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Biomedical subjects

A F Doubell

Publications and source records attributed to A F Doubell.

At least 19 recordsLinked to original sources
PubMed2006

The role of histopathology in establishing the diagnosis of tuberculous pericardial effusions in the presence of HIV.

AIMS: To establish the influence of human immunodeficiency virus (HIV) infection on the histopathological features of patients presenting with tuberculous pericarditis. METHODS AND RESULTS: A prospective study was carried out at Tygerberg Academic Hospital, South Africa; 36 patients with large pericardial effusions had open pericardial biopsies under general anaesthesia and were included in the study. Patients underwent pericardiocentesis, followed by daily intermittent catheter drainage; a comprehensive diagnostic work-up (including histopathology of the pericardial tissue) was also performed. Histological tuberculous pericarditis was diagnosed according to predetermined criteria. Tuberculous pericarditis was identified in 25 patients, five of whom were HIV+. The presence of granulomatous inflammation (with or without necrosis) and/or Ziehl-Neelsen positivity yielded the best test results (sensitivity 64%, specificity 100% and diagnostic efficiency 75%). CONCLUSIONS: Co-infection with HIV impacts on the histopathological features of pericardial tuberculosis and leads to a decrease in the sensitivity of the test. In areas which have a high prevalence of tuberculosis, the combination of a sensitive test such as adenosine deaminase, chest X-ray and clinical features has a higher diagnostic efficiency than pericardial biopsy in diagnosing tuberculous pericarditis.

AIDS-Related Opportunistic Infections↗
PubMed2005

Epidemiology of pericardial effusions at a large academic hospital in South Africa.

The aim was to establish the prevalence of large pericardial effusions in the Western Cape Province of South Africa, and to determine the incidence of various types of effusions. A total of 233 patients presented with large pericardial effusions. Each patient underwent tests for HIV, sputum smear and culture, blood culture, blood biochemistry and serological testing. Tuberculous pericardial effusions were diagnosed according to pre-determined criteria. Eighty-four patients (36.1%) were found to be HIV positive; 81 of these (96.4 %) had tuberculous pericarditis. More than 65% of the study population was aged between 15 and 39 years. The prevalence of HIV amongst unemployed individuals was 49.0% compared to 30.0% amongst employed individuals. Tuberculous pericarditis was the most common cause of pericardial effusions (69.5%, n=162). It was concluded that tuberculosis (TB) is a leading cause of pericarditis in this province of South Africa. The prevalence of TB confounded by HIV co-infection is steadily increasing, burdening the health-care facilities.

Adolescent↗
PubMed2005

Large pericardial effusions due to systemic lupus erythematosus: a report of eight cases.

The aim of this study was to describe the clinical, echocardiographic and laboratory characteristics of large pericardial effusions and cardiac tamponade secondary to systemic lupus erythematosus (SLE). An ongoing prospective study was conducted at Tygerberg Academic Hospital, South Africa between 1996 and 2002. All patients older than 13 years presenting with large pericardial effusions (> 10 mm) requiring pericardiocentesis were included. Eight cases (out of 258) were diagnosed with SLE. The mean (SD) age was 29.5 (10.7) years. Common clinical features were Raynaud's phenomenon, arthralgia and lupus nephritis class III/IV. Echocardiography showed Libman-Sacks endocarditis (LSE) in all the mitral valves. Two patients developed transient left ventricular dysfunction; both these patients had pancarditis. Typical serological findings included antinuclear antibodies, anti-double stranded DNA antibodies, low complement C4 levels and low C3 levels. CRP was elevated in six cases. Treatment consisted of oral steroids and complete drainage of the pericardial effusions. No repeat pericardial effusions or constrictive pericarditis developed amongst the survivors (3.1 years follow up). This study concludes that large pericardial effusions due to SLE are rare, and associated with nephritis, LSE and myocardial dysfunction. Treatment with steroids and complete drainage is associated with a good cardiac outcome.

Adolescent↗
PubMed2003

Infective endocarditis in the Western Cape Province of South Africa: a three-year prospective study.

