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Biomedical subjects

M Stafford-Smith

Publications and source records attributed to M Stafford-Smith.

18 recordsLinked to original sources
PubMed2006

Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.

BACKGROUND: The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. METHODS AND RESULTS: We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). CONCLUSIONS: Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

Aged↗
PubMed2006

Time of day effects on the incidence of anesthetic adverse events.

BACKGROUND: We hypothesized that time of day of surgery would influence the incidence of anesthetic adverse events (AEs). METHODS: Clinical observations reported in a quality improvement database were categorized into different AEs that reflected (1) error, (2) harm, and (3) other AEs (error or harm could not be determined) and were analyzed for effects related to start hour of care. RESULTS: As expected, there were differences in the rate of AEs depending on start hour of care. Compared with a reference start hour of 7 am, other AEs were more frequent for cases starting during the 3 pm and 4 pm hours (p < 0.0001). Post hoc inspection of data revealed that the predicted probability increased from a low of 1.0% at 9 am to a high of 4.2% at 4 pm. The two most common event types (pain management and postoperative nausea and vomiting) may be primary determinants of these effects. CONCLUSIONS: Our results indicate that clinical outcomes may be different for patients anesthetized at the end of the work day compared with the beginning of the day. Although this may result from patient related factors, medical care delivery factors such as case load, fatigue, and care transitions may also be influencing the rate of anesthetic AEs for cases that start in the late afternoon.

Anesthesiology↗
PubMed2005

Genetic factors contribute to bleeding after cardiac surgery.

BACKGROUND: Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter-patient variability poorly explained by clinical, procedural, and biological markers. OBJECTIVE: We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. PATIENTS/METHODS: Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two-way gene-gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. RESULTS: Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T, GPIb alpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). CONCLUSIONS: We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Aged↗
PubMed2005

Neuron specific alpha-adrenergic receptor expression in human cerebellum: implications for emerging cerebellar roles in neurologic disease.

Recent data suggest novel functional roles for cerebellar involvement in a number of neurologic diseases. Function of cerebellar neurons is known to be modulated by norepinephrine and adrenergic receptors. The distribution of adrenergic receptor subtypes has been described in experimental animals, but corroboration of such studies in the human cerebellum, necessary for drug treatment, is still lacking. In the present work we studied cell-specific localizations of alpha1 adrenergic receptor subtype mRNA (alpha 1a, alpha 1b, alpha 1d), and alpha2 adrenergic receptor subtype mRNA (alpha 2a, alpha 2b, alpha 2c) by in situ hybridization on cryostat sections of human cerebellum (cortical layers and dentate nucleus). We observed unique neuron-specific alpha1 adrenergic receptor and alpha2 adrenergic receptor subtype distribution in human cerebellum. The cerebellar cortex expresses mRNA encoding all six alpha adrenergic receptor subtypes, whereas dentate nucleus neurons express all subtype mRNAs, except alpha 2a adrenergic receptor mRNA. All Purkinje cells label strongly for alpha 2a and alpha 2b adrenergic receptor mRNA. Additionally, Purkinje cells of the anterior lobe vermis (lobules I to V) and uvula/tonsil (lobules IX/HIX) express alpha 1a and alpha 2c subtypes, and Purkinje cells in the ansiform lobule (lobule HVII) and uvula/tonsil express alpha 1b and alpha 2c adrenergic receptor subtypes. Basket cells show a strong signal for alpha 1a, moderate signal for alpha 2a and light label for alpha 2b adrenergic receptor mRNA. In stellate cells, besides a strong label of alpha 2a adrenergic receptor mRNA in all and moderate label of alpha 2b message in select stellate cells, the inner stellate cells are also moderately positive for alpha 1b adrenergic receptor mRNA. Granule and Golgi cells express high levels of alpha 2a and alpha 2b adrenergic receptor mRNAs. These data contribute new information regarding specific location of adrenergic receptor subtypes in human cerebellar neurons. We discuss our observations in terms of possible modulatory roles of adrenergic receptor subtypes in cerebellar neurons responding to sensory and autonomic input signals, and review species differences in cerebellar adrenergic receptor expression.

Aged↗
PubMed2001

Report of a substudy on warm versus cold cardiopulmonary bypass: changes in creatinine clearance.

