Biological significance of the different erythropoietic factors secreted by normal human early erythroid cells

Evidence is accumulating that autocrine/paracrine regulatory mechanisms play an important role in regulating normal hematopoiesis. To support this, various growth factors, cytokines and chemokines are expressed and secreted by normal early and differentiated hematopoietic cells. In this review, we summarize recent advances in the identification and understanding of the role of autocrine/paracrine axes in normal human erythropoiesis. We will also address a biological significance of the secretion of (i) metalloproteinases which in addition to growth factors and cytokines are secreted by normal erythroid cells and (ii) membrane-derived microvesicles (MV), that are shed from the surface of maturating erythroblasts/reticulocytes, and as we postulate may also play a role in intercellular communication. We hypothesize that all these factors together play an important role in a crosstalk between erythroid cells and their environment. A better understanding of intercellular crosstalk operating in normal erythropoiesis and of the mechanisms regulating synthesis of these endogenously produced factors may allow us to develop more efficient therapeutic strategies to treat various erythropoietic disorders.     

The present neurosurgical interventions in the treatment of mental disorders

The article presents contemporary views on various types of neurosurgical intervention in the treatment of mental disorders. Indications to surgical management in such cases, as well as the principles of patients qualification and exclusion criteria are discussed.     

Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice.

PURPOSE: The aim of the present study was to potentiate the antitumor effectiveness of photodynamic therapy (PDT). A cDNA microarray analysis was used to evaluate the gene expression pattern after Photofrin-mediated PDT to find more effective combination treatment with PDT and inhibitor(s) of the identified gene product(s) overexpressed in tumor cells. EXPERIMENTAL DESIGN: Atlas Mouse Stress Array was used to compare the expression profile of control and PDT-treated C-26 cells. The microarray results have been confirmed using Western blotting. Cytostatic/cytotoxic in vitro assay as well as in vivo tumor models were used to investigate the antitumor effectiveness of PDT in combination with cyclooxygenase (COX) 2 inhibitors. RESULTS: PDT induced the expression of 5 of 140 stress-related genes. One of these genes encodes for COX-2, an enzyme important in the tumor progression. Inhibition of COX-2 in vitro with NS-398, rofecoxib, or nimesulide, or before PDT with nimesulide did not influence the therapeutic efficacy of the treatment. Administration of a selective COX-2 inhibitor after PDT produced potentiated antitumor effects leading to complete responses in the majority of treated animals. CONCLUSIONS: COX-2 inhibitors do not sensitize tumor cells to PDT-mediated killing. However, these drugs can be used to potentiate the antitumor effectiveness of this treatment regimen when administered after tumor illumination.     

Kidney and hypertension

There is a unique relationship between the kidney and blood pressure (BP): on the one hand, renal dysfunction and particularly renal disease cause an increase in BP, while on the other hand, high BP accelerates loss of function of the diseased kidney. Transplantation studies, both in experimental animals and humans, documented that "blood pressure goes with the kidney," a normotensive recipient of a kidney genetically programmed for hypertension (HT) will develop HT, while conversely hypertensive patients with renal failure receiving the kidney of a normotensive donor may develop normotension. Family studies showed higher BP values and more frequent HT in first degree relatives of patients with primary glomerulonephritis or diabetic nephropathy, both type 1 and type 2. The notion that HT accelerates the loss of renal function has been proposed at the turn of the century, but definite evidence by observational and interventional studies has only been provided in the last two decades. The issue has been much confounded by the mistaken believe that damaged kidneys require higher BP values in order to function properly. The mechanisms of BP increase in renal disease comprise: salt retention, inappropriate activity of the renin-angiotensin system (RAS) and of the sympathetic nerve system as well as impaired endothelial cell-mediated vasodilatation. There is ample evidence both in primary renal disease (AIPRI and REIN trials) and in nephropathy of type 1 and type 2 diabetes (IDNT, RENAAL) that pharmacological blockade of the RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers has BP-independent renoprotective effects. More recently, it has also been shown that blockade of the sympathetic nerve system has BP-independent effects on albuminuria and on glomerulosclerosis.     

Physiological responses to a natural antioxidant flavonoid mixture,silymarin, in BALB/c mice: I induction of transforming growth factor beta1 and c-myc in liver with marginal effects on other genes

Silymarin, a mixture of flavonolignans isolated from Silybum marianum, is known for its hepatoprotective properties. We investigated the expression of cytokines in mouse liver following treatment with 0, 10, 50, and 250 mg/kg of silymarin once daily for 5 days. A dose-related but insignificant decrease of circulating alanine aminotransferase and aspartate aminotransferase after silymarin treatment was observed, suggesting that silymarin treatment did not induce hepatic damage. Silymarin treatment caused significant increases in the expressions of transforming growth factor (TGF) beta1 and c-myc in liver. No significant difference was detected among these treatments in the expression of hepatocyte growth factor, interferon gamma, tumor necrosis factor alpha, and class II major histocompatibility complex. These results suggest that alterations of TGFbeta1 and c-myc expression in the liver may be involved in the hepatoprotective effects of silymarin observed in other studies.     

