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Biomedical subjects

A Advani

Publications and source records attributed to A Advani.

17 recordsLinked to original sources
PubMed2006

Inflammation in cardiovascular disease and regulation of the actin cytoskeleton in inflammatory cells: the actin cytoskeleton as a target.

Cardiovascular disease is prevalent in developed countries causing very large burdens to health services. The underlying pathology is atheromatous plaque in the sub-endothelial region of the vascular wall. High levels of low density lipoprotein cholesterol and high blood pressure cause endothelial damage. Atheroma develop from a response to this injury that is perpetuated to chronic inflammation. The invasion of inflammatory leukocytes into atheroma during its development and in the precipitation of acute thrombotic events is mediated by adhesion molecules on the cell surface. These are regulated by the actin filament cytoskeleton which also mediates intracellular signalling from them. The actin cytoskeleton is central to NADPH oxidase activation that produces superoxide which is an intracellular signalling molecule for the hypertensive and inflammatory actions of angiotensin II. There are polymorphisms in actin filament proteins such as adducin and caldesmon and in the promoter regions of tropomyosins that may cause individual variation in these processes. Many signalling molecules in the actin filament response to inflammatory stimuli and in signalling downstream from actin filaments are small G-proteins that require post-transcriptional modification by isoprenoids from the cholesterol synthetic pathway. Statins deplete the isoprenoids and so down regulate G-proteins that mediate the inflammatory response. Angiotensin converting enzyme inhibitors and angiotensin II receptor type 1 antagonists decrease angiotensin II stimulated superoxide production thus decreasing not only blood pressure but also inflammation. The anti-inflammatory effects of these drugs, involving altered actin filament function, are a major contributor to their benefits in the treatment of cardiovascular disease. The feasibility of modifying the behaviour of actin filament proteins as a therapeutic approach for cardiovascular disease is considered.

Actins↗
PubMed2005

Life-threatening hypokalaemia on a low-carbohydrate diet associated with previously undiagnosed primary hyperaldosteronism [corrected].

BACKGROUND: Low-carbohydrate diets are popular and fashionable for weight loss despite lack of evidence about long-term effects. Many individuals attempting to lose weight have hypertension, especially those with diabetes, and the prevalence of hyperaldosteronism among hypertensive patients is higher than previously recognized. We present a patient with Type 2 diabetes and previously undiagnosed hyperaldosteronism who developed life-threatening hypokalaemia while following a low-carbohydrate diet. CASE REPORT: A 60-year-old man with diet-treated Type 2 diabetes and hypertension presented with generalized muscle weakness and serum potassium of 1.9 mmol/l. He had succeeded in losing three and a half stones during the previous 4 months by adhering strictly to a low-carbohydrate diet. HbA(1c) was 4.8% and plasma aldosterone:renin ratios were elevated suggestive of increased aldosterone secretion. On a low-calorie mixed diet serum potassium levels were maintained in the low-normal range over the following 165 days. The adrenals were normal on CT scanning and blood pressure responded dramatically to the addition of spironolactone on day 212 (125/83 mmHg). CONCLUSIONS: The prevalence of primary hyperaldosteronism in the hypertensive population, based on elevation of plasma renin:aldosterone ratio, is approximately 6%. The majority of these people are normokalaemic and remain undiagnosed. However, when carbohydrate intake is restricted such individuals are at increased risk of potentially life-threatening metabolic derangements.

Aldosterone↗
PubMed2005

Analysis of Bordetella pertussis populations in European countries with different vaccination policies.

