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Biomedical subjects

A Holmes

Publications and source records attributed to A Holmes.

At least 73 records · Page 4Linked to original sources
PubMed2000

Reconstruction of cardiac ventricular geometry and fiber orientation using magnetic resonance imaging.

An imaging method for the rapid reconstruction of fiber orientation throughout the cardiac ventricles is described. In this method, gradient-recalled acquisition in the steady-state (GRASS) imaging is used to measure ventricular geometry in formaldehyde-fixed hearts at high spatial resolution. Diffusion-tensor magnetic resonance imaging (DTMRI) is then used to estimate fiber orientation as the principle eigenvector of the diffusion tensor measured at each image voxel in these same hearts. DTMRI-based estimates of fiber orientation in formaldehyde-fixed tissue are shown to agree closely with those measured using histological techniques, and evidence is presented suggesting that diffusion tensor tertiary eigenvectors may specify the orientation of ventricular laminar sheets. Using a semiautomated software tool called HEARTWORKS, a set of smooth contours approximating the epicardial and endocardial boundaries in each GRASS short-axis section are estimated. These contours are then interconnected to form a volumetric model of the cardiac ventricles. DTMRI-based estimates of fiber orientation are interpolated into these volumetric models, yielding reconstructions of cardiac ventricular fiber orientation based on at least an order of magnitude more sampling points than can be obtained using manual reconstruction methods.

Animals↗
PubMed2000

Electrophysiological modeling of cardiac ventricular function: from cell to organ.

Three topics of importance to modeling the integrative function of the heart are reviewed. The first is modeling of the ventricular myocyte. Emphasis is placed on excitation-contraction coupling and intracellular Ca2+ handling, and the interpretation of experimental data regarding interval-force relationships. Second, data on use of diffusion tensor magnetic resonance (DTMR) imaging for measuring the anatomical structure of the cardiac ventricles are presented. A method for the semi-automated reconstruction of the ventricles using a combination of gradient recalled acquisition in the steady state (GRASS) and DTMR images is described. Third, we describe how these anatomically and biophysically based models of the cardiac ventricles can be implemented on parallel computers.

Animals↗
PubMed2000

Candida albicans: adherence, signaling and virulence.

The focus of this symposium was to present new information on the morphogenesis of Candida albicans, particularly how it relates to signal transduction pathways and other genes involved in the regulation of morphogenesis. In addition, we discuss the role of adherence and colonization of the oral cavity by the organism and discuss the role of mannan as an adhesin that recognizes the human red blood cell. C. albicans utilizes at least two signal pathways to regulate its conversion from a yeast form to filamentous growth (hyphae). One of these two pathways is similar to the Saccharomyces cerevisiae pseudohyphal/mating pathway, which utilizes the regulatory protein, Cphlp. The other pathway is not totally defined but requires a second regulatory protein, referred to as Efg1p. Other signal pathways may exist, which include a two-component histidine kinase and response regulator proteins. The latter pathway(s) may include proteins such as Chk1p, Ssk1p, Shi1p and Cos1p/Nik1p. Mutations in strains, which specifically target these proteins, result in morphogenesis defects and avirulence or attenuation of strains. A growth regulatory gene has also been recently defined whose expression is associated with growth cessation and which appears to be a necessary prerequisite in conversion of the organism to a filamentous growth form. Starvation of yeast cells induces exponentially grown cells (and usually non-germinative) to germinate. This phenomenon is also observed in cells that are transiently treated with metabolic inhibitors. During each of these treatments (starvation, metabolic inhibition), expression of a growth regulatory gene (CGRI) increases. Adherence of C. albicans to host cells and tissues is complex; several proteins, which appear to have host recognition functions, have been defined. In the oral cavity, C. albicans selectively adheres to salivary proteins, which are absorbed to many oral surfaces. This mechanism enables the cells to colonize surfaces of the oral cavity. An understanding of these interactions may lead to strategies to prevent oral disease. Mannan from C. albicans may provide a host recognition function for C. albicans. Recent experiments indicate that mannan binds to human red blood cells and causes hemolysis. Binding of mannan to the band 3 protein of human red blood cells has been established. This activity may be associated with the ability of the organism to utilize hemoglobin (and iron).

Candida albicans↗
PubMed1999

Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze.

