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Biomedical subjects

J Chambers

Publications and source records attributed to J Chambers.

At least 55 records · Page 3Linked to original sources
PubMed2000

The patient with a systolic murmur: severe aortic stenosis may be missed during cardiovascular examination.

Significant aortic stenosis is prevalent amongst elderly people. It may be subclinical, manifesting only as a murmur, but can still cause unexpected death with little warning after symptoms develop. Recent studies have highlighted the unreliability of the classical clinical signs of severe aortic stenosis, leading to concern that some patients may not be referred appropriately for echocardiography. Here, we review the evidence for the accuracy of each sign. We suggest that the assessment of the patient with a systolic murmur should be reappraised, and offer guidelines toward improving the recognition of aortic stenosis in the community.

Aged↗
PubMed2000

5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors.

In an effort to develop selective radioligands for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs), we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with (125)I and (123)I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[(125)I]iodo-A-85380 for alpha4beta2 nAChRs in rat and human brain is defined by K(d) values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the alpha4beta2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing alpha3 and beta4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at alpha7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[(125)I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the beta2 subunit of nAChRs. Binding of 5-[(125)I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor-ligand complex (t(1/2) for dissociation approximately 2 h). These properties, along with other features observed previously in in vivo experiments (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with (125)I or (123)I, is superior to other radioligands available for in vitro and in vivo studies of alpha4beta2 nAChRs, respectively.

Animals↗
PubMed2000

A comparison of the classical and modified forms of the continuity equation in the On-X prosthetic heart valve in the aortic position.

BACKGROUND AND AIM OF THE STUDY: The use of echocardiography to determine prosthetic valve hemodynamics has become generally accepted; however, there are still many differing methodologies in use. The continuity equation, which uses the ratio of the subaortic and transaortic velocity-time integrals for determining aortic effective orifice area (EOA), has been established as an accurate method. Another method using the more easily measured peak velocities in ratio has also been employed. These methods were compared to determine if the simpler method gave equivalent results. METHODS: Early postoperative echocardiographic data on prosthetic valves from the MCRI Multicenter Trial were used to compare the two methods of calculating EOA (A2). Results using the two methods were compared by paired t-tests, the Wilcoxon signed rank test, regression and Bland-Altman analysis. RESULTS: Despite a good correlation between the two methods (r = 0.91), results were different when compared by a paired t-test. On average, results by the modified method were 0.2 cm2 lower, but in 28% of cases they were in fact higher than the classical method. CONCLUSION: The modified continuity equation based on the peak velocity ratio does not give the same result as the classical formula based on the velocity-time ratio. The modified method cannot reliably be substituted for the classical method in normally functioning On-X valves.

Adult↗
PubMed2000

When is an aortic valve prosthesis too small? The need for dobutamine stress echocardiography.

We describe a patient who had undergone aortic valve replacement with a small prosthesis 10 years previously and who presented with exertional breathlessness. The resting transaortic pressure gradient was only 30 mmHg but increased to 165 mmHg on dobutamine stress. Conventional resting echocardiography may fail to demonstrate abnormal prosthetic aortic valve function; in the presence of symptoms, dobutamine stress echocardiography should be considered.

Adult↗
PubMed2000

An echocardiographic description of the Sulzer Carbomedics Synergy ST (Labcor) porcine valve in the aortic position.

BACKGROUND AND AIM OF THE STUDY: The Synergy ST (previously Labcor) valve is constructed from three separate porcine aortic cusps mounted on a scalloped, flexible, acetal copolymer stent. To date, no hemodynamic data describing this valve have been published. The aim of this study was to describe the echocardiographic findings in a population of unselected patients. METHODS: One investigator, who was blinded to valve size, studied 84 patients (31 females, 53 males; mean age 58 years; range: 19-83 years) at four centers in Brazil. The valves were studied at a mean of 31 months after implantation (range: 1-116 months). Mean gradient was calculated using the long modified Bernoulli equation, effective orifice area (EOA) using the classical from of the continuity equation, and resistance as mean gradient/flow. RESULTS: There were no significant differences in peak transaortic velocity and mean gradient between valves of different annulus size. However, EOA was directly related (p = 0.0075) and resistance indirectly related to valve size (p = 0.021, ANOVA). Trivial or mild regurgitation was seen in 31 patients (37%), moderate in three (4%) and severe in two (2%). The regurgitation was solely paraprosthetic in five patients, solely through the valve in 23, and both in seven. Regurgitation through the valve usually occurred adjacent to the commissures. CONCLUSION: The Synergy ST porcine valve has hemodynamics of forward flow similar to that of other stented porcine valves.

