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 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.

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.

Magnetic resonance imaging of acute stroke.

In the investigation of ischemic stroke, conventional structural magnetic resonance (MR) techniques (e.g., T1-weighted imaging, T2-weighted imaging, and proton density-weighted imaging) are valuable for the assessment of infarct extent and location beyond the first 12 to 24 hours after onset, and can be combined with MR angiography to noninvasively assess the intracranial and extracranial vasculature. However, during the critical first 6 to 12 hours, the probable period of greatest therapeutic opportunity, these methods do not adequately assess the extent and severity of ischemia. Recent developments in functional MR imaging are showing great promise for the detection of developing focal cerebral ischemic lesions within the first hours. These include (1) diffusion-weighted imaging, which provides physiologic information about the self-diffusion of water, thereby detecting one of the first elements in the pathophysiologic cascade leading to ischemic injury; and (2) perfusion imaging. The detection of acute intraparenchymal hemorrhagic stroke by susceptibility weighted MR has also been reported. In combination with MR angiography, these methods may allow the detection of the site, extent, mechanism, and tissue viability of acute stroke lesions in one imaging study. Imaging of cerebral metabolites with MR spectroscopy along with diffusion-weighted imaging and perfusion imaging may also provide new insights into ischemic stroke pathophysiology. In light of these advances in structural and functional MR, their potential uses in the study of the cerebral ischemic pathophysiology and in clinical practice are described, along with their advantages and limitations.

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.

Early reperfusion in the 'spectacular shrinking deficit' demonstrated by single-photon emission computed tomography.

The "spectacular shrinking deficit" (SSD) refers to a syndrome of profound hemispheric ischemia that resolves rapidly over hours to days, leaving patients with minimal residual neurologic deficits. The SSD is postulated to result from rapid embolic lysis, fragmentation, and migration along the internal carotid/middle cerebral artery axis, leading to restored tissue perfusion before irreversible tissue damage has occurred. We performed serial single-photon emission computed tomographic (SPECT) cerebral perfusion measurements during the first 48 hours in 36 patients admitted with major hemispheric ischemia, to compare the cerebral perfusion changes between patients who developed SSD (n = 5) and those who did not (n = 31). The two groups were similar for severity of neurologic deficit, time of SPECT study, and size of perfusion defect on the SPECT images. Patients with SSD were younger (p = 0.02, Mann-Whitney U), demonstrated significantly greater tissue reperfusion during the first 48 hours (p < 0.01), and had smaller infarcts on CT (p = 0.02). This syndrome provides an opportunity to understand the mechanism by which early reperfusion may result in early tissue salvage and clinical recovery.

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.

Streptokinase in acute stroke: effect on reperfusion and recanalization. Australian Streptokinase Trial Study Group.

The Australian Streptokinase Trial was a randomized, double-blind, placebo-controlled trial, in which streptokinase (SK, 1.5 million IU I.V.) was given within 4 hours of stroke onset. In a subset of 37 patients, 99mTc-labeled D,L-hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT) and/or transcranial Doppler (TCD) studies were performed before and after therapy to test the hypothesis that SK may improve the hemodynamic measures of reperfusion/recanalization rates (TCD parameter) within 24 hours. Eighteen patients received SK and 19 placebo. Baseline characteristics were similar in both groups, and there were no differences in clinical outcomes assessed at 3 months after stroke. Although there was no increase in the group mean perfusion defect or volume on SPECT after thrombolytic therapy, a larger number of patients demonstrating the combined end point of reperfusion or recanalization was seen in the SK group (13/14, 93%) than in the placebo group (7/14, 50%; p = 0.01). Although SK given within 4 hours of acute ischemic stroke appears to improve arterial patency/tissue reperfusion, this effect is neither early nor extensive enough to influence overall clinical outcome.

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.

Clinical experience with diffusion-weighted MR in patients with acute stroke.