It has been widely reported that the anxiolytic efficacy of benzodiazepines in the elevated plus-maze test is abolished in subjects (rats or mice) that have been given a single prior undrugged experience of the test apparatus. The present series of experiments was designed to further characterise the key experiential determinants of this intriguing phenomenon in Swiss Webster mice. Using a standard 5 min test duration for both trials, Experiment 1 confirmed the anxiolytic efficacy of chlordiazepoxide (CDP; 5-20 mg/kg) in mice naive to the plus-maze, but a virtual elimination of drug effects in animals that had been pre-exposed to the maze 24 h earlier. Experiments 2 and 3 demonstrated that, while extending the duration of initial exposure to 10 min did not prevent the loss of CDP (10 mg/kg) efficacy in a standard-duration second trial, increasing the duration of both trials reinstated an anxiolytic profile for the compound. Finally, although trial 1 confinement to an open arm did not compromise CDP efficacy when animals were subsequently allowed to freely explore the maze (Experiment 4), closed arm confinement during initial exposure abolished the drug's anxiolytic action upon retest (Experiment 5). In contrast to previous findings in rats, these data suggest that the experientially induced loss of benzodiazepine efficacy in the mouse plus-maze depends rather critically upon prior discovery and exploration of relatively safe areas of the maze (i.e. closed arms). Results are discussed in relation to the hypothesis that the absence of an anxiolytic response to benzodiazepines in plus-maze-experienced subjects reflects the acquisition of an open arm phobia during trial 1.

Animals↗
PubMed1999

Booking systems for elective services: the New Zealand experience.

This article provides a brief overview of New Zealand's experience in implementing booking systems for elective services in public hospitals. It identifies the basic features of the booking systems policy and explores the rationale and objectives for these policy settings. Progress with implementation of booking systems is explored and some of the challenges and recent developments are also outlined. The authors argue that booking systems represent a major improvement on waiting lists for patients, providers, purchasers and policy-makers.

Appointments and Schedules↗
PubMed1999

An epidemic of burkholderia cepacia transmitted between patients with and without cystic fibrosis.

Burkholderia cepacia is an important pathogen in cystic fibrosis (CF) and an infrequent cause of nosocomial infection in non-CF patients. This report describes a large hospital outbreak that appeared to involve both patient groups, a previously unrecognized phenomenon. Ribotype restriction fragment length polymorphism (RFLP) profiles and pulsed-field gel electrophoresis-resolved macrochromosomal RFLPs were analyzed, a ribotype-based phylogenic tree was constructed, and case-control and cohort studies were performed. A single dominant clone was found in both CF and non-CF groups. Phylogenic analysis suggests that it has evolved independently and that such highly transmissible strains can emerge rapidly and randomly. Acquisition risk in the CF patients was linked to hospitalization (odds ratio=5.47, P=.0158, confidence interval=1. 28-26.86) and was associated with significantly increased mortality rates. Infection control policies must now consider this threat of transmission between non-CF and CF patients.

Adolescent↗
PubMed1999

Practical considerations in the performance of physical examinations on women with disabilities.

There are over 28 million women with disabilities in the United States (1). This includes women with mobility and self-care limitations of varying degrees. Many of these women have difficulty obtaining comprehensive, accessible, and dignified physical examinations. Additionally, patients and clinicians are often misinformed about issues pertaining to healthcare needs of women with disabilities (2). This article outlines strategies to overcome physical barriers and gaps in knowledge, and proposes creative solutions for common problems encountered during the performance of the basic physical examination of a woman who has disabilities. It discusses the reality of sexually transmitted disease, promotes awareness of abuse in the population of women with disabilities, and offers guidelines physicians can follow in assisting their patients in resolving this abuse.

Battered Women↗
PubMed1999

Tuberculosis.

Explore the source record for details and available documents.

Humans↗
PubMed1998

Saccharomyces Ku70, mre11/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage.

Saccharomyces cells suffering a single unrepairable double-strand break (DSB) exhibit a long, but transient arrest at G2/M. hdf1 cells, lacking Ku70p, fail to escape from this RAD9/RAD17-dependent checkpoint. The effect of hdf1 results from its accelerated 5' to 3' degradation of the broken chromosome. Permanent arrest in hdf1 cells is suppressed by rad50 or mre11 deletions that retard this degradation. Wild-type HDF1 cells also become permanently arrested when they experience two unrepairable DSBs. Both DSB-induced arrest conditions are suppressed by a mutation in the single-strand binding protein, RPA. We suggest that escape from the DNA damage-induced G2/M checkpoint depends on the extent of ssDNA created at broken chromosome ends. RPA appears to play a key intermediate step in this adaptation.

Adaptation, Physiological↗
PubMed1998

In-frame elimination of exon 10 in Cftrtm1Unc CF mice.

