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Biomedical subjects

B Guthrie

Publications and source records attributed to B Guthrie.

At least 19 recordsLinked to original sources
PubMed2000

Data acquisition, data storage, and data presentation in a modern genetics laboratory.

Modern genetic analysis can be divided into three main areas of investigation. The first is data acquisition, in the form of genomic sequence and the cataloguing of polymorphism data of the single nucleotide polymorphism variety (so called SNPs). Once identified, such genetic information can be adapted into high throughput tests to examine genetic information in large populations, making the analysis of sufficiently large numbers both cost and time effective so that relatively low-penetrant genetic effects can be accurately detected. The third step is correlating variation with phenotype (e.g. disease susceptibility or resistance) for a variety of disorders is paramount in our motivation and indeed is a common goal of modern human genetic analysis. While the technology to acquire vast amounts of genetic data is now well established and continues to expand, the ability to deal with such data, from the process of acquisition, storage, and analysis depends fundamentally on a solid informatics infrastructure as an essential component. Indeed, most of the major gains in productivity in this field are to be realized on the informatics front, and involve automating data acquisition, defining and sorting data in databases for quality control and analysis and facilitating access to data for the large variety of data analyses. Informatics-related issues including those relating to data acquisition, database structure, and analysis tools are summarized here in an effort to define some of the issues relevant to establishing informatics infrastructure in a small genetics laboratory focused on resequencing human immune response genes. From inherited diseases to drug efficacy to the specific genetic changes occurring during tumor development, this new field of medical genetics promises a profound impact on the state of human health. Ultimately, any and all advances in this field will continue to depend on major investments in informatics.

Computational Biology↗
PubMed1999

Design considerations for a transcranial Doppler coupled to a stereotactic position arm.

We present the localization error analysis for a stereotactic positioning arm, transcranial Doppler (TCD) system. Localization displacement errors were determined with a custom phantom head. A bubble apparatus was built to measure sample volume (SV). From interface plane relationships, biological material properties, and human computerized tomography (CT) scan data, an algorithm for computing the actual TCD signal path was developed. Localization resolution was diminished by constraints intrinsic to the TCD instrument (+/-1 mm) and the positioning arm (1.9+/-0.9 mm). The overall SV localization error ranged from 3.3 mm from the target, to complete signal loss at a critical cumulative angle of 31, one third of which may be reached at the TCD probe/skin interface. Any stereotactic ultrasound system must include correction for the beam path. The "failed ultrasound window," may be predicted by signal loss based on refraction alone. The use of stereotactic TCD may enhance the clinical applications of TCD.

Equipment Design↗
PubMed1999

Paradoxical labeling of radiosurgically treated quiescent tumors with Ki67, a marker of cellular proliferation.

Ki67 (also known as MIB) is a monoclonal antibody staining agent, which is routinely used as a marker of cellular proliferation. It is used to evaluate the proliferative potential of malignant tumors, since it is thought to stain only those cells undergoing active division. The paradoxical elevation of the Ki67 labeling index observed in radiosurgically treated benign and malignant tumors is reported. Ten patients, who had previously undergone either linac or Gamma Knife radiosurgery, underwent surgical resection for a radiographically quiescent tumor. One patient underwent autopsy after dying from complications of radiosurgery. All were thought to be suffering from adverse radiation effect (ARE) and were refractory to conservative management. None were thought to have a recurrent tumor. All of the resected tumors were subjected to analysis with Ki67 staining. Despite the radiographic stability of the tumors, all manifested significantly elevated populations of cells exhibiting positivity for Ki67 antigen. This staining pattern would suggest a significant proliferative potential, which did not match the observed clinical course. The literature is reviewed and possible mechanisms to explain the paradoxical findings are presented.

Adenocarcinoma↗
PubMed1998

Eph signaling is required for segmentation and differentiation of the somites.

Somitogenesis involves the segmentation of the paraxial mesoderm into units along the anteroposterior axis. Here we show a role for Eph and ephrin signaling in the patterning of presomitic mesoderm and formation of the somites. Ephrin-A-L1 and ephrin-B2 are expressed in an iterative manner in the developing somites and presomitic mesoderm, as is the Eph receptor EphA4. We have examined the role of these proteins by injection of RNA, encoding dominant negative forms of Eph receptors and ephrins. Interruption of Eph signaling leads to abnormal somite boundary formation and reduced or disturbed myoD expression in the myotome. Disruption of Eph family signaling delays the normal down-regulation of her1 and Delta D expression in the anterior presomitic mesoderm and disrupts myogenic differentiation. We suggest that Eph signaling has a key role in the translation of the patterning of presomitic mesoderm into somites.