BACKGROUND: The last 50 years have seen major changes in the epidemiology of infective endocarditis (IE). AIM: To evaluate local patient characteristics, risk factors, clinical sequelae, microbiology, morbidity and mortality in patients with definite IE. DESIGN: Prospective observational study. METHODS: Over a three-year period, patients referred with probable IE were prospectively enrolled. All received a standardized diagnostic evaluation. Epidemiological data were documented; underlying risk factors for IE were sought. Initial evaluation and follow-up (to 6 months) included the documentation of vascular or immunological phenomena, morbidity and mortality. RESULTS: Of 92 patients referred with probable IE, 47 had definite IE. These patients had a mean age of 37.7 years with a male predominance (1.6:1). Rheumatic heart disease was present in 36 (76.6%). Eight had prosthetic valves. Three had congenital heart disease, mitral valve prolapse or multiple central intravascular catheters, respectively. All denied the use of intravenous recreational drugs and only one tested seropositive for HIV. Renal involvement (59.6%) and clubbing (29.8%) were commonly observed. The 6-month mortality rate was 35.6%, while 44.7% needed valvular replacement. An aetiological diagnosis was made in 21, with viridans streptococci the most common isolate. DISCUSSION: Infective endocarditis in the Western Cape of South Africa is a disease of younger adults, with a male predominance. Rheumatic heart disease is the major predisposing factor. Degenerative heart disease and intravenous drug abuse are not important risk factors. Our data do not support the notion that HIV infection is an independent risk factor for IE. Local mortality rates are much higher than recent international figures, as is the proportion of 'culture-negative' IE.

Adult↗
PubMed2002

Cytokine production in patients with tuberculous pericarditis.

SETTING: An academic hospital in the Western Cape, South Africa. OBJECTIVE: To evaluate cytokine production (interferon-gamma [IFN-gamma], interleukin-1 [IL-1], interleukin-2 [IL-2], interleukin-6 [IL-6], interleukin-10 [IL-10], interleukin-4 [IL-4] and tumour necrosis factor-alpha [TNF-alpha]) in patients with tuberculous pericarditis. DESIGN: Subpopulation of a consecutive prospective case series. PATIENTS: Thirty patients presenting with pericardial effusions due to tuberculosis (n = 19), malignancy (n = 6) and non-tuberculous infections (n = 5), and five control subjects who had undergone open heart surgery. RESULTS: The concentration of IFN-gamma was significantly higher in tuberculous pericardial effusions than in the other diagnostic classes (P < 0.0005). The concentration of TNF-alpha was similar in both infective and tuberculous effusions, but was significantly higher than that of malignant effusions. IL-1 and IL-2 were undetectable in malignant effusions, but elevated in both infective and tuberculous pericardial effusions. The levels of IL-1 and IL-2 were furthermore significantly higher in pericardial effusions due to infective compared to tuberculous causes. The concentration of IL-6, while elevated in all diagnostic classes, was significantly higher in the malignant group. Elevated levels of IL-10 and undetectable levels of IL-4 were observed in all three diagnostic groups. CONCLUSION: These findings suggest that tuberculous pericardial effusions arise due to a hypersensitivity reaction that is orchestrated by the TH-1 lymphocytes.

Adult↗
PubMed2001

Pregnancy outcome in women with prosthetic heart valves.

The pregnancy outcome of 59 pregnancies in 38 women with prosthetic heart valves, managed at a tertiary referral centre from 1989-98 were reviewed. Ten women underwent valve replacement during pregnancy. The main outcome measures were major maternal complications and perinatal outcome. The maternal mortality rate for pregnancies following valve replacement surgery was 6.1%, with a 21% pregnancy loss before viability and a perinatal loss of 8%. Major morbidity in this group was as follows: haemorrhage 29.8%, cardiac failure 12.8%, thromboembolism 8.5%, infective endocarditis 6.4% and valve thrombosis 4.3%. No maternal mortality occurred among those who underwent valve replacement during pregnancy but their perinatal loss was 25%. We conclude that although maternal mortality and morbidity rates in women with prosthetic heart valves who became pregnant were high, the perinatal outcome was good except for women who underwent valve replacement during pregnancy who experienced a high perinatal loss rate.

Journal Article↗
PubMed1994

Identification of a calcium dependent atrial secretory binding protein as calmodulin.

