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Clients with severe mental illness received intensified vocational rehabilitation services within the context of a five-year investigation conducted at the Program of Assertive Community Treatment (PACT) in Madison, Wisconsin. The demographic, clinical, and vocational characteristics of the participants (N=63) are described, as well as the interventions and services provided. Employment outcomes are discussed, with over half the clients (n=35) achieving successful closure status. Implications of these findings for the rehabilitation of people with severe mental illness are discussed. [ABSTRACT FROM AUTHOR]

Wnt-initiated signaling through a frizzled receptor and the low-density lipoprotein-related receptor-5 coreceptor instructs key anabolic events during skeletal development, homeostasis, and repair. Recent studies indicate that Wnt signaling also regulates the intermediary metabolism of osteoblastic cells, inducing glucose consumption in osteoprogenitors and fatty acid utilization in mature osteoblasts. In this study, we examined the role of the canonical Wnt-signaling target, β-catenin, in the control of osteoblast metabolism. In vitro, Wnt ligands and agonists that stimulated β-catenin activation in osteoblasts enhanced fatty acid catabolism, whereas genetic ablation of β-catenin dramatically reduced oleate oxidation concomitant with reduced osteoblast maturation and increased glycolytic metabolism. Temporal ablation of β-catenin expression in osteoblasts in vivo produced the expected low-bone-mass phenotype and also led to an increase in white adipose tissue mass, dyslipidemia, and impaired insulin sensitivity. Because the expression levels of enzymatic mediators of fatty acid β-oxidation are reduced in the skeleton of β-catenin mutants, these results further confirm the role of the osteoblast in lipid metabolism and indicate that the influence of Wnt signaling on fatty acid utilization proceeds via its canonical signaling pathway., (Copyright © 2018 Endocrine Society.)

Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/β-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost -/- mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost -/- mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost -/- mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin's effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue., Competing Interests: The authors declare no conflict of interest.

Wnt signaling through the low-density lipoprotein-related receptor 5 (Lrp5) coreceptor regulates osteoblast maturation, matrix mineralization, and intermediary metabolism. In the mature osteoblast, signals downstream of Lrp5 are required for normal long-chain fatty acid β-oxidation. Mice rendered deficient for this coreceptor in osteoblasts and osteocytes accumulate body fat with elevated serum lipid levels but retain normal insulin sensitivity. In the present study, we challenged Lrp5-mutant mice with a high-fat diet (HFD) to determine whether they were more susceptible to diet-induced disturbances in glucose homeostasis. The HFD-fed Lrp5 mutant mice maintained a low bone mass phenotype with an increase in adipose tissue mass and hypertriglyceridemia and hypercholesterolemia. Examination of glucose metabolism revealed that Lrp5 deficiency in the osteoblast also resulted in hyperglycemia and hyperinsulinemia, with reductions in glucose tolerance, insulin sensitivity, and serum undercarboxylated osteocalcin. The results from in vivo genetic epistasis and in vitro studies suggest that this phenotype proceeds via the accumulation of diacylglycerol species and impaired insulin signaling in Lrp5-deficient osteoblasts. In turn, glucose uptake and osteocalcin production are diminished in mutant osteoblasts. Taken together, these data identify a link between Wnt-Lrp5 signaling and insulin signaling in the osteoblast that has the potential to influence energy balance and compound the detrimental effects of a HFD on whole-body metabolism., (Copyright © 2017 Endocrine Society.)

Postnatal bone formation is influenced by nutritional status and compromised by disturbances in metabolism. The oxidation of dietary lipids represents a critical source of ATP for many cells but has been poorly studied in the skeleton, where the prevailing view is that glucose is the primary energy source. Here, we examined fatty acid uptake by bone and probed the requirement for fatty acid catabolism during bone formation by specifically disrupting the expression of carnitine palmitoyltransferase 2 (Cpt2), an obligate enzyme in fatty acid oxidation, in osteoblasts and osteocytes. Radiotracer studies demonstrated that the skeleton accumulates a significant fraction of postprandial fatty acids, which was equal to or in excess of that acquired by skeletal muscle or adipose tissue. Female, but not male, Cpt2 mutant mice exhibited significant impairments in postnatal bone acquisition, potentially due to an inability of osteoblasts to modify fuel selection. Intriguingly, suppression of fatty acid utilization by osteoblasts and osteocytes also resulted in the development of dyslipidemia and diet-dependent modifications in body composition. Taken together, these studies demonstrate a requirement for fatty acid oxidation during bone accrual and suggest a role for the skeleton in lipid homeostasis.