Amino Acid Sequence↗
PubMed1998

Cloning and characterization of a specific receptor for mouse oncostatin M.

Oncostatin M (OSM) is a member of a family of cytokines that includes ciliary neurotrophic factor, interleukin-6, interleukin-11, cardiotrophin-1, and leukemia inhibitory factor (LIF). The receptors for these cytokines consist of a common signaling subunit, gp130, to which other subunits are added to modify ligand specificity. We report here the isolation and characterization of a cDNA encoding a subunit of the mouse OSM receptor. In NIH 3T3 cells (which endogenously express gp130, LIF receptor beta [LIFRbeta], and the protein product, c12, of the cDNA described here), mouse LIF, human LIF, and human OSM signaled through receptors containing the LIFRbeta and gp130 but not through the mouse OSM receptor. Mouse OSM, however, signaled only through a c12-gp130 complex; it did not use the LIF receptor. Binding studies demonstrated that mouse OSM associated directly with either the c12 protein or gp130. These data highlight the species-specific differences in receptor utilization and signal transduction between mouse and human OSM. In mouse cells, only mouse OSM is capable of activating the mouse OSM receptor; human OSM instead activates the LIF receptor. Therefore, these data suggest that all previous studies with human OSM in mouse systems did not elucidate the biology of OSM but, rather, reflected the biological actions of LIF.

3T3 Cells↗
PubMed1997

Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy.

Hypothalamic hamartomas and gelastic seizures are often associated with cognitive deterioration, behavioral problems, and poor response to anticonvulsant treatment or cortical resections. The origin and pathophysiology of the epileptic attacks are obscure. We investigated 3 patients with this syndrome and frequent gelastic seizures. Ictal single-photon emission computed tomography performed during typical gelastic seizures demonstrated hyperperfusion in the hamartomas, hypothalamic region, and thalamus without cortical or cerebellar hyperperfusion. Electroencephalographic recordings with depth electrodes implanted in the hamartoma demonstrated focal seizure origin from the hamartoma in 1 patient. Electrical stimulation studies reproduced the typical gelastic events. Stereotactic radiofrequency lesioning of the hamartoma resulted in seizure remission without complications 20 months after surgery. The functional imaging findings, electrophysiological data, and results of radiofrequency surgery indicate that epileptic seizures in this syndrome originate and propagate from the hypothalamic hamartoma and adjacent structures.

Adult↗
PubMed1997

Risky behavior and risk in adolescents with IDDM.

PURPOSE: To determine: (1) the frequency of risky behaviors (alcohol and other drug use, smoking cigarettes, smokeless tobacco use, and unprotected intercourse); (2) the perception of general risks and diabetes-related risks from risky behaviors; (3) if perception of risk is related to engaging in risky behaviors; and (4) if perception of general risks and diabetes-related risks are influenced by age, gender, or race in adolescents with insulin dependent diabetes mellitus (IDDM). Decreasing risky behaviors in youth with IDDM is important because of their increased vulnerability to specific disease related physiologic and pathologic changes. METHODS: A descriptive, cross-sectional design was used. Data on risky behavior and perception of risk were obtained by self-report during a regularly scheduled clinic visit. One hundred and fifty-five adolescents between ages of 10-20 years participated. Correlational and student's t-test analyses were used to test relationships and group differences (age, race, gender). RESULTS: Thirty-nine percent of the sample reported alcohol use, 34% reported smoking cigarettes, 8% reported smokeless tobacco use, 10% reported drug use, and 29% reported unprotected intercourse. Perception of risk to peers from these behaviors was significantly higher (t = 8.1, df 153; p < .001) than risk to self. Females reported significantly lower (t = 3.08, df 52; p < .002) risk to self than males. There was no difference in perception of risk between youth who reported participating in risky behaviors (N = 38%) and those who did not (62%). Not surprisingly, the frequency of risky behavior increased with age (F = 15.46; p < .001). CONCLUSIONS: Compared to community samples of middle school children, our sample had lower rates for most risky behaviors. As with community samples, the physical risks were known and perceived to be higher for peers than self. Perception of risk was not related to self-reports of risky behaviors. The lower rate of risky behaviors might reflect the success of educational efforts directed toward diabetes management or may be due to later initiation of behaviors, especially if personal social development is delayed. Additional research is indicated in order to understand the timing and trajectory of risky behavior and whether or not perception of risk deters youth with IDDM from engaging in risky behavior.