OBJECTIVE: The role of calcium in the regulation of atrial natriuretic factor (ANF) secretion has focused attention on calcium binding proteins as regulatory components of the secretory machinery for ANF. Two members of the annexin family of calcium binding proteins have emerged as candidates for this role. The aim of this paper is to report the isolation, purification, and identification of another calcium dependent atrial secretory granule binding protein. METHODS: A 20 kDa calcium binding protein was isolated from rat cardiac tissue by affinity chromatography and purified by ion exchange high pressure liquid chromatography followed by reverse phase high pressure liquid chromatography. Identification of the protein was based on its electrophoretic mobility, chromatographic properties, amino acid composition, and ability to stimulate the activity of calmodulin dependent phosphodiesterase. RESULTS: Analysis of this protein and its interaction with atrial secretory granules revealed that it was identical to calmodulin and that the calcium dependent interaction with atrial secretory granules takes place at physiological calcium concentrations. CONCLUSIONS: The study identifies calmodulin as a calcium dependent atrial secretory binding protein. The interaction of calmodulin with atrial secretory granules at physiological calcium concentrations suggest a possible role for calmodulin in the regulation of ANF release from the secretory granules.

Animals↗
PubMed1994

Calcium is involved in both positive and negative modulation of the secretory system for ANP.

The calcium dependence of the atrial natriuretic peptide (ANP) secretory system is controversial. Some studies clearly support a stimulatory role, whereas others favor an inhibitory role for calcium in this endocrine system. We demonstrate that calcium is involved in both a positive modulatory role and a negative modulatory role, thereby providing some explanation for the seemingly irreconcilable findings previously published. The negative modulatory role performed by calcium is evident during basal secretion, whereas the positive modulatory role is especially evident in the sustained phase of the secretory response to stimulation. Furthermore, we demonstrate the calcium dependence of processing of the prohormone to the mature circulating form in a cell culture system. This supports the concept that processing is a function of the atrial myocyte rather than of the mesenchymal cells of the atrium. We have demonstrated previously that calcium is important for packaging of the prohormone into secretory granules. Together these findings support a multifaceted role for calcium in the regulation of the secretory apparatus for ANP.

Animals↗
PubMed1994

Endothelin-stimulated secretion of natriuretic peptides by rat atrial myocytes is mediated by endothelin A receptors.

Endothelin (ET), a potent vasoconstrictor peptide, is known to enhance the secretion of atrial natriuretic factor (ANF) by the heart. In the present study, we investigated the potency of ET isopeptides to stimulate ANF and brain natriuretic peptide (BNP) secretion in primary cultures of neonatal atrial myocytes, and we characterized the receptor mediating these effects. All ET isopeptides caused a twofold increase of ANF and BNP secretion with the following order of potency: ET-1 approximately ET-2 > sarafotoxin 6b >> ET-3. Secretion of the natriuretic peptides was blocked by BQ-123, an ETA-receptor antagonist, but was not affected by either IRL-1620 or [Ala1,3,11,15]ET-1, two ETB-receptor agonists. ET receptors were localized by autoradiography on the surface of atrial myocytes, indicating that contaminating cells were not responsible for 125I-ET-1 binding. Competition binding analyses were then used to assess the ET-receptor subtype on atrial myocyte membrane preparations. A high-affinity (100 pmol/L) binding site with high density (approximately 1500 fmol/mg) was found to preferentially bind the ET isopeptides in the following order: ET-1 > or = ET-2 > or = sarafotoxin 6b > ET-3. Binding was totally displaced by BQ-123 but not by IRL-1620. The ET binding site therefore had the characteristics of an ETA-like receptor. Analysis by cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that it possessed a molecular mass of approximately 50 kD. Northern blot analysis of both ETA- and ETB-receptor mRNAs allowed only the detection of the former, indicating that the ETB receptor may be expressed in very small amounts. These results demonstrate that ANF and BNP secretion by atrial myocytes is enhanced by ET via binding to an ETA-like receptor.

Animals↗
PubMed1993

Identification and immunolocalisation of annexins V and VI, the major cardiac annexins, in rat heart.

OBJECTIVE: The heart contains proteins of the annexin family, a unique group of calcium binding proteins. This study was aimed at identifying the major cardiac annexins and determining their distribution in the rat heart. METHODS: Annexins were isolated by affinity chromatography and purified by ion exchange high pressure liquid chromatography. Identification of isolated proteins by immunoblotting was confirmed by partial amino acid sequence determination. Antisera raised against the isolated proteins were used for immunohistochemistry by the avidin-biotin-peroxidase technique. RESULTS: Two annexins were isolated and purified. Amino acid sequencing confirmed their identities as annexin V and VI. Immunohistochemistry showed that both annexins were present in cardiac myocytes and non-myocytes, but a distinct pattern of distribution was seen for each annexin. Annexin V immunoreactivity was enhanced in the atria compared with the ventricles, whereas annexin VI was more uniformly distributed. In individual cardiac myocytes annexin V was distributed throughout the cell by contrast with annexin VI, which localised to the sarcolemma. Intercalated discs displayed immunoreactivity for both annexins, most prominently for annexin VI. The most striking immunoreactivity for annexin V occurred in vascular endothelial cells, both in the microcirculation and in the major coronary vessels. Immunoreactivity for annexin VI in vascular structures was localised to the nuclei of endothelial and smooth muscle cells. CONCLUSIONS: Annexins V and VI are the major cardiac annexins. The localisation of these annexins to different components of cardiac myocytes will serve to direct the search for their functions in the heart. The striking immunoreactivity for annexins, particularly annexin V, in the coronary vessels indicates that the functions of cardiac annexins include a role in the coronary circulatory system.