BACKGROUND: Renal dysfunction remains a major complication of cardiac operations. There is concern regarding the possibility of increased renal injury during warm cardiopulmonary bypass (CPB). Therefore, we tested the hypothesis that warm CPB is associated with a greater reduction in creatinine clearance after cardiac surgery than hypothermic CPB. METHODS: We randomly assigned 300 patients who had elective coronary artery bypass grafting to warm (35.5 to 36.5 degrees C) or cold (28 degrees C to 30 degrees C) CPB. Preoperative and peak postoperative serum creatinine values were recorded. Creatinine clearance was estimated using the Cockroft Gault equation. Univariate and multivariable analyses were performed to test the association of CPB temperature and perioperative change in creatinine clearance. RESULTS: Demographic variables were similar between groups. Multivariable analysis did not confirm an association between temperature and change in creatinine clearance (p = 0.87). CONCLUSIONS: We did not confirm an association between warm CPB and increased renal dysfunction after cardiac operations compared with hypothermic CPB.

Aged↗
PubMed2001

Apolipoprotein E polymorphisms and age at first coronary artery bypass graft.

UNLABELLED: Apolipoprotein E (apoE) polymorphisms are heritable determinants of total and low-density lipoprotein cholesterol. The impact of apoE4 genotypes on the severity of atherosclerosis has been debated; however, recent studies have identified a correlation between apoE4 genotype and atherosclerosis. We assessed the impact of apoE4 genotype on age at first coronary artery bypass graft (CABG), hypothesizing that patients with the apoE4 allele are predisposed to coronary artery disease and present earlier for coronary revascularization. We assessed individual apoE genotypes and age in 560 patients undergoing primary CABG, by using analysis of variance (ANOVA) and controlling for gender. Because of the small number of patients in individual genotype groups, we compared patients with one or more copies of the apoE4 allele with those having no copies of the allele, again controlling for gender. A comparison of patients with one or more copies of the apoE4 allele with patients without the allele showed an earlier age at first CABG for those with the allele (P: = 0.032). Gene-dose analysis was also significant (P: = 0.012); patients with two copies of the allele presented at 54.2 +/- 6.9 yr. We report that the apoE4 allele is linked to age at first CABG. Identifying at-risk individuals may help prevent atherosclerosis. Further study is needed to define the mechanism of this association, and to define which coronary intervention is appropriate, based on long-term outcome. IMPLICATIONS: A correlation exists between apolipoprotein E (apoE) genotypes and the severity of atherosclerosis. We hypothesized that patients with the apoE4 allele are predisposed to coronary artery disease and present earlier for coronary artery bypass graft (CABG). Individuals with the apoE4 allele presented earlier for CABG, and the apoE4 allele is linked to age at first CABG.

Age Factors↗
PubMed2000

Off-pump versus on-pump coronary artery bypass surgery and postoperative renal dysfunction.

UNLABELLED: Renal dysfunction is a serious complication after coronary bypass surgery with cardiopulmonary bypass (CABG). Because duration of cardiopulmonary bypass (CPB) is associated with renal outcome, it has been proposed that avoidance of CPB with off-pump coronary bypass (OPCAB) may reduce perioperative renal insult. We therefore tested the hypothesis that OPCAB is associated with less postoperative renal dysfunction compared with CABG surgery. With IRB approval, we gathered data for 690 primary elective coronary bypass patients (OPCAB, 55; CABG, 635). Perioperative change in creatinine clearance (DCrCl) was calculated by using preoperative (CrPre) and peak postoperative (CrPost) serum creatinine values, and the Cockroft-Gault equation (DCrCl = CrPreCl - CrPostCl). Univariate and linear multivariate tests were used in this retrospective analysis; P: < 0.05 was considered significant. Multivariate analysis did not identify OPCAB surgery as an independent predictor of DCrCl. However, previously reported associations of PreCrCl, age, and diabetes with DCrCl were confirmed. Power analysis demonstrated an 80% power to detect a 7.0 mL/min DCrCl difference between study groups. In this retrospective study, we could not confirm that OPCAB significantly reduces perioperative renal dysfunction compared with CABG surgery. Our findings suggest that reduction of renal risk alone should not be an indication for OPCAB over CABG surgery. IMPLICATIONS: Retrospective analysis did not identify any significant difference in perioperative change in creatinine clearance after coronary revascularization with cardiopulmonary bypass compared with off-pump coronary surgery.

