Plasmodium falciparum-infected erythrocytes induce tissue factor expression in endothelial cells and support the assembly of multimolecular coagulation complexes.

BACKGROUND: Plasmodium falciparum malaria infects 300-500 million people every year, causing 1-2 million deaths annually. Evidence of a coagulation disorder, activation of endothelial cells (EC) and increase in inflammatory cytokines are often present in malaria. OBJECTIVES: We have asked whether interaction of parasitized red blood cells (pRBC) with EC induces tissue factor (TF) expression in vitro and in vivo. The role of phosphatidylserine-containing pRBC to support the assembly of blood coagulation complexes was also investigated. RESULTS: We demonstrate that mature forms of pRBC induce functional expression of TF by EC in vitro with productive assembly of the extrinsic Xnase complex and initiation of the coagulation cascade. Late-stage pRBC also support the prothrombinase and intrinsic Xnase complex formation in vitro, and may function as activated platelets in the amplification phase of the blood coagulation. Notably, post-mortem brain sections obtained from P. falciparum-infected children who died from cerebral malaria and other causes display a consistent staining for TF in the EC. CONCLUSIONS: These findings place TF expression by endothelium and the amplification of the coagulation cascade by pRBC and/or activated platelets as potentially critical steps in the pathogenesis of malaria. Furthermore, it may allow investigators to test other therapeutic alternatives targeting TF or modulators of EC function in the treatment of malaria and/or its complications.

Clinical-histopathological correlation of the abnormal retinal vessels in cerebral malaria.

BACKGROUND: Clinically abnormal retinal vessels unique to cerebral malaria have previously been shown to be associated with a poor outcome in African children. There have been no studies of the histopathological correlates of these vessels. DESIGN: This is a descriptive study of the clinical-histopathological correlates of the retinal vessels of 11 children who died with cerebral malaria. RESULTS: The retinal vessels in children with cerebral malaria contained many parasitized red blood cells; these cells tended to cluster at the periphery of vessels or, in the case of capillaries, to fill the vessel. Those with late-stage parasites had markedly reduced amounts of hemoglobin. The pattern of dehemoglobinization corresponds to the pattern of clinically abnormal vessels. CONCLUSIONS: The sequestration of late-stage parasitized red blood cells with reduced amounts of hemoglobin accounts for the unique white and pale orange retinal vessels seen in cerebral malaria. Clinical examination of these "marked" vessels offers a method to monitor a basic pathophysiological process of cerebral malaria in vivo. Arch Ophthalmol. 2000;118:924-928

Oligoclonal immunoglobulin heavy chain gene rearrangement in a childhood immunoblastic lymphoma. Presentation as a polyphenotypic atypical lymphoproliferative reaction.

The authors describe a diagnostically difficult case of childhood lymphoma that presented as an atypical polyphenotypic lymphoproliferative reaction. Initial immunophenotyping revealed the presence of IgG, IgA, kappa, and lambda within the neoplastic lymphocytes. The patient had circulating plasmacytoid lymphocytes and a polyclonal hypergammaglobulinemia. The patient died of widespread immunoblastic lymphoma in two months. Postmortem tumor DNA showed a oligoclonal pattern of immunoglobulin heavy chain gene rearrangement. Blots for T-cell receptor beta-chain rearrangement showed germline bands. Epstein-Barr virus DNA was present within tumor cells, but there was no history of prior immunosuppression or serologic evidence of Epstein-Barr virus infection. The apparent polyclonal nature of the immunoproliferation delayed the institution of chemotherapy.

Pathophysiology of fatal falciparum malaria in African children.

Children living in sub-Saharan Africa bear the brunt of the mortality from falciparum malaria, yet there is a dearth of relevant post-mortem data. Clinical studies from centers in Africa suggest that the pathophysiology of severe malaria is different in children and adults. Three overlapping clinical syndromes, metabolic acidosis manifesting as hyperpnea, cerebral malaria, and severe anemia, are responsible for nearly all the deaths in African children. Despite improvements in antimalarial treatment, there has not been a significant reduction in mortality. We review the pathology and pathophysiology of fatal falciparum malaria in African children. Many questions remain, the answers to which would facilitate the development and evaluation of new approaches to the management of this disease.