Amino Acid Sequence↗
PubMed1992

Binding and aggregation of pro-atrial natriuretic factor by calcium.

Analysis of atrial secretory granule content by sodium dodecyl sulfate-gel electrophoresis followed by a 45Ca2+ overlay assay indicates that a 17,000 protein binds 45Ca2+. This protein, which can be immunostained by atrial natriuretic factor (ANF) antiserum, corresponds to proANF. Ca2+ binding is proportional to the amount of proANF and pH dependent. Generation of ANF-(1-98) by thrombin digestion of proANF does not affect Ca2+ binding. Blocking the carboxyl groups of proANF and the use of NH2-terminal fragments bearing those carboxyl groups demonstrated that the Ca(2+)-interaction site is probably located within the highly acidic portion (11-30) of the propeptide. Ca2+ binding to proANF induces its aggregation that can be verified by sedimentation. ProANF aggregation is Ca2+ dependent, being optimal at 10 mM, partially pH dependent, and greatly increased by high concentrations of proANF. However, because of its relatively low-binding affinity, Ca2+ can be substituted by other divalent cations such as Sr2+, Ba2+, or Mg2+. The high level of Ca2+ in atrial secretory granules and the aggregation of proANF in the presence of Ca2+ suggest a possible involvement of these physicochemical properties in the condensed state of the matrix of secretory granules. Indeed, detergent solubilization of the membrane of the secretory granules in presence of Ca2+ resulted only in a partial dissolution of the dense core matrix. We therefore postulate that, in the Golgi complex, proANF and Ca2+ associate to form a condensed aggregate that helps package secretory material into secretory vesicles.

Animals↗
PubMed1991

Annexins V and VI: major calcium-dependent atrial secretory granule-binding proteins.

Atrial natriuretic peptide is stored by atrial myocytes in secretory granules, known as atrial specific granules, and is released from these granules by exocytosis. We have isolated a group of atrial proteins by affinity chromatography that bind to atrial specific granules in a calcium-dependent manner. The two major proteins isolated (32.5 kd and 67 kd) are calcium-binding proteins and have been identified as annexins V and VI by immunoblotting with specific antisera. The calcium dependence of their binding to atrial specific granules has been characterized in vitro and indicates that this interaction takes place at micromolar levels of calcium. In addition, the group of proteins isolated includes another calcium-binding protein of 20 kd, as well as GTP-binding proteins of 22 to 26 kd. Membrane interactions during exocytosis are presumably mediated by the interaction of specific proteins with the granule membrane. The properties of the proteins described here, and their ability to bind to atrial specific granules in a calcium-dependent manner, make them likely candidates in the search for regulatory proteins mediating atrial natriuretic peptide secretion.

Animals↗
PubMed1990

Electron microscopic analysis of the specific granule content of human atria. An investigation of the role of atrial pressure and atrial rhythm in the release of atrial natriuretic peptide.

Knowledge about the stimulus for the release of atrial natriuretic peptide (ANP) from human atria is incomplete. Atrial stretch is known to be a stimulus and atrial tachyarrhythmias are thought to be another. The effects of atrial size (by two-dimensional echocardiography) and atrial fibrillation on the atrial specific granule content of human atria were studied to gain insight into the secretory mechanisms of ANP. An electron microscopic analysis of the atrial granule content was used to study 12 patients--5 with mitral stenosis and sinus rhythm, 3 with mitral stenosis and atrial fibrillation and 4 controls. Granules were counted using a free count and montage method. This is the first report of such a morphometric analysis in humans. Granule counts were significantly raised in the patients with mitral stenosis compared with controls (P less than 0.014). This observation probably reflects a high turnover state induced by elevated atrial pressures. Further support for this conclusion is provided by the demonstration of a positive correlation between granule counts and left atrial size (r = 0.86; P less than 0.01). The tendency for higher counts in patients with atrial fibrillation may be related to the rhythm disturbance itself, but clinical and echocardiographic data suggest more severe atrial pressure overload in this group.