Recent studies have identified the osteoblast as an insulin responsive cell that participates in global energy homeostasis. Here, we show that glucose transporter-4 (Glut4) is required for insulin-dependent uptake and oxidation of glucose in mature osteoblasts. In primary cultures of mouse osteoblasts, insulin increased uptake and oxidation of 14 C-glucose in a dose-dependent fashion but did not significantly affect uptake or oxidation of 14 C-oleate. In vitro, undifferentiated osteoblasts expressed 3 high-affinity Gluts: Glut1, Glut4, and Glut3. However, although levels of Glut1 and Glut3 remained constant during the course of osteoblast differentiation, Glut4 expression increased by 5-fold in association with enhanced insulin-stimulated glucose uptake. Glut4 ablation in osteoblasts in vitro eliminated insulin-stimulated glucose uptake, reduced proliferation and diminished measures of osteoblast maturation. In vivo, Glut4 expression was observed in osteoblasts, osteocytes, and chondrocytes at a level approaching that observed in adjacent skeletal muscle. To determine the importance of Glut4 in bone in vivo, we generated mice lacking Glut4 in osteoblasts and osteocytes (ΔGlut4). ΔGlut4 mice exhibited normal bone architecture but exhibited an increase in peripheral fat in association with hyperinsulinemia, β-cell islet hypertrophy, and reduced insulin sensitivity. Surprisingly, the expression of insulin target genes in liver, muscle, and adipose from ΔGlut4 mice were unchanged or increased, indicating that alterations in glucose homeostasis were the result of reduced clearance by bone. These findings suggest that Glut4 mediates insulin-stimulated glucose uptake by mature osteoblasts/osteocytes and that the magnitude of glucose use by bone cells is sufficient to impact global glucose disposal in the mouse.

Background and Purpose: A large number of patients with symptoms of acute cerebral ischemia are stroke mimics (SMs). In this study, we sought to develop a scoring system (FABS) for screening and stratifying SM from acute cerebral ischemia and to identify patients who may require magnetic resonance imaging to confirm or refute a diagnosis of stroke in the emergency setting., Methods: We designed a scoring system: FABS (6 variables with 1 point for each variable present): absence of Facial droop, negative history of Atrial fibrillation, Age <50 years, systolic Blood pressure <150 mm Hg at presentation, history of Seizures, and isolated Sensory symptoms without weakness at presentation. We evaluated consecutive patients with symptoms of acute cerebral ischemia and a negative head computed tomography for any acute finding within 4.5 hours after symptom onset in 2 tertiary care stroke centers for validation of FABS., Results: A total of 784 patients (41% SMs) were evaluated. Receiver operating characteristic curve (C statistic, 0.95; 95% confidence interval [CI], 0.93-0.98) indicated that FABS≥3 could identify patients with SM with 90% sensitivity (95% CI, 86%-93%) and 91% specificity (95% CI, 88%-93%). The negative predictive value and positive predictive value were 93% (95% CI, 90%-95%) and 87% (95% CI, 83%-91%), respectively., Conclusions: FABS seems to be reliable in stratifying SM from acute cerebral ischemia cases among patients in whom the head computed tomography was negative for any acute findings. It can help clinicians consider advanced imaging for further diagnosis., (© 2016 American Heart Association, Inc.)

The Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of β-catenin and thereby induce the expression of key enzymes required for fatty acid β-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

The hypoxia inducible factors (Hifs) are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1α in osteoanabolic signaling, we assessed the effect of Hif-1α loss-of-function on bone formation in response to intermittent parathyroid hormone (PTH). Mice lacking Hif-1α in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1α protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1α-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1α functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1α function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.

