Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes.

Sequence-specific single-stranded DNA-binding protein 2 (SSBP2) is a candidate tumor suppressor for human acute myelogenous leukemia (AML). Inducible expression of SSBP2 causes growth arrest and partial differentiation in AML cells. Here, we report that the adenoviral oncoprotein E1B55K directly binds to endogenous SSBP2 protein and sequesters it into juxtanuclear bodies in adenovirally transformed human embryonic kidney (HEK) 293 cells. Similarly, transient expression of E1B55K in IMR90 fibroblasts and HeLa cells result in the formation of juxtanuclear bodies containing SSBP2. When nuclear export of E1B55K is prevented, SSBP2 remains associated with E1B55K in nuclear foci. A requirement for intact microtubules to retain the integrity of the juxtanuclear bodies suggests them to be E1B55K containing aggresomes. The adenoviral E1B55K protein has been shown to localize to the Mre11 complex and p53 to aggresome structures; together with the viral E4orf6 protein, E1B55K recruits a cellular E3 ubiquitin ligase that induces degradation of Mre11 and p53. However, our present studies reveal that E1B55K does not degrade SSBP2. These data demonstrate that E1B55K targets the candidate leukemia suppressor SSBP2 and suggest that subverting its function may contribute to cell transformation by viral oncoproteins.

Baseline NIH stroke scale responses estimate the probability of each particular stroke subtype.

BACKGROUND: Emergency treatment of ischemic stroke should ideally be mechanism specific, but acute subtype diagnosis is problematic. Since different subtypes often are associated with specific patterns of neurological deficits, we hypothesize that scores on baseline NIH stroke scale (NIHSS) items may help emergently stratify patients by their probability of having a particular stroke subtype. METHODS: We performed multivariate polytomous logistic regression analyses on 1,281 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). We tested the predictive value of individual items to the baseline NIHSS exam, and syndromic combinations of those items, in anticipating the TOAST stroke subtype at 3 months adjusting for atrial fibrillation. We then used the most significant NIHSS items to construct a predictive model. RESULTS: The NIHSS items that discriminate between stroke subtypes are language, neglect, visual field and brachial predominance of weakness. Among patients without atrial fibrillation, a normal score for these 4 variables conveys a 46% chance of lacunar stroke, 12% of atherothrombotic stroke and 10% of cardioembolism. This pattern gradually reverses with increased numbers of abnormal responses. Those with abnormalities in all 4 items have a 0.1% chance of lacunar stroke, 50% of atherothrombotic stroke and 39% of cardioembolism. CONCLUSIONS: Language, neglect, visual fields and brachial predominance of weakness in the baseline NIHSS help discriminate between subtypes, particularly between lacunar and nonlacunar strokes. Clinical trials testing interventions aimed to particular stroke mechanisms may use these NIHSS items to emergently stratify patients based on their probability of having a particular stroke subtype.

Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia: a matched-pair analysis. Berlin-Frankfurt-Münster Study Group.

PURPOSE: The translocation t(9;22)(q34;q11), known as Philadelphia chromosome (Ph1) or its molecular equivalent the expression of BCR-ABL-mRNA, is one of the most striking and well-characterized cytogenetic abnormalities in leukemia. Although investigated for more than 30 years, it remains unclear whether the Ph1 is an independent risk factor for outcome of leukemia or not. METHODS: A matched-pair analysis was performed within a homogeneous group of patients, which consisted of children who presented with a first relapse of acute lymphoblastic leukemia (ALL) who were treated according to ALL relapse trials (ALL-REZ BFM) protocols. A total of 307 patients were eligible for this analysis: 30 positive and 277 negative for Ph1. Positive patients were matched exactly for time point of relapse (on [during] or off [after cessation of] front-line therapy), site, and immunophenotype, and as close as possible for duration of first remission, peripheral blast-cell count, WBC count, and year of relapse diagnosis. RESULTS: The probability of event-free survival is 0.46 at 5 years for negative and 0.11 for positive patients, respectively (P = .0006). Multivariate analysis showed risk ratios of 4.229 for relapse on therapy, 3.561 for Ph1 and/or expression of BCR-ABL- mRNA, 1.691 for high peripheral blast-cell count, and 0.232 for bone marrow transplantation. CONCLUSION: It was shown that the Ph1 is indeed an independent risk factor in childhood relapsed ALL. There are striking similarities between these patients and children at initial diagnosis, as well as adult patients. Therefore, it is highly suggestive that the Ph1 is also an independent risk factor under all of these circumstances.

