Obstructive sleep apnea intensifies stroke severity following middle cerebral artery occlusion.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a sleep disorder caused by transient obstruction of the upper airway and results in intermittent hypoxia, sleep fragmentation, sympathetic nervous system activation, and arousal which can have an adverse effect on cardiovascular disease. It is theorized that OSA might intensify stroke injury. Our goal here was to develop a new model of experimental OSA and test its ability to aggravate behavioral and morphological outcomes following transient brain ischemia/reperfusion. METHODS: We used a 3D printed OSA device to expose C57BL6 mice to 3 h of OSA (obstructive apnea index of 20 events per hour) for three days. These mice were then subjected to ischemia/reperfusion using the middle cerebral artery occlusion model (MCAO) stroke and examined for overall survival, infarct size and neurological scoring. RESULTS: We found that OSA transiently decreased respiration and reduced oxygen saturation with bradycardia and tachycardia typical of human responses during apneic events. Brain injury from MCAO was significantly increased by OSA as measured by infarct size and location as well as by intensification of neurological deficits; mortality following MCAO was also increased in OSA animals. CONCLUSIONS: Our findings suggest that our new model of OSA alters respiratory and cardiovascular physiological functions and is associated with enhanced ischemia/reperfusion mediated injury in our non-invasive, OSA intensified model of stroke.

Characterization of autoantigenic sites on isolated dog heart mitochondria.

1. Anti-heart mitochondria autoantibodies were developed in serum from dogs following experimental myocardial infarction. 2. Heart mitochondria frozen and thawed repeatedly in a sucrose/Tris-chloride buffer retained both their functional integrity as measured by the respiratory control ratio and their ability to serve as an antigen in a complement fixation test. Mitochondria frozen and thawed in a potassium chloride/Tris-chloride buffer lost both their functional integrity and their autoantigenic activity after one freeze-thaw cycle. 3. Extraction of the heart mitochondria with acetone/water mixtures to remove phospholipids from the membrane led to a complete loss of the ability of the mitochondria to react in the complement fixation test but did not affect the ability of the membranes to bind autoantibody in absorption experiments. 4. Treatment of the mitochondrial membranes with increasing concentrations of trypsin caused a loss of up to approximately 50% of the membrane protein with a gradual decrease in the autoantigenic activity of the membrane without impairment of the ability of the membrane to bind autoantibody. 5. Removal of up to 90% of the sialic acid of the mitochondrial membrane with neuraminidase resulted in a considerable increase in the complement-fixing autoantigenic activity of the membrane without changing the apparent ability of the membrane to bind autoantibody in absorption experiments. 6. Exposure of mitochondrial membranes to autoantibody and complement caused an inhibition of both an inner mitochondrial membrane enzyme, i.e. cytochrome oxidase (48%) and an outer mitochondrial membrane enzyme, i.e. NADH cytochrome c reductase (rotenone insensitive) (37%).

Intestinal absorption of dietary fat from a liquid diet perfused in rats at a submaximum level.

The small intestine of rats was perfused in vivo for 2 h with a nutritionally complete liquid diet (68% calories from fat as corn oil). As the perfusion increased from 106 mg/2 h, the intestinal disappearance of the 14C-triolein marker remained proportional to the load up to 2,359 mg fat/2 h. Despite a decrease in absorption from 70 to 17%, this represents a very large fat intake. Fat absorption improved when medium-chain triglycerides or octanoic acid replaced corn oil (both p less than 0.01). Linoleic acid was absorbed from the diet less than corn oil (p less than 0.01). Dry ox bile reduced fat absorption (p less than 0.05); lipase and an antacid had no effect. Corn oil perfused alone was absorbed better than from the diet (p less than 0.01). Data with 14C-triolein was confirmed by dry-weight disappearance of the diet and by net intestinal water balance. Usual feeding underutilizes a large reserve for fat absorption. This reserve should be considered in therapeutic nutrition.

Cerebral transmural angiitis and ruptured aneurysm: a complication of systemic lupus erythematosus.

A 29-year-old woman with a five-year history of systemic lupus erythematosus was seen after having had a grand mal convulsion, her first manifestation of a seizure disorder. A lumbar puncture revealed the presence of subarachnoid blood, and angiography demonstrated a fusiform aneurysm of the left posterior communicating artery. The patient's neurological status deteriorated despite the use of corticosteroids in high dosage, and she died three weeks after admission. Necropsy disclosed focal transmural angiitis at the site of the ruptured aneurysm. This report describes a radiographically and pathologically confirmed case of CNS lupus producing focal angiitis of a medium-sized cerebral vessel with secondary aneurysm formation.