Insulin signaling in osteoblasts regulates global energy balance by stimulating the production of osteocalcin, a bone-derived protein that promotes insulin production and action. To identify the signaling pathways in osteoblasts that mediate insulin's effects on bone and energy metabolism, we examined the function of the tuberous sclerosis 2 (Tsc2) protein, a key target important in coordinating nutrient signaling. Here, we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and destabilizes Irs1, causing osteoblasts to differentiate poorly and become resistant to insulin. Young Tsc2 mutant mice demonstrate hypoglycemia with increased levels of insulin and undercarboxylated osteocalcin. However, with age, Tsc2 mutants develop metabolic features similar to mice lacking the insulin receptor in the osteoblast, including peripheral adiposity, hyperglycemia, and decreased pancreatic β cell mass. These metabolic abnormalities appear to result from chronic elevations in undercarboxylated osteocalcin that lead to downregulation of the osteocalcin receptor and desensitization of the β cell to this hormone. Removal of a single mTOR allele from the Tsc2 mutant mice largely normalizes the bone and metabolic abnormalities. Together, these findings suggest that Tsc2 serves as a key checkpoint in the osteoblast that is required for proper insulin signaling and acts to ensure normal bone acquisition and energy homeostasis.

Background and Purpose: Although transesophageal echocardiography (TEE) is the gold standard for right to left shunt detection, we observed that transcranial Doppler (TCD) was more sensitive and sought an explanation., Methods: We retrospectively evaluated results of TCD and TEE in 118 patients with cryptogenic stroke and transient ischemic attacks. TCDs were done as per modification of a published performance protocol and interpreted by a neurologist and radiologist. TEEs were performed and interpreted by five cardiologists without standardized protocol. Statistical methodology included χ(2) tests, Fisher exact tests, and ANOVA., Results: Overall agreement between TCD and TEE was found for 76 of 118 patients. Sensitivities of TCD and TEE were 93.8% and 53.1%. Sensitivities for TCD interpreters were 61.1% and 64.1%. Sensitivities for TEE operators varied from 46.7% to 75.7%. We were unable to find a performance protocol for TEE microbubble studies in either published literature or certification organizations., Conclusions: TEEs and TCDs are operator dependent and thus subject to false negatives. The lower yield and interoperator variability in TEE results appear to reflect the lack of performance protocols and engender concern about false negatives in community use. Consensus performance protocols and certification criteria for both modalities should have an impact on accuracy of shunt detection., (Copyright © 2012 by the American Society of Neuroimaging.)