Adult↗
PubMed1999

Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1.

The underlying causes of obesity are poorly understood but probably involve complex interactions between many neurotransmitter and neuropeptide systems involved in the regulation of food intake and energy balance. Three pieces of evidence indicate that the neuropeptide melanin-concentrating hormone (MCH) is an important component of this system. First, MCH stimulates feeding when injected directly into rat brains; second, the messenger RNA for the MCH precursor is upregulated in the hypothalamus of genetically obese mice and in fasted animals; and third, mice lacking MCH eat less and are lean. MCH antagonists might, therefore, provide a treatment for obesity. However, the development of such molecules has been hampered because the identity of the MCH receptor has been unknown until now. Here we show that the 353-amino-acid human orphan G-protein-coupled receptor SLC-1 expressed in HEK293 cells binds MCH with sub-nanomolar affinity, and is stimulated by MCH to mobilize intracellular Ca2+ and reduce forskolin-elevated cyclic AMP levels. We also show that SLC-1 messenger RNA and protein is expressed in the ventromedial and dorsomedial nuclei of the hypothalamus, consistent with a role for SLC-1 in mediating the effects of MCH on feeding.

Alternative Splicing↗
PubMed1999

Characterization of the mouse proteasome regulator PA28b gene.

The proteasome regulator PA28, which can be upregulated by IFN, is important in the modulation of proteasome activity. Since the proteasome has been implicated in the processing of the major histocompatibility complex (MHC) class I antigens, it was of interest to determine the regulatory elements of PA28 at the genomic level. Although PA28 has been found in different species, the gene layout on the chromosome was not determined. In this study, the genetic organization of mouse PA28b was characterized. Two copies of the PA28b gene, namely b1 and b2, were found by restriction fragment mapping and Southern hybridization. By fluorescence in situ hybridization, the location of the two PA28b genes was determined on chromosomes 11 and 14. PA28b1 has 11 exons, whereas PA28b2 has no introns and appears to be a nonfunctional pseudogene. The 5' promoter region of PA28b1 contains several transcriptional factor binding sites including two IFN responsive elements. The expression levels of PA28 and other gene products involved in MHC class I antigen presentation appear to be correlated in various tissues. Notably, PA28 is expressed at high levels in immunological tissues such as spleen and peripheral blood leukocytes. Taken together, PA28 seems to be co-regulated with other molecules involved in MHC class I antigen presentation.

Animals↗
PubMed1999

The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle.

OBJECTIVE: To develop a monoclonal antibody that recognises an epitope of the native beta3-adrenoceptor expressed on the extracellular surface of human cells and tissues. DESIGN: A high affinity monoclonal antibody, Mab72c, was raised against the human beta3-adrenoceptor expressed on a transfected mammalian cell line. RESULTS: In CHO (Chinese hamster ovary) cells transfected with beta3-adrenoceptor cDNA, antibody labelling was found to be proportional to receptor density measured by the binding of the radiolabelled beta-adrenoceptor antagonist, [125I]-iodocyanopindolol. The use of Mab 72c has demonstrated the expression of the beta3-adrenoceptor in a variety of human tissues, including gall bladder, prostate and colon, where a mRNA signal had been detected previously. This study also provides the first direct demonstration of the expression of beta3-adrenoceptors in human skeletal muscle, atrium and adipose tissue. CONCLUSION: The development of this antibody represents an important addition to the armentarium of reagents that are available to study the localisation of beta3-adrenoceptors in human tissues.

Adipose Tissue↗
PubMed1999

Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor.

The cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory disorders, in particular asthma, for which the CysLT receptor antagonists pranlukast, zafirlukast, and montelukast, have been introduced recently as novel therapeutics. Here we report on the molecular cloning, expression, localization, and pharmacological characterization of a CysLT receptor (CysLTR), which was identified by ligand fishing of orphan seven-transmembrane-spanning, G protein-coupled receptors. This receptor, expressed in human embryonic kidney (HEK)-293 cells responded selectively to the individual CysLTs, LTC(4), LTD(4), or LTE(4), with a calcium mobilization response; the rank order potency was LTD(4) (EC(50) = 2.5 nM) > LTC(4) (EC(50) = 24 nM) > LTE(4) (EC(50) = 240 nM). Evidence was provided that LTE(4) is a partial agonist at this receptor. [(3)H]LTD(4) binding and LTD(4)-induced calcium mobilization in HEK-293 cells expressing the CysLT receptor were potently inhibited by the structurally distinct CysLTR antagonists pranlukast, montelukast, zafirlukast, and pobilukast; the rank order potency was pranlukast = zafirlukast > montelukast > pobilukast. LTD(4)-induced calcium mobilization in HEK-293 cells expressing the CysLT receptor was not affected by pertussis toxin, and the signal appears to be the result of the release from intracellular stores. Localization studies indicate the expression of this receptor in several tissues, including human lung, human bronchus, and human peripheral blood leukocytes. The discovery of this receptor, which has characteristics of the purported CysLT(1) receptor subtype, should assist in the elucidation of the pathophysiological roles of the CysLTs and in the identification of additional receptor subtypes.

Amino Acid Sequence↗
PubMed1999

DNA microarrays of the complex human cytomegalovirus genome: profiling kinetic class with drug sensitivity of viral gene expression.

We describe, for the first time, the generation of a viral DNA chip for simultaneous expression measurements of nearly all known open reading frames (ORFs) in the largest member of the herpesvirus family, human cytomegalovirus (HCMV). In this study, an HCMV chip was fabricated and used to characterize the temporal class of viral gene expression. The viral chip is composed of microarrays of viral DNA prepared by robotic deposition of oligonucleotides on glass for ORFs in the HCMV genome. Viral gene expression was monitored by hybridization to the oligonucleotide microarrays with fluorescently labelled cDNAs prepared from mock-infected or infected human foreskin fibroblast cells. By using cycloheximide and ganciclovir to block de novo viral protein synthesis and viral DNA replication, respectively, the kinetic classes of array elements were classified. The expression profiles of known ORFs and many previously uncharacterized ORFs provided a temporal map of immediate-early (alpha), early (beta), early-late (gamma1), and late (gamma2) genes in the entire genome of HCMV. Sequence compositional analysis of the 5' noncoding DNA sequences of the temporal classes, performed by using algorithms that automatically search for defined and recurring motifs in unaligned sequences, indicated the presence of potential regulatory motifs for beta, gamma1, and gamma2 genes. In summary, these fabricated microarrays of viral DNA allow rapid and parallel analysis of gene expression at the whole viral genome level. The viral chip approach coupled with global biochemical and genetic strategies should greatly speed the functional analysis of established as well as newly discovered large viral genomes.

Base Sequence↗
PubMed1999

The relation between transaortic pressure difference and flow during dobutamine stress echocardiography in patients with aortic stenosis.

OBJECTIVE: To investigate the relation between transaortic pressure difference and flow in patients with aortic stenosis. METHODS: 50 asymptomatic patients with all grades of aortic stenosis were studied using dobutamine stress echocardiography. Individual plots of mean pressure drop against flow were drawn. Comparisons were made between grades of aortic stenosis as defined by the continuity equation. RESULTS: A significant linear relation between pressure difference and flow was found in 34 patients (68%). There was a significant curvilinear relation in four (8%), while no significant regression line could be fitted in 12 (24%). In the 34 patients with linear fits, the slopes (mean (SD)) were 0.08 (0.07) in mild, 0.10 (0.04) in moderate, and 0.22 (0.16) in severe aortic stenosis (p = 0. 0055). CONCLUSIONS: Transaortic pressure difference can be related directly to flow in many patients with all grades of aortic stenosis. However, there are individual differences in slope and intercept suggesting that resistance calculated at rest may not always be representative. Raw pressure drop/flow plots may be an alternative method of describing valve function.

Adult↗