Despite the widespread use of pertussis vaccines during the last decades, pertussis has remained an endemic disease with frequent epidemic outbreaks. Currently two types of vaccines are used: whole-cell vaccines (WCVs) and recently developed acellular vaccines (ACVs). The long-term aim of our studies is to assess the effect of different vaccination policies on the population structure of Bordetella pertussis and ultimately on the disease burden in Europe. In the present study, a total of 102 B. pertussis isolates from the period 1998 to 2001 from five European countries (Finland, Sweden, Germany, The Netherlands, and France) were characterized. The isolates were analyzed by typing based on variable number of tandem repeats (VNTR); by sequencing of polymorphic genes encoding the surface proteins pertussis toxin S1 and S3 subunits (ptxA and ptxC), pertactin (prn), and tracheal colonization factor (tcfA); and by fimbrial serotyping. The results reveal a relationship between geographic location and VNTR types, the frequency of the ptxC alleles, and serotypes. We have not observed a relationship between the strain characteristics we studied and vaccination programs. Our results provide a baseline which can be used to reveal changes in the B. pertussis population in Europe in the coming years.

Adolescent↗
PubMed2004

Impaired neutrophil store-mediated calcium entry in Type 2 diabetes.

BACKGROUND: In Type 2 diabetes impaired neutrophil function leads to increased bacterial infection and cardiovascular disease. Many neutrophil functions depend on calcium signalling, which involves release of calcium from intracellular stores and subsequently translocation of stores via the cytoskeleton to the plasma membrane, causing store-mediated calcium entry (SMCE) into the cell. We hypothesized that in Type 2 diabetes there would be a defect in SMCE. MATERIALS AND METHODS: Neutrophils were prepared from patients with Type 2 diabetes (DM, n=15) and controls (NC, n=15). Free cytosolic calcium [Ca2+]i was measured with Fura-2 in resting cells and after stimulation of calcium release with fMLP and thapsigargin. RESULTS: Baseline [Ca2+]i was higher in neutrophils from the patients than the controls (NC 65 +/- 5 nm, DM 80 +/- 4 nm, P<0.05). However, after fMLP-treatment [Ca2+]i was significantly lower in the patients (NC 301 +/- 28 nm, DM 210 +/- 20 nm, P<0.01). The greater increase in controls was not observed when cells were treated with fMLP in the absence of extracellular calcium (-fold increase NC 2.9 +/- 0.5, DM 2.7 +/- 0.3). Treatment of cells with thapsigargin caused a similar greater increase in [Ca2+]i in the controls than in the patients that was not seen in the absence of extracellular calcium (-fold increase with Ca2+ NC 5.2 +/- 1.0, DM 3.0 +/- 0.4, P<0.05; fold increase without Ca2+ NC 2.5 +/- 0.4, DM 2.2 +/- 0.2). CONCLUSIONS: In Type 2 diabetes there is a defect in neutrophil calcium signalling which results in a lesser increase in free cytosolic calcium owing to impaired influx across the plasma membrane. Abnormal calcium signalling is likely to be important in the pathogenesis of diabetic complications.

Calcium↗
PubMed2004

Increasing neutrophil F-actin corrects CD11b exposure in Type 2 diabetes.

BACKGROUND: Leukocyte dysfunction contributes to the pathogenesis of diabetic vascular complications. Neutrophils adhere to the endothelium through the beta(2)integrin CD11b/CD18. In Type 2 diabetes, neutrophil surface CD11b expression is increased and is associated with impaired actin polymerization. This study aimed to determine whether increasing neutrophil actin polymerization could correct the defect in CD11b exposure. DESIGN: Neutrophil actin polymerization was stimulated with the tyrosine phosphatase inhibitor phenylarsine oxide (PAO), and cytoskeletal phosphotyrosine was monitored by immunoblotting Triton X-100 insoluble fractions of cells. Neutrophil F-actin was measured with phalloidin-FITC staining, and surface CD11b expression was determined with anti-CD11b-PE before analysis with flow cytometry. RESULTS: Phenylarsine oxide caused an increase in phosphotyrosine in neutrophils from both patients with Type 2 diabetes (DM) and controls (NC) (-fold increase: NC, 1.43 +/- 0.16; DM, 1.46 +/- 0.10). The response to PAO in terms of phalloidin-binding was impaired in neutrophils from patients [phalloidin-FITC MFI area under the curve, NC 200 +/- 5 (x 10(3)), DM 124 +/- 9 (x 10(3)), P < 0.0001]. Phenylarsine oxide at concentrations < 10 micro mol L(-1) also caused loss of CD11b from neutrophil surfaces that was impaired in samples from patients [CD11b sites area under the curve NC 90 +/- 6 (x 10(3)), DM 121 +/- 9 (x 10(3)), P < 0.002]. However, in neutrophils from patients, incubation with PAO at a concentration of > 10 micro mol L(-1) caused a significant increase in intracellular F-actin and CD11b down-regulation equivalent to that observed in controls. CONCLUSION: In Type 2 diabetes, impaired neutrophil actin polymerization even in response to increasing cytoskeletal phophotyrosine suggests a downstream defect. Furthermore, increasing actin polymerization, above a minimum threshold level, corrects the defect in integrin exposure. Correction of the actin polymerization defect in Type 2 diabetes could improve the prognosis of diabetic vascular complications.