This is the first published qualitative assessment of a yoga program applied in a high school setting. This qualitative interview study was nested in a randomized, controlled trial studying the effects of a yoga program offered in place of a semester of physical education classes at a rural public high school. Student interviews were conducted after taking part in a semester of the yoga program. A formal passive consent with information about the qualitative study was sent home to parents/guardians of all students in the parent study before the interviews. Most students enjoyed the yoga classes and felt benefits. Negative reports of yoga practice were associated with gender as most males sensed peer pressure against practicing yoga. Despite this finding, most students wanted to continue yoga and would continue if it were offered in school. Positive reports include a greater kinesthetic awareness, which some students associated with a greater respect for the body and improved self-image. Among students reporting psychological benefits, many cited stress reduction; many used yoga to manage negative emotions; and some propagated more optimism. Most thought yoga could reduce interest in the use of drugs and alcohol and increase social cohesion with family and peers. We found that a yoga program is feasible in this sample of 9th and 10th graders, especially after benefits are perceived. We also found evidence that yoga may lead to emergent positive benefits in health behaviors not directly prescribed by the program. These results suggest that school-based yoga programs may be appropriate for promoting healthy behaviors at a societal level by focusing on the prevention of negative patterns during the adolescent transition., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Many patients with stroke-mimicking conditions receive treatment with intravenous fibrinolysis (IVF), a treatment associated with potentially serious complications. We sought to determine if any clinical or radiographic characteristics can help predict stroke mimics among IVF candidates., Methods: This retrospective study was carried out at a single institution. Patients treated with intravenous recombinant tissue plasminogen activator (rt-PA; n = 193) were divided into 3 categories: acute ischemic stroke (n = 142), aborted stroke (n = 21), and stroke mimics (n = 30). Analysis of variance and the chi-square test were used to assess differences, while logistic regression models were computed to predict groups., Results: Mimics treated with rt-PA did not experience complications (intracranial bleeding, systemic hemorrhage, or angioedema), and had better neurologic and functional outcomes than stroke patients (P < .05). Several variables helped differentiate strokes from mimics, including atherosclerosis on computed tomographic angiography (odds ratio [OR] 23.6; 95% confidence interval [CI] 8.4-66.2), atrial fibrillation (OR 11.4; 95% CI 1.5-86.3), age >50 years (OR 7.2; 95% CI 2.8-18.5), and focal weakness (OR 4.15; 95% CI 1.75-9.8). Other variables decreased chances of stroke: migraine history (OR 0.05; 95% CI 0.01-0.4), epilepsy (OR 0.13; 95% CI 0.02-0.8), paresthesia (OR 0.1; 95% CI 0.04-0.3), and precordialgia (OR 0.045; 95% CI 0.002-0.9). A regression model using focal weakness, computed tomographic angiography findings, and precordialgia had a 90.2% predictive accuracy., Conclusions: IVF has low complication rates in stroke mimics. Certain clinical characteristics appear predictive of stroke mimics, particularly normal computed tomographic angiography. If confirmed, this may help prevent giving IVF to patients without stroke., (Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Protein superfamilies can exhibit considerable diversification of function among their members in various organisms. The DJ-1 superfamily is composed of proteins that are principally involved in stress response and are widely distributed in all kingdoms of life. The model flowering plant Arabidopsis thaliana contains three close homologs of animal DJ-1, all of which are tandem duplications of the DJ-1 domain. Consequently, the plant DJ-1 homologs are likely pseudo-dimeric proteins composed of a single polypeptide chain. We report that one A. thaliana DJ-1 homolog (AtDJ1C) is the first DJ-1 homolog in any organism that is required for viability. Homozygous disruption of the AtDJ1C gene results in non-viable, albino seedlings that can be complemented by expression of wild-type or epitope-tagged AtDJ1C. The plastids from these dj1c plants lack thylakoid membranes and granal stacks, indicating that AtDJ1C is required for proper chloroplast development. AtDJ1C is expressed early in leaf development when chloroplasts mature, but is downregulated in older tissue, consistent with a proposed role in plastid development. In addition to its plant-specific function, AtDJ1C is an atypical member of the DJ-1 superfamily that lacks a conserved cysteine residue that is required for the functions of most other superfamily members. The essential role for AtDJ1C in chloroplast maturation expands the known functional diversity of the DJ-1 superfamily and provides the first evidence of a role for specialized DJ-1-like proteins in eukaryotic development.

Background: International Consensus Criteria (ICC) consider right-to-left shunt (RLS) present when Transcranial Doppler (TCD) detects even one microbubble (microB). Spencer Logarithmic Scale (SLS) offers more grades of RLS with detection of >30 microB corresponding to a large shunt. We compared the yield of ICC and SLS in detection and quantification of a large RLS., Subjects and Methods: We prospectively evaluated paradoxical embolism in consecutive patients with ischemic strokes or transient ischemic attack (TIA) using injections of 9 cc saline agitated with 1 cc of air. Results were classified according to ICC [negative (no microB), grade I (1-20 microB), grade II (>20 microB or "shower" appearance of microB), and grade III ("curtain" appearance of microB)] and SLS criteria [negative (no microB), grade I (1-10 microB), grade II (11-30 microB), grade III (31100 microB), grade IV (101300 microB), grade V (>300 microB)]. The RLS size was defined as large (>4 mm) using diameter measurement of the septal defects on transesophageal echocardiography (TEE)., Results: TCD comparison to TEE showed 24 true positive, 48 true negative, 4 false positive, and 2 false negative cases (sensitivity 92.3%, specificity 92.3%, positive predictive value (PPV) 85.7%, negative predictive value (NPV) 96%, and accuracy 92.3%) for any RLS presence. Both ICC and SLS were 100% sensitive for detection of large RLS. ICC and SLS criteria yielded a false positive rate of 24.4% and 7.7%, respectively when compared to TEE., Conclusions: Although both grading scales provide agreement as to any shunt presence, using the Spencer Scale grade III or higher can decrease by one-half the number of false positive TCD diagnoses to predict large RLS on TEE.

