Hemorheological alterations in sickle cell anemia and their clinical consequences: the role of genetic modulators

Sickle cell anemia (SCA) is an autosomal recessive chronic hemolytic anemia, caused by homozygosity for the HBB:c.20A>T mutation. The disease presents with high clinical heterogeneity, stroke being the most devastating manifestation. This study aimed to identify genetic modulators of severe hemolysis and stroke risk in children with SCA, as well as understand their consequences at the hemorheological level. Sixty-six children with SCA were categorised according to their degree of cerebral vasculopathy (Stroke/Risk/Control). Relevant data were collected from patients’ medical records. Several polymorphic regions in genes related to vascular cell adhesion and tonus were characterized by molecular methodologies. Data analyses were performed using R software. Several in silico tools (e.g. TFBind, MatInspector) were applied to investigate the main variant consequences. Some genetic variants in vascular adhesion molecule-1 gene promoter and endothelial nitric oxide synthase gene were associated with higher levels of hemolysis and stroke events. They modify important transcription factor binding sites or disturb the corresponding protein structure/function. Our findings emphasize the relevance of the genetic variants in modulating the degree of hemolysis and development of cerebral vasculopathy due to their effect on gene expression, modification of protein biological activities related with erythrocyte/endothelial interactions and consequent hemorheological abnormalities in SCA.

Behavioural and histopathological alterations in mice with cerebral malaria.

Different features of sensorimotor function and behaviour were studied in murine cerebral malaria (CM) and malaria without cerebral involvement (non-CM) applying the primary screen of the SHIRPA protocol. Histopathological analysis of distinct brain regions was performed and the relative size of haemorrhages and plugging of blood cells to brain vasculature was analysed. Animals suffering from CM develop a wide range of behavioural and functional alterations in the progressive course of the disease with a statistically significant impairment in all functional categories assessed 36 h prior to death when compared with control animals. Early functional indicators of cerebral phenotype are impairments in reflex and sensory system and in neuropsychiatric state. Deterioration in function is paralleled by the degree of histopathological changes with a statistically significant correlation between the SHIRPA score of CM animals and the mean size of brain haemorrhage. Furthermore, image analysis yielded that the relative area of the brain lesions was significantly larger in the forebrain and brainstem compared with the other regions of interest. Our results indicate that assessment of sensory and motor tasks by the SHIRPA primary screen is appropriate for the early in vivo discrimination of cerebral involvement in experimental murine malaria. Our findings also suggest a correlation between the degree of functional impairment and the size of the brain lesions as indicated by parenchymal haemorrhage. Applying the SHIRPA protocol in the functional characterization of animals suffering from CM might prove useful in the preclinical assessment of new antimalarial and potential neuroprotective therapies.

Apoptosis in experimental cerebral malaria: spatial profile of cleaved caspase-3 and ultrastructural alterations in different disease stages

Cerebral malaria (CM) is associated with high mortality and morbidity as a certain percentage of survivors suffers from persistent neurological sequelae. The mechanisms leading to death and functional impairments are yet not fully understood. This study investigated biochemical and morphological markers of apoptosis in the brains of mice infected with Plasmodium berghei ANKA. Cleaved caspase-3 was detected in the brains of animals with clinical signs of CM and immunoreactivity directly correlated with the clinical severity of the disease. Caudal parts of the brain showed more intense immunoreactivity for cleaved caspase-3. Double-labelling experiments revealed processing of caspase-3 primarily in neurons and oligodendrocytes. These cells also exhibited apoptotic-like morphological profiles in ultrastructural analysis. Further, cleavage of caspase-3 was found in endothelial cells. In contrast to neurons and oligodendrocytes, apoptosis of endothelial cells already occurred in early stages of the disease. Our results are the first to demonstrate processing of caspase-3 in different central nervous system cells of animals with CM. Apoptosis of endothelial cells may represent a critical issue for the development of the disease in the mouse model. Neurological signs and symptoms might be attributable, at least in part, to apoptotic degeneration of neurons and glia in advanced stages of murine CM.

Remarks on county courts and on the alterations proposed by the late bill : with suggestions for their improvement.

Mode of access: Internet.

The covenant in the cherubim : so the Hebrew writings perfect. Alterations by Rabbies forged ... /

ESTC,

The Odyssey of Homer, translated into English blank verse, with copious alterations and notes, prepared for the press by the translator, William Cowper, esq., and published with a preface by his kinsman, J. Johnson ...

Binder's title: Cowper's works.

Aircraft alterations : plane sense.

Mode of access: Internet.

Zechariah : a new translation with notes, critical, philological, and explanatory with an appendix, in reply to Dr. Eveleigh's sermon on Zechariah II. 8-11. to which is added, (a new edition with alterations) a dissertation on Daniel IX. v. 20. to the end. /

Mode of access: Internet.

Modern geography : a description of the empires, kingdoms, states, and colonies ; with the oceans, seas, and isles ; in all parts of the world : including the most recent discoveries, and political alterations, digested on a new plan /

Mode of access: Internet.

Shakespere's plays : the separate editions of with the alterations done by various hands /

Cover title.

Report of the royal commission on the aged poor : appointed to consider whether any alterations in the system of poor law relief are desirable, in the case of persons whose destitution is occasioned by incapacity for work resulting from old age, or whether assistance could otherwise be afforded in those cases.

Mode of access: Internet.

Tabulae atomicae : the chemical tables for the calculation of quantitative analyses of H. Rose. Recalculated for the more recent determinations of atomic weights, and with other alterations and additions /

Mode of access: Internet.

Geometry without axioms; or the first book of Euclid's elements. With alterations and familiar notes; and an intercalary book in which the straight line and plane are derived from properties of the sphere ... To which is added an appendix ...

Mode of access: Internet.

The liturgy of the French Protestant church, translated from the editions of 1737 and 1772, published at Neuchatel, with additional prayers carefully selected, and some alterations. Arranged for the use of the congregation in the city of Charleston, S.C.

Acquisition date: 15Ja'45Del.

Communications between the Colonial Office and the governors of Upper and Lower Canada, on the subject of the civil government of Canada, as established by the Act of 31 Geo.III, and respecting alterations therein; and the state of the executive and legislative councils between January 1828 and January 1830.

Mode of access: Internet.