Biomarkers↗
PubMed2000

The association of epsilon-aminocaproic acid with postoperative decrease in creatinine clearance in 1502 coronary bypass patients.

UNLABELLED: Renal dysfunction is a common serious complication after cardiac surgery. Reports of proteinuria and hyperkalemia after cardiac surgery with epsilon-aminocaproic acid (EACA) have therefore raised concerns for renal safety. Since EACA renders these markers unreliable, we used perioperative change in creatinine clearance (DCrCl) to test the hypothesis that EACA is associated with greater reductions in creatinine clearance after heart surgery, particularly for patients with renal disease. We evaluated data from all elective primary coronary bypass patients during EACA introduction at our institution (July 1, 1991-December 31, 1992; 10 g iv bolus pre-cardiopulmonary bypass, then 1 g/h for 5 h). DCrCl was calculated using preoperative (CrPre) and postoperative peak serum creatinine values, using the Cockroft-Gault equation. Patients with CrPre > or = 133 micromol/L were also separately analyzed. Evaluated patients (n = 1502, +/-EACA; 581/905, 16 exclusions) included 233 with CrPre > or = 133 micromol/L (+/-EACA; 98/135). Multivariate analyses confirmed several known risk factors, but no association between DCrCl and EACA in all patients (P: = 0.66), and the subgroup with CrPre > or = 133 micromol/L (P: = 0.42). IMPLICATIONS: In a large population of primary Coronary Artery Bypass Graft including a subset with preoperative renal dysfunction, there were no postoperative reductions in creatinine clearance attributable to epsilon-aminocaproic (EACA) administration. This retrospective study suggests that moderate epsilon-aminocaproic acid dosing during cardiac surgery is safe for the kidney; however, this inference is based on a single marker of renal dysfunction and requires prospective confirmation using a variety of tests of renal function.

Aged↗
PubMed2000

Alpha2-adrenergic receptors in human dorsal root ganglia: predominance of alpha2b and alpha2c subtype mRNAs.

BACKGROUND: Nonselective alpha2-adrenergic receptor (alpha2AR) agonists (e.g., clonidine) mediate antinociception in part through alpha2ARs in spinal cord dorsal horn; however, use of these agents for analgesia in humans is limited by unwanted sedation and hypotension. The authors previously demonstrated alpha2a approximately alpha2b > > > alpha2c mRNA in human spinal cord dorsal horn cell bodies. However, because 20% of dorsal horn alpha2ARs derive from cell bodies that reside in the associated dorsal root ganglion (DRG), it is important to evaluate alpha2AR expression in this tissue as well. Therefore, the authors evaluated the hypothesis that alpha2b mRNA, alpha2c mRNA, or both are present in human DRG. METHODS: Molecular approaches were used to determine alpha2AR expression in 28 human DRGs because of low overall receptor mRNA expression and small sample size. After creation of synthetic competitor cDNA and establishment of amplification conditions with parallel efficiencies, competitive reverse transcription polymerase chain reaction was performed using RNA isolated from human DRG. RESULTS: Overall expression of alpha2AR mRNA in DRG is low but reproducible at all spinal levels. alpha2b and alpha2cAR subtype mRNAs predominate (alpha2b approximately alpha2c), accounting for more than 95% of the total alpha2AR mRNA in DRG at all human spinal nerve root levels. CONCLUSIONS: Predominance of alpha2b and alpha2cAR mRNA in human DRG is distinct from alpha2AR mRNA expression in cell bodies originating in human spinal cord dorsal horn, where alpha2a and alpha2b predominate with little or absent alpha2c expression. These findings also highlight species heterogeneity in alpha2AR expression in DRG. If confirmed at a protein level, these findings provide an additional step in unraveling mechanisms involved in complex neural pathways such as those for pain.

Adult↗
PubMed2000

Preliminary report on the association of apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients.

