No abstract

It is widely assumed that, after ovulation, the human endometrium undergoes specific changes and becomes receptive to the implantation of embryo during the mid-secretory phase. When implantation does not take place, further changes occur which eventually result in the shedding of human endometrium. The present study was carried out to examine whether there are changes in the cytokine gene expression in human endometrium which are correlated with endometrial function in various phases of the menstrual cycle. The RNase protection assay was performed on carefully dated endometria from normal subjects to characterize the expression of cytokines which potentially contribute to endometrial function. These included: tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6, IL-8, leukaemia inhibitory factor (LIF), transforming growth factor beta1 (TGF-beta1), macrophage colony stimulating factor (MCSF or colony stimulating factor-1), and vascular endothelial growth factor (VEGF) mRNAs. A low level of expression of these cytokine mRNAs was found during the proliferative and early secretory phase. Expression of cytokine mRNA increased during the mid-secretory phase and rose to a peak in the late secretory phase. The level of cytokine mRNA expression during gestation was most akin to that observed during the mid-secretory phase. Individuals with habitual abortion presented with an abnormal expression of IL-1beta and IL-6 mRNA in endometrium, during the mid-secretory phase. Taken together, these findings are consistent with a progressive rise in the expression of cytokines in human endometrium during the secretory phase in natural cycles. Furthermore, the findings show that habitual abortion is associated with the abnormal expression of IL-1beta and IL-6 in the mid-secretory phase.

Lymphocyte division has been the subject of many studies from the point of view of cellular immunology and antibody synthesis. Blast cell transformation and mitosis occur both in vitro and in vivo under stimulus from a number of agents which act on the cell surface, particularly in experimental situations by lectins (1).Although the sequence of events which connect the mitogenic stimulus to DNA synthesis is still incompletely known and several different cell types may be involved, a nmnber of preliminary changes have been recognized. Thus, for example, the cyclic AMP level in lymphocyte cultures rises within 2 rain of stimulation (2), membrane biosynthesis increases within 1/4 h of stimulation (3), nuclear template activity increases within 2 h (4). I t is of considerable importance to an understanding of the neoplastic change in lymphoid cells to know the extent to which such processes and factors controlling them are retained in replicating lymphoma cells, and the extent to which they are altered.We here report a comparison, between the effects of certain thiols and disulfides which we have found to be necessary for the growth of mouse lymphoma cells in vitro, and their effects in enhancing the action of mitogens on splenic lymphocytes.Our observations stem from the finding that mouse lymphoma cells of the line L1210 (V) which had previously been established in culture only with great difficulty (5), proliferate in a medium formulated by Balk (6). The specific growth promoting component of this medium was found to be its high concentration of added L-cysteine (1.5 mM) (7). As will be described, a number of thiols and disulfides can substitute for L-cysteine, some at very low concentration (to < 1 #M). Precise structure activity relationships exist. Furthermore, 13 of 23 other mouse leukemic and neoplastic lymphoid cell lines were also thiol-disulfide dependent in vitro.

