Long-term survival in children under 3 years of age with low-grade astrocytoma

Objective The purpose of this study is to analyze clinical aspects and disease-free survival (DFS) in children less than 3 years of age diagnosed with low-grade astrocytoma. Methods In a period of 24 years (1980–2004), a total of 43 (5.4%) children were registered with these characteristics. Twenty-three patients had pilocytic astrocytoma, 18 diffused, and 2 mixed. Thirty-one (72.1%) children had incomplete surgical tumor resection and 12 (27.9%) had a complete tumor resection. Twelve (27.9%) patients had cranial radiotherapy and 17 (39.5%) received chemotherapy. Overall survival was recorded in 23 (53%). DFS was 50% at 250 months of follow-up for the whole group. DFS for the supratentorial group was 60% at 250 months, whereas, for the infratentorial, it was 22% at 120 months (p = 0.008). Conclusion The only favorable prognostic pattern was the supratentorial presentation. Radiotherapy and chemotherapy did not alter the outcome.     

Comparison between Low Frequency Magnetic Field Stimulation and Nerve Growth Factor Treatment of Cultured Chromaffin Cells, on Neurite Growth, Noradrenaline Release, Excitable Properties, and Grafting in Nigrostriatal Lesioned Rats

Adrenal chromaffin cells in vitro respond to nerve growth factor (NGF) by expressing neuronal traits. Low frequency magnetic (LFM) field stimulation, while inducing a variety of effects on several cell types, has never been studied as to its effects on chromaffin cell cultures. The purpose of this study was to compare the effects of LFM field stimulation with that of NGF on the morphological phenotype, on noradrenaline (NA) release, and on membrane excitability of cultured chromaffin cells. We also tested the effects of grafting LFM and NGF-treated chromaffin cells into the caudate nucleus of rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. The results of this study showed that LFM field stimulation produced neurite growth of cultured chromaffin cells in a manner similar to that of NGF exposure. The combination of the two procedures did not induce changes above those observed by NGF alone. Both NGF- and LFM-treated chromaffin cells released [³H]NA equally in response to a depolarizing concentration of KCl. On the other, Na⁺ current density of LFM field stimulation increased, but to a lesser extent than that seen in NGF-treated cells. In addition both types of cells when transplanted into nigrostriatal-lesioned animals induced a similar decrease in the motor asymmetries produced by the lesion. When NGF- or LFM-treated chromaffin cells where compared to untreated control cells, no significant differences were observed in [³H]NA release, on Na⁺ current densities, or on postgraft motor asymmetries. The results are discussed in terms of the fact that LFM-stimulated cells can be differentiated in a manner similar to NGF-treated cells, by acquiring sympathetic like traits which in turn can diminish motor asymmetries when grafted into nigrostriatal-lesioned rats.     

Serotonergic receptors in the brain of in utero undernourished rats

In this study, we report that 5-HT(1A) receptors are already present in fractions of axonal growth cones, from the normal rat fetal brain (E-17). Also, in utero undernourished (UN) rat pups at birth show a noteworthy enhancement in the B(max) of [3H]5-hydroxytryptamine (5-HT) and [3H]8-hydroxy-(2-N,N-dipropilamin)-tetralin (([3H])8-OH-DPAT), in the brainstem and cerebral cortex up to the second week after birth. Afterwards, there is a significant decrease in the binding of these ligands. [125I]Cyanopindolo binding in the cerebral cortex only showed a decrease in the same period. An elevation of brain serotonin in both regions was also present. These findings together, suggest that the mechanisms of regulation of serotonergic receptors' expression during the period studied, may not depend on the amount of neurotransmitter in the synaptic cleft, because in the early UN brain it would be expected only a lower receptor's density due to the chronic serotonin increase. On this basis, we propose that developmental activation of brain serotonin biosynthesis observed in early UN animals may disrupt the mechanism regulating the expression of 5-HT receptors during development.     