Cerebral ischemia in the presence of lupus anticoagulant.

Two patients with manifestations of cerebral ischemia were found to have a circulating coagulation inhibitor. This immunoglobulin, termed lupus anticoagulant, results in a prolonged partial thromboplastin time. Paradoxically, it is usually associated with a thrombotic tendency rather than a bleeding diathesis. It is most commonly found in systemic lupus erythematosus, which our patients did not have. These two patients represent the interesting phenomenon of cerebral ischemia in the presence of an endogenous inhibitor of coagulation.

Unusual effects of metrizamide lumbar myelography. Constellation of aseptic meningitis, arachnoiditis, communicating hydrocephalus, and Guillaine-Barré syndrome.

A clinical constellation of aseptic meningitis, arachnoiditis, communicating hydrocephalus, and a Guillain-Barré syndrome occurred following lumbar myelography with metrizamide. To our knowledge, Guillain-Barré syndrome has not been previously described following myelography with any contrast agent. Meningeal reactions and hydrocephalus have been reported with other agents, but this is the first instance with metrizamide.

Transcranial Doppler ultrasonography of the middle cerebral artery in the hemodynamic assessment of internal carotid artery stenosis.

We performed transcranial Doppler ultrasonography of the middle cerebral arteries in 43 patients who underwent cerebral angiography. Twelve patients had normal arteriograms, 18 had internal carotid artery stenosis, and 13 had complete occlusion. Parameters measured included: flow velocity (mean, maximum, and peak systolic), flow acceleration, systolic-to-diastolic ratio, and pulsatility index. Patients with 75% to 100% stenosis had lower average ipsilateral flow acceleration and mean velocity than did normal subjects. Correlation analysis revealed an inverse relationship between degree of stenosis and ipsilateral flow acceleration, as well as ipsilateral mean velocity. These correlations were no longer significant when we excluded normals, however. There was a linear relationship between right and left velocity values for both normal subjects and patients with occlusion but not for patients with stenosis. This technique has potential for the reliable assessment of the hemodynamic effect of carotid stenosis on intracranial circulation.

Thyroid function in Parkinson disease.

We conducted a prospective study of thyroid function in 46 patients with Parkinson disease and 46 age- and sex-matched controls with other neurologic disease. There was no statistical difference in serum thyroxine (T4) and T3 resin uptake (T3U) between the two groups. Neither the duration nor the quantity of L-dopa or carbidopa/L-dopa (Sinemet) therapy influenced these assessments of thyroid function. However, 3 of 46 Parkinson patients were hypothyroid, whereas none of 46 controls was hypothyroid. There was one hyperthyroid individual in each group. Early evaluation of thyroid function in all patients with Parkinson disease is recommended because of the unexpected frequency of hypothyroidism and because hypothyroid symptoms may be masked.

Cerebral ischemia and atrial fibrillation: prospective study.

The frequency of recurrent cerebral ischemia and death was determined prospectively in 36 patients who presented with ischemic stroke and had atrial fibrillation. Patients were followed an average of 2.3 months (range, 3 weeks to 9 months). The recurrence rate for cerebral ischemia was 33%, and the mortality rate was 22%. A beneficial effect of anticoagulation, given nonrandomly, was observed when we compared treated versus untreated patients followed for a similar length of time. Nine patients (25%), however, had CT evidence of hemorrhage associated with cerebral embolic infarction.

Sensitivity and specificity of transcranial Doppler ultrasonography in the detection of high-grade carotid stenosis.

We evaluated the ability of transcranial Doppler ultrasonography (TCD) of the middle cerebral artery to detect internal carotid artery luminal area stenosis of 70% or greater by comparing TCD with cerebral angiography in 79 subjects, including 22 with normal cerebral arteriograms and 57 with 30% to 100% internal carotid artery stenosis on at least one side. Of six TCD measurements assessed, the flow acceleration provided the greatest sensitivity (82%) and specificity (73%) in distinguishing 70% to 100% carotid stenosis from lesser degrees of stenosis. The overall accuracy of the flow acceleration was 78%, and the positive predictive value was 79%. A flow acceleration of 351.6 cm/sec2 or less was useful for detecting high-grade stenosis, but there was difficulty in distinguishing unilateral from bilateral high-grade stenosis. TCD measurement of the flow acceleration allows for fairly reliable detection of high-grade stenosis and can thus serve as a useful indirect component of a carotid noninvasive battery.

