Genome-wide association study identifies genomic regions of association for cruciate ligament rupture in Newfoundland dogs.

Cranial cruciate ligament rupture (CCLR) is the most common cause of pelvic limb lameness in dogs. To investigate the genetic basis of canine CCLR, we conducted a genome-wide association study using a canine SNP array in Newfoundland pedigree dogs with and without CCLR (n = 96). We identified three main chromosomal regions of CCLR association (on chromosomes 1, 3 and 33). Each of these regions was confirmed by Sequenom genotyping in a further cohort of Newfoundlands (n = 271). The results, particularly SNPs identified in the SORCS2 and SEMA5B genes, suggest that there may be neurological pathways involved in susceptibility to canine CCLR.

Salivary immunoglobulins and prevalent coronary artery disease.

Previous studies examined the serum immunoglobulin levels in relation to coronary artery disease (CAD). We hypothesized that the salivary immunoglobulins might better estimate oral infections in this relationship. Multivariate logistic regression analyses utilizing the data from 256 angiographically confirmed CAD patients and 250 non-CAD individuals that controlled for age, sex, smoking, diabetes, total/HDL cholesterol ratio, hypertension, and education revealed the trends that salivary IgA was positively and salivary IgG was inversely associated with CAD. The odds ratios (OR) of each increasing quartile of salivary IgA were 1.00 (first and second quartiles combined), 1.97, and 1.37 (p-value for trend = 0.06), while those for salivary IgG were 1.00, 0.77, 0.60, and 0.51 (p-value for trend = 0.02). Additionally, salivary IgA correlated positively with C-reactive protein and Asymptotic Dental Score (dental infection score), while IgG was inversely associated with these inflammation markers. Salivary IgA warrants further studies to confirm its role in the risk assessment of CAD.

Salivary lysozyme and prevalent hypertension.

Although the etiology of essential hypertension is not clearly understood, endothelial dysfunction from chronic infection and/or impaired glucose metabolism may be involved. We hypothesized that salivary lysozyme, a marker for oral infection and hyperglycemia, might display a significant relationship with hypertension, an early stage of cardiovascular disease. Logistic regression analyses of the Kuopio Oral Health and Heart Study demonstrated that persons with higher lysozyme levels were more likely to have hypertension, after adjustment for age, gender, smoking, BMI, diabetes, the ratio of total cholesterol to HDL cholesterol, and C-reactive protein. The exposure to increasing quartiles of lysozyme was associated with adjusted Odds Ratios for the outcome, hypertension, 1.00 (referent), 1.25, 1.42, and 2.56 (linear trend p < 0.003). When we restricted the sample to the individuals without heart disease (N = 250), we observed a non-significant trend for increasing odds. Our hypothesis--"high salivary lysozyme levels are associated with the odds of hypertension"--was confirmed.

Blood genomic profiling: novel diagnostic and therapeutic strategies for stroke?

Findings from gene expression profiling studies are leading to new diagnostic and therapeutic strategies that can be applied in medical practice, especially in the field of oncology. Promising results of gene expression profiling of the peripheral blood in patients with ischaemic stroke have been obtained in recent pilot studies, demonstrating a partially reproducible gene signature of acute cerebral ischaemia. However, questions remain. Given that blood is at least in part a surrogate tissue for ischaemic stroke, the specificity of these signatures needs to be evaluated. Furthermore, it needs to be determined whether standardization of this methodology is required and whether clinical signatures can be identified that are improvements over the tools currently used in clinical practice. Clinically useful signatures would include those of haemorrhagic as well as ischaemic stroke, reclassification of stroke type and prognosis, and vascular disease risk. If these conditions are met, then it should be possible to develop cost-effective and rapid assays.

Circulating endothelial microparticles in acute ischemic stroke: a link to severity, lesion volume and outcome.