BACKGROUND: Renal dysfunction after cardiac surgery occurs in up to 8% of patients and is associated with major increases in morbidity, mortality, and cost. Genetic polymorphisms have been implicated as a factor in the progression of chronic renal disease, but a genetic basis for the development of acute renal impairment has not been investigated. The authors therefore tested the hypothesis that apolipoprotein E alleles are associated with different postoperative changes in serum creatinine after cardiac surgery. METHODS: The authors performed a prospective observational study with use of data from 564 coronary bypass surgical patients who were enrolled in an ongoing investigation of apolipoprotein E genotypes and organ dysfunction at a university hospital between 1989-1999. Renal function was assessed among apolipoprotein E genotype groups by comparisons of preoperative (CrPre), peak in-hospital postoperative (CrMax) and perioperative change (DCr) in serum creatinine values. RESULTS: The epsilon4 allele grouping (E2 = 2/2,2/3,2/4; E3 = 3/3; E4 = 3/4,4/4) was associated with a smaller increase in postoperative serum creatinine (perioperative change: E4, +0.17; E3, +0.26; E4, +0.27 mg/dl) and a lower peak postoperative creatinine than the epsilon2 and epsilon3 in univariate and multivariate analysis (peak in-hospital postoperative serum creatinine multivariate P = 0.015 vs. epsilon3, P = 0.038 vs. epsilon2). There was no difference in baseline creatinine among allele groups. CONCLUSIONS: Inheritance of the apolipoprotein epsilon4 allele is associated with reduced postoperative increase in serum creatinine after cardiac surgery, compared with the epsilon3 or epsilon2 allele. This is the first report of a possible genetic basis for acute renal impairment. These data may contribute to renal risk stratification for cardiac surgery and raise questions regarding apolipoprotein E and the pathophysiology of acute renal injury.

Acute Disease↗
PubMed1999

Comparison of direct aortic and femoral cannulation for port-access cardiac operations.

BACKGROUND: Differences in outcome after direct aortic cannulation (AORT) in the chest versus standard femoral arterial cannulation (FEM) have not been defined for minimally invasive cardiac operations utilizing the port-access approach. METHODS: A retrospective study was performed of 165 patients undergoing port-access cardiac mitral valve operation (n = 126) or coronary artery bypass grafting (n = 39). In 113 patients, FEM was used, while in 52 patients, AORT was accomplished through a port in the first intercostal space. RESULTS: AORT eliminated endoaortic balloon clamp migration (0/36 [0%] vs. 17/95 [18%]), and groin wound or femoral arterial complications (0/52 [0%] vs. 11/113 [10%]) without changing procedure times (363+/-55 vs. 355+/-70 minutes). Complications attributable to AORT were injury to the right internal mammary artery and aortic cannulation site bleeding in 1 patient each. CONCLUSIONS: Direct aortic cannulation is technically easy, allows use of an endoaortic clamp, and avoids aorto-iliac arterial disease, the groin incision, and possible femoral arterial injury associated with femoral arterial cannulation. Direct arterial cannulation should expand the pool of patients eligible for port-access operation, and may become the standard for port-access procedures.

Adult↗
PubMed1999

Acute renal failure following cardiac surgery.

BACKGROUND: Acute renal failure requiring dialysis (ARF-D) occurs in 1.5% of patients following cardiac surgery, and remains a cause of major morbidity and mortality. While some preoperative risk factors have been characterized, the influence of preoperative and intraoperative factors on the occurrence of ARF following cardiac surgery is less well understood. METHODS: Preoperative and intraoperative data on 2843 consecutive adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) from February 1, 1995 to February 1, 1997 were recorded and entered into a computerized database. Two definitions of renal failure were employed: (i) ARF defined as a rise in serum creatinine (Cr) of 1 mg/dl above baseline; and (ii) ARF-D defined as the development of ARF for which some form of dialytic therapy was required. The association between preoperative and intraoperative variables and the development of ARF was assessed by multivariate logistic regression. RESULTS: A total of 2672 of the 2844 patients underwent isolated coronary artery bypass grafting (CABG) surgery, the remaining 172 underwent valve surgery with or without bypass grafting. Of the CABG patients 7.9% developed ARF and 0.7% developed ARF-D. The mortality for patients who developed ARF was 14% (OR 15, P = 0.0001) compared with 1% among those who did not develop ARF. The mortality for CABG patients who developed ARF-D was 28% (OR 20, P = 0.0001) compared with 1.8% among those who did not require dialysis. Variables that were significantly associated with the development of ARF by multivariate analysis included: increased age, elevated preoperative serum Cr, duration of CPB, presence of a carotid artery bruit, presence of diabetes, reduced cardiac ejection fraction and increased body weight. Variables independently associated with ARF-D included serum Cr, duration of CPB, carotid artery bruit and presence of diabetes. The utility of these models for predicting the development of ARF and ARF-D was confirmed by bootstrapping techniques. Because of the small number of patients who underwent valve surgery, none of these variables were significantly associated with the development of ARF or ARF-D in this group of patients. CONCLUSION: The development of ARF or ARF-D is associated with a high mortality following CABG surgery. We have identified perioperative variables, which may be useful in stratifying risk for the development of ARF.