Objective: Multiple sources document a higher proportion of intraparenchymal hemorrhage (HEM) in Hispanic (HIS) than white (WHI) patients with stroke. We sought an explanation for this phenomenon through analysis of multiple variables in our hospital-based stroke population., Methods: We performed univariate and multivariate analysis of risk factors in our HIS and WHI patients with stroke to identify differences that might account for a greater propensity for HEM in HIS patients., Results: Multivariate analysis disclosed that the risk of HEM correlated significantly with untreated hypertension (HTN), HIS ethnicity, and heavy alcohol intake. A negative correlation was found for hyperlipidemia and diabetes. Our HIS patients with stroke had a greater prevalence of untreated HTN and heavy alcohol intake, with HIS men being at greatest risk., Conclusions: HIS patients with stroke in our hospital-based population appear relatively more prone to HEM than do WHI patients. This risk correlates with a greater likelihood of having untreated HTN and heavy alcohol intake, more so for HIS men. The explanation appears to be a relative lack of health awareness and involvement in our health care system. The possibility that HIS ethnicity itself constitutes a biological risk factor for HEM remains a matter of speculation. Validation of this work with community data should lead to remediation through a community-based effort.

We adopted an expanded transcranial Doppler (TCD) protocol to evaluate if additional injections of agitated saline in different positions would improve shunt detection or grading. We report the safety and feasibility of this expanded contrast TCD protocol. Patients with ischemic stroke were evaluated. The standard protocol for RLS detection was followed and expanded after the initial injection in the supine position to the right lateral decubitus, upright sitting, and sitting with right lateral leaning. Changes in blood pressure, heart rate, and any subjective complaints were noted. Changes in body position and additional agitated saline injections were tolerated. Right-to-left shunt (RLS) was detected in 35% of patients (n = 55). If the initial supine testing was negative, all subsequent positions/injections were also negative for RLS. However, if the supine injection was positive for RLS, the change in body positions increased the microbubble (microB) count in eight of 19 (42%) RLS-positive patients. The mean microB count in RLS-positive patients was 20 (95% CI: 9-32). The use of three additional body positions increased the microB count to 73 (95% CI: 13-132). The highest microB yield was achieved in the upright sitting position. Our findings support the safety and feasibility of the expanded TCD protocol. If the initial supine Valsalva-aided contrast TCD test is negative, there may be no need to study the patient in additional positions. However, if microB are detected in the supine position, additional testing for RLS in alternative positions may be found to be worthwhile.

Although common carotid artery (CCA) occlusions are rare, acute clinical presentations vary from mild to devastating strokes primarily due to tandem occlusions in the intracranial arteries. Three patients with acute CCA occlusions were treated with systemic tissue plasminogen activator (TPA). Blood pressures were kept at the upper limits allowed with TPA therapy with fluid balance and the 'head-down' position. Recanalization occurred in intracranial vessels only. Marked early neurological improvement occurred in two of three patients. CCA occlusions should not be considered contra-indication to systemic thrombolysis.

Objective: To review the 8-year experience with recombinant tissue plasminogen activator (rtPA) for stroke, with commentary on ramifications for the approach to stroke treatment, directions in stroke research, and sociological aspects of stroke as a disease of concern in our society., Background: Approved in 1996, rtPA remains the only drug indicated for the treatment of ischemic stroke. Stroke treatment and research have evolved rapidly in response to opportunities and discoveries related to the advent of rtPA. The presence of rtPA has engendered an increased level of awareness about all aspects of stroke., Methodology: Literature review was performed, focusing on topics that in the author's view are of greatest relevance to the use of rtPA in clinical practice and to the directions in which the presence of rtPA is moving the field of stroke treatment, research, and politics., Results: Challenges have been raised, and met, regarding the validity of the data upon which the approval for rtPA was based. Limitations in the use of rtPA include the brief time available for treatment, the need for rapid imaging and blood-pressure control, and the fact that large-artery occlusions respond poorly. The major risk of treatment is brain hemorrhage, and although predictors of hemorrhage are known, their presence does not constitute an absolute contraindication to treatment. A virtual subindustry has evolved to enhance the benefit and applicability of rtPA through refined imaging technology and the use of rtPA intra-aterially, as well as in combination with other agents and devices. Sociopolitically, rtPA has elevated the level of awareness of stroke and provided impetus for the stroke center movement and federal legislation to stop stroke., Conclusion: The development of rtPA has been the most effective advance in the field of stroke. It has generated healthy debate regarding the design, performance, and interpretation of stroke trials, including cost-benefit considerations. rtPA has stimulated research in a multitude of areas, enhanced our understanding of stroke pathophysiology, and defined important limits and risks for urgent intervention. rtPA is the cornerstone of the stroke center movement, as well as legislation in behalf of stroke at the congressional level.

