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Biomedical subjects

James Kennedy

Publications and source records attributed to James Kennedy.

At least 19 recordsLinked to original sources
PubMed2007

Novel 5-HTTLPR allele associates with higher serotonin transporter binding in putamen: a [(11)C] DASB positron emission tomography study.

BACKGROUND: The serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR) has two frequent alleles, designated long (L), and short (S). The S allele is associated with lower levels of 5-HTT mRNA and lower 5-HTT expression in human cell lines. A functional single nucleotide variant was detected within L, designated L(A) and L(G). Only L(A) is associated with high levels of in vitro 5-HTT expression, whereas L(G) is low expressing and more similar to S. We examined the possible influence of the long (A/G) variant on 5-HTT density in the living human brain using 3-(11)C-amino-4-(2-dimethylaminomethylphenyl-sulfanyl) benzonitrile ([(11)C]DASB) positron emission tomography. METHODS: The 5-HTT binding potential (5-HTT BP), an index of 5-HTT density, was found in 43 healthy subjects genotyped for 5-HTTLPR long (A/G), and in an ethnically homogenous subsample of 30 Caucasian-Canadians. RESULTS: The L(A)/L(A) was associated with higher 5-HTT BP in putamen (p = .026, not corrected). This association became stronger in the Caucasian subsample (p = .004) and was significant even after correcting for multiple comparisons. CONCLUSIONS: The 5-HTTLPR long (A/G) polymorphism influences 5-HTT density leading to higher putamen 5-HTT BP in healthy L(A)/L(A) carriers of Caucasian ancestry. This finding extends the role of this polymorphism from in vitro reports of higher 5-HTT expression with the L(A)/L(A) genotype into in vivo brains of healthy human subjects.

Alleles↗
PubMed2007

Lead and mercury exposures: interpretation and action.

Lead and mercury are naturally occurring elements in the earth's crust and are common environmental contaminants. Because people concerned about possible exposures to these elements often seek advice from their physicians, clinicians need to be aware of the signs and symptoms of lead and mercury poisoning, how to investigate a possible exposure and when intervention is necessary. We describe 3 cases of patients who presented to an occupational medicine specialist with concerns of heavy metal toxicity. We use these cases to illustrate some of the issues surrounding the investigation of possible lead and mercury exposures. We review the common sources of exposure, the signs and symptoms of lead and mercury poisoning and the appropriate use of chelation therapy. There is a need for a clear and consistent guide to help clinicians interpret laboratory investigations. We offer such a guide, with information about population norms, lead and mercury levels that suggest exposure beyond that seen in the general population and levels that warrant referral for advice about clinical management.

Adult↗
PubMed2005

Statins are associated with better outcomes after carotid endarterectomy in symptomatic patients.

BACKGROUND AND PURPOSE: Statins have been associated with a reduction in mortality from noncardiac surgery. This study aimed to determine whether statin use on admission to hospital for carotid endarterectomy was associated with a reduction of in-hospital adverse outcomes. METHODS: Data describing patient characteristics, surgical indication, statin treatment, and in-hospital outcomes of death, ischemic stroke or death and cardiac outcomes were collected from a chart review of all patients (3360) undergoing carotid endarterectomy in Western Canada from January 2000 to December 2001. Outcomes of patients on statins versus those not on statins were compared using logistic regression to account for differences in patient characteristics, and propensity score methods to account for factors influencing patient allocation to statins. RESULTS: Eight hundred and fifteen of 2031 symptomatic patients and 665 of 1252 asymptomatic patients were on a statin at the time of hospital admission. Statin use by symptomatic patients was associated with reduced in-hospital mortality and in-hospital ischemic stroke or death, but not in-hospital cardiac outcomes (adjusted odds ratio 0.25 [CI, 0.07 to 0.90], 0.55 [CI, 0.32 to 0.95], 0.87 [CI, 0.49 to 1.54], respectively). The improvement in outcomes was robust when tested using propensity score matching. This association was not seen in asymptomatic patients on statins (adjusted odds ratio, in-hospital mortality 0.54 [CI, 0.13 to 2.24]; in-hospital ischemic stroke or death 1.34 [CI, 0.61 to 2.93]; in-hospital cardiac outcomes 1.37 [CI, 0.73 to 2.58]). CONCLUSIONS: These findings are suggestive of a protective effect of statin therapy in symptomatic patients pre-treated at the time of carotid endarterectomy, though this needs confirmation in a randomized controlled trial.

Aged↗
PubMed2005

Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging.

