Background and Purpose Arteriopathy is the leading cause of childhood arterial ischemic stroke (AIS). Mechanisms are poorly understood but may include inherent abnormalities of arterial structure. Extracranial dissection is associated with connective tissue disorders in adult stroke. Focal cerebral arteriopathy (FCA) is a common syndrome where pathophysiology is unknown but may include intracranial dissection or transient cerebral arteriopathy (TCA). We aimed to quantify cerebral arterial tortuosity in childhood AIS, hypothesizing increased tortuosity in dissection. Methods Children (1month-18 years) with AIS were recruited within the Vascular Effects of Infection in Pediatric Stroke (VIPS) study with controls from the Calgary Pediatric Stroke Program. Objective, multi-investigator review defined diagnostic categories. A validated imaging software method calculated mean arterial tortuosity of the major cerebral arteries using 3D time-of-flight MR angiography source images. Tortuosity of unaffected vessels was compared between children with dissection, TCA, meningitis, moyamoya, cardioembolic strokes and controls (ANOVA, post-hoc Tukey). Trauma-related versus spontaneous dissection was compared (Student's t-test). Results One hundred fifteen children were studied (median 6.8 years, 43% female). Age and sex were similar across groups. Tortuosity means and variances were consistent with validation studies. Tortuosity in controls (1.346±0.074,n=15) was comparable to moyamoya (1.324±0.038, n=15, p=0.998), meningitis (1.348±0.052, n=11, p=0.989) and cardioembolic (1.379±0.056, n=27, p=0.190) cases. Tortuosity was higher in both extracranial dissection (1.404±0.084, n=22, p=0.021) and TCA (1.390±0.040, n=27, p=0.001) children. Tortuosity was not different between traumatic versus spontaneous dissection (p=0.70). Conclusion In children with dissection and TCA cerebral arteries demonstrate increased tortuosity. Quantified arterial tortuosity may represent a clinically relevant imaging biomarker of vascular biology in pediatric stroke.
In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.
Myeloid progenitor cell cultures (CFU-C) were established in a double- layer agar system with peripheral blood mononuclear cells from 13 patients with the hypereosinophilic syndrome (HES). Normal controls produced 49% +/- 3.5% eosinophil colonies; results in 7 of the 13 HES patients were within the normal range, while in 5, the proportion of eosinophil colonies was greater than 3 standard deviations above the normal mean, and in 1 patient there was a low proportion of eosinophil colonies. The production of an increased proportion of eosinophil colonies correlated with more aggressive disease. Experiments in which normal progenitor cells were cultured over feeder layers of mononuclear cells demonstrated that cells of 3 of the 5 patients had an excess production of eosinophil colony-stimulating activity. When HES patients progenitor cells were cultured over normal feeder layers, 2 of the 5 patient samples continued to produce an increased proportion of eosinophil colonies, suggesting that these patients have an excess proportion of progenitor cells committed to eosinophil differentiation. Thus, the results demonstrated heterogeneity of growth characteristics for the HES patients. None, however, had the colony growth characteristic of acute or chronic myelogenous leukemia.
Myeloid progenitor cell cultures (CFU-C) were established in a double- layer agar system with peripheral blood mononuclear cells from 13 patients with the hypereosinophilic syndrome (HES). Normal controls produced 49% +/- 3.5% eosinophil colonies; results in 7 of the 13 HES patients were within the normal range, while in 5, the proportion of eosinophil colonies was greater than 3 standard deviations above the normal mean, and in 1 patient there was a low proportion of eosinophil colonies. The production of an increased proportion of eosinophil colonies correlated with more aggressive disease. Experiments in which normal progenitor cells were cultured over feeder layers of mononuclear cells demonstrated that cells of 3 of the 5 patients had an excess production of eosinophil colony-stimulating activity. When HES patients progenitor cells were cultured over normal feeder layers, 2 of the 5 patient samples continued to produce an increased proportion of eosinophil colonies, suggesting that these patients have an excess proportion of progenitor cells committed to eosinophil differentiation. Thus, the results demonstrated heterogeneity of growth characteristics for the HES patients. None, however, had the colony growth characteristic of acute or chronic myelogenous leukemia.
Approximately half of the colony-forming units-culture (CFU-C) from normal peripheral blood are eosinophilic. The purpose of our study was to determine: (1) whether progenitor cells committed to eosinophil or neutrophil maturation would be differentially affected by feedback inhibition, and (2) whether mature eosinophils added to the feeder layers of the culture would inhibit the proliferation of CFU-C in a manner similar to that described for neutrophils. Concentrated eosinophils and neutrophils, obtained by separation on a metrizamide gradient, were added to feeder layers containing either 10(6) autologous whole mononuclear cells (WMNC) or 0.1 ml of leukocyte conditioned media (LCM). The average number of colonies was 123/10(6) nonadherent cells (NAC) cultured. When neutrophils or eosinophils were added to the WMNC feeder layer, the percent inhibition of growth was 40.2% +/- 1.6% (mean +/- SEM) and 42.3% +/- 5.4%, respectively, but the ratio of neutrophil to eosinophil colonies remained constant. No effect was seen when neutrophils or eosinophils were added to an LCM feeder layer. Thus, it appears that the differential control of neutrophil versus eosinophil production in vitro is not regulated through feedback inhibition by mature granulocytes. In addition, these studies suggest that eosinophils, as well as neutrophils, cause inhibition of CFU-C growth when intact cells are the source of colony-stimulating factor (CSF).
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