Cerebral blood flow and cerebrovascular CO2 reactivity in stroke-age normal controls.

We used the noninvasive 133-xenon inhalation technique to determine cerebral hemodynamics in 55 normal volunteers aged 18 to 88. Values for cerebral blood flow and cerebrovascular CO2 reactivity in fast-clearing tissue (flow gray) and slow-clearing tissue (flow white) were examined as functions of age and in relation to hematocrit, blood pressure, and evidence of extracranial vascular disease. Flow gray declined linearly with age, but no corresponding change was found in flow white or in CO2 reactivity. The data suggest that the progressive fall in flow gray is due to a physiologic aging process.

Two behavioral states studied in a single PET/FDG procedure: error analysis.

In a previous publication the theory, procedure, and results of a method were described for making two sequential measurements of cerebral metabolic rate for glucose (CMRglc), within a 2-hr period, using [18F]fluorodeoxyglucose. The error that is specific to this technique was estimated using computer simulations. CMRglc for the second state was sensitive to errors in (a) the values of the rate constants, (b) alignment of PET slices between the two scans, and (c) subtraction of one PET image from another. The root mean square of the average error from each error source was 6.4%, which gives the theoretical reliability of this method. The measured reproducibility, taken from our previous publication, was 4.2-6.2%, which is in good agreement with the present result. This method contributes a small additional error above that expected for two independent scans. However, independent scans done on different days are likely to be subject to larger physiological variations in CMRglc than would occur using this method.

Difficult prenatal diagnosis in mild Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 7-dehydrocholesterol (7DHC) reductase gene (DHCR7). We present our experience with prenatal diagnosis of an affected fetus with a very mild form of SLOS. The mother underwent prenatal diagnosis by chorionic villus (CV) sampling at 11 2/7 weeks because of having two prior affected sons with SLOS. The 7DHC/total-sterol ratio in the fetus was higher than in normal control fetuses but lower than the ratio observed in CV of three other fetuses in whom SLOS was diagnosed prenatally. The pregnancy was terminated at 13 2/7 weeks. The level of 7DHC in amniotic fluid (AF) obtained at the time of pregnancy termination was unequivocally elevated, confirming the diagnosis of SLOS. This report illustrates the difficulties with the interpretation of biochemical prenatal diagnosis based on the determination of 7DHC/total-sterol ratio in CV sample in a case of mild SLOS, whereas biochemical testing of amniotic fluid clearly manifests the biochemical defects of SLOS as early as 13 weeks of gestation.

Interferon (IFN)-beta 1a and IFN-beta 1b block IFN-gamma-induced disintegration of endothelial junction integrity and barrier.

Recent clinical trials indicate the efficacy of interferon (IFN)-beta 1b in reducing relapse rate in relapsing-remitting multiple sclerosis (MS), whereas a surge of IFN-gamma precedes and provokes acute relapses. Disruption of the cerebral endothelial barrier and transendothelial migration of inflammatory cell migration into the brain play a significant role in pathogenesis of MS and may be driven by this surge in IFN-gamma. However, the molecular mechanisms underlying the beneficial effects of IFN-beta 1b against the deleterious effects of IFN-gamma on the barrier formed by the junctional proteins remain to be characterized. The authors investigated the effects of IFN-beta 1b, IFN-beta 1a, and IFN-gamma on the integrity of two endothelial junctional proteins, occludin and vascular endothelial-cadherin (VE-cadherin). Human umbilical vein endothelial cell (HUVEC) layers were treated with IFN-beta 1b, IFN-beta 1a, IFN-gamma, IFN-beta 1b plus IFN-gamma, or IFN-beta 1a plus IFN-gamma. IFN-beta 1b, IFN-beta 1a, and IFN-gamma effects on occludin and VE-cadherin integrity and electrical resistance were assessed by Western blotting and immunofluorescence. IFN-gamma significantly reduced occludin expression and produced gaps in endothelial monolayers. VE-cadherin expression was decreased to a lesser extent in endothelial cells exposed to IFN-gamma. IFN-beta 1b significantly attenuated the IFN-gamma-induced decrease in occludin and VE-cadherin expression. The protective effects of IFN-beta 1a on IFN-gamma-treated endothelial cells were similar to those of IFN-beta 1b. IFN-gamma also significantly reduced endothelial monolayer electrical resistance; this effect was blocked by either IFN-beta 1a or IFN-beta 1b. IFN-beta 1a and IFN-beta 1b effectively prevent the IFN-gamma-induced disintegration of the endothelial tight junctions and sustain barrier against the effects of IFN-gamma. The protective effects of IFN-beta on occludin and VE-cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN-beta on blood brain barrier in MS.