We examined whether the presence of diffusion-weighted imaging (DWI) lesions and vessel occlusion on acute brain magnetic resonance images of minor stroke and transient ischemic attack patients predicted the occurrence of subsequent stroke and functional outcome. 120 transient ischemic attack or minor stroke (National Institutes of Health Stroke Scale < or = 3) patients were prospectively enrolled. All were examined within 12 hours and had a magnetic resonance scan within 24 hours. Overall, the 90-day risk for recurrent stroke was 11.7%. Patients with a DWI lesion were at greater risk for having a subsequent stroke than patients without and risk was greatest in the presence of vessel occlusion and a DWI lesion. The 90-day risk rates, adjusted for baseline characteristics, were 4.3% (no DWI lesion), 10.8% (DWI lesion but no vessel occlusion), and 32.6% (DWI lesion and vessel occlusion) (p = 0.02). The percentages of patients who were functionally dependent at 90 days in the three groups were 1.9%, 6.2%, and 21.0%, respectively (p = 0.04). The presence of a DWI lesion and a vessel occlusion on a magnetic resonance image among patients presenting acutely with a transient ischemic attack or minor stroke is predictive of an increased risk for future stroke and functional dependence.

Acute Disease↗
PubMed2005

Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?

The use of diethylstilbestrol (DES) for high risk pregnancy has exposed millions of mothers to an increased risk of breast cancer, and also resulted in a generation of women with genital tract abnormalities, such as vaginal adenosis. It is still too early to say that exposure to DES will also result in an increased risk of breast cancer in the offspring, though there is some preliminary evidence to support this. The employment of optimal hormonal therapy (for breast cancer) in this special population may be hampered by the fact that agents with oestrogen agonistic activity (such as tamoxifen) may be contraindicated. Though some of the newer hormonal agents, such as the pure anti-oestrogen Fulvestrant and the aromatase inhibitors, could be considered interesting alternatives for postmenopausal patients, their safety in this population has never been evaluated. Finally, the prevalence prenatal exposure to DES may have been underestimated patients diagnosed with breast cancer, though this information might have major implications in their management. We report on the interesting example of a young woman with a history of vaginal adenosis, who was also diagnosed with early breast cancer.

Adult↗
PubMed2005

Inhibition of motor responses in siblings concordant and discordant for attention deficit hyperactivity disorder.

OBJECTIVE: The authors sought to determine whether nonaffected siblings of ADHD probands have a motor response inhibition deficit and to assess concordance for this inhibition deficit in ADHD-concordant and ADHD-discordant sibling pairs. METHOD: ADHD-concordant pairs (21 probands and their affected siblings), ADHD-discordant pairs (18 probands and their nonaffected siblings), and a group of unrelated, demographically balanced, healthy individuals (N=24) were compared on measures of response inhibition, ADHD behavior, impairment, and environmental risk. RESULTS: Concordant-pair probands, their affected siblings, and discordant-pair probands exhibited inhibitory control impairment relative to healthy comparison subjects. The performance of nonaffected siblings was intermediate between that of ADHD children and the healthy comparison subjects. Group differences persisted after age was controlled, and performance was not correlated with the number of ADHD symptoms. In ADHD-concordant sibling pairs, there was a significant relationship between proband and sibling inhibition deficit. In ADHD-discordant sibling pairs, inhibition deficit was evident in half of the nonaffected siblings of probands with an inhibition deficit. Groups did not differ in exposure to environmental risks. CONCLUSIONS: Impaired inhibitory control aggregates in the family members of individuals with ADHD and may serve as an indicator of genetic vulnerability to the disorder.

Attention Deficit Disorder with Hyperactivity↗
PubMed2005

Bedside emergency transcranial Doppler diagnosis of severe carotid disease using orbital window examination.