Cerebral infarction (stroke) is a potentially disastrous complication of diabetes mellitus, principally because the extent of cortical loss is greater in diabetic patients than in nondiabetic patients. The etiology of this enhanced neurotoxicity is poorly understood. We hypothesized that advanced glycation endproducts (AGEs), which have previously been implicated in the development of other diabetic complications, might contribute to neurotoxicity and brain damage during ischemic stroke. Using a rat model of focal cerebral ischemia, we show that systemically administered AGE-modified bovine serum albumin (AGE-BSA) significantly increased cerebral infarct size. The neurotoxic effects of AGE-BSA administration were dose-and time-related and associated with a paradoxical increase in cerebral blood flow. Aminoguanidine, an inhibitor of AGE cross-linking, attenuated infarct volume in AGE-treated animals. We conclude that AGEs may contribute to the increased severity of stroke associated with diabetes and other conditions characterized by AGE accumulation.Stroke damage caused by brain infarction is a devastating complication of diabetes mellitus, killing or permanently disabling more than 60% of diabetic patients who survive into their seventh decade (1-6). Diabetic patients are more likely to develop a stroke than nondiabetic patients, and moreover, strokes in diabetic patients are larger and more disabling than those in nondiabetic patients. Although a number of factors have been implicated in enhancing diabetic stroke-related neurotoxicity, a complete understanding of the biochemical basis for increased stroke size associated with diabetes remains elusive. Recent investigation into the pathogenesis of stroke indicates that a number of factors may directly influence the volume of brain infarction after occlusion of a cerebral artery (7-10). These studies suggest that such neurotoxic factors can transform ischemic but potentially viable brain tissue into an irretrievably infarcted lesion, resulting in larger strokes in terms of both parenchymal necrosis and corresponding functional impairment.Advanced glycation endproducts (AGEs) have been implicated in the development of diabetic complications such as accelerated atherosclerosis, renal dysfunction, and neuropathy (11,12). AGE modifications accumulate by nonenzymatic reactions as permanent adducts and cross-linking structures on long-lived body proteins (for instance, collagen) as a function of age and glucose concentration. AGE-modified proteins in tissues may subsequently undergo receptor-mediated or proteolytic cleavage into smaller, reactive AGE-peptides which are released into the circulation, where they may ultimately either reattach covalently to tissue proteins or be eliminated from the circulation by the kidneys (13, 14). Previous observations suggest that high levels of AGE-proteins and AGE-The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance wi...

In the biology of a cell, the central role of p53 in controlling functions such as G1/S transition (check point) and DNA damage repair, and as a trigger of apoptosis, is well established. Somatic mutations or other changes in P53 have been reported in numerous tumor types, and in some of these, they are associated with poor prognosis. In this study, we examined 237 cytogenetically characterized B-cell non-Hodgkin's lymphomas (B-NHLs) for somatic changes in P53 by Southern blot analysis, by single-strand conformation polymorphism analysis (SSCP) of exon 5 through 9, and by direct sequencing of SSCP variants to determine the frequency and types of mutations and their clinical significance. In a portion of these (173 tumors), we also studied p53 expression by immunostaining. On Southern blots, no gross change was identified in P53 and no mutation was identified in exon 9. In exons 5 through 8, 27 different mutations were identified in 25 patients (23 single-base substitutions, 3 deletions, 1 duplication). Mutations in P53 were identified in 25 of 237 tumors (10.5%), which included 1 of 45 small lymphocytic lymphomas (SLLs), 2 of 38 follicular small cleaved-cell lymphomas (FSCCs), 2 of 35 follicular mixed small cleaved-cell and large-cell lymphomas (FMxs), 1 of 4 follicular large-cell lymphomas (FLCs), 1 of 14 diffuse small cleaved-cell lymphomas (DSCCs), 2 of 17 diffuse mixed small- and large-cell lymphomas (DMxs), and 16 of 84 diffuse large-cell lymphomas (DLCCs); the difference between the histologic groups was significant (P < .01). Among mantle-cell lymphoma (MC) patients, 3 of 10 had mutations. In 16 patients, the mutation was identified in specimens obtained at diagnosis. Mutation of transition type and transversion type occurred at a relative frequency of 2:1. Thirty percent occurred at CpG dinucleotide sequences and the codon for arginine was most frequently affected. Nineteen of 99 tumors with complex cytogenetic abnormalities, but none of 69 tumors with simple cytogenetic abnormalities, had mutations (P < .001). Similarly, 11 of 25 tumors with an abnormality of 17p and 8 of 143 tumors with apparently normal 17p had mutations (P < .0001). Positive correlations were found between a mutation and p53 expression (P < .001), between missense type mutations and p53 expression (P < .005), and between 17p abnormalities and p53 expression (P < .05). Twenty-two of 49 patients without mutation and 14 of 17 patients with mutations died (P < .05), but there was no significant difference in median survival. Similarly, 21 of 26 p53 positive patients died, whereas only 1 of 24 p53-negative patients died on-study (P < .001). Among p53-negative patients, mutation (P < .01) was positively associated with a fatal outcome. These findings indicate that in B-NHL, somatic changes in P53 were present in diagnostic specimens of all histologic types, but at a higher frequency in DLC and MC tumors. P53 mutation and/or expression has a negative influence on survival, and therefore can serve as prognostic indicators. Immunostaining for p53 is an effective way to screen for P53 changes in these tumors.