Cell therapy for stroke

Increasing experimental evidence suggests that cell transplantation can enhance recovery from stroke in animal models of focal cerebral ischemia. Clinical trials have been investigating the effects of a human immortalized neuronal cell line and porcine fetal neurons in stroke victims with persistent and stable deficits. Preclinical studies are focusing on the effects of human stem cells from various sources including brain, bone marrow, umbilical cord, and adipose tissue. This review presents an overview of preclinical and clinical studies on cell therapy for stroke. We emphasize the current, limited knowledge about the biology of implant sources and discuss special conditions in stroke that will impact the potential success of neurotransplantation in clinical trials.     

Safety of latest-generation self-expanding stents in patients with NASCET-ineligible severe symptomatic extracranial internal carotid artery stenosis

BACKGROUND: Patients with symptomatic extracranial internal carotid artery stenosis (> or =70%) benefit from carotid endarterectomy when compared with medical management. However, independent risk factors can significantly increase the combined stroke and death risk after carotid endarterectomy. Carotid angioplasty and stenting (CAS) is a therapeutic option in patients who are otherwise at high risk or ineligible for carotid endarterectomy. Previous-generation self-expanding stents were hampered by length foreshortening, which limited their application in multifactorial occlusive extracranial internal carotid artery stenosis. METHODS: This is a single-center, prospective, open-label, safety study of CAS with the latest-generation self-expanding stents in patients with extracranial internal carotid artery symptomatic stenosis (> or =70%). All patients included were adjudicated to be ineligible for carotid endarterectomy by a vascular surgeon and/or a neurologist according to the exclusion criteria. Primary adverse events included death and all strokes (ipsilateral and contralateral). Secondary adverse events included transient ischemic attack, myocardial infarction, stent thrombosis, need for reintervention, and presence of hematomas. All adverse events were recorded at 24 hours, 30 days, and 6 months after CAS. RESULTS: Between June 1, 2001, and January 30, 2003, 23 consecutive patients (14 women and 9 men; mean age, 65 years; age range, 48-85 years) underwent 24 extracranial CAS procedures with the latest-generation self-expanding stents. All patients had one or multiple criteria for ineligibility according to the North American Symptomatic Carotid Endarterectomy Trial. Extracranial CAS was successful in all patients, with average residual stenosis of less than 20%. One patient (4%) experienced a stroke by the 30-day periprocedure examination. The total number of primary adverse events at 6 months after CAS was 2 strokes (9%), 1 of which was contralateral to the stent placement; there were no deaths. Twenty-two patients were asymptomatic at 6 months, with a modified Rankin scale score of 1 or less. Of the 2 patients who had a stroke, 1 had a follow-up modified Rankin scale score of 3. CONCLUSION: Extracranial CAS with the latest-generation self-expanding stents is a valid alternative treatment in high-risk or North American Symptomatic Carotid Endarterectomy Trial-ineligible patients.     

The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) is a potentially lethal complication during the first 6 months after allogeneic bone marrow transplantation (BMT). To determine whether deficiencies of EBV-specific cellular immunity contribute to EBV-LPD susceptibility and distinguish patients at risk, we performed limiting dilution analysis to quantify anti-EBV cytotoxic T-lymphocyte precursor (CTLp) frequencies in 26 recipients of unmodified or T-cell-depleted (TCD) grafts from EBV-seropositive donors. At 3 months post-BMT (n = 26), only five patients had EBV CTLp frequencies in the range of seropositive normal controls, irrespective of the type of transplant administered. By 6 months post-BMT, 9 of 13 patients tested had EBV CTLp frequencies within the normal range. The time period in which these patients had deficient cellular immunity to EBV corresponds to the period in which we have observed EBV-LPD in most prior patients. One patient with a low EBV CTLp frequency at 4 months post-BMT developed an EBV-LPD. Within 2 weeks of receiving an infusion of donor peripheral blood mononuclear cells (PBMC) providing less than 1,200 EBV- specific cytotoxic T-cell precursors, populations of EBV-specific CTL in the circulation were restored to levels detected in normal seropositive adults. Concurrently, the patient achieved a regression of the EBV-LPD, which has been sustained without further therapy. These studies indicate that recipients of both unmodified and TCD marrow grafts have profound deficiencies of EBV-specific T cell-mediated immunity early posttransplant, and that the period of risk for EBV-LPD closely corresponds to this interval of severe deficiency. Treatment of one patient with EBV-LPD with marrow donor-derived PBMC induced a rapid expansion of EBV-specific cytotoxic T-cell populations that occurred contemporaneously with the clinical regression of disease.     