Actins↗
PubMed2004

Evaluating provider adherence in a trial of a guideline-based decision support system for hypertension.

Measurement of provider adherence to a guideline-based decision support system (DSS) presents a number of important challenges. Establishing a causal relationship between the DSS and change in concordance requires consideration of both the primary intention of the guideline and different ways providers attempt to satisfy the guideline. During our work with a guideline-based decision support system for hypertension, ATHENA DSS, we document a number of subtle deviations from the strict hypertension guideline recommendations that ultimately demonstrate provider adherence. We believe that understanding these complexities is crucial to any valid evaluation of provider adherence. We also describe the development of an advisory evaluation engine that automates the interpretation of clinician adherence with the DSS on multiple levels, facilitating the high volume of complex data analysis that is created in a clinical trial of a guideline-based DSS.

Decision Support Systems, Clinical↗
PubMed2002

Impaired neutrophil actin assembly causes persistent CD11b expression and reduced primary granule exocytosis in Type II diabetes.

AIMS/HYPOTHESIS: Neutrophil dysfunction has a role in the pathogenesis of complications in Type II (non-insulin-dependent) diabetes mellitus. Neutrophils adhere through expression of the beta(2)integrin CD11b/CD18 which closely associates with the actin cytoskeleton. The aim of this study was to investigate the effect of actin polymerisation on CD11b expression and exocytosis of the primary granule marker CD69 in neutrophils from patients with Type II diabetes. METHODS: Neutrophils were activated with fMLP or PMA, actin polymerisation was inhibited with cytochalasin D. Cells were stained for CD11b and CD69 expression and intracellular F-actin was measured with phalloidin-FITC. Cellular fluorescence was measured by flow cytometry. Actin content of Triton X-100 fractions of cells was measured by SDS-PAGE and Coomassie blue staining. RESULTS: PMA caused an increase in neutrophil F-actin that was greater in control subjects than in patients with Type II diabetes (50.8% vs 33.4%, p<0.001) and correlated with actin integrated optical density (IOD) by SDS-PAGE ( r=0.74, p=0.01). Loss of CD11b from cell surfaces only occurred in neutrophils with high F-actin. The proportion of cells losing CD11b was lower in patients than in control subjects (23.1% vs 37.5%, p<0.001) and lowest in patients with additional cardiovascular risk markers (20.1% vs 27.7%; p<0.05). Cytochalasin D prevented loss of CD11b ( p<0.001). CD69 expression was reduced in patients with Type II diabetes (22.6% vs 36.4%, p<0.001) and correlated with F-actin content ( r=0.78, p<0.0001). CONCLUSION/INTERPRETATION: In Type II diabetes impaired neutrophil actin polymerisation leads to persistent expression of CD11b and reduced exocytosis of primary granules and could contribute to the pathogenesis of diabetic complications.

Actins↗
PubMed2001

Medical quality assessment by scoring adherence to guideline intentions.

Quality assessment of clinician actions and patient outcomes is a central problem in guideline- or standards-based medical care. In this paper we describe an approach for evaluating and consistently scoring clinician adherence to medical guidelines using the intentions of guideline authors. We present the Quality Indicator Language (QUIL) that may be used to formally specify quality constraints on physician behavior and patient outcomes derived from medical guidelines. We present a modeling and scoring methodology for consistently evaluating multi-step and multi-choice guideline plans based on guideline intentions and their revisions.