BACKGROUND: Endothelial membrane microparticles (EMP) in plasma are elevated in several vascular diseases. OBJECTIVES: To test the hypothesis that EMP would be increased in patients with acute ischemic stroke and would correlate with stroke severity, brain lesion volume and outcome. PATIENTS AND METHODS: Forty-one patients were studied and divided into two groups based on the National Institutes of Health Stroke Scale (NIHSS) score: 20 patients with mild stroke (NIHSS score < 5) and 21 patients with moderate-severe stroke (NIHSS score > or = 5). Lesion volume was measured using diffusion-weighted magnetic resonance imaging and discharge outcome was based on the discharge Barthel and Rankin scores. Twenty-three age-matched control subjects were also studied. Using flow cytometry, endoglin-positive EMP: CD105+ CD41a-CD45- (E(+)EMP), specific endothelial EMP expressing VE-cadherin and endoglin: CD105+CD144+ (C(+)EMP), EMP expressing phosphatidylserine: CD105+PS+ CD41a- (PS(+)EMP) and EMP expressing ICAM-1: CD105+CD54+ CD45- (I(+)EMP) were analyzed. RESULTS: Significantly higher PS(+)EMP counts were observed in the group of acute ischemic stroke patients [median 59 (25th-75th percentile: 28-86) MP microL(-1)] relative to the controls [28 (14-36) MP microL(-1)] (P = 0.002). All four EMP phenotypes studied were elevated in the subgroup of moderate-severe stroke patients relative to the controls (all P < 0.05). In the patients with acute ischemic stroke three EMP phenotypes (E(+)EMP, PS(+)EMP and I(+)EMP) correlated significantly with brain lesion volume, with I(+)EMP (P = 0.002) showing the strongest correlation. Admission counts of C(+)EMP (P = 0.0003) and E(+)EMP (P = 0.003) correlated significantly with discharge clinical outcome. CONCLUSIONS: Certain circulating EMP phenotypes may be associated with severity, lesion volume and outcome of acute ischemic stroke. EMP analysis shows promising contribution to understanding stroke pathophysiology.

Does periodontal treatment improve glycemic control in diabetic patients? A meta-analysis of intervention studies.

Previous analyses regarding effects of periodontal treatment on glycemic control included studies where causal association might not be assumed, or the results were reported non-quantitatively. We initiated this meta-analysis of 10 intervention studies to quantify the effects of periodontal treatment on HbA1c level among diabetic patients, to explore possible causes for the discrepant reports, and to make recommendations for future studies. Data sources were MEDLINE (January, 1980, to January, 2005), the EBMR, Cochrane Register, and bibliographies of the published articles. Three investigators extracted data regarding intervention, outcomes, and effect size. A total of 456 patients was included in this analysis, with periodontal treatment as predictor and the actual change in hemoglobin A1c level as the outcome. The weighted average decrease in actual HbA1c level was 0.38% for all studies, 0.66% when restricted to type 2 diabetic patients, and 0.71% if antibiotics were given to them. However, none was statistically significant.

Assessment of CE-MRA for the rapid detection of supra-aortic vascular disease.

BACKGROUND: Contrast-enhanced MR angiography (CE-MRA) using a combined head and neck coil permits non-invasive imaging of the vasculature from the aortic arch through to the Circle of Willis in less than 2 minutes. OBJECTIVE: To determine the accuracy of CE-MRA for the detection of vascular pathology, in particular vascular stenoses, using digital subtraction angiography (DSA) as the gold standard. METHODS: In a prospective study of 81 patients referred for DSA, CE-MRA and DSA studies were performed within 72 hours of each other. CE-MRA was performed on a 1.5 Tesla clinical MRI scanner using a five-channel neurovascular array (head and neck coil), with dynamic tracking of the IV gadolinium bolus. CE-MRAs and DSA films were read by two interventional neuroradiologists blinded to the clinical presentation of the patient. RESULTS: On DSA, there were 77 vascular stenoses > or =50% identified, 51 extracranial and 26 intracranial. The overall sensitivity of CE-MRA using the neurovascular array for the detection of vascular stenoses > or =50% was 57% (95% CI: 46 to 68%) with a specificity of 98% (97 to 99%). The sensitivity for the detection of extracranial vascular stenoses > or =50% was 82% (72 to 93%) with a specificity of 97% (96 to 98%). However, the sensitivity for the detection of intracranial vascular stenoses > or =50% was only 8% (0 to 18%), with a specificity of 99% (98 to 100%). CONCLUSIONS: At this stage Contrast-enhanced MR angiography using a neurovascular coil shows promise as a rapid, specific, and noninvasive screening method for extracranial vascular disease, but not for intracranial vascular disease.