The use of tissue plasminogen activator (tPA) in community hospitals has been limited by a lack of neurologic support. The authors developed a telephone network to support community emergency departments (EDs) in the use of tPA. Their experience demonstrates equivalent results for patients treated by telephone and those treated in-house. Their number of tPA-treated patients increased 72%. Requirements included willingness of community EDs to use tPA and willingness of the stroke center to provide support.

Background and Purpose: Identification of specific features of stroke in minority populations should lead to more effectively focused treatment and prevention., Methods: We examined 1290 white (WHI), 242 Hispanic (HIS), 83 Native American (NA), and 101 other stroke and transient ischemic attack (TIA) patients hospitalized at the Barrow Neurological Institute from 1990 through 1996., Results: Chi-square analysis detected significant (P<.05) differences as follows: (1) Stroke types--lacunes more prevalent in NA than WHI and HIS (30% versus 16% and 15%); cardioembolic more prevalent in WHI than HIS (16% versus 9%, NA 14%); hemorrhages more prevalent in HIS than WHI and NA (48% versus 37% and 27%); (2) Risk factors--hypertension more prevalent in HIS than WHI (72% versus 66%; NA 71%); diabetes more prevalent in NA than HIS and WHI (62% versus 36% and 17%); cigarette smoking more prevalent in WHI than HIS and NA (61% versus 46% and 41%); cardiac disease more prevalent in WHI than HIS (34% versus 24%; NA 27%); heavier alcohol intake in NA than HIS than WHI (43% versus 24% versus 17%). There were no significant outcome differences between races for any stroke type. ANOVA detected significantly lower mean age at stroke onset in NA than HIS than WHI (56 versus 61 versus 69 years)., Conclusions: There are significant differences in prevalence of risk factors and stroke types between WHI, HIS, and NA in our hospital-based population. Although the three races appear to respond to risk factors similarly, Hispanics may be especially susceptible to hemorrhage. Further evaluation of these observations in community-based studies will be important.

A recent study reporting pontine lesions on magnetic resonance imaging in three patients with idiopathic narcolepsy postulated that the lesions represented tissue change secondary to long duration of disease. We studied twelve narcoleptic patients with MRI to validate these findings. The diagnosis of narcolepsy was established with both clinical and electrophysiological criteria in all twelve patients. Pontine lesions were present in two patients, both of whom were hypertensive. The lesions were associated with similar lesions in the hemispheres and were indistinguishable from ischemic change. No lesions were evident in the other ten patients, eight of whom were normotensive, and six of whom had narcolepsy for more than 37 years. We were unable to confirm the presence of pontine lesions specific to narcolepsy.

Background: Atherosclerotic stenosis of the middle cerebral artery (MCA) is uncommon and long-term prognosis is not well defined. Methods of treating stenosis of the MCA range from the administration of anticoagulants to endarterectomy., Methods: We present two cases of patients with focal symptomatic stenosis of the MCA with evidence of focally decreased cerebral blood flow and compromise of cerebral blood flow reserves on xenon-enhanced computed tomography (Xe CT) scanning. Endarterectomies were performed after unsuccessful anticoagulation therapy., Results: Both patients underwent successful endarterectomies of the MCA. Improvement in cerebral blood flow postoperatively was documented for both patients. At last follow-up neither patient had demonstrated any additional ischemic episodes., Conclusions: Atherosclerotic stenosis of the MCA may be responsible for distal emboli and compromised hemodynamics, and endarterectomy of this vessel may provide definitive therapy.

Intraarterial thrombolysis for acute cerebrovascular occlusion has achieved recanalization at a 50-90% rate. Clinical outcome has been unpredictable. The authors sought to test the hypothesis that intrathrombus administration of recombinant tissue plasminogen activator (rt-PA) would improve recanalization rate and to assess the possibility that clinical outcome would be predicted by the extent of collateral flow. Seven patients with acute cerebrovascular occlusion (less than six hours in 6, twenty-four hours in 1) were treated with intrathrombus rt-PA at 1 mg/minute. Examinations were scored on a five-point motor scale. Collateral flow was assessed angiographically. Vessels recanalized in 5 patients, 3 of whom had good outcomes. Vessels failed to recanalize in 2 patients, 1 of whom had good outcome. Good collateral flow was evident in all 4 patients with good outcome and in none of those with poor outcome. Intrathrombus administration of rt-PA is technically feasible. Favorable clinical outcome is more likely in the presence of good collateral flow. In the absence of good collateral flow, ultra-early intervention may be necessary.

