 kb upstream of H19 is paternally methylated throughout development, and these sequences are necessary for the imprinted expression of both H19 and the 5'-neighboring Igf2 gene. In particular, on the maternal chromosome this element appears to insulate the Igf2 gene from enhancers located downstream of H19. We analyzed the chromatin organization of this element by assaying its sensitivity to nucleases in nuclei. Six DNase I hypersensitive sites (HS sites) were detected on the unmethylated maternal chromosome exclusively, the two most prominent of which mapped 2.25 and 2.75 kb 5' to the H19 transcription initiation site. Five of the maternal HS sites were present in expressing and nonexpressing tissues and in embryonic stem (ES) cells. They seem, therefore, to reflect the maternal origin of the chromosome rather than the expression of H19. A sixth maternal HS site, at 3.45 kb upstream of H19, was detected in ES cells only. The nucleosomal organization of this element was analyzed in tissues and ES cells by micrococcal nuclease digestion. Specifically on the maternal chromosome, an unusual and strong banding pattern was obtained, suggestive of a nonnucleosomal organization. From our studies, it appears that the unusual chromatin organization with the presence of HS sites (maternal chromosome) and DNA methylation (paternal chromosome) in this element are mutually exclusive and reflect alternate epigenetic states. In addition, our data suggest that nonhistone proteins are associated with the maternal chromosome and that these might be involved in its boundary function.

Age Factors↗
PubMed1999

Remote village survey for agents causing hepatosplenic disease in the Republic of Yemen.

The objective of this study was to epidemiologically describe potential infectious agents among rural people in the Republic of Yemen. This would aid clinicians in designing empirical therapy and public health officials in planning disease prevention. We sought to examine evidence for the geographical distribution of pathogens causing human hepatic and splenic disease among villagers and domestic animals living in three remote areas with differing altitudes. In June 1992, a cross-sectional survey was conducted at three survey sites of differing altitudes: 3080, 1440 and 250 m above sea level. Questionnaires, parasitic and serological tests were administered to 627 human volunteers. Additionally 317 domestic animals were studied. Malaria, schistosomiasis, and hepatitis B and C infections were found to be likely causes of human hepatic or splenic disease. Additionally, evidence of human and animal infections with the agents of brucellosis and Q fever was found: IgG antibodies against hepatitis E virus were discovered in two (2.0%) of the 100 volunteers. The prevalence of markers for human and animal disease was often lowest at the village of highest elevation, suggesting that increasing altitude, as a surrogate or a true independent risk factor, was protective against infection with the agents studied.

Adolescent↗
PubMed1999

Identification and pharmacological characterization of a series of new 1H-4-substituted-imidazoyl histamine H3 receptor ligands.

A new series of 1H-4-substituted imidazole compounds were synthesized and identified as potent and selective histamine (HA) H3 receptor ligands. These ligands establish that HA H3 antagonists exhibit stereoselective and conformational preferences in their binding to the HA H3 receptor. Structure-activity relationships were determined in vitro by HA H3 receptor-binding affinities using [3H]Nalpha-methylhistamine and rat cerebral cortical tissue homogenates. Several derivatives containing olefin, amide, and acetylene functional groups were identified as potent HA H3 receptor ligands. In the olefin series, GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) was identified as a potent HA H3 receptor ligand with a Ki of 4.2 +/- 0.6 nM, while the trans isomer (GT-2228) displayed a reduced potency (Ki = 15.2 +/- 2.4 nM). GT-2227 was also found to have excellent central nervous system penetration in an ex vivo binding paradigm (ED50 = 0.7 mg/kg i.p.). In the acetylene series, GT-2260 and GT-2286 both exhibited high affinity (Ki = 2.9 +/- 0.2 and 0.95 +/- 0.3 nM) and excellent central nervous system penetration profiles (ED50 = 0.43 and 0.48 mg/kg i.p., respectively). As a prototype for the series, GT-2227 showed high affinity for the human HA H3 receptor (3.2 nM) and minimal affinity for the human HA H1 (Ki = 13,407 +/- 540 nM) and H2 (Ki = 4,469 +/- 564 nM) receptor subtypes. GT-2227 also showed good selectivity for the HA H3 receptor over a broad spectrum of other neurotransmitter receptors (IC50 >/= 1 microM). Furthermore, GT-2227 improved acquisition in a cognitive paradigm without behavioral excitation or effect on spontaneous locomotor activity. In summary, the present studies demonstrate the development of novel HA H3-selective ligands, and lend support for the use of such agents in the treatment of disorders associated with cognitive or attentional deficits.

