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Biomedical subjects

J Hunter

Publications and source records attributed to J Hunter.

At least 73 records · Page 4Linked to original sources
PubMed1998

Subtype- and response element-dependent differences in transactivation by peroxisome proliferator-activated receptors alpha and gamma.

Peroxisome proliferator-activated receptors (PPAR) modulate transcription by binding to specific peroxisome proliferator-response elements (PPRE) through heterodimerization with the 9-cis retinoic acid receptor (RXR). To investigate potential subtype- and response element-dependent differences in transcriptional activation by PPARs, we expressed PPARalpha or PPARgamma2, along with RXRalpha, in the yeast Saccharoromyces cerevisiae and compared their ability to activate transcription of reporter genes containing a PPRE from either the rat acyl-CoA oxidase (AOx) or hydratase-dehydrogenase (HD) gene. PPARgamma2 and RXRalpha, when coexpressed from low copy vectors, potently and synergistically activated transcription of the AOx-PPRE reporter gene, but only weakly stimulated transcription of the HD-PPRE reporter gene. This response element preference, which was also observed in mammalian cells, could not be attributed to differences in binding affinity of PPARgamma2/RXRalpha heterodimers to these elements in vitro. Interestingly, PPARgamma2 expressed from a high copy vector was able to strongly activate transcription of the HD-PPRE reporter gene, even in the absence of coexpressed RXRalpha. In comparison to the findings with PPARgamma2, the HD-PPRE served as a significantly more robust response element for PPARalpha as compared to the AOx-PPRE. PPRE-dependent transcriptional activation by PPARalpha correlated with binding efficiencies of PPARalpha/RXRalpha to the response element. Our findings demonstrate that the transactivation potential of PPAR subtypes can be differentially modulated by distinct PPREs.

Acyl-CoA Oxidase↗
PubMed1998

Down-regulation of the novel gene melastatin correlates with potential for melanoma metastasis.

We have used differential cDNA display to search for genes whose expression correlates with an aggressive phenotype in variants of the B16 murine melanoma line, B16-F1 and B16-F10. This analysis identified a novel gene, termed melastatin, that is expressed at high levels in poorly metastatic variants of B16 melanoma and at much reduced levels in highly metastatic B16 variants. Melastatin was also found to be differentially expressed in tissue sections of human melanocytic neoplasms. Benign nevi express high levels of melastatin, whereas primary melanomas showed variable melastatin expression. Melastatin transcripts were not detected in melanoma metastases. Within the set of human primary cutaneous melanomas examined, melastatin expression appeared to correlate inversely with tumor thickness. The expression pattern observed suggests that loss of melastatin expression is an indicator of melanoma aggressiveness.

Amino Acid Sequence↗
PubMed1998

Pancreatic necrosis: results of necrosectomy, packing, and ultimate closure over drains.

OBJECTIVE: The treatment of pancreatic necrosis at a tertiary referral center was reviewed to effect better patient outcome. SUMMARY BACKGROUND DATA: Pancreatic necrosis is a devastating disease that leads to death in 10% to 50% of cases. Infected necrosis is particularly deadly because 80% of deaths from necrosis are due to infection or its complications. Therapeutic strategies center on aggressive support of organ systems and prevention and treatment of infectious complications. METHODS: Records of all patients who underwent pancreatic necrosectomy from 1990 to 1996 at Emory University Hospital were reviewed. Patients with infected necrosis were debrided as soon as the diagnosis was made. Reoperation for completion necrosectomy with ultimate closure over lavage catheters was performed as necessary. RESULTS: Of the 244 patients admitted with acute pancreatitis in the study period, 50 underwent pancreatic debridement. The mean age was 52 years, and 74% of patients were transferred from other institutions. Eighty-four percent of patients had infected necrosis, and all patients underwent sequential debridement with eventual closure over drains. Organ failure occurred in 72% of cases, and the overall mortality rate was 12%. The mean length of stay was 54 days. CONCLUSIONS: The management of pancreatic necrosis demands the allocation of extensive resources. An aggressive operative strategy of multiple debridements with ultimate closure over drains can lead to a low mortality rate in patients with this complex disease, but the determination of when to explore patients with sterile necrosis remains difficult.

Acute Disease↗
PubMed1998

Rotational imaging of complex acetabular fractures.

Understanding complex acetabular fractures is difficult and may require three-dimensional reformatted computed tomographic (CT) images. This paper evaluates a technique, digital rotational imaging (DRI), that displays multiple oblique images of the pelvis and acetabulum. When viewed statically, DRI provides optimal iliac and obturator oblique projections, often differing in obliquity from the conventional 45-degree orthogonal views. Dynamic DRI viewing in rapid sequence provides a three-dimensional effect that improves perception of acetabular fracture relationships.