Effect of prior aspirin use on stroke severity in the trial of Org 10172 in acute stroke treatment (TOAST).

BACKGROUND AND PURPOSE: Although the efficacy of aspirin in reducing stroke incidence is clear, its role in reducing stroke severity is disputed. This study compares stroke severity between patients who did or did not take aspirin in the week before stroke and enrollment in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). METHODS: Of 1275 patients randomized, 509 reported aspirin use in the week before stroke; 766 did not. Clinical stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Supplementary Motor Examination (SME) at trial entry and at 3 months. Using these scales, we compared the categorization of stroke severity (mild, moderate, and severe) and mean scores between aspirin users and nonusers. RESULTS: The difference in distribution of baseline NIHSS scores was statistically significant between aspirin users and nonusers (P=0.006), with a greater percentage of milder strokes among aspirin users. The difference in mean baseline NIHSS scores was also significantly lower in aspirin users (8.2) and nonusers (9.3) (P=0.003). The distribution of baseline SME scores and mean SME scores also showed lower stroke severity in aspirin users than in nonusers (P=0.048 and P=0.004, respectively). At 3 months, differences in stroke severity measured by the SME but not the NIHSS remained statistically significant. Seven-day and 3-month mortality did not differ significantly. CONCLUSIONS: In this study aspirin use is associated with milder clinical deficits at stroke onset. These deficits may affect prognosis and influence response to treatment. Future clinical trials should ensure that prestroke aspirin use is comparable in study groups.

Treating ischemic stroke as an emergency.

The success of treatment with tissue plasminogen activator serves as an impetus to approach stroke as a medical emergency; diagnosis and treatment must be accurate and prompt. The initial evaluation should be straightforward and aimed at confirming ischemic stroke as the cause of the patient's acute neurologic impairments. Until the usefulness of diagnostic tests to demonstrate an arterial occlusion is established in emergent management, their application before treatment should not be mandated. Most individuals with acute ischemic stroke will receive their initial, key treatment in a community setting. Thus, strategies for emergent treatment should aim at management of patients whose strokes are diagnosed and first treated by emergency treatment and primary care physicians with the collaboration of neurologists.

Usefulness of heparin in initial management of patients with recent transient ischemic attacks.

We evaluated the efficacy of short-term intravenous heparin therapy in 74 patients with recent transient ischemic attacks (TIAs). The patients were treated after hospitalization until operation or long-term medical treatment was instituted. Heparin was given in a continuous infusion to maintain an activated partial thromboplastin time of 1 1/2 to 2 1/2 times control values. During the treatment period, 12 patients (16.2%) had recurrent TIAs and five (6.8%) had cerebral infarction. Bleeding complications occurred in nine patients (12.2%). In this limited series, heparin did not prevent recurrent TIAs or cerebral infarction among high-risk patients with recent TIAs.

Neurologic aspects of hereditary hemorrhagic telangiectasia. Report of two cases.

The several neurologic manifestations of hereditary hemorrhagic telangiectasia (HHT) may be caused by complications of pulmonary arteriovenous fistulae or associated central nervous system vascular malformations. The presence of skin and mucosal telangiectases should alert the clinician to the possibility of the disorder and in turn of its potential for associated neurologic disease, including cerebral hemorrhage and abscess. This report describes two cases and demonstrates that the clinical spectrum of HHT should be enlarged to include its admittedly rare, but serious, neurologic aspects.

Nontraumatic intracerebral hemorrhage in young adults.

We reviewed our experience with 72 patients, aged 15 to 45 years, who were hospitalized for nontraumatic intracerebral hemorrhages (ICHs) between 1978 and 1985. Evaluation included arteriography in 61 patients. Computed tomography demonstrated 41 lobar, 11 putaminal, four thalamic, four pontine, four intraventricular, two caudate, two midbrain, two cerebellar, one globus pallidum, and one corpus callosum hemorrhage. Forty-three patients, with either progressive neurologic deterioration, arteriovenous malformations (AVMs), or saccular aneurysms underwent surgery. The overall in-hospital survival, including those patients treated medically, was 87.5%. A presumed cause for the ICH was found in 55 (76.4%) patients. The main causes were ruptured arteriovenous malformations (21), hypertension (11), ruptured saccular aneurysms (seven), and sympathomimetic drug abuse (five). Surgical explorations demonstrated a necrotizing angiitis in one patient and arteriovenous malformations in two patients who had negative arteriograms. Young patients with nontraumatic ICHs represent a heterogeneous group. A cause can be established in most patients. Arteriovenous malformations account for less than one third of the hemorrhages in young adults, and other causes should be sought.

