Search PubMed⌕ Search

Biomedical subjects

D Carr

Publications and source records attributed to D Carr.

At least 37 records · Page 2Linked to original sources
PubMed1999

Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

Administration, Oral↗
PubMed1999

The identification of markers segregating with resistance to Schistosoma mansoni infection in the snail Biomphalaria glabrata.

Both snail and parasite genes determine the susceptibility of the snail Biomphalaria glabrata to infection with the trematode Schistosoma mansoni. To identify molecular markers associated with resistance to the parasite in the snail host, we performed genetic crosses between parasite-resistant and -susceptible isogenic snails. Because resistance to infection in adult snails is controlled by a single locus, DNA samples from individual F2 and F1 backcross progeny, segregating for either the resistant or susceptible phenotypes, were pooled (bulked segregant). Genotypes for both parents were determined with 205 arbitrary decamer primers by random amplified polymorphic DNA-PCR. Of the 205 primers, 144 were informative, and the relative allele frequencies between the pools for these primers were determined. Two primers, OPM-04 and OPZ-11, produced fragments in the resistant parent of one cross that were inherited in a dominant fashion in the resistant F2 and backcross-bulked segregant progeny. Subsequent typing of DNA samples of individual progeny snails showed that the 1.2-kb marker amplified by primer OPM-04 and the 1.0-kb marker produced by primer OPZ-11 segregated in the same dominant fashion with the resistant phenotype. Sequence analysis of the 1.2-kb marker showed that it corresponds to a repetitive sequence in the snail genome with no homology to existing DNA sequences in the public databases. Analysis of the 1. 0-kb marker showed that it also corresponds to a repetitive sequence in the B. glabrata genome that contains an imperfect ORF, with homology to retrovirus-related group-specific antigens (gag) polyprotein.

Animals↗
PubMed1999

Analysis of a residual diamine in a pharmaceutical polymer using solid phase extraction with analysis by gas chromatography mass spectrometry.

A method was developed for the analysis of 4,4'-methylenebiscyclohexylamine (DMDA) and 4,4'-methylenedicyclohexylisocyanate (DMDI) in a pharmaceutical polymer. The DMDA was extracted from the polymer with either buffer (0.1 M potassium phosphate pH 3.1) and the extract was passed through a SCX solid phase extraction cartridge. It was eluted from the cartridge with methanolic ammonia and then converted to its heptafluorobutyramide (HFB) derivative prior to analysis by gas chromatography-negative chemical ionisation mass spectrometry (GC-MS) in the negative ion chemical ionisation (NICI) mode. It was not possible to directly measure DMDI and it was thus analysed by selecting extraction conditions such that it would decompose to DMDA. The quantification of the residues in the polymer was based on the method of standard additions since this gave a better indication of the recovery from the complex matrix.

Cyclohexylamines↗
PubMed1999

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Alkyl and Aryl Transferases↗
PubMed1999

Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group.

A randomized, double-blind trial comparing oral fluconazole (400 mg daily) with placebo as prophylaxis for adult patients receiving intensive cytotoxic therapy for acute leukemia or autologous bone marrow transplantation was conducted in 14 Canadian university-affiliated hospitals. Although fluconazole prophylaxis did not obviate the need for parenteral antifungal therapy compared with placebo (81 [57%] of 141 vs. 67 [50%] of 133, respectively), its use resulted in fewer superficial fungal infections (10 [7%] of 141 vs. 23 [18%] of 131, respectively; P = .02) and fewer definite and probable invasive fungal infections (9 vs. 32, respectively; P = .0001). Fluconazole recipients had fewer deaths attributable to definite invasive fungal infection (1 of 15 vs. 6 of 15, respectively; P = .04) and achieved more frequent success without fungal colonization (52 [37%] of 141 vs. 27 [20%] of 133, respectively; P = .004; relative risk reduction, 85%) than did placebo recipients. Patients benefiting the most from fluconazole prophylaxis included those with acute myeloid leukemia who were undergoing induction therapy with cytarabine plus anthracycline-based regimens and those receiving marrow autografts not supported with hematopoietic growth factors. Fluconazole prophylaxis reduces the incidence of superficial fungal infection and invasive fungal infection and fungal infection-related mortality among patients who are receiving intensive cytotoxic chemotherapy for remission induction.

