Predictors for poststroke outcomes: the Tel Aviv Brain Acute Stroke Cohort (TABASCO) study protocol.

BACKGROUND: Recent studies have demonstrated that even survivors of mild stroke experience residual damage, which persists and in fact increases in subsequent years. About 45% of stroke victims remain with different levels of disability. Identifying factors associated with poststroke cognitive and neurological decline could potentially yield more effective therapeutic opportunities. AIMS AND HYPOTHESIS: We hypothesize that data based on biochemical, neuroimaging, genetic and psychological measures can, in aggregate, serve as better predictors for subsequent disability, cognitive and neurological deterioration, and suggest possible interventions. DESIGN: The Tel-Aviv Brain Acute Stroke Cohort (TABASCO) study is an ongoing, prospective cohort study that will recruit approximately 1125 consecutive first-ever mild-moderate stroke patients. It is designed to evaluate the association between predefined demographic, psychological, inflammatory, biochemical, neuroimaging and genetic markers, measured during the acute phase, and long-term outcome: subsequent cognitive deterioration, vascular events (including recurrent strokes), falls, affect changes, functional everyday difficulties and mortality. DISCUSSION: This study is an attempt to comprehensively investigate the long-term outcome of mild-moderate strokes. Its prospective design will provide quantitative data on stroke recurrence, the incidence of other vascular events and the evaluation of cognitive, affective and functional decline. Identifying the factors associated with poststroke cognitive and functional decline could potentially yield more effective therapeutic approaches.

Thrombolytic therapy reduces red blood cell aggregation in plasma without affecting intrinsic aggregability.

Red blood cell (RBC) aggregation may contribute to occlusion of the coronary microcirculation during myocardial infarction. We studied the effect of thrombolytic therapy on RBC aggregation in patients with acute myocardial infarction (AMI). Compared with patients with myocardial infarction who did not receive thrombolytic therapy, those treated with systemic thrombolysis exhibited significantly reduced RBC aggregation, reduced plasma fibrinogen levels and increased plasma D-dimer levels. Using measurement of RBC aggregation in a standardized dextran-500 solution, reduction in RBC aggregation after thrombolysis was shown to be plasma dependent. Thrombolytic therapy had no direct effect on intrinsic RBC aggregability in patients with AMI. We conclude that thrombolytic therapy has rheologic consequences that may contribute to its overall efficacy. Inhibition of RBC aggregation by thrombolytic therapy may result from the degradation of fibrinogen, a key factor in the formation of RBC aggregates, and from the generation of fibrinogen degradation products capable of disaggregating RBCs.

Increased erythrocyte adhesiveness and aggregation in peripheral venous blood of women with pregnancy-induced hypertension.

OBJECTIVE: To study the state of erythrocyte adhesiveness/aggregation in the peripheral blood of women with pregnancy-induced hypertension as well as in matched controls using a simple slide test and image analysis. METHODS: We recruited 25 women with pregnancy-induced hypertension. Twenty-five age- and gestational age-matched normotensive volunteers took part in the study and served as controls. Blood smears were evaluated by an image analysis system (INFLAMET). Quantitative measures of erythrocyte aggregation were used to describe the state of erythrocyte adhesiveness/aggregation such as vacuum radius, which measures the spaces between the aggregated erythrocytes. The number of participants was established by power analysis (given alpha of 0.05 and 80% power and considering a minimum difference to detect 4 microm in vacuum radius with a standard deviation of approximately 5). RESULTS: A significant (P =.002) increment in the state of erythrocyte aggregation was noted in the study group compared with the controls, the vacuum radius values being 16.1 +/- 1.3 and 10.3 +/- 1.2, respectively. Erythrocyte sedimentation rate but not fibrinogen concentration was significantly elevated in the study group. The increased aggregation correlated significantly with fibrinogen concentration, systolic, and diastolic blood pressures. CONCLUSION: We observed increased aggregability of red blood cells in hypertensive conditions of pregnancy. Our findings are significant in that they reveal blood pressure-related increment in red cell adhesiveness/aggregation despite there being no significant increment in clottable fibrinogen concentrations.

Reduced leukocyte adhesiveness in response to viral versus nonviral infection/inflammation.

