Complicated migraine and migraine variants.

Curr Pain Headache Rep. 2002;6:233-239.
This article reviews the less frequently encountered varieties of migraine. It is suggested that these disorders be approached by evaluating possible underlying etiologies before positively diagnosing migraine. This decreases the likelihood of "missing" structural or metabolic disorders. The classification, diagnostic evaluation, differential diagnosis, and treatment options of these disorders is reviewed and a selection of references appended for additional information.
Comment: Dr. Rothner is one of the most prominent pediatric neurology headache specialists in the country, and he sees a variety of atypical presentations of migraine. This is an excellent review of such presentations. SJT     

The effect of the Fanconi anemia polypeptide, FAC, upon p53 induction and G2 checkpoint regulation

Fanconi anemia (FA) is an autosomal recessive disease marked by developmental defects, bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA cross-linking and alkylating agents and accumulate in the G2 phase of the cell cycle in response to these agents. FA cells also display genomic instability, suggesting a possible defect in the p53 pathway. To test the effect of heterologous expression of FAC cDNA on drug-induced cytotoxicity, G2 accumulation, and p53 induction in FA cells, we compared two isogenic FA cell lines: HSC536N (mock), a FA type C cell line sensitive to mitomycin C (MMC), and the same cell line transfected (corrected) with wild-type FAC cDNA (HSC536N [+FAC]). HSC536N (+FAC) cells showed a 30-fold increase in resistance to MMC concentration. Similarly, increases in resistance were observed following exposure to cisplatin, carboplatin, and cyclophosphamide. In addition, HSC536N (+FAC) cells showed a twofold lower G2 accumulation following MMC treatment. To analyze the possible interaction of FAC with the p53 pathway, we analyzed p53 induction in mock and corrected cell lines following exposure to MMC. HSC536N (mock) cells induced p53 at lower MMC concentrations than HSC536N (corrected). Caffeine, a known G2 checkpoint inhibitor, not only inhibited G2 accumulation seen in both cell lines but also caused the resistant HSC536N (+FAC) to become as sensitive to MMC as HSC536N (mock) cell line. We conclude that the FAC protein has a specific cytoprotective effect and may function as a cell cycle regulator of the G2 phase of the cell cycle.     

Soluble CD4, soluble CD8, soluble CD25, lymphopoieitic recovery, and endogenous cytokines after high-dose chemotherapy and blood stem cell transplantation

Mononuclear cell preparations from peripheral blood after mobilization with hematopoietic growth factors have been shown to induce accelerated neutrophil and platelet recovery as compared with that induced by autologous bone marrow transplantation after myeloablative chemotherapy. Because these mononuclear cell products contain many immunocompetent cells other than hematopoietic progenitors, these accessory cells might contribute to the rapid immunohematopoietic reconstitution. We have monitored the concentrations of soluble CD4 (sCD4), sCD8, and sCD25; the recovery of the lymphocyte subsets and of natural killer (NK) cells; and the endogenous levels of granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3), IL-6, and granulocyte-macrophage-CSF (GM-CSF) in 12 patients who underwent high- dose chemotherapy supported by blood stem cells that were obtained by mobilization with chemotherapy and GM-CSF. The concentrations of both G- CSF and IL-6 peaked at 7 days after reinfusion of stem cells, and this transient elevation preceded the increase in the white blood cell count by approximately 5 to 7 days. The levels of sCD4 and sCD8 increased to a maximum on day 21, and the time to peak levels coincided with the maximum increase in white blood cell count, absolute neutrophil count, or lymphocytes. The levels of sCD25 were found to be elevated from day 7 to day 21. Statistically, the increases in sCD4, sCD8, sCD25, G-CSF, and IL-6 were highly significant, whereas there were no significant changes in IL-3 and GM-CSF. A rapid recovery of the NK activity was found in all 8 of the patients who could be monitored for this assay. Therefore, our study suggests that recovery of CD4+ cells, CD8+ cells, and NK activity coincided with that of neutrophils, which is preceded by a marked, but transient, elevation of IL-6 and G-CSF.     

Binding of factor VIIa to tissue factor permits rapid antithrombin III/heparin inhibition of factor VIIa

Because free factor VIIa is inactivated only very slowly by a plasma concentration of antithrombin III (AT III) even in the presence of heparin, it has been assumed that AT III plays no significant role in regulating the initiation of tissue factor-dependent blood coagulation. However, in the present study, we present evidence that factor VIIa bound to tissue factor, unlike free factor VIIa, is readily inactivated by AT III in the presence of heparin. In a reaction mixture containing calcium ions and approximately equimolar concentrations of relipidated tissue factor (8.9 nmol/L) and factor VIIa (10 nmol/L), AT III (100 micrograms/mL) plus heparin (1 U/mL) inhibited 50% of the factor VIIa coagulant activity of the reaction mixture within 5 minutes. AT III/heparin was also shown to inhibit the catalytic activity towards factor X of factor VIIa/tissue factor complexes formed on monolayers of an ovarian carcinoma cell line (OC-2008) that constitutively expresses surface membrane tissue factor. AT III, even in the absence of exogenously added heparin, substantially inhibited the functional activity of factor VIIa/cell surface tissue factor complexes on intact monolayers. AT III alone and AT III/heparin, to a greater extent, also inhibited factor VIIa on "nonfunctional" factor VIIa/tissue factor complexes on intact monolayers, with resultant inhibition of their expression of factor VIIa/tissue factor catalytic activity toward factor X after cell lysis. The potential physiologic significance of these findings is discussed.     