Elevated pro-inflammatory CD4+CD28- lymphocytes and stroke recurrence and death.

OBJECTIVE: To determine if the CD4+CD28- T-cell subset is expanded in patients with recurrent stroke or death after acute ischemic stroke. This subset of the peripheral blood T-cell lymphocyte population has a strong pro-inflammatory and tissue-damaging potential. METHODS: Consecutive patients within the first 48 hours of ischemic stroke were prospectively studied. Peripheral blood CD4+CD28- cells were quantified by flow cytometry. The study endpoint was recurrent stroke or death from any cause during 1 year of follow-up. RESULTS: One hundred six patients (mean age 75.0 +/- 13.5 years; 50 women) were studied. The median CD4+CD28- cell count was 4.5% (range 0.2 to 72.2%). Twenty-seven endpoints (10 recurrent strokes and 17 deaths) occurred during follow-up. Stroke recurrence/death rates were significantly associated with increasing CD4+CD28- counts, rising from 14.2% in patients with CD4+CD28- levels of <1.0 to 48.1% for those with CD4+CD28- counts of >8.0% (p = 0.003, Cochran linear test of trend). Higher CD4+CD28- counts were also present in patients with a history of prior stroke (p = 0.03). After adjustment for age, admission NIH Stroke Scale score, prior stroke, and atrial fibrillation, CD4+CD28- counts of >8.0% were associated with a cumulative hazard ratio of 5.81 (95% CI: 1.58 to 21.32) for stroke recurrence or death. CONCLUSIONS: Rising counts of circulating CD4+CD28- cells are associated with an increasing risk of stroke recurrence and death, in addition to an observed association with prior stroke. Expansion of this T-cell subset presumably represents a biomarker and possibly a contributory pathogenic mechanism of recurrent stroke and death after ischemic stroke.

Relationship between magnetic resonance arterial patency and perfusion-diffusion mismatch in acute ischemic stroke and its potential clinical use.

BACKGROUND: In patients with acute ischemic stroke the magnetic resonance (MR) perfusion-diffusion mismatch pattern (perfusion lesion at least 20% larger than the lesion on diffusion-weighted imaging) may indicate ischemically threatened but viable tissue. To our knowledge, the relationship of this MR pattern to serial changes in MR angiography (MRA) has not been reported. OBJECTIVES: To investigate the relationship between MRA changes and patterns of diffusion-weighted imaging and perfusion abnormalities and to determine if the information obtained could be used in clinical management. METHODS: The MR studies of 35 patients who had undergone sequential multimodality MR imaging studies within the first 4 days of stroke were reviewed. All lesions were in the internal carotid artery territory distribution. Magnetic resonance angiographies were read by 2 observers blinded to the clinical data. RESULTS: During the first 24 hours a perfusion-diffusion mismatch was present in 22 (92%) of the 24 patients with an MRA arterial occlusive lesion. (At this time 5 [46%] of the 11 patients with a normal MRA [P =.006] also had a mismatch.) Two to 4 days after stroke, of these 22 patients resolution of the mismatch occurred in 8 (87%) of 9 patients with recanalization on MRA compared with 5 (39%) of 13 patients without arterial recanalization (P =.03). Resolution of mismatch occurred in 3 (60%) of 5 patients with a normal MRA and a mismatch at the first time point. CONCLUSIONS: Concordance between MRA and the MR perfusion-diffusion mismatch pattern provides supportive evidence for an arterial vascular basis for this MR signature in acute stroke. Discordance between MRA lesions and mismatch may result from arterial branch occlusions undetected by MRA or from an alternate mechanism for the mismatch. The MR imaging patterns identified extend our understanding of the pathophysiology of stroke and may contribute to the improvement of stroke management in the future.

A three-item scale for the early prediction of stroke recovery.

