Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme

In the central nervous system (CNS) complex endothelial tight junctions (TJs) form a restrictive paracellular diffusion barrier, the blood-brain barrier (BBB). During inflammation, BBB properties are frequently lost, resulting in brain edema. To investigate whether BBB leakiness correlates with molecular changes at BBB TJs, we performed immunofluorescence stainings for TJ molecules in a mouse model of experimental autoimmune encephalomyelitis (EAE) and in human tissue with glioblastoma multiforme (GBM). In TJs of healthy CNS vessels in both mouse and man we detected occludin, ZO-1, claudin-5 and claudin-3. In EAE brain and spinal cord sections we observed the selective loss of claudin-3 immunostaining from TJs of venules surrounded by inflammatory cuffs, whereas the localization of the other TJ proteins remained unchanged. In addition, selective loss of claudin-3 immunostaining was also observed in altered cerebral microvessels of human GBM. Our data demonstrate the selective loss of claudin-3 from BBB TJs under pathological conditions such as EAE or GBM when the integrity of the BBB is compromised, and therefore suggest that claudin-3 is a central component determining the integrity of BBB TJs in vivo.     

Linear scleroderma "en coup de sabre" coexisting with plaque-morphea: neuroradiological manifestation and response to corticosteroids

A 24 year old woman in the 33rd week of pregnancy developed progressive neurological complications with right sided hemiparesis in association with the occurrence of linear scleroderma "en coup de sabre" (LSCS) and pre-existing plaque-morphea, already being treated by balneophototherapy. Further progression of neurological symptoms led to a caesarean section with the delivery of a healthy child. Brain magnetic resonance imaging (MRI) showed focal T2 signal increases in the left frontoparietal region directly adjacent to the area of LSCS. Cerebrospinal fluid analysis revealed oligoclonal bands, suggesting an intracerebral inflammatory process. Subsequent pulsed corticosteroid treatment led to a remission of neurological symptoms and to a marked resolution of the MRI lesions.     

Diet Variety is Associated With Socio-economic Factors

This study examines the relationship between diet variety and socio-economic factors. The analysis included a 24-h recall and measures of socio-economic status from 6545 Koreans aged ≥ 19. Three variety measures (VM), including two diet variety scores were calculated. The more highly educated consumed a greater variety of foods than the less educated. Results suggest that VM increases faster among less educated when income increases. In summary, the diet variety of Koreans depends on their income, education, and area of residence. Among the less educated, diet variety depends more on income than it does among higher educated. Health implications of dietary variety consumed in Korea requires further attention.     

Ultrastructural evidence of calcium involvement in experimental autoimmune gray matter disease

Experimental studies have suggested that increased calcium and inappropriate calcium handling by motoneurons might have a significant role in motoneuron degeneration. To further define the involvement of calcium in motoneuron loss we used the oxalate-pyroantimonate technique for calcium fixation and monitored the ultrastructural distribution of calcium in spinal motoneurons in experimental autoimmune gray matter disease (EAGMD). In cervical and hypoglossal motoneurons from animals with relatively preserved upper extremity and bulbar function, increased calcium precipitates were present in the cytoplasm as well as in mitochondria, endoplasmic reticulum and Golgi complex without significant morphologic alterations. In surviving lumbar motoneurons of animals with hindlimb paralysis, however, there was massive morphological destruction of intracellular organelles but no significant accumulation of calcium precipitates. These findings suggest that altered calcium homeostasis is involved in motoneuron immune-mediated injury with increased calcium precipitates early in the disease process and decreased to absent calcium precipitates later in the pathogenesis of motoneuron injury.     

CD34(+) or CD34(-): which is the more primitive?

Remarkable progress has been achieved in the characterization and isolation of primitive hematopoietic stem cells (HSC). HSC represent a very small subset of hematopoietic cells and provide self-renewal, possess differentiation capacity and allow a constant supply of the entire hematopoietic cell spectrum. Until recently, CD34 has been used as a convenient marker for HSC, since CD34(+) cells have been shown to possess colony-forming potential in short-term assays, maintain long-term colony-forming potential in in vitro cultures and allow the expression and differentiation of blood cells from different hematopoietic lineages in in vivo models. Clinical and experimental protocols have targeted CD34(+) cells enriched by a variety of selection models and have readily used these for transplantation, purging and gene therapies and targets for future organ replacement. Recent studies in murine and human models, however, have indicated that CD34(-) HSC exist as well, which possess engraftment potential and distinct HSC characteristics. These studies challenge the dogma that HSC are uniformly found in the CD34(+) subset, and question whether primitive HSC are CD34(+) or CD34(-). In this review, results on murine and human CD34(+) and CD34(-) HSC, differences between them and their possible interactions are examined.     

Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture

We studied telomerase regulation and telomere length in hematopoietic progenitor cells from peripheral blood and bone marrow from patients with acute and chronic leukemia and myeloproliferative diseases. CD34+ cells from a total of 93 patients with either acute myeloid leukemia (AML; n = 25), chronic myeloid leukemia (CML; n = 21), chronic lymphocytic leukemia (CLL; n = 18), polycythemia vera (PV; n = 16), or myelodysplastic syndromes (MDS; n = 13) were analyzed before and in 19 patients after ex vivo expansion in the presence of multiple cytokines (kit ligand, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor plus erythropoietin). Compared with hematopoietic progenitor cells from normal donors (n = 108), telomerase activity (TA) was increased 2- to 5-fold in chronic phase (CP)-CML, CLL, PV, and MDS. In AML, accelerated phase (AP) and blastic phase (BP)-CML, basal TA was 10- to 50-fold higher than normal. TA of CP-CML CD34+ cells was up-regulated within 72 h of ex vivo culture, peaked after 1 week, and decreased below detection after 2 weeks. In contrast, TA in AP/BP-CML and AML CD34+ cells was down-regulated after 1 week of culture and decreased further thereafter. The expansion potential of CD34+ cells from patients with leukemia was considerably decreased compared with CD34+ cells from normal donors. The average expansion of cells from leukemic individuals was 6.5-, 2.3-, 0.6-, and 0.2-fold in weeks 1, 2, 3, and 4, respectively, whereas expansion of normal cells was 5- to 15-fold higher. In serial expansion culture, a median telomeric loss of 0.7 kbp was observed during 3-4 weeks of expansion. Our results demonstrate that up-regulation of telomerase is similar in CD34+ cells from CP-CML, CLL, PV, and MDS patients and in normal hematopoietic cells during the first week of culture, whereas in AML and AP/BP-CML, telomerase is high at baseline and down-regulated during expansion culture. High levels of telomerase in leukemic progenitors at baseline may be a feature of both the malignant phenotype and rapid cycling. Telomerase down-regulation during culture of leukemic cells may be due to the decreased expansion potential or repression of normal hematopoiesis, or in AML it may be due to the partial differentiation of AML cells, shown previously to be associated with loss of TA. Telomere shortening during ex vivo expansion correlated with low levels of TA, particularly in chronic leukemic and MDS progenitors where telomerase was insufficient to protect against telomere bp loss during intense proliferation.