Algorithms↗
PubMed2001

Patient safety in guideline-based decision support for hypertension management: ATHENA DSS.

The Institute of Medicine recently issued a landmark report on medical error.1 In the penumbra of this report, every aspect of health care is subject to new scrutiny regarding patient safety. Informatics technology can support patient safety by correcting problems inherent in older technology; however, new information technology can also contribute to new sources of error. We report here a categorization of possible errors that may arise in deploying a system designed to give guideline-based advice on prescribing drugs, an approach to anticipating these errors in an automated guideline system, and design features to minimize errors and thereby maximize patient safety. Our guideline implementation system, based on the EON architecture, provides a framework for a knowledge base that is sufficiently comprehensive to incorporate safety information, and that is easily reviewed and updated by clinician-experts.

Artificial Intelligence↗
PubMed2000

Implementing clinical practice guidelines while taking account of changing evidence: ATHENA DSS, an easily modifiable decision-support system for managing hypertension in primary care.

This paper describes the ATHENA Decision Support System (DSS), which operationalizes guidelines for hypertension using the EON architecture. ATHENA DSS encourages blood pressure control and recommends guideline-concordant choice of drug therapy in relation to comorbid diseases. ATHENA DSS has an easily modifiable knowledge base that specifies eligibility criteria, risk stratification, blood pressure targets, relevant comorbid diseases, guideline-recommended drug classes for patients with comorbid disease, preferred drugs within each drug class, and clinical messages. Because evidence for best management of hypertension evolves continually, ATHENA DSS is designed to allow clinical experts to customize the knowledge base to incorporate new evidence or to reflect local interpretations of guideline ambiguities. Together with its database mediator Athenaeum, ATHENA DSS has physical and logical data independence from the legacy Computerized Patient Record System (CPRS) supplying the patient data, so it can be integrated into a variety of electronic medical record systems.

Artificial Intelligence↗
PubMed1999

Multiple insertions of fimbrial operons correlate with the evolution of Salmonella serovars responsible for human disease.

On centisome 7, Salmonella spp. contain a large region not present in the corresponding region of Escherichia coli. This region is flanked by sequences with significant homology to the E. coli tRNA gene aspV and the hypothetical E. coli open reading frame yafV. The locus consists of a mosaic of differentially acquired inserts forming a dynamic cs7 region of horizontally transferred inserts. Salmonella enterica subspecies I, responsible for most Salmonella infections in warm-blooded animals, carries a fimbrial gene cluster (saf) in this region as well as a regulatory gene (sinR). These genes are flanked by inverted repeats and are inserted in another laterally transferred region present in most members of Salmonella spp. encoding a putative invasin (pagN ). S. enterica subspecies I serovar Typhi, the Salmonella serovar that causes the most severe form of human salmonellosis, contains an additional insert of at least 8 kb in the sinR-pagN intergenic region harbouring a novel fimbrial operon (tcf ) similar to the coo operon encoding the CS1 fimbrial adhesin expressed by human-specific enterotoxigenic E. coli. It is suggested that the multiple insertions of fimbrial genes that have occurred in the cs7 region have contributed to phylogenetic diversity and host adaptation of Salmonella spp.

Chromosome Mapping↗
PubMed1999

Integrating a modern knowledge-based system architecture with a legacy VA database: the ATHENA and EON projects at Stanford.

We present a methodology and database mediator tool for integrating modern knowledge-based systems, such as the Stanford EON architecture for automated guideline-based decision-support, with legacy databases, such as the Veterans Health Information Systems & Technology Architecture (VISTA) systems, which are used nation-wide. Specifically, we discuss designs for database integration in ATHENA, a system for hypertension care based on EON, at the VA Palo Alto Health Care System. We describe a new database mediator that affords the EON system both physical and logical data independence from the legacy VA database. We found that to achieve our design goals, the mediator requires two separate mapping levels and must itself involve a knowledge-based component.