Adolescent↗
PubMed1999

The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus.

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.

Abatacept↗
PubMed1998

The influence of epidural analgesia on cesarean delivery rates: a randomized, prospective clinical trial.

OBJECTIVE: The effects of epidural analgesia on the progress of labor are controversial. The objective of this study was to determine the effect of epidural analgesia on cesarean delivery rates in a population of patients randomly assigned to receive either epidural analgesia or intravenous opioids for intrapartum pain relief. STUDY DESIGN: From January 1995 to May 1996, 318 spontaneously laboring, term, nulliparous patients were randomly assigned to receive either intravenous opioids or epidural analgesia for pain relief. Labor was managed according to the principles of active management of labor. Cesarean delivery was performed for obstetric indications. Data analysis was conducted on an intent-to-treat basis. A subanalysis was subsequently performed on patients who were compliant with the allocated form of treatment. RESULTS: One hundred sixty-two patients were randomly assigned to receive intravenous meperidine and 156 were randomly assigned to receive epidural analgesia. Maternal age, gravidity, race, gestational age, and cervical dilatation at admission and at first analgesic dose did not differ between the groups. Intent-to-treat data analysis revealed no significant difference in the cesarean delivery rate between the 2 groups, being 13.6% in the opioid group and 9.6% in the epidural group (relative risk 0.70, 95% confidence interval 0.38-1.31, P >.05). Cesarean delivery rates for the indication of dystocia also did not differ, being 10.5% in the opioid group and 5.8% in the epidural group (relative risk 0.56, 95% confidence interval 0.26-1.21, P >.05). Subanalysis of the data from patients who were compliant with the allocated form of treatment revealed that patients in the epidural group (n = 147) were 3 times more likely to have an active phase duration >/=8 hours and were 10 times more likely to require >/=2 hours in the second stage of labor than were those in the opioid group (n = 78). There were no significant differences in cesarean delivery rates in this subanalysis, being 7.7% in the opioid group and 8.8% in the epidural group (relative risk 1.15, 95% confidence interval 0.45-2.91, P >. 05). The cesarean delivery rates for dystocia were also similar in the subanalysis, being 3.8% in the opioid group and 5.5% in the epidural group (relative risk 1.42, 95% confidence interval 0.39-5. 22, P >.05). CONCLUSION: Epidural analgesia provides safe and effective intrapartum pain control and may be administered without undesirable effects on labor outcome.

Adolescent↗
PubMed1998

A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1.

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterized by autoimmune hypoparathyroidism, autoimmune adrenocortical failure, and mucocutaneous candidiasis. Recently, an autoimmune regulator gene (AIRE-1), which is located on chromosome 21q22.3, has been identified, and mutations in European kindreds with APS1 have been described. We used SSCP analysis and direct DNA sequencing to screen the entire 1,635-bp coding region of AIRE-1 in 12 British families with APS1. A 13-bp deletion (964del13) was found to account for 17 of the 24 possible mutant AIRE-1 alleles, in our kindreds. This mutation was found to occur de novo in one affected subject. A common haplotype spanning the AIRE-1 locus was found in chromosomes that carried the 964del13 mutation, suggesting a founder effect in our population. One of 576 normal subjects was also a heterozygous carrier of the 964del13 mutation. Six other point mutations were found in AIRE-1, including two 1-bp deletions, three missense mutations (R15L, L28P, and Y90C), and a nonsense mutation (R257*). The high frequency of the 964del13 allele and the clustering of the other AIRE-1 mutations may allow rapid molecular screening for APS1 in British kindreds. Furthermore, the prevalence of the 964del13 AIRE-1 mutation may have implications in the pathogenesis of the more common autoimmune endocrinopathies in our population.

Alleles↗
PubMed1998

Recurrence of recipient Langerhans' cell histiocytosis following bilateral lung transplantation.

Langerhans' cell histiocytosis may cause irreversible respiratory failure due to progressive destruction of lung parenchyma and widespread cystic change. Transplantation offers a therapeutic option. A case is described of recurrence of Langerhans' cell histiocytosis which was associated with deterioration in lung function four years following bilateral lung transplantation. Patients transplanted for Langerhans' cell histiocytosis should be followed up with this complication in mind.