Acetabulum↗
PubMed1998

Effects of the novel high-affinity 5-HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries.

The contractile actions of the novel high-affinity 5-hydroxytryptamine (5-HT(1B/1D)) ligand, frovatriptan (formerly VML 251/SB-209509) were investigated in human isolated basilar and coronary arteries in which the endothelium had been removed. Basilar arteries were obtained post mortem, and coronary arteries were obtained from patients undergoing heart transplant (recipient) or from donor hearts that were not suitable for transplant. Frovatriptan was a potent contractile agent in isolated basilar artery with a -log mean effective concentration (EC50) value of 7.86 +/- 0.07 and intrinsic activity of 1.25 +/- 0.10 relative to 5-HT (n = 4). Frovatriptan was 8.5-fold more potent than sumatriptan, which produced a -log EC50 value of 6.93 +/- 0.09 and intrinsic activity 11.1 +/- 0.08 relative to 5-HT (n = 4). In coronary arteries, frovatriptan produced contraction with -log EC50 values of 7.38 +/- 0.12 and 7.81 +/- 0.2 in recipient (n = 7) and donor (n = 3) arteries, respectively. The relative degree of contraction of frovatriptan was lower than that of 5-HT, with relative intrinsic activities of 0.42 +/- 0.06 and 0.40 +/- 0.09, respectively. Sumatriptan produced contraction of human recipient and donor arteries with -log EC50 values (intrinsic activity) of 6.57 +/- 0.13 (0.79 +/- 0.27; n = 6) and 7.35 (1.41; n = 2), respectively. Furthermore, marked bell-shaped responses were apparent for frovatriptan in coronary arteries, with relaxation occurring at concentrations >6 microM in some tissues. In contrast, no bell-shaped concentration-response curves were apparent for sumatriptan or 5-HT. Threshold concentrations for frovatriptan-induced contractions were also different between basilar (>2 nM) and coronary arteries (>20 nM). No separation of threshold activity was observed with sumatriptan or 5-HT. These data show that frovatriptan produces constriction of human isolated basilar and coronary arteries. However, frovatriptan produces a complex pharmacologic response in the coronary artery, with threshold contractile activity requiring approximately 10-fold greater concentrations of agonist than in the basilar artery. Frovatriptan also shows a differential pharmacologic profile compared with sumatriptan in coronary arteries, with reversal of tone predominating at high concentration.

Basilar Artery↗
PubMed1998

A group therapy approach to facilitate integration of risk information for women at risk for breast cancer.

OBJECTIVE: To describe and illustrate elements of a group counselling approach designed to enhance the communication of risk information on breast cancer (BC) to women with a family history of this disease. Breast cancer is a leading cause of female cancer death. The most important risk factor for BC is a positive family history in at least 1 first-degree relative, and approximately one-third of women with BC have a family history of the disease. Recent evidence suggests that there is a significant psychological impact associated with having a family history of BC, and this may influence the psychological adjustment and response to being counselled for personal risk. New counselling approaches are required. METHOD: This paper describes a group therapy approach that incorporates principles of supportive-expressive therapy designed to address the emotional impact of being at risk for BC and to promote accuracy of perceived risk. The key elements of the intervention are described along with clinical illustrations from groups that are part of an ongoing study to develop and standardize the group therapy. CONCLUSION: Qualitative data from the groups suggest that this model of therapy is both feasible and effective.

Adaptation, Psychological↗
PubMed1998

Propylene glycol toxicosis in a mare.

Propylene glycol and mineral oil are commonly used in the veterinary profession for treatment of bovine ketosis and equine impactions, respectively. Accidental administration of 6.0 ml propylene glycol/kg of body weight in horses causes severe depression, ataxia and malodorous breath and feces. However, appropriate medical therapy can result in successful treatment of this toxicosis.

Animals↗
PubMed1997

Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis.

Activated protein C resistance caused by an Arg506Gln mutation in the factor V gene (factor V Leiden mutation) is the most common cause of familial thrombosis. This mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is not a significant risk factor for ischemic stroke in adults. We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden mutation. One infant had multiple thrombi in the fetal placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of in utero cerebrovascular disease and hemiplegic cerebral palsy.

Brain Ischemia↗
PubMed1997

Standardizing laparoscopic procedure time and determining the effect of patient age/gender and presence or absence of surgical residents during operation. A prospective multicenter trial.