Cystic fibrosis (CF) is a severe autosomal-linked inherited disease in humans. Transgenic CF animals play a crucial role in the study of molecular mechanisms underlying disease pathology. In the present study, CFTR mRNA expression was examined in different tissues from one CF mouse model that contains a disruption in exon 10 sequence of the CF transmembrane conductance regulator (CFTR) gene. Multiple tissue samples were collected from new-born normal (+/+), homozygous (-/-), and heterozygous (+/-) mice and compared for their CFTR mRNA expression. Total RNA samples were prepared from eight different tissues (nasal mucosa, trachea, lung, colon, intestine, pancreas, liver, gonads, and brain) and then analyzed by reverse transcription polymerase chain reaction (RT-PCR) amplification. A 329-bp fragment comprising exon 9 through exon 11 of the CFTR gene was amplified from all tissues of the normal mouse. In contrast, a 137-bp fragment was observed in tissue samples from homozygous CF mice. Both the 329-bp and 137-bp fragments were detected in samples from heterozygous mice. Direct sequencing analysis of the amplified fragments showed an exon 9-exon 11 splice junction, indicating that the entire exon 10 sequence was eliminated from homozygous CF mice. RT-PCR analysis of the 3' end of CFTR mRNA showed the presence of a 682-bp, exon 20-24 fragment in -/- and +/- mice. These results demonstrate that an alternately spliced CFTR mRNA is produced in this CF 'knock-out' mouse. A semi-quantitative comparison of the wild-type and exon 10 minus CFTR (CFTR-E10) mRNA in heterozygote animals indicated that less (but a detectable amount) mutant CFTR mRNA was present in all organs tested. There was, however, a significant reduction of CFTR-E10 mRNA in the liver and the pancreas. Since the deletion of exon 10 is in-frame, the significance of the CFTR-E10 mRNA in terms of CFTR protein and function requires further analysis.

Animals↗
PubMed1998

Prevalence of hearing loss among children 6 to 19 years of age: the Third National Health and Nutrition Examination Survey.

CONTEXT: Hearing loss in children influences the development of communication and behavioral skills, but few studies in the United States have used pure-tone audiometry to derive hearing loss prevalence estimates for children. OBJECTIVE: To describe the prevalence of hearing loss among US children by sociodemographic characteristics, reported hearing loss, and audiometric screening factors. DESIGN: National population-based cross-sectional survey with an in-person interview and audiometric testing at 0.5 to 8 kHz. SETTING/PARTICIPANTS: A total of 6166 children aged 6 to 19 years completed audiometry in the mobile examination center of the Third National Health and Nutrition Examination Survey conducted between 1988 and 1994. MAIN OUTCOME MEASURE: Hearing loss, defined as audiometric threshold values of at least 16-dB hearing level based on a low or high pure-tone average. RESULTS: A total of 14.9% of children had low-frequency or high-frequency hearing loss of at least 16-dB hearing level, 7.1% had low-frequency hearing loss of at least 16-dB hearing level, and 12.7% had high-frequency hearing loss of at least 16-dB hearing level. Most hearing loss was unilateral and slight in severity (16- to 25-dB hearing level). Of those with measured hearing loss, 10.8% were reported to have current hearing loss during the interview. CONCLUSIONS: This analysis indicates that 14.9% of US children have low-frequency or high-frequency hearing loss of at least 16-dB hearing level in 1 or both ears. Among children in elementary, middle, and high school, audiometric screening should include low-frequency and high-frequency testing to detect hearing loss.

Adolescent↗
PubMed1998

Second generation "peptoid" CCK-B receptor antagonists: identification and development of N-(adamantyloxycarbonyl)-alpha-methyl-(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile.

We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key alpha-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S*)2 beta]-[2-[(2-hydroxycyclohexyl)amino]-1-(1H-indol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a Ke of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 microgram/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HP beta CD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI-988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.

Adamantane↗
PubMed1998

Event-related fMRI: characterizing differential responses.

We present an approach to characterizing the differences among event-related hemodynamic responses in functional magnetic resonance imaging that are evoked by different sorts of stimuli. This approach is predicated on a linear convolution model and standard inferential statistics as employed by statistical parametric mapping. In particular we model evoked responses, and their differences, in terms of basis functions of the peri-stimulus time. This facilitates a characterization of the temporal response profiles that has a high effective temporal resolution relative to the repetition time. To demonstrate the technique we examined differential responses to visually presented words that had been seen prior to scanning or that were novel. The form of these differences involved both the magnitude and the latency of the response components. In this paper we focus on bilateral ventrolateral prefrontal responses that show deactivations for previously seen words and activations for novel words.

Evoked Potentials↗