Acute Kidney Injury↗
PubMed1998

Mitral valve operation via Port Access versus median sternotomy.

OBJECTIVE: The advantages and disadvantages of minimally invasive Port Access mitral valve operation have not been defined relative to standard median sternotomy. A study was therefore designed to delineate differences in outcome from mitral operation via Port Access versus sternotomy in comparable patients. METHODS: The records of 41 consecutive patients undergoing isolated mitral valve replacement (n = 14) or repair (n = 27) were examined. All operations were performed using cardioplegic arrest through either median sternotomy (n = 20) or a small right anterolateral thoracotomy using an endoaortic clamp and catheter system (Heartport, Redwood City, CA) to arrest and decompress the heart (Port Access, n = 21). RESULTS: Both groups were well matched for age, mitral pathology, ejection fraction, and comorbidity. except that Port Access patients were less likely to be female. Three patients had undergone previous cardiac operations. Surgical procedure time was longer for Port Access patients (384+/-80 vs. 263+/-41 min, P < 0.05). Port Access provided significantly smaller incision length (8+/-2 vs. 26+/-2 cm, P < 0.01) and similar or shorter hospital stay (6+/-4 vs. 7+/-3 days). Port Access provided excellent visualization of the mitral valve and subvalvular apparatus, generally better than sternotomy, to allow complex mitral valve repairs. The greatest advantage of Port Access mitral operation was that Port Access patients returned to normal activity more rapidly (4+/-2 vs. 9+/-1 weeks, P = 0.01) than did patients undergoing standard median sternotomy. CONCLUSIONS: By avoiding a sternotomy, Port Access mitral valve operation provided a smaller incision and a dramatically more rapid return to normal activity than did median sternotomy. Port Access cardioplegic arrest with the Heartport system allowed visualization of the mitral valve superior to median sternotomy and has become the standard approach at this institution.

Case-Control Studies↗
PubMedDate not supplied

Central nervous system serotonin function and cardiovascular responses to stress.

OBJECTIVE: The objective of this study was to evaluate the impact of indices of central nervous system (CNS) serotonin function on cardiovascular reactivity to mental stress. METHODS: Lumbar puncture was performed on 54 healthy volunteers to obtain cerebrospinal fluid (CSF) for determination of 5-hydroxyindoleacetic acid (5HIAA) levels. Genotypes were determined with respect to a functional polymorphism of the serotonin transporter gene promoter region (5HTTLPR). Subjects then underwent mental stress testing. RESULTS: Persons with one or two long (l) 5HTTLPR alleles had CSF levels of the major serotonin metabolite, 5HIAA, that were 50% higher than those of persons with the s/s 5HTTLPR genotype. Persons with one or two l alleles or higher CSF 5HIAA levels also exhibited greater blood pressure and heart rate responses to a mental stress protocol. CONCLUSIONS: These findings suggest the 5HTTLPR polymorphism affects CNS serotonin function, and they are consistent with the general hypothesis that CNS serotonin function is involved in the regulation of potentially health-damaging biobehavioral characteristics. In particular, the l allele could contribute, through its association with increased cardiovascular reactivity to stress, to increased risk of cardiovascular disease.

Adult↗