Animals↗
PubMed1999

Development of trans-2-[1H-imidazol-4-yl] cyclopropane derivatives as new high-affinity histamine H3 receptor ligands.

Previously, a novel series of 1H-4-substituted imidazole compounds were described as potent and selective histamine (HA) H3 receptor ligands (Yates et al., 1999). The present studies extend the structure-activity relationships for optimal HA H3 receptor affinity and central nervous system penetration by incorporation of a conformationally restricted cyclopropane nucleus. Moreover, the current studies extend our understanding of ligand-receptor interactions at the HA H3 receptor with the development of high affinity HA H3 receptor antagonists containing a stereochemical presentation. Structure-activity relationships were established from in vitro HA H3 receptor-binding affinities using [3H]Nalpha-methylhistamine and rat cortical tissue homogenates. Systematic optimization of multiple structural features critical for HA H3 receptor affinity provided some of the most potent HA H3 receptor agents described. For example, GT-2331 was determined to bind to a single population of HA H3 receptors with a Ki of 0.125 nM. In vivo, GT-2331 has a favorable central nervous system penetration profile with an ED50 of 0.08 mg/kg (i.p.) in rats and a long duration of action (T1/2 > 4 h). In addition, GT-2331 was extremely selective for the HA H3 receptor versus other HA receptors and a battery of neurotransmitter, neuropeptide, hormone, or enzyme systems. Several compounds were tested in vitro which suggested HA H3 receptor heterogeneity and are discussed in terms of structure-activity relationships for the HA H3 receptor.

Animals↗
PubMed1998

Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. The New Approaches to Brain Tumor Therapy.

BACKGROUND: High grade astrocytomas remain uniformly fatal despite aggressive surgery and radiotherapy. As existing chemotherapeutic agents are of limited benefit, clinical trials are underway to screen new drugs, such as 9-aminocamptothecin (9-AC), for activity in high grade astrocytomas. PURPOSE: This study was designed to estimate the efficacy of 9-AC in patients with newly diagnosed glioblastoma multiforme and recurrent high grade astrocytomas. The planned dose of 9-AC for this trial was 850 microg/m2 per 24 h as a 72-h continuous intravenous infusion every 2 weeks. This was the maximum tolerated dose (MTD) on this schedule in multiple phase I studies in patients with systemic malignancies. However, we found this dose subtherapeutic in our patient population. As a result, the purpose of the study was altered to determine the MTD. METHODS: A group of 32 patients were studied using 850 microg/m2 per 24 h with a provision to escalate to 1000 microg/m2 per 24 h if the first three cycles of 9-AC were without significant hematologic toxicity. Once it was determined that myelosuppression did not occur in patients on anticonvulsants, dose escalations were initiated using the continual reassessment method. Dose escalations were conducted independently in newly diagnosed and recurrent patients and in those taking and not taking hepatic enzyme-inducing anticonvulsants. Pharmacologic studies were conducted during the first cycle of 9-AC. Toxicity was determined using the NCI common toxicity criteria and efficacy was assessed using serial volumetric brain scans. RESULTS: 9-AC was administered to 59 patients, 31 with newly diagnosed glioblastoma multiforme and 28 with recurrent high grade astrocytomas. No grade III-IV myelosuppression was noted in the 29 patients (128 cycles) on phenytoin, carbamazepine, phenobarbital, and/ or valproic acid who received 850 microg/m2 per 24 h. In contrast, two of three patients (five cycles) who were not taking anticonvulsants developed grade IV myelosuppression. Steady-state total 9-AC plasma levels were lower in patients on anticonvulsants (median 25.3 nM) than in patients who were not taking anticonvulsants (median 76.5 nM). Dose escalations performed in 27 additional patients determined the MTD in patients taking anticonvulsants to be 1776 microg/m2 per 24 h for patients with newly diagnosed tumors and 1611 microg/m2 per 24 h for patients with recurrent disease. CONCLUSIONS: We describe a new and unexpected drug interaction between 9-AC and anticonvulsants. This is similar to recent findings with paclitaxel, and suggests that higher than "usual" doses of some chemotherapeutic agents are required in patients on anticonvulsants. Prospectively defined dose escalations and pharmacologic studies are essential for the careful evaluation of new chemotherapeutic agents in patients with brain tumors.

