Ratio between positive lymph nodes and total dissected axillaries lymph nodes as an independent prognostic factor for disease-free survival in patients with breast cancer

The number of positive axillary lymph nodes involved by tumor is one of the main prognostic factors for women with locoregional breast cancer (BC) for whom adjuvant chemotherapy is being considered. The prognostic importance of the ratio (P/D) between positive lymph nodes (P) and total dissected lymph nodes (D), previously demonstrated in the high-dose chemotherapy (HDC) setting has not yet been tested, however, in the conventional adjuvant chemotherapy setting. The data of 168 patients who were from 2 institutions and who were treated with adjuvant chemotherapy for BC were retrospectively analyzed, and univariate and multivariate analysis were performed, including the other traditional prognostic factors and P/D ratio as possible predictors of disease free survival (DFS). Disease-free survival for quartile 4 of P/D ratio (ratio >0.30) was statistically different from that for the other quartiles (log-rank test p < 0.001). Mean DFS for this series was not reached as well as for quartiles 1, 2, and 3, while mean DFS for quartile 4 was 44.5 months. In univariate analysis, number of positive lymph nodes (r2 = 0.055; p = 0.023), P/D ratio (r2 = 0.213; p < 0.001), and stage (r2 = 0.105; p = 0.002) were predictive of relapse, while in multivariate analysis, only P/D ratio remained an independent predictor of relapse (r2 = 0.213; p < 0.001). It is concluded that P/D ratio could become a simple, inexpensive, and easily available prognostic factor for patients undergoing conventional chemotherapy for BC.     

Magnitude and impact of treatment delays on weeknights and weekends in patients undergoing primary angioplasty for acute myocardial infarction (the cadillac trial)

In 2,082 patients in the CADILLAC trial, the outcomes of patients presenting during peak hours were compared with those presenting during peak hours (Monday to Friday 8a.m. to 8 p.m., n = 1,047, 51%) were compared with those of patients presenting during off-peak hours (weeknights from 8 p.m. to 8 a.m. and weekends, n = 989, 49%). Although treatment times to percutaneous coronary intervention (PCI) were delayed approximately 21 minutes, in patients with acute myocardial infarctions occurring on weeknights and weekends, this modest delay did not adversely affect procedural success, myocardial recovery, or survival after PCI.     

Endothelial cell-astrocyte interactions and TGF beta are required for induction of blood-neural barrier properties

We sought to establish a blood-neural barrier (BNB) model of astrocyte contact with endothelial cells (EC) to test the hypothesis that transforming growth factor beta (TGF beta) promotes an EC barrier-phenotype. Astrocyte-EC contact induced BNB properties in EC. Transendothelial resistance was augmented by direct contact between astrocytes-EC, but not by astrocyte-conditioned medium or astrocyte-EC coculture conditioned medium. Coculture of EC and astrocytes led to significant increase in endothelial occludin levels and junctional localization. EC gamma-glutamyl-transferase (GGT) activity was increased by direct contact with astrocytes, by conditioned medium from cocultures or by TGF beta1. Coculture inhibited EC proliferation with no effect on astrocyte proliferation. A neutralizing antibody to TGF beta decreased GGT activity in cocultures and increased cell number. Whereas total TGF beta was not significantly altered by coculture, activated TGF beta increased in astrocyte-EC cocultures. In summary, astrocyte-EC contact induces BNB characteristics in EC and locally activated TGF beta is responsible for part of the induction.     

Differential effects of “Advanced glycation endproducts” and β-amyloid peptide on glucose utilization and ATP levels in the neuronal cell line SH-SY5Y

Summary. -amyloid peptide (A) and Advanced glycation endproducts (AGEs) are components of the senile plaques in Alzheimers disease patients. It has been proposed that both AGEs and A exert many of their effects, which include the upregulation of pro-inflammatory cytokines, through RAGE (receptor for advanced glycation endproducts). To investigate whether A and AGEs cause similar or identical effects on cell survival and energy metabolism, we have compared the effects of a model-AGE and A on cell viability, ATP level, glucose consumption and lactate production in the neuroblastoma cell line SH-SY5Y. The results show that AGEs and A increase glucose consumption and decrease ATP levels in a dose dependent manner. Furthermore, both compounds decrease mitochondrial activity measured by the MTT assay. However, only AGEs decrease the number of cells and significantly increase lactate production. These data indicate that both AGEs and A can cause differential disturbances in neuronal metabolism, which may contribute to the pathophysiological findings in Alzheimers disease. However, their signalling pathways are apparently quite distinct, a fact which should stimulate a more detailed investigation in this field, e.g. for the purpose of a rational design of potential neuroprotective RAGE antagonists.     