Adolescent↗
PubMed1997

Titrated intravenous opioids from the same syringe: an infection risk?

OBJECTIVE: (1) To compare the rate of contamination of syringes prepared under laminar flow conditions in pharmacy with those prepared by nurses in the emergency department; (2) to determine whether the time elapsed since preparation or number of doses given affected the contamination rate; (3) to determine whether any adverse effects resulted from bacterially contaminated drugs. METHODS: Prospective, blinded trial exploring the effect of method of preparation, time since preparation, and number of doses given on contamination rates and infective adverse events associated with bacterially contaminated specimens. RESULTS: The rate of bacterial contamination was 12% (95% confidence interval 6% to 18%). There was no difference in contamination rate in respect of method of preparation, number of doses given, or time since preparation. No infective complications were identified. CONCLUSIONS: Abandonment of titrated intravenous opioids is not justified by the results. However, there is concern about the use of this technique of pain control for immunocompromised patients and those with prosthetic heart valves.

Analgesia↗
PubMed1997

Two Eph receptor tyrosine kinase ligands control axon growth and may be involved in the creation of the retinotectal map in the zebrafish.

The isolation and characterisation of two zebrafish Eph receptor ligand cDNAs which we have called zfEphL3 and zfEphL4 is described. These genes are expressed in the presumptive midbrain of developing embryos from 6 somites. By 24 hours L3 is expressed throughout the midbrain including the region of the presumptive tectum whereas L4 is strongly expressed in the midbrain caudal to the presumptive tectum. At later stages of development L3 is expressed in a graded fashion throughout the tectum and L4 is maintained at its posterior margin. Growth cone collapse and pathway selection assays demonstrate that both these proteins have a collapse activity for retinal ganglion cells. When faced with a choice of substrate on which to grow, temporal axons from chick retinal ganglion cells selectively avoided membranes from Cos cells transfected with L3, whereas nasal axons did not. Both temporal and nasal axons avoided membranes from Cos cells transfected with L4. The expression patterns together with the functional data suggest that although both ligands may be able to guide retinal ganglion cells axons in vitro, they have different roles in the guidance of retinotectal projections in vivo. The expression of L3 is consistent with a role in the guidance of retinal ganglion cells to their targets on the tectum whereas that of L4 suggests a role in delineating the posterior boundary of the optic tectum.

Amino Acid Sequence↗
PubMed1996

Functional MRI of lateral occipitotemporal cortex during pursuit and motion perception.

We performed functional imaging with a conventional 1.5-T magnetic resonance scanner in 9 normal subjects. We used a gradient-echo technique to examine changes in signal between periods when subjects viewed a stationary black-and-white grating, a moving grating, and when they followed a moving spot. We located image pixels with significant differences between the viewing conditions. In 7 subjects, these occurred in the lateral occipitotemporal cortex, a region previously identified as a putative human homologue of the motion-sensitive middle temporal area (MT, or V5) of monkeys. Signal intensity was greater during pursuit of the moving dot than during viewing of the moving grating with the eyes still, despite the fact that the moving grating generated more retinal image motion. In contrast, signal intensity in striate cortex was least during pursuit of the moving dot. These findings suggest that the lateral occipitotemporal cortex has extraretinal signals during pursuit. Such signals may include attentional input, corollary eye movement information, or even a pursuit command. Extraretinal signals suggest that the lateral occipitotemporal cortex may contain a human homologue not only of MT but also of other components of the monkey V5 complex, such as the medial superior temporal area.

Adult↗
PubMed1996

Are people with HIV in London able to die where they plan?

Being able to die where you plan is a measure of quality of life near death, in that it implies awareness of diagnosis and prognosis, adequate symptom control and involvement in decision-making in late-stage HIV disease. This study presents trends in place of death for patients attending a large central London HIV centre and examines whether patients dying over a 6-month period in 1994 were able to die where they planned. Early in the epidemic almost all people with HIV died in hospital, but in the late 1980s there was an increase in death at home and in hospices. Of people attending this hospital in 1994, 46% died in hospital, 31% at home, 20% in hospices and 2% abroad. A total of 59% of deaths were where the dying person had planned. Most unplanned deaths were in hospital, two-thirds being due to an unexpected deterioration which precluded planning. The rest were a mixture of people waiting for discharge to die elsewhere, and people who wished to continue active treatment. This pattern of place of death is unlikely to change in the near future. It is therefore essential that hospitals can provide for the needs of patients dying on acute wards.

Choice Behavior↗