Insulin, cortisol and catecholamines do not regulate circadian variations in fibrinolytic activity.

To evaluate possible hormonal regulators of the diurnal rhythm in fibrinolytic activity, we measured tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor activity (PAI-1), t-PA antigen, insulin, cortisol, and catecholamines in 6 healthy males (age 34 +/- 5) every 2 hours for 24 hours. Fibrinolysis was characterized by a peak in PAI-1 activity and a trough in t-PA activity at 0600 h. PAI-1 activity increased 92% and t-PA activity decreased 56% between 2400 h and 0600 h. t-PA antigen (principally a measure of t-PA/PAI-1 complex), peaked at 0800 h. In comparison, insulin levels were lowest at night when PAI-1 activity was rising. The weak inverse correlation between insulin and PAI-1 activity (r = -0.28, p less than 0.02), was not sufficient to explain the diurnal change in fibrinolysis. While cortisol demonstrated the expected circadian change, the increase in cortisol did not occur until 0400 h, 4-6 hours after the rise in PAI-1 and decrease in t-PA activity started. Supine resting plasma epinephrine and norepinephrine showed no circadian rhythm. From this data, we hypothesize that the increased level of PAI-1 in the morning consumes t-PA, leading to decreased t-PA activity and increased t-PA/PAI-1 complex. Further, we conclude that insulin, cortisol, and catecholamines are not responsible for the circadian rhythm of fibrinolysis.

Rhabdomyoma of the retroperitoneum. A report of a tumor with both adult and fetal characteristics: a study by light and electron microscopy, histochemistry, and immunochemistry.

An unusual benign tumor of skeletal muscle origin is described. The tumor was located in the left retroperitoneum of a newborn female. The tumor contained features of both an adult and fetal rhabdomyoma when studied by light and electron microscopy, immunocytochemistry, and histochemistry. This is the only report of this type of neoplasm in the literature.

Survey of alpha-amylase activity and isoamylases in autopsy tissue.

We quantified total amylase and its isoenzymes in 22 different human tissues obtained at autopsy. Isoenzymes were separated by use of wheat-germ inhibition (WI) and electrophoresis on cellulose acetate (CA) and agarose (AG). Mean (+/- SD) total activity was highest in salivary glands (parotid 1710 +/- 897 U/g, submandibular 605 +/- 354 U/g), and pancreas (258 +/- 137 U/g). All other tissues contained 100- to 1000-fold less amylase. As assessed with WI, pancreas, jejunum, liver, placenta, testis, skeletal muscle, and spleen contained more than 90% pancreatic isoamylase. Salivary glands and thyroid contained more than 90% salivary isoamylase. All other tissues contained a mixture of the two isoenzymes. CA and AG often produced different results. For both CA and AG the most common pancreatic isoforms were P2 and S1. Salivary gland homogenates demonstrated a band migrating in the P3 position on CA. We conclude that both types of amylase isoenzymes can be found in tissues other than salivary gland and pancreas, but that their low total amylase concentrations diminish their clinical importance.

Three methods compared for isoamylase separation in tissue homogenates.

Using homogenates of autopsy tissue, we compared three widely available techniques for separating amylase isoenzymes: wheat-germ inhibition (WI), and electrophoresis on cellulose acetate (CA) or agarose (AG). WI separated amylase into two isoforms, CA into seven (three pancreatic and four salivary), and AG into nine (five pancreatic and four salivary). CA and WI had similar isoamylase detection limits (8-10 U/L) and similar imprecision in measuring percent S-type vs P-type isoamylase (within-run SD 1-2%), and they demonstrated a linear response to added S or P isoamylase. In contrast, the AG method had higher detection limits (10-15 U/L), greater imprecision (within-run SD 3%), and showed a nonlinear response to added S or P isomylase. We conclude that CA and WI have essentially equivalent assay attributes, superior to AG, but that CA resolves more amylase isoforms than WI.