Biomedical subjects
Publications and source records attributed to J Chambers.
Mitral valve disease remains common, and requires regular clinical and echocardiographic review. Surgery is indicated soon after the development of symptoms or at the first sign of left ventricular decompensation in mitral regurgitation or of the right ventricle in mitral stenosis.
The aim of this study was to determine the incidence of echocardiographically detectable patent foramen ovale (PFO) in elderly patients who have strokes from cerebral infarction, as well as to assess the association between PFOs and other risk factors for stroke disease. Forty-three patients aged > or = 65 years admitted consecutively with cerebral infarction shown on computerised tomography of the brain were assessed using transoesophageal echocardiography. A PFO was present in 8 (19%) of the 43 patients. Four patients (50%) in this PFO group had stroke risk factors. Two were in atrial fibrillation and, of the six patients in sinus rhythm, a risk factor was present in two, both of whom had diabetes mellitus. A PFO was not detected in 35 patients. Twenty-nine (83%) of the patients in this group had risk factors, with 18 having two or more. Seven patients were in atrial fibrillation. Of the 28 patients in sinus rhythm, risk factors were present in 22 (78%).
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The biological actions of extracellular nucleotides are mediated by two distinct classes of P2 receptor, P2X and P2Y. The G protein-coupled P2Y receptors comprise five mammalian subtypes, P2Y(1-11). The P2Y1 subtype is expressed abundantly throughout the human brain and is specifically localized to neuronal structures. In the present study, the distribution of the P2Y1 receptor was investigated in Alzheimer's disease (AD) brains. In contrast to control human brain, the P2Y1 receptor was localized to a number of characteristic AD structures such as neurofibrillary tangles, neuritic plaques and neuropil threads. Immunoblot analysis showed that this specific immunostaining observed over tangles was not a result of cross-reactivity between the anti-P2Y1 antiserum and abnormal tau protein, the major constituent of tangles. The significance of this altered P2Y1 cellular distribution in AD brains is at present unclear.
The biological actions of extracellular nucleotides are exerted via two families of P2 receptors, P2X and P2Y. The metabotropic P2Y receptors comprise at least 7 distinct subtypes, which have been cloned from a number of species. However, none of the P2Y receptor proteins have been visualised yet in human brain. In the present study, the regional and cellular distribution of the P2Y(1) receptor was investigated in the human brain by using immunohistochemistry. Polyclonal antibodies were raised against a synthetic peptide from the C-terminus of the P2Y(1) protein. Immunoblot analysis demonstrated that P2Y(1) antiserum specifically recognised a 63-kDa band in human and rat brain membranes. Similarly, the antiserum specifically detected the human P2Y(1) receptor in transfected 1321N1 cells. Immunohistochemical analysis on perfusion-fixed human brain tissue showed a widespread distribution for this receptor throughout the brain. At the cellular level, the P2Y(1) receptor was strikingly localised to neuronal structures of the cerebral cortex, cerebellar cortex, hippocampus, caudate nucleus, putamen, globus pallidus, subthalamic nucleus, red nucleus, and midbrain. Expression of the P2Y(1) receptor was not detected in other non-neuronal cell types. These results provide the first characterisation of the cellular distribution of a P2Y receptor in the human brain. The widespread and abundant distribution of the P2Y(1) receptor suggests its involvement in a number of important functions within the human brain. The neuronal localisation of this receptor points towards a possible role in neurotransmission, and also highlights a major role for extracellular nucleotides as signaling molecules within the brain.
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with serious consequences for the mother and fetus. Two pedigrees have been reported with ICP in the mothers of children with a subtype of autosomal recessive progressive familial intrahepatic cholestasis (PFIC) with raised serum gamma-glutamyl transpeptidase (gamma-GT). Affected children have homozygous mutations in the MDR3 gene (also called ABCB4 ), and heterozygous mothers have ICP. More frequently, however, ICP occurs in women with no known family history of PFIC and the genetic basis of this disorder is unknown. We investigated eight women with ICP and raised serum gamma-GT, but with no known family history of PFIC. DNA sequence analysis revealed a C to A transversion in codon 546 in exon 14 of MDR3 in one patient, which results in the missense substitution of the wild-type alanine with an aspartic acid. We performed functional studies of this mutation introduced into MDR1, a closely related homologue of MDR3. Fluorescence activated cell sorting (FACS) and western analysis indicated that this missense mutation causes disruption of protein trafficking with a subsequent lack of functional protein at the cell surface. The demonstration of a heterozygous missense mutation in the MDR3 gene in a patient with ICP with no known family history of PFIC, analysed by functional studies, is a novel finding. This shows that MDR3 mutations are responsible for the additional phenotype of ICP in a subgroup of women with raised gamma-GT.
BACKGROUND: Social capital describes the notion that the social processes in an area can lead to benefits in health. As Super Profiles describe the social character of an area and they are easy for health authorities to use, they could provide a simple method for local assessment of how social organization affects health. METHODS: We calculated the expected mean birthweight for the enumeration districts of Birmingham based upon marital status, registration details of the child, year of birth, the mother's country of birth, fetal sex and deprivation as judged by the Townsend score using data from 138,696 live-born singleton births for the years 1986-1996 inclusive. We classified enumeration districts into Target Markets, derived from Super Profiles. For each Target Market, we calculated the observed mean birthweight and the difference and 95 per cent confidence interval between the observed and expected birthweights. We used information in Super Profiles to speculate about the social processes that led to some Target Markets having mean birthweights that were significantly different from those expected. RESULTS: Fifteen of the 40 Target Markets had significant differences between predicted and observed mean birthweight, but these differences were less than 50 g. There were no common characteristics of Target Markets that were consistently advantageous for birthweight and none that were disadvantageous. CONCLUSION: The information in the Super Profiles does not illuminate the way that social processes affect health, and the variation in mean birthweight between areas explained by social processes as measured by Super Profiles is small.
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.
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.
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.
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.
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.
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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.
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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.
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.
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