Limb-shaking carotid transient ischemic attacks successfully treated with modification of the antihypertensive regimen.

Involuntary episodic movements associated with transient cerebral ischemia are a rare but well-described presentation of carotid artery occlusive disease. We describe a young man with a left carotid artery occlusion who presented with daily episodes of involuntary movements of the right side that occurred for months. His symptoms virtually disappeared after his antihypertensive drug was reduced. This case supports the possibility of noninvasive management of this condition, which is traditionally treated with revascularization procedures.

Early computed tomographic abnormalities following profound cerebral hypoxia.

A patient became deeply comatose following a prolonged episode of cerebral hypoxia. Computed tomography performed within the first 24 hours showed marked hypodensity of the cerebral and cerebellar cortices, and the caudate and lenticular nuclei. These findings paralleled the distribution of typical hypoxic changes noted at postmortem examination. Computed tomographic abnormalities such as these may prove useful in establishing an early diagnosis of profound cerebral hypoxia.

Stroke in renal transplant recipients.

Cerebrovascular events are the most common neurological complications seen in renal transplant recipients. Cerebral infarction and transient ischemic attacks are the most common events and may occur years after transplantation. Recipients older than 40 years at the time of transplantation and those with diabetes mellitus are at greater risk. No instances of aneurysmal subarachnoid hemorrhage occurred among 31 patients with polycystic kidney disease who had undergone transplantation.

Nonhemorrhagic cerebral infarction in young adults.

We evaluated 144 patients (81 males and 63 females) aged 15 to 45 years who had nonhemorrhagic cerebral infarction. Atherosclerotic cerebral infarction was diagnosed in 38 patients. Potential cardiac causes of cerebral embolism were found in 33 patients. Only three events could be attributed to mitral valve prolapse. Hematologically related disorders were diagnosed in 21 patients, while 38 patients had nonatherosclerotic vasculopathies. Young patients with cerebral infarction are a heterogeneous group. A potential cause can be found in most patients. We found more than 40 possible etiologies among our patients. Mitral valve prolapse apparently is not a common cause of cerebral infarction among young adults. Cerebral infarction should not be ascribed to oral contraceptives or migraine until other possible causes have been eliminated.

Hemiplegic migraine induced by exertion.

BACKGROUND: It is known that exertion can aggravate migraine headache. However, the relationship between exertion and migraine aura is unknown. OBJECTIVE: To study the relationship between exertion and migraine aura. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENT: A 67-year-old man presented with recurrent attacks of exertion-induced hemiplegic migraine. Since the hemiparetic attacks were exertion induced, they were initially ascribed to recurrent transient ischemic attacks. However, the clinical picture, normal findings on cerebral angiography and neuroimaging (during the period of hemiparesis), lack of response to treatment with antiplatelets and anticoagulants, and successful treatment with verapamil suggested that the hemiparesis was not due to ischemia, but was indeed a migraine aura. We suggest that exertion induced the aura of hemiparesis by lowering the threshold for the development of cortical spreading depression. Even though our patient had no family history of hemiplegic migraine, a mutation in an ion channel gene (eg, the CACNA1A gene on chromosome 19) might account for his episodic attacks. CONCLUSION: Migraine aura should be included in the differential diagnosis of exertion-induced focal neurologic deficit.

Intracranial hemorrhage produced by spontaneous dissecting intracranial aneurysm.

Two patients with intracranial dissecting aneurysms were seen initially because of acute hemorrhage. One patient died, and a false dissecting aneurysm secondary to atherosclerosis was found at autopsy. In the other patient, the appearance of the carotid arteriogram was typical of a dissection. Because of the propensity of these aneurysms to rupture, caution is indicated in the use of anticoagulants or vasopressors in patients with evolving cerebral infarction secondary to intracranial arterial dissection.

Antifibrinolytic therapy in patients with aneurysmal subarachnoid hemorrhage. A report of the cooperative aneurysm study.

