Epidural malignant lymphomas of the spine: collected experiences with epidural malignant lymphomas of the spinal canal and their treatment

STUDY DESIGN: Retrospective study of 13 patients treated by the authors. OBJECTIVE: To examine the course of the disease of malignant lymphoma (ML) presenting in the epidural area of the spine. SETTING: Department of Neurosurgery, Third Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. SUBJECTS AND METHODS: The epidural presentation in eight patients was heralded by motor signs (paraparesis and plegia), in one by a lesion of the posterior columns of the spinal cord (ataxia), and in three by pain. One patient was free of complaints and symptoms. The affected epidural area was diagnosed previously by myelography and computerized tomography (CT), and later by magnetic resonance (MR), over the course of which the location was verified as thoracic in eight patients, cervical in one, and lumbar in four. The authors recommended surgical intervention in 9 out of 13 cases, in seven cases of Hodgkin's and six cases of non-Hodgkin's lymphoma. Seven patients were treated for recognized manifestations of malignant lymphoma while six were diagnosed by intraoperative-histological examination. RESULTS AND CONCLUSION: The decompression operations for tumors resulted in limited improvement in seven patients (reduction in pain and return of ability to walk). Four patients were not operated on, two of which had significant improvement in their neurological symptoms. Paraparesis remained unchanged in one patient. One patient remained symptom-free. The authors emphasize the importance of interdisciplinary consultation and weighing individual priorities in the indications for operation on epidural ML.     

Dendritic nicotinic receptors modulate backpropagating action potentials and long-term plasticity of interneurons

Stratum radiatum interneurons, unlike pyramidal cells, are rich in nicotinic acetylcholine receptors (nAChRs); however, the role of these receptors in plasticity has remained elusive. As opposed to previous physiological studies, we found that functional α7-subunit-containing nAChRs (α7-nAChRs) are abundant on interneuron dendrites of rats. Moreover, dendritic Ca²⁺ transients induced by activation of α7-nAChRs increase as a function of distance from soma. The activation of these extrasynaptic α7-nAChRs by cholinergic agonists either facilitated or depressed backpropagating action potentials, depending on the timing of α7-nAChR activation. We have previously shown that dendritic α7-nAChRs are involved in the regulation of synaptic transmission, suggesting that α7-nAChRs may play an important role in the regulation of the spike timing-dependent plasticity. Here we provide evidence that long-term potentiation is indeed boosted by stimulation of dendritic α7-nAChRs. Our results suggest a new mechanism for a cholinergic switch in memory encoding and retrieval.     

Bayesian spatial risk prediction of Schistosoma mansoni infection in western Côte d'Ivoire using a remotely-sensed digital elevation model

An important epidemiologic feature of schistosomiasis is the focal distribution of the disease. Thus, the identification of high-risk communities is an essential first step for targeting interventions in an efficient and cost-effective manner. We used a remotely-sensed digital elevation model (DEM), derived hydrologic features (i.e., stream order, and catchment area), and fitted Bayesian geostatistical models to assess associations between environmental factors and infection with Schistosoma mansoni among more than 4,000 school children from the region of Man in western C?te d'Ivoire. At the unit of the school, we found significant correlations between the infection prevalence of S. mansoni and stream order of the nearest river, water catchment area, and altitude. In conclusion, the use of a freely available 90 m high-resolution DEM, geographic information system applications, and Bayesian spatial modeling facilitates risk prediction for S. mansoni, and is a powerful approach for risk profiling of other neglected tropical diseases that are pervasive in the developing world.     

Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters

Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells.     

On sampling of fragment space

Fragment-based lead discovery has over the years matured into an attractive alternative to high-throughput screening (HTS) for lead generation. Several techniques for screening libraries of typically 10(3)-10(4) fragments have been reported. In this work, the practical success rates that can be expected from the screening of fragment-like libraries was investigated via interrogating medicinal chemistry databases for several programs with virtual libraries created from commercially available reagents or with libraries of commercially available fragments. The results suggest that hits more potent than typically discovered in today's fragment-based screens can consistently be identified from realistically accessible compound sets under screening conditions similar to commonly used HTS protocols.     

Einfluß der Hypophysenexstirpation auf den Kalkhaushalt

Zusammenfassung Bei hypophysektomierten Hunden zeigt der Blutkalkspiegel einen vorübergehenden Abfall. Eine intravenös verabreichte Kalkmenge verbleibt lÄngere Zeit im Kreislauf als bei normalen Tieren. Diese VerÄnderungen sind wahrscheinlich der der Hypophysenexstirpation folgenden verÄnderten Nebenschilddrüsenfunktion zuzuschreiben.     