BACKGROUND: Identifying internal carotid artery (ICA) stenosis in the acute stroke setting can provide clinically useful information. Transcranial Doppler (TCD) through the orbital window is an easy test to perform and to track and identify different vessels. Previous TCD studies have suggested that a reversed ophthalmic artery (OA) flow is a useful collateral pattern to predict ICA disease. The authors sought to evaluate the TCD orbital window for predicting cervical ICA (cICA) stenosis in the setting of acute stroke and TIA. METHOD: Power M-mode/TCD was performed in acute stroke and transient ischemic attack patients at 2 institutions. Each orbital window depth was detected on M-mode and evaluated for the direction of flow and resistance pattern. Gold standard for comparison was carotid evaluation using carotid duplex, computed tomography angiogram, or conventional angiography. The assessment of cICA disease was categorized by degree of stenosis or occlusion. RESULTS: A total of 216 transorbital exams were performed in 117 patients. Twenty-five cICA occlusions and 8 critical cICA stenoses (>or=95%) were identified by gold standard imaging. Reversed OA flow at 50 to 60 mm depth revealed high specificity (100%; confidence interval [CI], 97.6%-100.0%) and good sensitivity (75%; CI, 53.3%-90.2%) for identifying cICA occlusion or critical stenosis (>or=95%). Low pulsatility index (<1.2) and mean flow velocity (<15 cm/s) discriminated critical severe ICA stenosis or occlusion when OA flow was anterograde with good sensitivity (87.2%) and specificity (95.2%). CONCLUSION: The reversed OA sign at 50 to 60 mm depth is very specific for identifying cICA occlusion or critical stenosis. When OA flow is anterograde, a low mean flow velocity or pulsatility index is also useful to identify cICA critical stenosis or occlusion.

Carotid Artery, Internal↗
PubMed2004

Variations in rates of appropriate and inappropriate carotid endarterectomy for stroke prevention in 4 Canadian provinces.

BACKGROUND: Carotid endarterectomy (CE), when performed on appropriate patients, reduces the incidence of stroke, yet there are marked variations in rates of this procedure. We sought to determine reasons for the variation in CE rates in 4 Canadian provinces. METHODS: We identified all CEs performed in 4 Canadian provinces between January 2000 and December 2001, inclusive. From chart review and expert assessment, we determined the proportion of these procedures that were appropriate, inappropriate or of uncertain appropriateness, using the RAND/UCLA Appropriateness Method. We sought to determine the variation in rates by province and whether the variation was due to differences in type of hospital, surgical specialty or surgical volume. RESULTS: Overall, 1656 (52.3%) of the 3167 CEs studied were performed for appropriate indications. The proportions of appropriate procedures were 78.2% (176/225) in Saskatchewan, 58.7% (481/819) in Alberta, 49.1% (350/713) in Manitoba and 46.0% (649/1410) in British Columbia (p < 0.001 across provinces). Rates of appropriate procedures per 100 000 population ranged from 44.3 in Manitoba to 16.2 in Saskatchewan (p < 0.001 across provinces). CEs were more likely to be appropriate when performed by a neurosurgeon compared with all other surgeons (74.4% v. 49.4% were appropriate; p < 0.001), when performed by surgeons doing fewer than 31 procedures over 2 years compared with surgeons doing more than 31 (70.1% v. 49.5% were appropriate; p < 0.001) and when performed in hospitals doing fewer than 135 procedures per year compared with hospitals doing more than 135 (63.4% v. 49.1% were appropriate; p < 0.001). Overall, 10.3% of procedures were done for inappropriate reasons. INTERPRETATION: Our findings suggest some overuse (for inappropriate or uncertain indications) but also some underuse (low population rates in some regions). High rates of CE are associated with lower rates of appropriateness for both surgeons and hospitals. That 1 in 10 CEs is done inappropriately suggests the need for preoperative assessment of appropriateness.

Adult↗
PubMed2004

An audit tool for assessing the appropriateness of carotid endarterectomy.

BACKGROUND: To update appropriateness ratings for carotid endarterectomy using the best clinical evidence and to develop a tool to audit the procedure's use. METHODS: A nine-member expert panel drawn from all the Canadian Specialist societies that are involved in the care of patients with carotid artery disease, used the RAND Appropriateness Methodology to rate scenarios where carotid endarterectomy may be performed. A 9-point rating scale was used that permits the categorization of the use of carotid endarterectomy as appropriate, uncertain, or inappropriate. A descriptive analysis was undertaken of the final results of the panel meeting. A database and code were then developed to rate all carotid endarterectomies performed in a Western Canadian Health region from 1997 to 2001. RESULTS: All scenarios for severe symptomatic stenosis (70-99%) were determined to be appropriate. The ratings for moderate symptomatic stenosis (50-69%) ranged from appropriate to inappropriate. It was never considered appropriate to perform endarterectomy for mild stenosis (0-49%) or for chronic occlusions. Endarterectomy for asymptomatic carotid disease was thought to be of uncertain benefit at best. The majority of indications for the combination of endarterectomy either prior to, or at time of coronary artery bypass grafting were inappropriate. The audit tool classified 98.0% of all cases. CONCLUSIONS: These expert panel ratings, based on the best evidence currently available, provide a comprehensive and updated guide to appropriate use of carotid endarterectomy. The resulting audit tool can be downloaded by readers from the Internet and immediately used for hospital audits of carotid endarterectomy appropriateness.