Antifibrinolytic therapy was used in 1,114 patients who had aneurysmal subarachnoid hemorrhage (SAH) and who were treated by the 13 institutions of the Cooperative Aneurysm Study. Patients were started on treatment within one week after SAH was diagnosed, and therapy was discontinued 14 days after the ictus. Rebleeding occurred in 10% of the treated patients. Overall mortality among the treated patients during the two weeks following hemorrhage was 10.7%. Though some minor and a few major side effects occurred, serious complications of therapy were infrequent.

Global aphasia without hemiparesis.

Three patients acutely developed global aphasia, but did not manifest the typical accompanying right hemiparesis. Computed tomography and magnetic resonance imaging studies demonstrated that the patients had two discrete left hemisphere lesions, one in the anterior language cortices or language-related subcortical areas, and one in the posterior language cortices. Cerebral angiography showed that two patients had complete occlusion of the left internal carotid artery, and the third had an intraluminal "clot" in the supraclinoid portion of the left internal carotid, findings suggestive of an embolic etiology. Our cases indicate that global aphasia without hemiparesis predicts two discrete lesions and a particularly good recovery of speech and language.

Intracranial operation within seven days of aneurysmal subarachnoid hemorrhage. Results in 150 patients.

We evaluated the results of intracranial operation in 150 consecutive patients surgically treated within seven calendar days of aneurysmal subarachnoid hemorrhage (SAH). Patients in all clinical grades, except those who were moribund, were treated. Those with either anterior or posterior circulation aneurysms were included. On follow-up assessment, favorable outcomes were noted in 107 patients (71%), 17 had major disabilities (11%), and 26 had died (17%). During hospitalization, vasospasm was diagnosed in 63 patients (42%) and rebleeding occurred in 39 (25%). Operations were performed throughout the first week after SAH; results of operation were similar on each day. A lower rate of good recovery was observed among patients operatively treated four to seven days after SAH than among those operated on earlier. The admitting neurologic condition influenced outcome after early operation, but age did not have a major impact. We find that aneurysm surgery can be performed within one week of SAH with acceptable results, although there is room for improvement.

Cigarette smoking. A risk factor for cerebral infarction in young adults.

To assess the impact of cigarette smoking on stroke in young adults (15 to 45 years old), we compared smoking data from 181 patients with cerebral infarction with that of 307 control subjects matched for age, gender, geographic location, and hospital admission dates. While controlling for these matching variables and hypertension, an analysis based on a conditional logistic regression model indicated that a smoker was 1.6 times more likely to have a cerebral infarction than a non-smoker (95% confidence interval, 1.07 to 2.42). There was a cumulative dose effect with each additional pack-year causing a greater risk of having a cerebral infarction. In fact, after adjusting for all other risk factors, there was a significant quadratic component to the dose-response relationships, with the result that individuals with a larger number of pack-years were invariably the stroke patients. There was no significant difference in smoking status among the various subtypes of cerebral infarction (atherosclerotic, nonatherosclerotic vasculopathy, cardioembolic, hematologic related, undetermined). These data indicate that cigarette smoking is an important risk factor for cerebral infarction in young adults. Risk factor modification through cessation of smoking may reduce the risk of ischemic stroke in young adults.

Magnetic resonance imaging in young adults with cerebral infarction due to moyamoya.

The number, size, and location of cerebral infarctions, and blood flow in the middle cerebral artery as seen on proton magnetic resonance imaging were assessed in six white adults with angiographically documented moyamoya. Findings were correlated with clinical presentation, computed tomography, and angiography. Large hemispheric infarctions were found in five hemispheres, predominantly in watershed regions. Subcortical infarctions (n = 56) were found in all hemispheres. They were predominantly located in the centrum semiovale, in the distal beds of supply of the penetrating branches of the anterior and middle cerebral arteries. Infarction of the putamen was found in three hemispheres, caudate nucleus in four, globus pallidus in two, and anterior limb of the internal capsule in two. There were none in the posterior limb of the internal capsule, thalamus, brain stem, or cerebellum. Middle cerebral artery flow was visualized as a signal-void flow sign in only three hemispheres. Cerebral infarctions due to moyamoya are bilateral, multiple, often small, and asymptomatic, affecting predominantly the carotid circulation in watershed regions. Subcortical infarctions in the centrum semiovale and large hemispheric infarctions in hemodynamically compromised areas are the predominant findings.