Asymmetric somatosensory activation with right- vs left-hand stimulation: a positron emission tomographic study.

Metabolic activation of the right and left somatosensory cortices (SSC) in response to an active sensorimotor task (palpation and sorting of mah jongg tiles) was studied in 16 right-handed normal volunteers using positron emission tomography (PET) and a double-injection [18F]fluorodeoxyglucose strategy. In 8 subjects with right-hand stimulation, cerebral metabolic rate for glucose (CMRglc) in the contralateral SSC increased by 16.7 +/- 5.1% (mean +/- S.D.); the increase in the ipsilateral SSC was 4.8 +/- 3.2%. In contrast, in the 8 subjects with left-hand stimulation, the contralateral increase was 12.0 +/- 2.9% and the ipsilateral increase was 5.9 +/- 1.5%. Thus, contralateral SSC activation was significantly higher with stimulation of the right hand, while the ipsilateral/contralateral symmetry of activation was greater when the left hand was stimulated.

Elevated platelet microparticles in transient ischemic attacks, lacunar infarcts, and multiinfarct dementias.

Platelets release microparticles (PMP) upon activation. Elevated levels of PMP were observed in patients with immune thrombocytopenic purpura (ITP), sometimes associated with a syndrome resembling transient ischemic attack (TIA), suggesting a thrombogenic potential for PMP. To determine if this association applies to TIA and other cerebrovascular accidents (CVA) without ITP, we studied PMP profiles in 71 patients with ischemic CVA: 28 with small vessel CVA (SCVA), either lacunar infarcts or TIA; 24 with large vessel CVA (LCVA); 19 with multiinfarct dementia (MID); 12 with Alzheimer's dementia (AD); and 31 healthy controls. The mean PMP values were: MID = 3.71 +/- 0.51; SCVA = 3.48 +/- 0.63; LCVA = 1.97 +/- 0.28; AD = 1.19 +/- 0.27; controls = 0.88 +/- 0.09, (all units x 10(7)/mL). PMP values in all groups except AD were significantly above normal (p < 0.01). However, the elevation in SCVA was more marked than in LCVA (p < 0.01). Administration of the calcium channel blocker, nifedipine, to 11 TIA patients reduced PMP significantly.

Stroke in the postoperative period.

Stroke in the postoperative period requires a certain level of sophistication in dealing not only with the patient, but also with the family and significant others. The consultant who is called in to assess the patient must deal with the delicate matter of addressing a presumably unforeseen complication; this often requires political deftness when the surgeon is reluctant to acknowledge that anything possibly could go awry. It is the ultimate hope of all involved that the patient will have a speedy and full recovery. It is important for the patient to be evaluated properly and thoroughly in an effort to prevent a minor, reversible deficit from becoming a major, irreversible neurologic disability. Family members should have all findings and the implications of such findings thoroughly explained to them. Efforts to minimize the potential ramifications of a postoperative stroke generally are not well received and can lead to questions about the integrity of the surgical team as well as the quality of care.

Selective increase in the right hemisphere transcranial Doppler velocity during a spatial task.

Transcranial Doppler ultrasonography of the middle cerebral arteries was performed during two tasks: sorting of mah-jongg tiles and vibratory stimulation. These tasks selectively increase cerebral blood flow by positron emission tomography. The purpose of this study was to determine if analogous increases in cerebral blood flow velocity could be detected. We measured flow velocity during right hand manipulation followed by left hand manipulation, or vice versa, with resting studies in between. The average increase in the mean velocity, by paired t-test, was significant for the right middle cerebral artery with both left hand (p < .0005) and right hand (p < .005) tile sorting. For the left middle cerebral artery, there was an increase in the mean velocity with right hand (p < .005) but not for left hand sorting (p = .13). These findings support the importance of the right hemisphere in the performance of this type of spatial task. No significant flow velocity increase occurred during vibratory stimulation.

Hyperkinetic movement disorders caused by corpus striatum infarcts: brain MRI/CT findings in three cases.

Three patients with hemichorea/hemiballismus/hemidystonia caused by discrete contralateral infarction of the corpus striatum are presented. The infarcts were all small on CT or MRI brain scan and were lacunar in type. Small discrete infarction of basal ganglionic structures allows such adventitious movements to be manifested. Involvement of contiguous areas, seen with larger infarcts, can suppress such movements. The infrequency of such hyperkinetic movement disorders, and the subtle infarct appearance on brain scan, can lead to a delay in the diagnosis.