Adolescent↗
PubMed1998

Nutrition Practice Guidelines for Type 1 Diabetes Mellitus positively affect dietitian practices and patient outcomes. The Diabetes Care and Education Dietetic Practice Group.

OBJECTIVES: Assess the acceptance and ease of use of Nutrition Practice Guidelines for Type 1 Diabetes Mellitus by dietitians in a variety of settings; determine if nutrition care activities of dietitians change when practice guidelines are available; measure changes in patient control of blood glucose level, measured as glycated hemoglobin (HbA1c); compare patient satisfaction with care and perceptions about quality of life. DESIGN: Using the approach of outcomes research, volunteer dietitians were recruited and assigned randomly to a usual care group or a practice guidelines group. Patients with type 1 diabetes were enrolled by dietitians and followed up for a 3-month period. Outcome measures included dietitian care activities, changes in patient HbA1c levels, and patient satisfaction and perceptions about quality of life. SUBJECTS/SETTINGS: Dietitians from across the United States who responded to a recruitment notice participated. Their work settings included diabetes referral centers, endocrinology clinics, primary care and community health clinics, hospitals, and a worksite clinic. They recruited patients from their setting for the study. Outcome data were available from dietitians providing care to 24 patients using the new practice guidelines and dietitians providing care to 30 patients using more traditional methods. STATISTICAL ANALYSIS: chi 2 Test, t test, and analysis of covariance. RESULTS: Dietitians in the practice guidelines group spent 63% more time with patients and were more likely to do an assessment and discuss results with patients than dietitians in the usual care group. Practice guidelines dietitians paid greater attention to glycemic control goals. Levels of HbA1c improved at 3 months in 21 (88%) of practice guidelines patients compared with 16 (53%) of usual care patients. Practice guidelines patients achieved greater reductions in HbA1c level than usual care patients (-1.00 vs -0.33). This difference was statistically significant and clinically meaningful. CONCLUSIONS/APPLICATIONS: Dietitians responded positively to practice guidelines for type 1 diabetes. Use of guidelines resulted in changes in dietitian practices and produced greater improvements in patient blood glucose outcomes at 3 months compared with usual care. Practice guidelines did not significantly influence patient satisfaction with care of perceived quality of life.

Adolescent↗
PubMed1998

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Gravitation↗
PubMed1998

Neuropsychological, neurological and functional outcome following pallidotomy for Parkinson's disease. A consecutive series of eight simultaneous bilateral and twelve unilateral procedures.

Intellectual, psychological and functional outcomes were evaluated in a consecutive series of 20 Parkinsonian patients who had unilateral (UPVP) or simultaneous bilateral posteroventral pallidotomy (BPVP) using Image Fusion and Stereoplan (Radionics Inc., Boston, Mass., USA) with stimulation for lesion localization. Comprehensive baseline and 3-month postoperative neuropsychological and neurological assessment protocols were administered together with questionnaire measures of functional disability, quality of life and psychological symptomatology. Changes in patients' clinical presentation and scores on psychometric tests, questionnaires and observational rating scales were then examined. We observed no new neuropsychiatric sequelae directly related to pallidotomy. Cognitive sequelae were restricted to selective reductions in categorical verbal fluency following UPVP (P < 0.001) and BPVP (P < 0.01) and a reduction in phonemic verbal fluency following BPVP (P < 0.01); these changes were not reported subjectively. A fall in diadochokinetic rates (P < 0.01) and some subjective reports of a worsening in pre-existing dysarthria, hypophonia and hypersalivation/drooling following BPVP also suggested changes in speech motor apparatus; however, these changes did not have significant functional consequences. There was one case of more generalized cognitive impairment following BPVP. We also observed significant symptomatic improvement on neurological rating scales; following UPVP, Total Unified Parkinson's Disease Rating Scale (UPDRS) scores improved by 27% (P < 0.01) and following BPVP the improvement was 53% (P < 0.05). Patients' perceptions of reduced postoperative functional disability and improvements in 'quality of life' also achieved statistical significance on a number of both physical and psychosocial questionnaire subscales.

Activities of Daily Living↗