Adult↗
PubMed1997

Characterization of Ha-ras, N-ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I.

Ras proteins are small GTP-binding proteins which are critical for cell signaling and proliferation. Four Ras isoforms exist: Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B. The carboxyl termini of all four isoforms are post-translationally modified by farnesyl protein transferase (FPT). Prenylation is required for oncogenic Ras to transform cells. Recently, it was reported that Ki-Ras4B is also an in vitro substrate for the related enzyme geranylgeranyl protein transferase-1 (GGPT-1) (James, G. L., Goldstein, J. L., and Brown, M. S. (1995) J. Biol. Chem. 270, 6221-6226). In the current studies, we compared the four isoforms of Ras as substrates for FPT and GGPT-1. The affinity of FPT for Ki-Ras4B (Km = 30 nM) is 10-20-fold higher than that for the other Ras isoforms. Consistent with this, when the different Ras isoforms are tested at equimolar concentrations, it requires 10-20-fold higher levels of CAAX-competitive compounds to inhibit Ki-Ras4B farnesylation. Additionally, we found that, as reported for Ki-Ras4B, N-Ras and Ki-Ras4A are also in vitro substrates for GGPT-1. Of the Ras isoforms, N-Ras is the highest affinity substrate for GGPT-1 and is similar in affinity to a standard GGPT-1 substrate terminating in leucine. However, the catalytic efficiencies of these geranylgeranylation reactions are between 15- and 140-fold lower than the corresponding farnesylation reactions, largely reflecting differences in affinity. Carboxyl-terminal peptides account for many of the properties of the Ras proteins. One interesting exception is that, unlike the full-length N-Ras protein, a carboxyl-terminal N-Ras peptide is not a GGPT-1 substrate, raising the possibility that upstream sequences in this protein may play a role in its recognition by GGPT-1. Studies with various carboxyl-terminal peptides from Ki-Ras4B suggest that both the carboxyl-terminal methionine and the upstream polylysine region are important determinants for geranylgeranylation. Furthermore, it was found that full-length Ki-Ras4B, but not other Ras isoforms, can be geranylgeranylated in vitro by FPT. These findings suggest that the different distribution of Ras isoforms and the ability of cells to alternatively process these proteins may explain in part the resistance of some cell lines to FPT inhibitors.

Alkyl and Aryl Transferases↗
PubMed1997

Reliability of the Washington University Road Test. A performance-based assessment for drivers with dementia of the Alzheimer type.

OBJECTIVE: To assess the reliability and stability of a standardized road test for healthy aging people and those with dementia of the Alzheimer type (DAT). DESIGN: A prospective study involving patients with DAT and age-matched healthy controls in which subjects' driving performance was evaluated by several raters in an initial and a follow-up road test. SETTING: Urban medical school and urban highways and streets. SUBJECTS: A convenience sample of 58 controls, 36 subjects with very mild DAT, and 29 subjects with mild DAT. RESULTS: Analysis of road test ability of controls (2 subjects [3%] failed the test), very mild DAT subjects (7 subjects [19%] failed), and mild DAT subjects (12 subjects [41%] failed) disclosed a significant association between driving performance and dementia status (chi 2[4] = 20.65 [N = 123]; P < .001; Kendall tau-b = 0.306). Interrater reliability for assessment of driving performance ranged from kappa = 0.85 to 0.96. One-month test-retest stability on the road test was 0.76 (quantitative scoring) and 0.53 (clinical judgment). CONCLUSIONS: Dementia adversely affects driving performance even in its mild stages, although some persons with DAT seem to drive safely for some time after disease onset. A traffic-interactive, performance-based road test that examines cognitive behaviors provides an accurate and reliable functional assessment of driving ability.

Aged↗
PubMed1997

Preoptic area infusions of morphine disrupt--and naloxone restores--parental-like behavior in juvenile rats.