BACKGROUND: Most of the expense of laparoscopic cholecystectomy (LC) is incurred while the patient is in the operating room (OR). Half of this operating room cost is equipment and the other half is personnel. What is an acceptable LC procedure time and how much variation is there? What are the effects of age, gender, and expertise on the mean LC procedure time? METHODS: A prospective, multicenter gathering of LC procedure times and task component times was performed through the cooperative effort of members of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES) at 11 hospitals. The effect of LC time of age, gender, and surgical resident was recorded. RESULTS: The mean LC time for 359 cases was 73 +/- 28 min. The percent of this LC time for the following component tasks included: to place and remove trocars, 34%; total dissection time, 40%; intraoperative cholangiogram, 15%; and removing the gallbladder, 7%. Age and gender did not change LC time, but the presence of a surgical resident prolonged LC time from 53 to 79 min due to an increase in all LC component task times. CONCLUSIONS: LC time was globally calibrated in 11 North American hospitals and was found to be affected by expertise but not by gender or age. The mean and standard deviation of LC time can be used for purposes of self-assessing quality performance.

Age Factors↗
PubMed1997

Skeletal status of men with early and late ankylosing spondylitis.

PURPOSE: To assess the influence of extent of disease on the skeletal status of men with ankylosing spondylitis (AS). PATIENTS AND METHODS: Fourteen men with AS were studied at entry and again after 15 months. Bone mineral density (BMD) was assessed by single photon absorptiometry (SPA), dual energy x-ray absorptiometry (DXA), and quantitative computed tomography (QCT). Calciotropic hormones and bone turnover were also assessed, and biopsies of iliac crest and skin were taken after tetracycline double-labeling from 10 subjects. Clinical evaluation and Health Assessment Questionnaires were used to assess functional status. RESULTS: Of the 14 participants, 7 had sacroiliitis alone without radiologic evidence of spinal involvement (early disease) and 7 had sacroiliitis with extensive vertebral calcifications and immobilization (late disease). QCT baseline lumbar spine BMD was very low in both groups compared with normative standards (Z score = -3.08 +/- 1.83, P < 0.0001) and did not change significantly over 15 months. This low BMD was more marked in late disease than in early disease subjects (P < 0.01). DXA BMD at the lumbar spine was lower than predicted in early disease subjects (Z score = -1.08 +/- 0.67, P = 0.005) but not in the late disease group. DXA BMD was also low at the all three hip sites (Z score = -0.96 +/- 0.86, P < 0.01). Significant differences between late disease group and normative values were apparent at all hip sites. Values in early disease subjects, however, did not differ from age-predicted norms. Bone mineral status did not change significantly over the 15-month period of observation. Circulating parathyroid hormone (PTH) and vitamin D metabolites were normal in both groups as were creatinine clearance and urinary excretion of calcium and hydroxyproline. Osteocalcin levels were normal in all but the two youngest subjects in the early disease group. Histomorphometry of the iliac crest showed no consistent change in bone turnover. Bone volume and trabecular width were low in many cases. Cancellous bone volume correlated with lumbar spine BMD by QCT (r = 0.69, P = 0.026) but not with DXA. Although beneficial changes occurred in exercise tolerance and pain over time, anthropometric measurements did not improve. CONCLUSION: BMD is low in both the axial and peripheral skeleton in men with AS and is independent of spinal immobilization. Anterioposterior lumbar spine DXA in late AS is less useful than QCT in determining the degree of osteopenia in late AS. Bone mineral deficits in AS do not reflect measurable metabolic derangement or hypogonadism. Although bone histomorphometry suggests both trabecular thinning and loss of structural elements as mechanisms involved in low bone volume, the exact cause of osteopenia in AS remains to be determined.

Absorptiometry, Photon↗
PubMed1997

A process-oriented reasoner about physiology.

This paper presents the RAP system: a reasoner about physiology. RAP performs two tasks: (1) it infers the behaviour of a complex physiological process using the behaviours of its subprocesses and the relationships between them; (2) it reasons about the effect of introducing a fault into the model. In order to reason about the behaviour of a complex process, RAP uses a mechanism which: (i) represents how subprocesses behave; (ii) establishes how these subprocesses affect each others behaviors; (iii) 'aggregates' these behaviors together to obtain the behavior of the top level process; (iv) gives that process a temporal context in which to act. RAP uses limited common sense knowledge about faults to reason about their effect in terms of the generation of new processes and the misbehavior of existing ones. The effects are then propagated throughout the model to obtain the overall effect of the fault.

Artificial Intelligence↗
PubMed1997

Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk.

BACKGROUND: CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk. MATERIALS AND METHODS: Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk. RESULTS: CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors. CONCLUSIONS: The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.

Adult↗