Contribution of interleukin 2 and interleukin 12 receptors in signal transduction during cell activation of the immune system

Interleukin-2 (IL-2) and interleukin-12 (IL-12) belong to lympho-hematopoietic cytokines and play a critical role in the promotion and enhancement of cellular response. IL-2 as the second signal of antigenic stimulation facilitates the transition of the cell cycle from phase G1 to phase S and is responsible for the regulation of T lymphocytes proliferation and the activation of cytotoxic T cells, natural killers, macrophages and granulocytes. IL-12 is the dominant factor in T helper cells polarization leading to the secretion of IFN-gamma. Receptors for both of the cytokines (IL-2R or IL-12R) represent class I cytokine receptors composed of multiple subunits. Generally, they contain a similar extracellular conserved motif of four cysteines, and amino acid sequence--WSXWS (interacting directly with ligand) but possess no catalytic domens in the intrinsic tail of the chains. For this reason, to transfer the impact, the association with number of signaling molecules, allowing the activation of the signaling pathways is required. The connections of IL-2R or IL-12R with their ligands recruit receptor-associated cytoplasmic proteins from the JAK family (JAK1/JAK3 or JAK2/TYK2, respectively), which catalyze the phosphorylation of themselves and intrinsic tyrosine residues on the receptor, creating STAT docking sites. This phosphorylated and subsequent dimerised proteins bind rapidly to DNA and activate it. This review, presents the differences and similarities between the signaling pathways triggered by IL-2R or IL-12R ligation.     

An attempt to use Computer Assisted Orthopedic Surgery in the diagnosis and treatment of hip deformations

Background. Computer Assisted Orthopaedic Surgery (CAOS) enables complex 3D planning of surgery and the precise navigation of surgical instruments or implants during the operation. This procedure may also be helpful in preparing pelvic osteotomies, by enabling a pre-operative, virtual assessment of the results of the surgery. The purpose of this paper is to present the possibilities of our "Super Pelvis" software in assisting the diagnostics and treatment of diseases of the hip. Material and methods. We have developed a soft-ware program called "Super Pelvis," which enables 3D reconstruction of any part of the skeleton based on CT scans. It also enables 3D qualitative assessment of the whole pelvis by rotation and magnification. The material consisted of 30 dry, healthy adult skeletons gained from a medieval cemetery. In every pelvis both acetabuli were examined three times to measure the modified center-edge angles (CEA) and the anterior and posterior sector angles. The first step was a morphologic examination based on two photographs taken in frontal and transverse view. X-rays were also taken in the same views as the photographs to assess the same parameters. Then these same parameters were measured using "Super Pelvis." Results and Conclusions. All three methods of measurement have high reproducibility and there is statistically significant correlation between them. The "Super Pelvis" soft-ware seems to be useful in the precise measurement of parameters describing the acetabulum. This is the first step in creating a software package for intra-operative navigation in pelvic surgery.     

Genetic association of the serotonin transporter in pulmonary arterial hypertension

RATIONALE: The bone morphogenetic receptor type II gene is the major genetic determinant for the inherited form of pulmonary arterial hypertension. However, deleterious mutations of this gene are not observed in the majority of subjects who develop the condition spontaneously and familial disease displays age- and sex-dependent penetrance, indicating the requirement for additional environmental and/or genetic modifiers for disease development. METHODS: We investigated polymorphic variation of the serotonin transporter gene, a biological candidate for predisposition to this vascular disorder. RESULTS: No significant evidence of association between alleles of the serotonin transporter gene and pulmonary hypertension was detected, nor did we observe a relationship with age of onset in familial and idiopathic disease. CONCLUSIONS: Variation of the serotonin transporter gene appears unlikely to confer significant susceptibility to pulmonary arterial hypertension. This study emphasizes the need for adequately powered cohorts for association analyses to identify not only genetic determinants of disease susceptibility but also inherited modifiers for disease development.     

Giant osteoma of the ethmoid and frontal sinuses

The authors present a case of a huge osteoma of the ethmoid and frontal sinuses. An operative technique enabling radical removal without fragmentation of the tumor with preservation of the bony margins of the fronto-orbital region was presented.