Natural killer-like T-cell lymphomas: aggressive lymphomas of T-large granular lymphocytes [see comments]

Natural killer (NK)-like T cells are major histocompatibility complex- unrestricted cytotoxic T cells that are surface CD3-positive, express NK-cell antigens, and rearrange their T-cell receptor. Most neoplasms arising from this T-cell subpopulation have been a chronic lymphoproliferative disease referred to as T-large granular lymphocyte (LGL) leukemia. Only 10 NK-like T-cell lymphomas have been described in detail previously; this study presents the clinicopathologic features of six others and distinguishes these lymphomas from T-LGL leukemia. All patients presented with B-symptoms and often had marked hepatosplenomegaly without significant peripheral lymphadenopathy. Four of the six patients were immunosuppressed. All had CD3, CD8, CD56- positive tumors, presumably of hepatosplenic (n = 3), intestinal (n = 1), pulmonary (n = 1), or nodal (n = 1) origin. Three patients had lymphomatous bone marrow infiltrates, and four had peripheral blood involvement by neoplastic large lymphocytes, some of which had a blastic appearance or resembled virocytes. Azurophilic granules, ultrastructurally corresponding to cytoplasmic dense core and/or double density granules, were seen in all cases. T-cell clonality was shown in five tumors by Southern blot analysis, and three had abnormal karyotypes. Two untreated patients died 20 days after presentation, and three patients who received combination chemotherapy died within 5 months of presentation. One patient remains in complete remission 22 months after treatment. These findings suggest NK-like T-cell lymphomas are aggressive, are clinicopathologically distinct from T-LGL leukemia, and should be in the differential diagnosis of extranodal T-cell lymphoproliferations, including those in immunosuppressed patients. Furthermore, the LGL morphology, phenotype, and tissue distribution of some NK-like T-cell lymphomas suggest they arise from thymic- independent T cells of the hepatic sinusoids and intestinal mucosa.     

High molecular weight kininogen: localization in the unstimulated and activated platelet and activation by a platelet calpain(s)

High mol wt kininogen (HMWK), the major cofactor-substrate of the contact phase of coagulation, is contained within and secreted by platelets. Studies have been performed to localize platelet HMWK in both the unstimulated and activated platelet and to ascertain the effect of platelet enzymes on HMWK itself. On platelet subcellular fractionation, platelet HMWK was localized to alpha-granules, and platelets from a patient with a deficiency of these granules (gray platelet syndrome) had 28% normal platelet HMWK. Platelet HMWK, in addition to being secreted from the platelet, was also localized to the surface of the platelet when activated. Using a competitive enzyme- linked immunosorbent assay for HMWK as an indirect antibody consumption assay, the external membrane of thrombin-activated platelets as well as the releasate from these stimulated platelets had 17 ng HMWK antigen/10(8) platelets available, whereas unstimulated platelets and their supernatant had only 4.9 and 4.2 ng HMWK/10(8) platelets present, respectively. The anti-HMWK antibody consumption by activated normal platelets was specific for membrane-expressed platelet HMWK, since activated platelets from a patient with total kininogen deficiency did not adsorb the anti-HMWK antibody. Enzymes in the cytosolic fraction of platelets cleaved 125I-HMWK (mol wt 120,000) into a mol wt 100,000 polypeptide as well as smaller products at mol wt 74,000, mol wt 62,000, mol wt 47,000, and a few components below mol wt 45,000. No cleavage products were observed when DFP and leupeptin were present. The cleavage of HMWK was specifically prevented by inhibitors of calcium-activated cysteine proteases (leupeptin, N-ethylmaleimide, iodoacetamide, and EDTA) but not by inhibitors of serine proteases (DFP, benzamidine, soybean trypsin inhibitor, or aprotinin). Platelet cytosol increased the coagulant activity of exogenous purified HMWK with maximum HMWK coagulant activity (35-fold) occurring within ten minutes of exposure to platelet cytosol. Treatment of platelet cytosol with leupeptin prevented the increase in the coagulant activity of exogenous HMWK. These studies indicate that activated platelets express platelet HMWK on their external membrane and platelet enzymes can cleave and increase the coagulant activity of exogenous HMWK.     

Intra-articular amphotericin B treatment of Sporothrix schenckii arthritis

Arthritis caused by Sporothrix schenckii may not respond satisfactorily to a full course of intravenous amphotericin B therapy. Left untreated, the fungus continues to be recovered from cultures of joint fluid, and the patient typically has serious joint disability. We have shown in one patient with sporotrichosis of the knee that direct low-dose injections of amphotericin B can be performed safely, resulting in eradication of the fungus. The patient has had continued useful range of motion and weight bearing on the involved knee.