Artificial Intelligence↗
PubMed1998

Intention-based critiquing of guideline-oriented medical care.

We present a methodology and tool for providing retrospective review and critiquing of guideline-based medical care given to patients. We show how our guideline representation language, Asbru, which supports the use of physicians intentions in addition to physician's actions, allows us to compare the care given to a patient at the level of the intention to treat in addition to the more detailed plan carried out. We have developed an algorithm based on this representation for retrospective quality assessment of guideline-based care. Our method takes the physician's and institution's preferences and policies into account in explaining or justifying physician deviations from the recommendations of a guideline.

Algorithms↗
PubMed1990

Different changes in spontaneous field potential oscillations precede epileptiform bursting in hippocampal slices perfused with penicillin or reduced magnesium.

Power spectra were used to analyse spontaneous field potentials (SFPs) recorded in the CA3 distal apical dendritic region of guinea pig hippocampal slices perfused with either penicillin or reduced Mg2+. High concentrations of penicillin (2000 IU/ml) progressively converted the low amplitude, irregular oscillations observed in control medium to higher amplitude, low frequency, rhythmic oscillations at approximately 2-3 Hz just prior to the onset of spontaneous, synchronized bursting. Low concentrations (50-300 IU/ml) increased the power of frequencies below 10 Hz and suppressed higher frequencies in a dose-dependent fashion. Although Mg2(+)-free medium also increased the magnitude of the SFPs prior to the onset of synchronous bursting, the changes were smaller than with penicillin and the frequency distribution was completely different. Low concentrations of Mg2+ (0.0-0.5 mM) increased the power across all frequencies, however, the maximal effect was on frequencies between 5 and 25 Hz. The transition from normal to epileptiform activity may proceed through at least 2 distinct intermediate states. When recurrent inhibition is blocked (penicillin), synchronous synaptic activity precedes the onset of bursting, whereas non-specific increases in excitability and activation of NMDA receptors (reduced Mg2+) produce an asynchronous transition state.

Action Potentials↗
PubMed1990

Corticospinal control of soleus motoneurons in man.

Electrical or magnetic stimulation of the human motor cortex causes a strong, short latency facilitation of tibialis anterior (TA) motoneurons but only weak, longer latency changes in the excitability of soleus (SOL) motoneurons. The facilitation of TA motoneurons has been attributed to the monosynaptic action of the "fast" corticospinal pathway. The present study further investigates the cortical control of soleus motoneurons in man. In tests of reaction time to auditory stimuli, normal subjects took significantly longer to activate soleus motoneurons than tibialis anterior motoneurons. Thus we could not demonstrate the existence of a "fast" pathway from the brain to SOL motoneurons that, for some reason, is not activated by magnetic stimulation. The hypothesis that the cortex might control soleus motoneurons indirectly by modulation of the Ia input from muscle spindles was tested. Magnetic stimulation of the cortex was used to condition the facilitation of soleus motoneurons resulting from the stimulation of group I fibres in the tibial nerve. There were no consistent changes in Ia facilitation. We conclude (i) that there is no evidence so far that SOL motoneurons are excited by a direct pathway from the cortex (similar to that projecting to TA motoneurons) and (ii) that the observed changes in firing probability of soleus motoneurons produced by magnetic stimulation over the motor cortex do not result from modulation of presynaptic inhibition of Ia afferents.

Adolescent↗
PubMed1989

Power spectral analysis of spontaneous field potentials in hippocampal slice.

Spontaneous field potential oscillations were recorded from the CA3 distal apical dendritic region of guinea pig hippocampal slices maintained in 'normal' artificial cerebrospinal fluid in vitro. Power spectral analysis revealed a mixture of frequencies mainly under 20 Hz without distinct peaks. High concentrations of extracellular Mg2+ blocked the activity. These findings suggest that the intrinsic spontaneous activity of the hippocampus is produced by partially synchronized synaptic potentials. This in vitro system may provide a suitable model for studying the mechanisms underlying the generation of EEG rhythms.

Action Potentials↗