Mantle Cell Lymphomas Lack Expression of p27kip1, a Cyclin-Dependent Kinase Inhibitor

p27^Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27^Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27^Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27^Kip1 expression in 116 non-Hodgkin’s lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27^Kip1gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin’s lymphoma other than MCL, p27^Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27^Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27^Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27^Kip1gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin’s lymphomas and normal lymphoid tissue, fail to correlate p27^Kip1 expression with the proliferation rate. This peculiar uncoupling of p27^Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.     

Development of DNA vaccines against hemolytic-uremic syndrome in a murine model

Shiga toxin type 2 (Stx2) produced by Escherichia coli O:157H7 can cause hemolytic-uremic syndrome in children, a disease for which there is neither a vaccine nor an effective treatment. This toxin consists of an enzymatically active A subunit and a pentameric B subunit responsible for the toxin binding to host cells, and also found to be immunogenic in rabbits. In this study we developed eukaryotic plasmids expressing the B subunit gene of Stx2 (pStx2B) and the B subunit plus the gene coding for the A subunit with an active-site deletion (pStx2 Delta A). Transfection of eukaryotic cells with these plasmids produced proteins of the expected molecular weight which reacted with specific monoclonal antibodies. Newborn and adult BALB/c mice immunized with two intramuscular injections of each plasmid, either alone or together with the same vector expressing the granulocyte and monocyte colony-stimulating factor (pGM-CSF), elicited a specific Th1-biased humoral response. The effect of pGM-CSF as an adjuvant plasmid was particularly notable in newborn mice and in pStx2B-vaccinated adult mice. Stx2-neutralizing activity, evaluated in vitro on VERO cell monolayers, correlated with in vivo protection. This is the first report using plasmids to induce a neutralizing humoral immune response against the Stx2.     

Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system.

The aim of the study was to determine epidermal growth factor receptor (EGFR) expression in gastric adenocarcinoma by standardized immunohistochemistry and to correlate EGFR expression with clinical features and patient survival. EGFR expression was investigated in paraffin sections of resection specimens of 89 gastric carcinomas from Mexican Mestizo patients using standardized immunohistochemistry with antigen retrieval (Dako EGFRpharmDx assay detection system). Membrane staining of EGFR was evaluated in the neoplastic cells and graded using a semiquantitative score (0-3+). Of the 89 carcinomas examined, staining of neoplastic cells was weak in 17 (19.1%, score 1+), moderate in 16 (18.0%, score 2+), and strong in nine cases (10.1%, score 3+). EGFR reactivity was heterogeneous, frequently showing completely negative up to 3+ positive areas within an individual tumor. EGFR reactivity score correlated with distant metastases (P=0.002) and clinical stage (P=0.033). EGFR score 0/1+ was significantly associated with an increase in patient survival when compared to score 2+/3+ (P=0.0006). In a multivariate analysis, EGFR positive cells in muscularis or subserosa (P=0.004), distant metastases (P=0.016) and residual disease (P=0.039) were significantly correlated with decreased survival. The prognosis was associated with the EGFR reactivity score (P=0.003), distant metastases (P=0.0001) and residual disease (P=0.012) in a univariate analysis. EGFR reactivity in neoplastic cells is an independent prognostic factor in gastric adenocarcinoma. The relevance of the heterogeneity in EGFR expression with regard to tumor progression, metastasis and anti-EGFR therapy needs to be studied.     

Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.     

Exposure to extremely low-frequency electromagnetic fields improves social recognition in male rats

The effect of exposure to low-frequency electromagnetic fields (ELF EMFs) on social recognition was studied. The test was based upon a comparison between two encounters of an adult rat and a conspecific juvenile, separated by an interexposure interval (IEI). The exposure to ELF EMF of 1 mT intensity during 2 h for 9 days increased the duration of short-term memory of adult male Wistar rats up to 300 min. These data indicate, for the first time, that ELF EMF improves social recognition memory in rats.