Algorithms↗
PubMed2004

Early risk of stroke after a transient ischemic attack in patients with internal carotid artery disease.

BACKGROUND: Transient ischemic attacks (TIAs) often herald a stroke, but little is known about the acute natural history of TIAs. Our objective was to quantify the early risk of stroke after a TIA in patients with internal carotid artery disease. METHODS: Using patient data from the medical arm of the North American Symptomatic Carotid Endarterectomy Trial, we calculated the risk of ipsilateral stroke in the territory of the symptomatic internal carotid artery within 2 and 90 days after a first-recorded hemispheric TIA. We also studied similar outcomes among patients in the trial who had a first-recorded completed hemispheric stroke. RESULTS: For patients with a first-recorded hemispheric TIA (n = 603), the 90-day risk of ipsilateral stroke was 20.1% (95% confidence interval [CI] 17.0%-23.2%), higher than the 2.3% risk (95% CI 1.0%-3.6%) for patients with a hemispheric stroke (n = 526). The 2-day risks were 5.5% and 0.0%, respectively. Patients with more severe stenosis of the internal carotid artery (> 70%) appeared to be at no greater risk of stroke than patients with lesser degrees of stenosis (adjusted hazard ratio 1.1, 95% CI 0.7-1.7). Infarct on brain imaging (adjusted hazard ratio 2.1, 95% CI 1.5-3.0) and the presence of intracranial major-artery disease (adjusted hazard ratio 1.9, 95% CI 1.3-2.7) doubled the early risk of stroke in patients with a hemispheric TIA. INTERPRETATION: Patients who had a hemispheric TIA related to internal carotid artery disease had a high risk of stroke in the first few days after the TIA. Early risk of stroke was not affected by the degree of internal carotid artery stenosis.

Aged↗
PubMed2004

Importance of the imaging modality in decision making about carotid endarterectomy.

OBJECTIVE: To determine the influence of all possible imaging strategies on the appropriateness ratings for carotid endarterectomy, because less accurate noninvasive techniques are replacing contrast angiography, which was used in the major efficacy trials. METHODS: An expert panel, using appropriateness methodology, rated 203 scenarios where endarterectomy might be performed. Each scenario was rated where internal carotid artery stenosis was determined using five different imaging sources: 1) conventional angiography, 2) ultrasound carotid Doppler only, 3) CT (CTA) or MR (MRA) angiography only, 4) concordant results from two noninvasive carotid imaging studies, and 5) discordant results from two noninvasive studies. The scenarios deemed appropriate by conventional angiography were identified. The effect of the other imaging modalities on these results was examined. RESULTS: Thirty-three scenarios were identified as being appropriate. Concordant imaging results had no effect on appropriateness ratings in symptomatic carotid artery disease when compared with conventional angiography. Single noninvasive imaging techniques were deemed appropriate for investigation only in the presence of severe symptomatic stenosis. In all other scenarios, single noninvasive imaging and discordant results reduced the appropriateness rating of scenarios to either uncertain benefit or inappropriateness. The single appropriate scenario for asymptomatic carotid artery stenosis was where severe stenosis was determined by concordant noninvasive imaging or by CTA or MRA alone. CONCLUSION: It is important to take into account both the clinical scenario and the imaging modalities utilized to determine the degree of internal carotid artery stenosis in the clinical decision making surrounding carotid endarterectomy.

Angiography↗
PubMed2004

Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes.