Secretion of phospholipase A2 induced by interactions of human platelets with monocytes

Summary Phospholipase A₂ (PLA₂) activity was found and measured in the cell-free supernatants of human mononuclear cells (monocytes and lymphocytes) cultured with platelets for 48 h at 37° C. The relative molecular mass of purified, calcium-dependent PLA₂ was 14 kD. The amount of PLA₂ in the supernatants correlated positively with the number of monocytes and platelets in the cultures. Electron microscopically, direct cell-to-cell interactions of monocytes and platelets were observed. Cultivation of suspensions of human mononuclear cells with platelets in serum-free medium was found to be an efficient way to produce and purify human secretable PLA₂. In the release of secretable PLA₂ in peripheral blood, the interactions between platelets and monocytes may play a considerable role.     

The role of protein kinase C isoenzymes in the regulation of calcineurin activity in human peripheral blood mononuclear cells

It is known that PMA (phorbol-12-myristate-13-acetate) can activate the classical and novel protein kinase C isoenzymes (cPKC alpha, beta, gamma and nPKC delta, epsilon, eta, theta), while the calcium ion can induce only the activity of cPKC. Calcineurin binding protein (Cabin 1) belongs to the group of endogenous inhibitors of calcineurin. Cabin 1 becomes hyperphosphorylated in response to PKC activation and may play a negative role in calcineurin signalling. It was observed that both PMA treatment and the increase in intracellular Ca2+ contributed to the reduction of calcineurin activity in human peripheral blood mononuclear cells without modulating the mRNA and the protein levels of calcineurin. PMA and Ca-ionophore (A23187), the activating agents of PKC, applied alone or in combination, significantly increased the phosphorylation state of Cabin 1 as revealed by immunoprecipitation of Cabin 1 detecting its phospho-Ser content by specific antibodies. GF109203X, an inhibitor of the classic and the novel protein kinase C isoenzymes, and G?6976, the selective inhibitor of the classical cPKC isoenzymes were able to abolish the effect of PMA or/and Ca-ionophore on the calcineurin activity with concomitant reversal of the hyperphosphorylation of Cabin 1. The calcineurin/Cabin 1 system was not influenced by Rottlerin, an inhibitor of PKC delta isoenzyme either in the absence or in the presence of Ca-ionophore and PMA. We presented evidence for the prominent role of cPKC alpha, beta, gamma isoenzymes in the inhibition of calcineurin as induced by PMA and Ca-ionophore. We demonstrated also that hyperphosphorylation of Cabin 1 by PMA/Ca2+-activated cPKC isoenzymes resulted in a simultaneous inhibition of calcineurin in peripheral blood mononuclear cells. These results suggest a negative regulatory role for Cabin 1 in calcineurin signalling and provide a possible mechanism of feedback inhibition through cross-talk between PKC and calcineurin.     

The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies

INTRODUCTION: It shows the importance of cerebrovascular diseases that they are the third main cause of death exceeded only by coronary artery diseases and cancer. Cerebral ischemia leads to irreversible brain damage, thereby it is important to rescue the hypoperfused areas. Patients without stroke but with chronic cerebral hypoperfusion can also benefit from the increasing of the cerebral blood flow. METHODS: The aim of this review was to summarize the indications and the potential effects of vinpocetine in acute and chronic cerebrovascular diseases based on clinical studies. RESULTS: There is no evidence that vinpocetine treatment is applicable in acute ischemic stroke, only few study with low patient number showed a slight but significant improvement in the patients conditions. In chronic cerebrovascular patients after single dose and long-term vinpocetine therapy, PET, TCD, SPECT and NIRS examinations showed increasing perfusion and elevated glucose and O 2 consumption of the examined areas, furthermore significant improvement of the rheologic factors was detected. A meta-analysis of international clinical studies showed a significant improvement in cognitive achievement in chronic stroke patients after oral therapy. CONCLUSION: The cited studies showed the potential multi-pharmacological effects of vinpocetine and its beneficial hemorheological potential. The drug also improves the blood flow and the metabolism of the affected brain areas. There is increasing evidence that vinpocetine improves the quality of life in chronic cerebrovascular patients.