BACKGROUND: Accurate assessment of prognosis in the first hours of stroke is desirable for best patient management. We aimed to assess whether the extent of ischaemic brain injury on magnetic reasonance diffusion-weighted imaging (MR DWI) could provide additional prognostic information to clinical factors. METHODS: In a three-phase study we studied 66 patients from a North American teaching hospital who had: MR DWI within 36 h of stroke onset; the National Institutes of Health Stroke Scale (NIHSS) score measured at the time of scanning; and the Barthel Index measured no later than 3 months after stroke. We used logistic regression to derive a predictive model for good recovery. This logistic regression model was applied to an independent series of 63 patients from an Australian teaching hospital, and we then developed a three-item scale for the early prediction of stroke recovery. FINDINGS: Combined measurements of the NIHSS score (p=0.01), time in hours from stroke onset to MR DWI (p=0.02), and the volume of ischaemic brain tissue on MR DWI (p=0.04) gave the best prediction of stroke recovery. The model was externally validated on the Australian sample with 0.77 sensitivity and 0.88 specificity. Three likelihood levels for stroke recovery-low (0-2), medium (3-4), and high (5-7)-were identified on the three-item scale. INTERPRETATION: The combination of clinical and MR DWI factors provided better prediction of stroke recovery than any factor alone, shortly after admission to hospital. This information was incorporated into a three-item scale for clinical use.

Prediction of the final infarct volume within 6 h of stroke using single photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime.

BACKGROUND: A simple method to predict the final infarct volume within 6 h of onset of hemispheric ischemic stroke based on the measurement of cerebral blood flow (CBF) using single photon emission computed tomography (SPECT) with techneticum-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO) was investigated in a clinical model involving patients without definite early reperfusion or clinical recovery. METHODS: A group of 16 patients (group 1) was used to establish the methodology, which was then validated in a second group of 14 patients (group 2). The final infarct volume was defined using computed tomography (CT) performed at least 7 days after stroke. The relative CBF threshold value, expressed as a percentage of the mean contralateral hemispheric value, which most closely estimated the final infarct size on coregistered CT was established for each patient. RESULTS: The mean threshold CBF value for group 1 was 63.7%. When this value was used to predict infarct size in group 2, a close correlation was observed between the actual and the estimated sizes (r = 0.973, p < 0.0001). This value was not time dependent. CONCLUSIONS: If no significant early reperfusion or clinical recovery occurs, a CBF threshold value of 63.7% on (99m)Tc-HMPAO SPECT performed within 6 h of stroke onset will reliably predict the final infarct size.

Clinical correlations of diffusion and perfusion lesion volumes in acute ischemic stroke.

The aim of this study was to describe the clinico-radiological correlations of magnetic resonance (MR) perfusion and diffusion-weighted imaging (DWI) abnormalities in ischemic stroke. Eighteen patients had undergone MR imaging and clinical evaluation within 24 h of symptom onset and at or after 7 days. During the first 24 h the volume of perfusion abnormality (measured on the relative mean transit time map) was larger than the DWI lesion in 12/18 patients. In 6/18 patients the DWI lesion volume was larger. Acutely (<24 h) all lesion volumes showed a significant correlation with acute clinical severity measured by the National Institutes of Health Stroke Scale score. The correlations of the hypoperfusion volume (rho = 0.86, p = 0.0001) and the volume 'tissue at risk' (larger than the DWI and perfusion lesion volumes, rho = 0.86, p = 0. 0001) with acute clinical severity were slightly higher than for the DWI lesion volume (rho = 0.76, p = 0.0001). The difference between the volume of tissue at risk (acutely) and the infarct on follow-up T(2)-weighted imaging correlated significantly with change in clinical severity from acute to chronic time points (rho = 0.72, p = 0.001). Such clinico-radiological relationships may support the use of DWI and perfusion MR in decisions concerning the administration and evaluation of stroke therapies.

Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in children.

BACKGROUND: The optimal treatment of acute Crohn's disease in children remains controversial. In adults, steroid therapy has been shown to be superior to exclusive enteral nutrition. However, enteral nutrition is effective at inducing a remission in many children with acute Crohn's disease. Steroid usage in children has been associated with adverse side effects, particularly with delayed growth and pubertal development. METHODS: Randomized clinical trials comparing exclusive enteral nutrition with corticosteroids were identified. Two independent reviewers extracted data from selected studies. Studies were assessed for heterogeneity and relative risks for remission induction with enteral nutrition were obtained. Sensitivity analyses were performed in partially randomized studies. Estimates were made of the number of studies needed to overturn the current result. Other outcome measures were qualitatively assessed. RESULTS: In five randomized clinical trials comprising 147 patients, enteral nutrition was as effective as corticosteroids at inducing a remission (RR = 0.95 [95% confidence interval 0.67, 1.34]). Addition of two further nonrandomized trials did not significantly alter the result. A minimum of 10 further studies, equal in size and outcome to the largest reported pediatric trial to date (n = 68, RR = 0.84), would be required to demonstrate a significant benefit of steroid therapy over enteral nutrition. CONCLUSIONS: There is no difference in efficacy between enteral nutrition and corticosteroid therapy in the treatment of acute Crohn's disease in children. Improved growth and development, without the side effects of steroid therapy, make enteral nutrition a better choice for first-line therapy in children with active Crohn's disease.