BACKGROUND: Viral infection differs from nonviral infection/inflammation by not producing a significant acute phase response. Since inflammation can cause increased adhesiveness of peripheral white blood cells (WBC), we compared these adhesive properties in individuals with viral infection to those with nonviral infection/inflammation. PATIENTS AND METHODS: The state of leukocyte adhesiveness/aggregation in the peripheral blood of patients with viral versus nonviral infection/inflammation was examined in 101 consecutive patients with acute febrile disease. RESULTS: A significant difference was found between the two groups; 13.6 +/- 7% for viral infection versus 22.8 +/- 8.5% for nonviral infection/inflammation (p < 0.0001). There was also a significant difference in the concentration of fibrinogen (361 +/- 109 mg/dl vs 554 +/- 172 mg/dl, p < 0.0001), and in the CD11b/CD18 cell surface expression (175 +/- 66 vs 210 +/- 100 in peripheral blood polymorphonuclear leukocytes). CONCLUSION: The results of this study could explain, at least in part, the differential adhesive behavior of the WBC in the peripheral blood in the two populations.

The erythrocyte adhesiveness/aggregation test in the peripheral blood of patients with ischemic brain events.

We adopted a simple slide test and image analysis to determine the state of erythrocyte adhesiveness/aggregation in the peripheral blood of 45 patients with acute ischemic stroke, 30 with TIA and 27 matched controls. A highly significant (P=0.005) difference was noted between patients and controls regarding the degree of erythrocyte adhesiveness/aggregation while there was no significant difference for both erythrocyte sedimentation rate or fibrinogen concentrations. We suggest that our slide test might be a low cost and real time method to detect the increased erythrocyte aggregability in the peripheral blood of patients with acute ischemic neurological events. These findings might be relevant in view of recent studies that suggest a favorable effect of therapeutic interventions directed at the improvements of this hemorrheological aspect in individuals with ischemic vascular conditions.

NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase.

Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.

Combined leukocyte and erythrocyte aggregation in the peripheral venous blood during sepsis. An indication of commonly shared adhesive protein(s).

We have used a simple slide test and image analysis to reveal the state of leukocyte and erythrocyte adhesiveness/aggregation in the peripheral blood of 28 patients with sepsis and 28 controls. A significant (P<0.00001) increment in both leukocyte and erythrocyte adhesiveness/aggregation was noted in patients compared with controls. Moreover, a significant (r=0.73, n=56, P<0.001) correlation was noted between the two adhesiveness/aggregation variables themselves, suggesting a common mechanism responsible for these adhesive phenomena. The significant correlation with fibrinogen suggests that this protein might be such a "non-specific glue." Our results indicate that a simple slide technique and image analysis can assess the aggregability of both white and red blood cells in septic patients. This might have clinical application when interventions to reduce cell aggregability are planned in order to improve blood flow in the microcirculation.

Fatal pulmonary artery thrombosis in a patient with Behçet's disease, activated protein C resistance and hyperhomocystinemia.

Behçet's disease (BD) is known for its tendency for thromboembolism, which is thought to be due to vascular injury. The important role of inherited thrombophilias is now becoming increasingly clear. However, conflicting data exist in terms of the contribution of these factors to the thrombotic risk in BD. In this case report, we describe a patient with BD who presented with severe cor pulmonale due to recurrent chronic venous thromboembolism and pulmonary artery thrombosis. The biochemical evaluation revealed that the patient was homozygotic for the factor V Leiden (R506Q) mutation and had increased levels of homocysteine. His condition deteriorated despite adequate anticoagulation treatment, and he died suddenly after 7 months of follow-up. We assume that the presence of thrombophilic risk factors augments and synergizes with the hypercoagulable state already existing in BD, leading to fatal thrombosis in this patient.

Initiation of neural induction by FGF signalling before gastrulation.

During neural induction, the 'organizer' of the vertebrate embryo instructs neighbouring ectodermal cells to become nervous system rather than epidermis. This process is generally thought to occur around the mid-gastrula stage of embryogenesis. Here we report the isolation of ERNI, an early response gene to signals from the organizer (Hensen's node). Using ERNI as a marker, we present evidence that neural induction begins before gastrulation--much earlier in development than previously thought. We show that the organizer and some of its precursor cells produce a fibroblast growth factor signal, which can initiate, and is required for, neural induction.