We assessed the utility of noninvasive methods for clinical decision-making in carotid stenosis. We compared the results from magnetic resonance angiography (MRA), carotid ultrasound (CUS), and conventional carotid angiography (CCA) for 39 arteries. Noninvasive studies were graded by a 5-point diameter scale. Conventional angiograms were evaluated for percent stenosis using the North American Symptomatic Carotid Endarterectomy Trial criteria and diameter of residual lumen by caliper. Agreement was 64% between MRA and CCA, 72% between CUS and CCA, and 77% between MRA and CUS. For vessels measuring greater than 60% stenosis by CCA, sensitivity was 100% for both MRA and CUS. Specificities were 65% (MRA) and 71% (CUS), reflecting the tendency for MRA and CUS to overestimate stenosis. MRA and CUS correlated with residual lumen, even in some cases where they disagreed with the percent stenosis. We conclude that patients with normal arteries or mild stenosis as determined by MRA and CUS may be excluded from further evaluation, whereas patients with highergrade lesions should be evaluated with CCA prior to consideration for surgery. Close correlation between the results of MRA and CUS, as well as their apparent correlation with residual lumen, suggests that MRA and CUS may more accurately reflect carotid flow than does calculated percent stenosis., (Copyright © 1995 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Unlabelled: BACKGROUND. Using antibodies to a putative natural killer (NK) cell receptor (pNKR), we recently cloned a novel cDNA and localized this gene to the short arm of human chromosome 3, region 3p21-3p24. Individuals susceptible to or clinically manifesting von Hippel-Lindau disease (VHL) have a genetic defect telomeric to this region on chromosome 3. This defect, resulting in VHL, is manifested by a high incidence of certain tumors., Purpose: Based on the location of this gene, we sought to determine if VHL patients have a defect in gene expression of pNKR., Methods: Because of the proximity of the VHL and pNKR genetic regions, the variable expression of VHL tumors, and the ability of NK cells to target tumor cells, we investigated NK cell activity and other aspects of the immunologic status in 40 members (four branches) of a family with a high incidence of VHL tumors., Results: Individuals affected with VHL and lacking in normal surface expression of pNKR had virtually no NK cell lytic activity. Analysis of genotypes and phenotypes of all subjects revealed that the greatest difference in NK cell lytic activity (P = .0002) was seen when family members exhibited both VHL and pNKR surface expression defects, compared with normal relatives who had neither defect. Furthermore, the lack of NK cell activity strongly correlated (P = .0005) with abnormal pNKR protein surface expression. Of particular interest, individuals who lacked NK cell activity had normal numbers of NK cells. In addition, analysis of leukocyte subsets indicated normal numbers of T and B cells, monocytes, and NK cells in both affected and normal individuals., Conclusions: These data indicate that although all affected individuals have the cell population responsible for NK cell activity, many have cells low in expression of pNKR and lack functional NK cell activity. Overall, these results indicate that, in addition to a predisposition to the development of neoplasms, VHL patients have a defect in a specific mechanism of natural immunosurveillance that correlates with a defect in expression of a novel large granular lymphocyte pNKR protein.

In an attempt to identify the target recognition molecule(s) involved in the interaction between CD3- large granular lymphocyte (LGL) and a tumor cell target, monoclonal antibodies (mAb) to NK-susceptible K562 tumor cell membrane glycoproteins were developed. After screening by ELISA for reactivity to K562 membrane glycoproteins, two monoclonal antibodies were identified (mAb 35 and mAb 36). One of the monoclonal antibodies (mAb 36) was found to inhibit conjugation between LGL and K562 target cells and also to inhibit lysis of K562 by LGL. Upon further testing, mAb 36 also inhibited the binding between LGL and other NK-susceptible target cells, e.g., Daudi and Molt 4. In contrast, mAb 35, even though binding to K562, did not inhibit the binding of LGL to tumor targets and therefore was used as an isotype control. When mAb 36 was utilized as an affinity matrix, bound proteins specifically inhibited CD3- LGL-K562 conjugation. Experiments involving tunicamycin treatment of tumor target cells demonstrated that mAb 36 recognized a carbohydrate moiety rather than the protein core. Therefore, these data suggested that the target cell recognition molecule which is recognized by mAb 36 appears to be a membrane carbohydrate-associated molecule.