As in the adult lactating female, opioids disrupt (and naloxone restores), parental behavior in juvenile rats (approximately 25 days of age). Because the preoptic area regulates the display of parental behavior in lactating females, we examined its parental behavior role in the juvenile rat. At 21 days of age, juvenile rats were implanted with bilateral cannulae aimed at the preoptic area using a modified Kopf stereotaxic and extrapolating from a developing-rat brain atlas [58], and divided into two groups: Initiation and maintenance. On day 25, the initiation group received bilateral infusions of either morphine (0.50 microgram), saline (0.25 microliter), or morphine plus naloxone (0.25 microgram). Thirty minutes later, they were exposed to three 1-6-day-old pups; the maintenance group was exposed to pups until they displayed 2 consecutive days of parental behavior, then infused. Morphine disrupted parental behavior in both the initiation and Maintenance groups, and naloxone restored the behavior to control/ saline levels. Parental behavior in the juvenile animal of both sexes, therefore, is under opioid regulation that parallels the adult female.

Animals↗
PubMed1997

Ras oncoprotein inhibitors: the discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex.

The nucleotide exchange process is one of the key activation steps regulating the ras protein. This report describes the development of potent, non-nucleotide, small organic inhibitors of the ras nucleotide exchange process. These inhibitors bind to the ras protein in a previously unidentified binding pocket, without displacing bound nucleotide. This report also describes the development and use of mass spectrometry, NMR spectroscopy and molecular modeling techniques to elucidate the structure of a drug-protein complex, and aid in designing new ras inhibitor targets.

Crystallography, X-Ray↗
PubMed1997

Antitumor 8-chlorobenzocycloheptapyridines: a new class of selective, nonpeptidic, nonsulfhydryl inhibitors of ras farnesylation.

Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor.

Animals↗
PubMed1997

Environmental cueing may effect performance on a road test for drivers with dementia of the Alzheimer type.

This paper examines the impact of environmental cueing on a road test for persons with dementia of the Alzheimer type (DAT). In an earlier study, we demonstrated the reliability and stability of the Washington University Road Test in a sample of 58 healthy elderly controls and 65 subjects with DAT. We found that dementia adversely affects driving performance even in its mild stages. Here were elaborate on the results of a follow-up road test conducted 1 month after the baseline test (n = 63) explore possible reasons why the stability of the follow-up road test was lower than expected. We conclude that environmental cueing may affect performance on a road test in DAT.

Aged↗
PubMed1997

Back pain among echocardiographers.

OBJECTIVE: By having to adopt unnatural postures, echocardiographers place themselves at risk of back injury. The present study sought to document the incidence and severity of back pain among echocardiographers, and to identify personal, lifestyle and occupational characteristics that may predict risk of back pain. DESIGN: A questionnaire concerning occupational, personal, and lifestyle characteristics, as well as the extent and severity of back pain was completed and returned by 183 echocardiographers. RESULTS: The standard echocardiography examination position of "machine on the left, patient on the right, and transducer held in the right hand" (used by 66% of respondents) greatly increased the risk of back pain (odds ratio (OR) = 4.9; 95% confidence interval (95% CI) = 1.49-16.4). Echocardiographers with more than 11 years experience in the field were also at risk of back pain (OR) = 3.4; 95% CI = 0.97-11.6). The intensity of back pain was strongly associated with the amount of time spent on echocardiography examinations (P = 0.035), limitation of lifestyle (P < or = 0.001), and interference with work (P < or = 0.001). There was a significantly higher relative risk of back pain for the respondents whose job involved frequent or occasional lifting compared with nonlifters (P = 0.01; OR = 4.8, 95% CI = 1.25-18.7). At least some limitation of lifestyle from back pain was reported by 56% of the respondents. CONCLUSIONS: There is a high incidence of back pain among echocardiographers, and specific tasks and activities increase the risk of back pain. Further research should focus on preventative measures and optimum work station designs that may serve as a guide to echocardiography departments.

Back Pain↗
PubMed1997

The future for radiography practice.

In evaluating the future face of radiography practice, a historical review of developments to date has been undertaken, together with a look at the changes which will face the profession into the new millennium. This article focuses on changing healthcare provision, changing radiographic practice, the changing face of the healthcare professions and the changing focus of education and training. The opportunities for further development of the profession are explored along with an overview of some of the possible barriers to progress. Our contention is that radiographers are more than adequately prepared for a rapidly changing future. To ensure that they are prepared, however, it is essential for the profession to adopt an appropriate vision, formulate an achievable strategy, and promote a culture of professional practice which is able to respond adequately to the problems facing its continued existence.

Forecasting↗