The appearance of L-selectin(low) polymorphonuclear leukocytes in the circulating pool of peripheral blood during myocardial infarction correlates with neutrophilia and with the size of the infarct.

BACKGROUND: It is assumed that not only leukocytosis, but also the activation of white blood cells (WBC) may play a role in the pathogenesis and prognosis of patients with myocardial infarction (MI). Activation of WBC includes upregulation of CD11b/CD18 and downregulation of CD62L (L-selectin) antigens. HYPOTHESIS: The activation of WBC is associated with the appearance of a larger MI. METHODS: CD11b/CD18 and CD62L were measured on the surface of WBC on Day 1 and Day 3 from the onset of MI. The size of the infarct with estimated by calculating the area under the curve of the creatine kinase enzyme, which was measured every 6 h. RESULTS: A negative correlation was noted between the absolute polymorphonuclear count and the availability of the CD62L on these cells during Day 1 (r = -0.46, p = 0.003) and Day 3 (r = -0.35, p = 0.05). There was a positive correlation between the size of MI and the WBC count (r = 0.46, p = 0.004) and a negative correlation with CD62L on polymorphonuclears (r = -0.35, p = 0.03). During Day 3, the CD11b/CD18 on the polymorphonuclears increased despite a decrement in the absolute number of these cells. CONCLUSION: The neutrophilia during the early phases of acute MI correspond to the appearance of the L-selectin(low) population of polymorphonuclear leukocytes. There is a correlation between the appearance of this population and the size of the infarct.

Dissociation between the state of leukocyte adhesiveness/aggregation in the peripheral blood and the availability of the CD11B/CD18 and CD62L antigens on the surface of the cells in patients with stress.

We adopted whole blood flow cytometry and direct labeling of the CD11b/CD18 and the CD62L antigens to study the relationship between their expression on the surface of peripheral leukocytes and the state of leukocyte adhesiveness/aggregation (LAA) as revealed by the leukergy test. We examined patients with infection/inflammation, acute stress and controls. The mean +/- S.D. channel fluorescence intensity of CD11b/CD18 antigen did not differ between patients with infection/inflammation (173 +/- 78) and controls (167 +/- 72). However, a significant (p < 0.0001) difference between these groups was noted regarding LAA state. There was a significant (p = 0.04) reduction in CD11b/CD18 in stress (135 +/- 60) and a significant (p < 0.001) increment in LAA. In both study groups, there was a significant reduction in CD62L. Patients were divided into those with CD11b/CD18 above and below the control's average. No correlation was found between the antigens and LAA. We assume that LAA in patients with stress state is CD11b/CD18 and CD62L independent.

Identified central neurons convey a mitogenic signal from a peripheral target to the CNS.

Regulation of central neurogenesis by a peripheral target has been previously demonstrated in the ventral nerve cord of the leech Hirudo medicinalis (Baptista, C. A., Gershon, T. R. and Macagno, E. R. (1990). Nature 346, 855-858) Specifically, innervation of the male genitalia by the fifth and sixth segmental ganglia (the sex ganglia) was shown to trigger the birth of several hundred central neurons (PIC neurons) in these ganglia. As reported here, removal of the target early during induction shows that PIC neurons can be independently induced in each side of a ganglion, indicating that the inductive signal is both highly localized and conveyed to each hemiganglion independently. Further, since recent observations (Becker, T., Berliner, A. J., Nitabach, M. N., Gan, W.-B. and Macagno, E. R. (1995). Development, 121, 359-369) had indicated that efferent projections are probably involved in this phenomenon, we individually ablated all possible candidates, which led to the identification of two central neurons that appear to play significant roles in conveying the inductive signal to the CNS. Ablation of a single ML neuron reduced cell proliferation in its own hemiganglion by nearly 50%, on the average. In contrast, proliferation on the opposite side of the ganglion increased by about 25%, suggesting the possibility of a compensatory response by the remaining contralateral ML neuron. Simultaneous ablation of both ML neurons in a sex ganglion caused similar reductions in cell proliferation in each hemiganglion. Deletion of a single AL neuron produced a weaker (7%) but nonetheless reproducible reduction. Ablation of the other nine central neurons that might have been involved in PIC neuron induction had no detectable effect. Both ML and AL neurons exhibit ipsilateral peripheral projections, and both arborize mostly in the hemiganglion where they reside. Thus, we conclude that peripheral regulation of central neurogenesis is mediated in the leech by inductive signals conveyed retrogradely to each hemiganglion by specific central neurons that innervate this target and the hemiganglion they affect.