The neuroprotective factor Wlds does not attenuate mutant SOD1-mediated motor neuron disease

Selective degeneration and death of motor neurons in SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS) is accompanied by axonal disorganization and reduced slow axonal transport in the three most frequently used mouse models of mutant SOD1-mediated ALS. To test whether suppression of axonal degeneration (frequently known as Wallerian degeneration) could slow disease development, we took advantage of a spontaneous mouse mutant Wld(s) (Wallerian degeneration slow) in which the programmed axonal degenerative process that is normally activated after axonal injury is significantly delayed. Despite its effectiveness in delaying axonal loss in other neurodegenerative models, the presence of Wld(s) did not slow disease onset, ameliorate mutant motor neuron death, axonal degeneration, or preserve synaptic attachments in mice that develop disease from ALS-linked SOD1 mutants SOD1G37R or SOD1G85R. However, presynaptic endings in both the presence and absence of Wld(s) showed high accumulations of mitochondria and synaptic vesicles, implicating errors of retrograde transport as a consequence of SOD1-mutant damage to axons.     

Brain-derived neurotrophic factor signalling in adult pig retinal ganglion cell neurite regeneration in vitro

Brain-derived neurotrophic factor (BDNF) has been implicated in stimulating retinal ganglion cell (RGC) survival and axonal regeneration in rodent animal models in vivo and in vitro, but very little data are available on neurotrophin effects in higher mammals. We hence analysed BDNF signalling in primary cultures of adult pig RGC. As detected by immunohistochemistry, HPLC analysis and RT-PCR, BDNF protein and mRNA were present within pig retina in vivo and in vitro, where it may be involved in baseline RGC neuritogenesis. Initial dose-response studies established optimal effects were induced by 20 ng/ml BDNF, leading to an approximately threefold increase in neurite length. We analysed the respective contributions of phosphatidyl inositol 3 kinase (PI3K) and mitogen activated protein kinase (MAPK) cascades to BDNF-induced neurite regeneration. Addition of either the PI3K inhibitor wortmannin or the MAPK inhibitor U0126 blocked 50-100% BDNF-induced neurite elongation; U0126 also significantly reduced neurite regeneration below untreated control levels. The trk receptor inhibitor K252a had no observable effect on neurite regeneration or morphology. These data hence demonstrate that BDNF is a potent stimulator of neurite growth in RGC prepared from an adult large mammal retina, and that at least two signalling pathways are causally involved. BDNF-based therapy may be of potential use in treating RGC degeneration in humans.     

The toppler mouse: a novel mutant exhibiting loss of Purkinje cells

We describe the genetic and neurological features of toppler, a spontaneous autosomal mutation that appeared in a colony of FVB/N mice and that manifests as severe ataxia appearing at around 12 days of age, worsening with age. The lifespan of affected mice is 8-12 months, with occasional mice living longer. Both homozygous males and females are fertile, and females are able to nurture litters. Histological examination of brain revealed no striking abnormalities other than the loss of cerebellar Purkinje cells. The toppler mutation was mapped to mouse chromosome 8, and to assess whether it was novel or a recurrence of a previously described chromosome 8 mouse mutant, toppler mice were crossed with the nervous and tottering mouse mutants. These studies demonstrate that toppler is a unique mouse mutation. Purkinje cell abnormalities in toppler mice were obvious around postnatal day (P) 14, i.e., toppler Purkinje cells already exhibited abnormal morphology. Staining for calbindin, a calcium binding protein enriched in Purkinje cells, showed altered dendritic morphology. Between P14 and P30, dramatic Purkinje cell loss occurred, although there were differences in the degree of Purkinje cell loss in each lobule. At P30, the surviving Purkinje cells expressed zebrin II. From P30 through 6 months, many of the remaining Purkinje cells gradually degenerated. Purkinje cell loss was analyzed by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL), and Purkinje cells were TUNEL-positive most abundantly at P21. In addition, Bergmann glia were TUNEL positive at P21, and they expressed activated caspase-3 at earlier time points. Interestingly, despite the apparent death of some Bergmann glia, there was up-regulation of glial fibrillary acidic protein, expressed in astrocytes as well as Bergmann glia. Given the changes in both Purkinje cells and glia in toppler cerebellum, this may be a very useful model in which to investigate the developmental interaction of Purkinje cells and Bergmann glia.     

Casting health messages in terms of responsibility for dietary change: increasing fruit and vegetable consumption

OBJECTIVE: To compare the effectiveness of messages emphasizing the importance of either personal or social responsibility for dietary behavior change in increasing fruit and vegetable intake. DESIGN/SETTING: Randomly assigned individually or socially oriented messages were delivered at baseline, 1 week, and 2 and 3 months later. Telephone surveys were conducted at baseline and 1 and 4 months later. PARTICIPANTS: 528 callers to a cancer information hotline who were not meeting the "5 A Day" dietary recommendation. INTERVENTIONS: A brief telephone-delivered message and 3 mailings of pamphlets and promotional items encouraging fruit and vegetable intake that emphasized either personal or social responsibility. MAIN OUTCOME MEASURES: Fruit and vegetable intake 1 and 4 months post baseline. ANALYSIS: Chi-square, t tests, and analyses of variance and covariance. RESULTS: Both types of messages increased intake substantially (P =.01). To some extent, the social responsibility message continued to motivate increased intake over time compared with the personal responsibility message. CONCLUSIONS AND IMPLICATIONS: These minimal interventions had a substantial impact on fruit and vegetable intake. Health messages might be more effective over the longer term if they are designed to emphasize the importance of social responsibility, although further study is needed to confirm the robustness of these findings.