BACKGROUND: Although brain serotonin transporter (5-HTT) density has been investigated in subjects with a history of major depressive episodes (MDE), there has never been an investigation of brain 5-HTT during a current MDE. Brain 5-HTT binding potential (BP) may have an important role during MDE due to major depressive disorder, because the 5-HTT regulates extracellular 5-HT. The BP is an index of receptor density. Carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) positron emission tomography (PET) is the first brain imaging technique that can measure the 5-HTT BP in cortical and subcortical brain regions in vivo. The purposes of this study were to investigate 5-HTT BP during MDE and to determine the relationship between 5-HTT BP and negativistic dysfunctional attitudes during MDE. Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. Our recent publication of increased serotonin2 BP in MDE with severely negativistic dysfunctional attitudes suggests that this subgroup of MDE subjects has very low levels of extracellular serotonin. METHODS: Regional 5-HTT BP was measured in 20 nonsmoking medication-free (> or =3 months) depressed subjects and 20 age-matched nonsmoking, medication-free, healthy subjects using [11C]DASB PET. Dysfunctional attitudes were measured using the Dysfunctional Attitudes Scale. RESULTS: No difference in regional 5-HTT BP was found between MDE and healthy subjects; however, the subgroup of MDE subjects with highly negativistic dysfunctional attitudes had significantly higher 5-HTT BP compared with healthy subjects in brain regions mainly sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, bilateral caudate, and bilateral putamen; average, 21% greater; F(1,26), 5.6-12.2 [P values, .03-.002]). In the MDE subjects, increased 5-HTT BP was strongly associated with more negativistic dysfunctional attitudes in brain regions primarily sampling serotonergic nerve terminals (prefrontal cortex, anterior cingulate, thalamus, caudate, and putamen; r = 0.64-0.74 [P values, .003 to <.001]). CONCLUSIONS: Serotonin transporters play an important role during depression. The magnitude of regional 5-HTT BP can provide a vulnerability to low levels of extracellular serotonin and symptoms of extremely negativistic dysfunctional attitudes.

Benzylamines↗
PubMed2004

Organization of regional and local stroke resources: methods to expedite acute management of stroke.

Proving the efficacy of thrombolysis in improving outcome from stroke has put time to assessment of patients at the forefront for healthcare providers when organizing stroke care. The chain of recovery begins with the patient. Efforts are being made to improve the general public's understanding of stroke. However, it appears at the moment that a greater effect in reducing the delay to initial medical assessment and treatment decision is to be gained through streamlining care as soon as 911 has been called. Emergency medical services dispatchers and technicians play a key role in recognizing that a patient is having a stroke and prioritizing the transport of the patient to an appropriate facility. Emergency departments need to have clear protocols in place to ensure that physicians can make prompt treatment decisions after having fully assessed and investigated the patient. Only with all these pieces in place is the initial phase of the chain of recovery complete, with the end result that more patients have the chance to have an improved outcome from stroke.

Canada↗
PubMed2003

Functional analysis of the N-terminal domain of the Myc oncoprotein.

Myc is a multifunctional nuclear phosphoprotein that can drive cell cycle progression, apoptosis and cellular transformation. Myc orchestrates these activities at the molecular level by functioning as a regulator of gene transcription to activate or repress specific target genes. Previous studies have shown that both the Myc N-terminal domain (NTD) and the C-terminal domain (CTD) are essential for Myc functions. The role of the CTD is relatively well understood as it encodes a basic helix-loop-helix leucine zipper motif important for DNA binding and protein-protein interactions. By contrast, the role of the NTD and the specific domains responsible for different Myc activities are not as well defined. To investigate the regions of the NTD necessary for Myc function and to determine whether these activities are overlapping or independent of one another, we have conducted a detailed structure-function analysis of the Myc NTD. We assessed the ability of a number of deletion and point mutants within the highly conserved regions of the Myc NTD to induce cell cycle progression, apoptosis and transformation as well as repress and activate expression of endogenous target genes. Our analyses highlight the complexity of the Myc NTD and extend previous studies. For example, we show most Myc mutants that were compromised as repressors of gene transcription retained the ability to activate gene transcription, reinforcing the concept that these activities can be uncoupled. Repression of two different target genes could be distinguished by specific mutants, further supporting the notion of at least two different Myc repression mechanisms. Mutants disabled at both inducing and repressing gene transcription could not maximally drive the biological activities of Myc, indicating these functions are tightly linked. Indeed, a close association of Myc repression and apoptosis was also observed.

Amino Acid Substitution↗
PubMed2003

Successful endovascular therapy for acute basilar thrombosis in an adolescent.

Pediatric stroke is an underrecognized, potentially treatable cause of childhood neurologic disease. Acute basilar artery thrombosis is a devastating disease rarely encountered in children. Acute interventions with both chemical and mechanical thrombolysis techniques can improve outcomes in adults with arterial thrombosis of the posterior cerebral circulation. We report a case of intervention with both intra-arterial alteplase (tissue plasminogen activator) and cerebral balloon angioplasty to treat a prolonged basilar artery occlusion secondary to idiopathic thrombosis in an adolescent. Despite the patient being clinically locked-in and intervention being delayed at least 20 hours from symptom onset, he obtained complete neurologic recovery. Issues of pediatric stroke, late therapeutic intervention, chemical thrombolysis, and cerebral angioplasty are discussed. This case highlights the underrecognition and subsequent delay in diagnosis of pediatric stroke and how acute intervention may cure otherwise catastrophic strokes in children.

Adolescent↗