Adult↗
PubMed1989

The effect of calcium antagonists on atrial natriuretic peptide (ANP) release from the rat heart during rapid cardiac pacing.

The diuresis associated with rapid atrial rhythms is a well recognized clinical entity (Wood, 1963). Atrial natriuretic peptide (ANP) levels are elevated during rapid atrial rhythms (Hirata et al., 1987), including during rapid atrial pacing (Rankin et al., 1986; Schiebinger and Linden 1986; Walsh et al., 1987), and may contribute to the associated diuresis. Calcium channel antagonists are often used to treat atrial tachycardias but the effect this may have on ANP secretion and subsequent compensatory responses, such as a diuresis, is unknown. Reported here are experiments demonstrating that the increase in ANP secretion that accompanies rapid atrial pacing of the isolated perfused rat heart is abolished by calcium channel antagonists. This effect is not limited to a single class of calcium channel antagonists and could be demonstrated with Verapamil and Nifedipine. Although extrapolation to the in vivo situation should always be done with care, the results reported here contribute towards clarifying the effect of the calcium channel antagonists on the ANP response to rapid heart rates.

Animals↗
PubMed1989

The second messenger system(s) mediating the secretion of atrial natriuretic peptide (ANP) from the isolated rat heart during rapid cardiac pacing.

This study demonstrates that rapid cardiac pacing elevates Atrial Natriuretic Peptide (ANP) levels, independently from atrial stretch. The second messenger system mediating this response was examined. The phosphoinositide system, generally regarded to be important in mediating ANP release, was shown to play only a modulating role during rapid cardiac pacing. The main mediator would appear to be calcium, and a non-calmodulin dependent, calcium mediated system controlling ANP release during rapid cardiac pacing is suggested.

Animals↗
PubMedDate not supplied

Mitogen-activated protein kinase (MAPK) in cardiac tissues.

Mitogen-activated protein kinase (MAPK) has recently emerged as a prominent role player in intracellular signalling in the ventricular myocyte with attention being focussed on its possible role in the development of ventricular hypertrophy. It is becoming clear that MAPK is also active in other cells of cardiac origin such as cardiac fibroblasts and possible functions of this signalling pathway in the heart have yet to be explored. In this report the mammalian MAPK pathway is briefly outlined, before reviewing current knowledge of the MAPK pathway in cardiac tissue (ventricular myocytes, vascular smooth muscle cells and cardiac fibroblasts). New data is also presented on the presence and activity of MAPK in two additional cardiac celltypes namely atrial myocytes and vascular endothelial cells from the coronary microcirculation.

Amino Acid Sequence↗
PubMedDate not supplied

Twelve-lead electrocardiography in tuberculous pericarditis.

OBJECTIVES: This study is part of an ongoing initiative started in 1995 to investigate the therapeutic efficacy of adjuvant corticosteroids in the management of tuberculosis (TB) pericarditis. In this retrospective, descriptive study we describe the changes found on the 12-lead electrocardiogram (ECG) in patients with TB pericarditis, with and without cardiac tamponade. We determined the diagnostic accuracy of ECG parameters for cardiac tamponade. METHODS: All patients referred to our department with echocardiographically confirmed large pericardial effusions underwent a thorough clinical assessment followed by pericardiocentesis and drainage using an indwelling pigtail catheter. The amount of drained effusion was measured, and fluid was sent for diagnostic assessment. Patients were grouped into those with or without cardiac tamponade. The following ECG parameters were assessed: rate, rhythm, microvoltage, electrical alternans, PR segment and ST segment abnormalities. RESULTS: Of the 157 patients assessed, 88 were diagnosed with TB pericarditis All had abnormal ECGs and 83% had changes of chronic pericarditis. Microvoltage in the extremity and/or precordial leads correlated with the presence of large effusions (> 750 ml). None of the studied parameters correlated with the presence of cardiac tamponade. CONCLUSIONS: Twelve-lead ECG is of supportive but not diagnostic value in cardiac tamponade. The presence of microvoltage suggests the presence of a large effusion. The absence of microvoltage makes the presence of cardiac tamponade unlikely.

Cardiac Tamponade↗