A retrospective review of 42 patients (mean age 61.4 years) with surgically managed symptomatic internal carotid artery occlusion is reported. A standardized surgical protocol aimed at restoration of flow in the vessel was used. Presenting symptoms included hemispheric transient ischemic attacks in 68% of patients, new fixed neurological deficits in 28%, amaurosis fugax in 28%, and stroke-in-evolution in 9%. Twenty-four arteries were successfully reopened. A proximal remnant angioplasty (stumpectomy) was performed alone in nine patients or in combination with an external carotid endarterectomy in nine. In four patients with persisting symptoms who failed to achieve primary restoration of flow, a superficial temporal-to-middle cerebral artery bypass procedure was performed. The permanent surgical morbidity rate was 2% and the surgical mortality rate was 0%. Transient postoperative deficits were present in three patients (7%). Follow-up review at a mean of 40 months was obtained in 39 patients (93%). Following surgical intervention, five patients died of unrelated causes, two had neurological events consistent with a transient cerebral ischemic attack, and two had vertebrobasilar insufficiency. No patient suffered from stroke. Of the 24 successfully reopened vessels, follow-up ultrasound evaluations were obtained in 17 (73%) at a mean of 28 months after surgery. In 15 patients (88%) the vessels were widely patent, one (5.8%) had stenosis greater than 70%, and one (5.8%) showed asymptomatic reocclusion. Reopening occluded internal carotid arteries in selected patients is associated with low surgical morbidity and mortality rates. Further studies are necessary to determine the impact of this surgical therapy on the natural history of this condition.

Because precipitous neurological deterioration occurred during blood pressure reduction in a seminal case of lacunar infarction, nine subsequent patients with acute partial or evolving lacunar deficits were treated with hemodilution and blood pressure nonintervention to test the hypothesis that lacunar infarction represents perfusion failure. Isovolemic hemodilution was performed using hetastarch with target hematocrit of 30-33. Pretreatment brain computed tomography, carotid ultrasound, and echocardiography were normal. Nine patients recovered normal neurological function, and two regained complete functional independence in close temporal correlation with hemodilution and within 7 days of symptom onset. Magnetic resonance imaging of the brain demonstrated appropriate single white matter lesions in nine cases. No specific risk factor combination could be identified. No patient has had recurrent stroke in follow-up from 18 to 36 months. Response to hemodilution suggests the possibility of a hemodynamic pathophysiology. Successful treatment requires (a) blood pressure nonintervention and (b) hemodilution prior to severe clinical deterioration. A controlled trial seems indicated., (Copyright © 1992 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

In an attempt to identify a molecule in target recognition by CD3- large granular lymphocytes (LGL), we have generated a rabbit antiidiotypic (anti-ID) serum against a monoclonal antibody (mAb 36) that reacted with the cell membrane of K562. Flow cytometry analysis demonstrated that the anti-ID serum bound selectively to CD3- LGL and that F(ab')2 fragments of the anti-ID serum blocked both target cell binding and lysis by NK cells. Stimulation of CD3- LGL with F(ab')2 fragments resulted in the release of serine esterases and the secretion of interferon gamma. Furthermore, anti-ID F(ab')2 antibodies crosslinked to anti-DNP F(ab')2 mediated directed cytotoxicity of a non-natural killer (NK)-susceptible mouse target (YAC-1) via this surface ligand. These functional reactivities were only removed by adsorption with the specific idiotype. Protein analysis showed that the anti-ID serum immunoprecipitated 80-, 110-, and 150-kD proteins. Using this anti-ID, a partial cDNA was cloned and an antipeptide antiserum was made against the portion of the predicted amino acid sequence that corresponded to a portion of the ID binding region. This antipeptide serum exhibited similar functional and biochemical reactivities to those observed with the anti-ID serum. These data suggest that the cell surface moiety recognized by the anti-ID and anti-p104 is novel and is selectively involved in both recognition and triggering of NK-mediated lytic function.