Multiple acute stroke syndrome: marker of embolic disease?

OBJECTIVE: To determine the frequency and etiologic significance of multiple acute ischemic lesions in stroke. BACKGROUND: Although patients may have more than one stroke during the course of their lives, acute ischemic stroke is usually thought of as a single event. Using diffusion-weighted imaging (DWI), an MRI technique that detects ischemic injury within minutes after onset, we have often observed multiple acute ischemic lesions. METHODS: The MRI scans of 59 consecutively studied patients were reviewed to determine the frequency and etiologic significance of multiple acute ischemic lesions on DWI. RESULTS: Multiple acute ischemic lesions were present in 10 (17%) of 59 patients. The lesions usually occurred within one major circulation (anterior or posterior), but in two patients (3%), lesions occurred in both cerebral hemispheres or in the anterior and the posterior circulations. The lesions often were small and resulted from presumed multiple emboli or the break-up of an embolus. Two patients had internal carotid artery occlusive disease and four had a cardiac or aortic source. In the other four patients the source was not determined. Lesions larger than 1 cm in diameter progressed to infarction, but some smaller lesions were not seen on follow-up T2-weighted imaging. CONCLUSIONS: Multiple acute stroke lesions on DWI are common and could be caused by multiple emboli or the breakup of an embolus. In some cases it might become possible to make early inferences concerning the stroke mechanism that could be of use for immediately directing the clinical work-up and treatment of the patient.

The ischemic penumbra: operationally defined by diffusion and perfusion MRI.

BACKGROUND: Identifying tissue at risk for infarction is important in deciding which patients would benefit most from potentially harmful therapies and provides a way to evaluate newer therapies with regard to the amount of ischemic tissue salvaged. OBJECTIVE: To operationally define and characterize cerebral tissue at risk for stroke progression. METHODS: We retrospectively selected 25 patients with an acute onset of a hemispheric stroke from our database who had undergone a combination of two diffusion-weighted MRI studies and a perfusion-weighted MRI study. We applied a logistic regression model using maps of the relative mean transit time and relative cerebral blood flow (rCBF) as well as three different maps of the relative cerebral blood volume (rCBV) to predict an operationally defined penumbra (region of mismatch between the diffusion lesion on day 1 and its extension 24 to 72 hours later). RESULTS: Maps of the rCBF and initial rCBV were significant predictors for identifying penumbral tissue. Our operationally defined penumbral region was characterized by a reduction in the initial rCBV (47% of contralateral control region [CCR]), an increase (163% of CCR) in the total rCBV, and a reduction (37% of CCR) in the rCBF, whereas the operationally defined ischemic core showed a more severe reduction in the rCBF (12% of CCR) and in the initial rCBV (19% of CCR). CONCLUSION: These MR indexes may allow the identification and quantification of viable but ischemically threatened cerebral tissue amenable to therapeutic interventions in the hyperacute care of stroke patients.

Imaging developing brain infarction.

Continued advances in neuroimaging technology have made it practical to image multiple aspects of evolving brain infarction during the potential window period of therapeutic opportunity in stroke. Recent methodologic developments include computed tomography angiography and perfusion, and the description of quantitative parameters for magnetic resonance blood oxygen level-dependent perfusion imaging. In pathophysiologic studies, metabolism and function in the ischemic focus and the peri-infarct tissue have been further characterized. Clinical studies have focused on the applications of computed tomography and magnetic resonance imaging for prethrombolysis patient selection. These methods have an important role in the evaluation and development of new pharmaceutical agents and will be increasingly used in clinical practice as new therapies become available.