PURPOSE: Our purpose was to evaluate the clinical efficacy, sensitivity, and specificity of echo-planar diffusion-weighted MR imaging in patients with acute infarction. METHODS: We retrospectively analyzed 194 cases of acute ischemic stroke diagnosed clinically within 24 hours of onset and studied with echo-planar diffusion-weighted MR imaging. Examinations were considered to be positive for infarction when an increase in signal was noted on images acquired at a high b value but absent on images with a low b value. A final clinical diagnosis of acute stroke was used as the standard of reference. A subset of 48 patients scanned within 6 hours was also analyzed. RESULTS: Diffusion-weighted MR imaging studies were positive in 133 of 151 cases of infarction (88% sensitivity) and negative in 41 of 43 cases with no infarction (95% specificity). Two cases identified as positive on diffusion-weighted images had nonischemic diagnoses (1.5% false-positive rate). Diffusion-weighted imaging had a positive predictive value of 98.5% and a negative predictive value of 69.5%. Use of T2-weighted sequences as well as diffusion-weighted imaging produced no false-positive findings. Of the negative scans, 69.5% corresponded to transient ischemic attacks or infarcts (mostly small brain stem infarcts). When only cases scanned within 6 hours of onset were considered, the sensitivity rose to 94% and the specificity to 100%. CONCLUSION: Despite bias due to dependence between diffusion-weighted imaging and the final diagnosis, this analysis suggests high sensitivity and specificity for echo-planar diffusion-weighted imaging in the diagnosis of acute cerebral infarction, although negative scans did not rule out an ischemic pathogenesis.

Turbo spin-echo diffusion-weighted MR of ischemic stroke.

PURPOSE: Our objective was to determine whether a multisection technique, diffusion-weighted half-Fourier single-shot turbo spin-echo (HASTE) imaging, can compensate for the drawbacks common to other diffusion-weighted techniques; specifically, the need for echo-planar technology and the presence of susceptibility artifacts in areas close to the skull base. METHODS: Forty subjects who were referred to the stroke service with signs of acute (less than 24 hour) neurologic dysfunction were included in this prospective study. MR imaging of the brain was performed with diffusion-weighted echo-planar and diffusion-weighted HASTE sequences. The images obtained with both sequences were analyzed for the presence of hyperintensities corresponding to ischemic lesions as well as for the presence of image artifacts and distortions. RESULTS: Diffusion-weighted HASTE images showed areas of hyperintensity corresponding to the infarcts present on diffusion-weighted echo-planar imaging studies without distortion or susceptibility artifacts in all the patients who had a stroke. Twelve patients had no acute ischemic lesions; of these, five had other findings, six had normal findings, and in one patient, a hyperintensity seen on diffusion-weighted echo-planar images proved to be an artifact on diffusion-weighted HASTE images. CONCLUSIONS: Diffusion-weighted HASTE is equal to diffusion-weighted echo-planar imaging in the detection of early ischemia. Because of the absence of significant image distortions and other artifacts, diffusion-weighted HASTE permits fast multiplanar imaging in artifact-prone regions, such as the posterior fossa and the inferior frontal and temporal lobes. Diffusion imaging can be performed on conventional systems with strengths of 1.5 T that do not have echo-planar imaging capabilities.

Diagnosis and imaging of stroke.

BACKGROUND: Less than 20 years ago the diagnosis of stroke was almost entirely based on clinical features. Since the mid-1970s sophisticated ultrasonography, computed tomography, magnetic resonance imaging, angiography and spectroscopy, single-photon emission computed tomography and positron emission tomography have been developed in rapid succession. CURRENT USE OF NEUROIMAGING IN STROKE PATIENTS: By using a combination of imaging modalities it is now possible to show nearly all of the vascular tree from the left ventricle of the heart through to small arteries within the brain. Depending on clinical need, in most cases, it should be possible to define the location and mechanism of any given vascular event affecting the brain, and thus design appropriate management. THE FUTURE: Neuroimaging, clinical diagnosis and therapy are closely linked. Neuroimaging will become even more important if potential neuroprotective or thrombolytic agents prove effective. Categorization of pathophysiological subtypes of haemorrhagic and ischaemic stroke will allow more precise management of patients. If the rate of development in neuroimaging of the previous 20 years is maintained, even more precise evaluation of stroke patients will become possible.

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.

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.

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.

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.

Mechanisms and clinical features of internal watershed infarction.

The mechanism of internal carotid watershed cerebral infarction is not well understood, but the phenomenon has been described in association with carotid occlusive disease, and more recently with distal middle cerebral artery occlusion beyond the origin of the lenticulostriate branches. The clinical correlates of these changes have not yet been described. We present 5 patients in whom acute internal watershed infarction had occurred, and correlate the clinical, neuropsychological and 99mTc-HMPAO SPECT (Single Photon Emission Computed Tomography using 99mtechnetium-hexamethylpropylene amine oxime) cerebral perfusion findings. Four patients had distal middle cerebral artery occlusion demonstrated on angiography, and one showed profound hemispheric depression in cerebral perfusion with only a small area of infarction. We have concentrated on the mechanism of distal middle cerebral artery occlusion to describe the "arc" of the watershed zone created. We propose that internal watershed infarcts can further be subdivided into anterior and posterior subtypes, outline the vascular territories involved, and propose an overall classification of cerebral watershed infarction.