Language in pediatric epilepsy

Purpose:   This study examined the severity and range of linguistic impairments in young, intermediate, and adolescent youth with epilepsy and how these deficits were associated with illness effects, nonverbal intelligence, psychopathology, and reading.
Methods:   Tests of language, intelligence, achievement, and structured psychiatric interviews were administered to 182 epilepsy youth, aged 6.3–8.1, 9.1–11.7, and 13.0–15.2 years, as well as to 102 age- and gender-matched normal children. Parents provided demographic, seizure-related, and behavioral information on their children.
Results:   Significantly more epilepsy subjects had language scores 1 standard deviation (SD) below average than the age-matched control groups did. The intermediate and adolescent epilepsy groups also had significantly lower mean language scores compared to their matched controls. The older compared to the younger epilepsy groups had more language impairment and a wider range of linguistic deficits. Longer duration of illness, childhood absence epilepsy, psychiatric diagnosis, and socioeconomic status were associated with linguistic deficits in the young group. Prolonged seizures, lower Performance IQ, and minority status predicted low language scores in the intermediate epilepsy group. In the adolescent group, language impairment was associated with poor seizure control, decreased Performance IQ, and lower socioeconomic status. Linguistic and reading deficits were significantly related in each epilepsy group.
Conclusions:   The age-related increase in linguistic impairment, different profiles of predictors in each age group, and the relationship of linguistic deficits with poor reading skills have important clinical, developmental, theoretical, and academic implications.     

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Anxiety,depression and childhood epilepsy

Anxiety and depression are relatively common in children with epilepsy: anxiety has been reported in 15–36% and depression in 8–35% of patients. In some cases these conditions may be related specifically to the epilepsy or its treatment. For example, some antiepileptic drugs are known to be associated with depression in adults and are likely to have a similar effect in young people. Emotional reactions to the epilepsy, for example anxieties and social phobia related specifically to the seizures, might be expected and require appropriate management. However, there is a growing recognition of the bidirectional relationship between epilepsy and psychiatric disorders, including depression, largely based on adult data. Cognitive behavioural therapy and serotonin reuptake inhibitors are used for treatment of both anxiety and depression in children with epilepsy. There is a need for greater understanding of the causes of these conditions in young people and there is also a need for better evidence for optimal treatment.     

Student–Teacher Relationships for Young Children with Autism Spectrum Disorder: Risk and Protective Factors

The quality of early student–teacher relationships (STRs) has been shown to predict children’s school adjustment, and children with autism spectrum disorder (ASD) are at risk for poor quality STRs. The present study examined 162 children with ASD (ages 4–7) and their teachers to evaluate student, teacher, and classroom characteristics that predicted concurrent and prospective STR quality across one school year. Child oppositional behavior, autism severity and teacher degree predicted changes in student–teacher conflict over a 1-year period, while child social skills and IQ positively predicted change in student–teacher closeness. Teacher preparedness, trainings in ASD, and classroom setting were unrelated to STR quality. Implications for intervention are discussed.     

Assessment of aldehyde dehydrogenase in viable cells

Cytosolic aldehyde dehydrogenase (ALDH), an enzyme responsible for oxidizing intracellular aldehydes, has an important role in ethanol, vitamin A, and cyclophosphamide metabolism. High expression of this enzyme in primitive stem cells from multiple tissues, including bone marrow and intestine, appears to be an important mechanism by which these cells are resistant to cyclophosphamide. However, although hematopoietic stem cells (HSC) express high levels of cytosolic ALDH, isolating viable HSC by their ALDH expression has not been possible because ALDH is an intracellular protein. We found that a fluorescent aldehyde, dansyl aminoacetaldehyde (DAAA), could be used in flow cytometry experiments to isolate viable mouse and human cells based on their ALDH content. The level of dansyl fluorescence exhibited by cells after incubation with DAAA paralleled cytosolic ALDH levels determined by Western blotting and the sensitivity of the cells to cyclophosphamide. Moreover, DAAA appeared to be a more sensitive means of assessing cytosolic ALDH levels than Western blotting. Bone marrow progenitors treated with DAAA proliferated normally. Furthermore, marrow cells expressing high levels of dansyl fluorescence after incubation with DAAA were enriched for hematopoietic progenitors. The ability to isolate viable cells that express high levels of cytosolic ALDH could be an important component of methodology for identifying and purifying HSC and for studying cyclophosphamide-resistant tumor cell populations.     

Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis

Because previous investigations have suggested that platelet activating factor and tumor necrosis factor-alpha (TNF-alpha) are important mediators of experimental necrotizing enterocolitis in the rat, we measured platelet activating factor, acetylhydrolase (the platelet activating factor breakdown enzyme), and TNF-alpha in the plasma of 12 human neonates with necrotizing enterocolitis and eight age-matched control subjects with similar gestational ages, postnatal ages, and weights. Almost all patients with necrotizing enterocolitis had elevated plasma platelet activating factor values (18.1 +/- 3.6 ng/ml vs. 3.1 +/- 0.9 ng/ml in control subjects, p less than 0.01). Plasma acetylhydrolase activity was lower in patients than in control subjects (10.6 +/- 0.7 nmol/ml/min vs 23.0 +/- 1.4 nmol/ml/min, p less than 0.01). Plasma TNF-alpha concentration was significantly elevated in patients with necrotizing enterocolitis (136 +/- 75 U/ml vs 1.5 +/- 0.8 U/ml, p less than 0.05), although the individual variation was high. There was no correlation between individual TNF-alpha and platelet activating factor levels. We conclude that platelet activating factor and TNF-alpha are elevated in patients with necrotizing enterocolitis and that suppressed platelet activating factor degradation contributes to the increased platelet activating factor levels; platelet activating factor and TNF-alpha may contribute to the pathophysiology of necrotizing enterocolitis.