Target-induced neurogenesis in the leech CNS involves efferent projections to the target.

During a critical period in leech embryogenesis, the sex nerves that connect the 5th and 6th midbody ganglia (MG5 and MG6) to the primordium of the male sexual organ carry a spatially localized signal that induces the birth of several hundred neurons specific to these ganglia. We examined particular cellular elements (afferents, efferents, non-neuronal components) within these nerves as potential conveyors of the inductive signal. We show that axons of peripheral sensory neurons in the male genitalia travel along the sex nerves and into MG5 and MG6, but reach the CNS after the critical period has elapsed and cannot, therefore, be involved in the induction. Of the six sex nerves, four contain non-neuronal cells that span the entire distance between the male genitalia and the sex ganglia. However, when male genitalia were transplanted to ectopic locations close to MG6, induction occurred frequently but only in MG6, mediated by ectopic nerves that do not contain these cells. Thus, non-neuronal cells specific to the normal sex nerves are not necessary for induction. In addition, dye injections into the target during the critical period failed to reveal migrating cells in the sex nerves that could convey the inductive signal to the CNS. Finally, we show that 11 pairs of central neurons in each ganglion project to the male organ early during the critical period. In the adult, at least 3 additional pairs of neurons in MG6 also innervate this target. We conclude that the only components of the sex nerves that connect the sex ganglia to the target during the critical period that could be associated with induced central mitogenesis are the axons of central neurons that innervate the male genitalia.

Neuropsychological deficits in adults with dyslexia.

Adults with severe dyslexia were compared with age-, sex-, IQ- and SES-matched controls on a neuropsychological and neuromotor test battery, and a contrast group who had recovered from dyslexia was also included. The severely dyslexic group was substantially impaired on tests of verbal fluency and learning, as well as on non-verbal temporal order judgements. These test scores were strong predictors of the degree of reading impairment, as was the rate of repetitive movement of the right hand and foot. The results suggest that adult dyslexia is not 'isolated', but is one expression of a widespread left-hemisphere dysfunction.

Sex, sin, and the church: The dilemma of homosexuality.

A parallel is suggested between the way blacks have been treated in this country with the way some people view homosexuality. A critique of the origins of the homosexuality taboo and of the argument that homosexual persons are uniquely pathological follows. Though the Judeo-Christian tradition seems to have played a negative role in the past, the contemporary church, in concert with other institutions, can generate a moral force to help overcome homophobia.

[The endocrine status in anorexia nervosa (author's transl)]. / Le status endocrinien dans l'anorexie mentale.

Alterations in the secretion of iodothyronines, cortisol, testosterone and growth hormone have previously been described in anorexia nervosa. We have studied prolactin and gonadotropins secretion in 23 cases of anorexia nervosa. Prolactin secretion was normal. Modifications in gonadotropins release were observed. However they could not be always related to weight loss since amenorrhea could either precede weight loss or still be present after return of the weight to normal. In all cases, FSH release after LHRH stimulation was normal. No increase in LH levels was observed after LHRH injection when the weight was 70% below the ideal weight. With increasing weight, LH release progressively recovered and normal LHRH-induced LH release was obtained when the weight was above 90% of the ideal weight. At normal weight, the ratio of LH/FSH was normal in patients menstruating less than 3 months after the test, while the ratio was low in non-menstruating females. In conclusion, when the weight was insufficient basal levels of FSH and LH and responses after LHRH stimulation corresponded to a prepuberal stage. An increase in the LH/FSH ratio and a normal LH/FSH ratio preceeded the recovery of menstruations. In about 1/3 of the cases, such an evolution was not observed without any satisfactory explanation. Other factors than weight may be involved, especially when the amenorrhea persists after weight recovery.

Phosphorylating-dephosphorylating enzymes of avian oviductal secretions.

Avian oviductal fluids contain phosphorylating-dephosphorylating enzymes that might function in sperm-oocyte interactions. Phosphorprotein phosphatase and protein kinase have been purified 20-fold and 40-fold, respectively. The latter easily aggregates and is highly labile. Other properties are comparable to those of holoenzymes.