Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities.

In a German multicenter treatment study, 354 patients with schizophrenia and schizoaffective disorder were followed for 2 years. The data collected were taken as a basis for the present predictor study. For the first time, the technique of classification and regression tree (CART) analysis has been employed for this purpose. CART yielded informative data and appeared to be a useful instrument in predictor research. On the outcome variables "relapse" and "rehospitalization," significant predictor variables were found in several areas: neuroleptic treatment, onset and previous course (precipitating factors, first manifestation, hospitalization in the preceding year, suicide attempts), psychopathology (residual type, schizoaffective disorder), social adjustment (marital status, employment, intensity of life, Phillips score), previous life experiences (traumatic experiences and psychiatric or developmental disturbances in childhood), and biology (gender, age). Our investigation confirmed the generally prevalent views regarding the value of neuroleptic treatment, the multifactorial etiology, and the vulnerability stress model of schizophrenia.

Prostaglandins of the E-series have been demonstrated to reduce extracellular accumulation of collagens in some models of glomerulonephritis. This effect is partially due to reduction of collagen formation by mesangial cells. The potential effects of prostaglandins on the expression of collagen degrading enzymes in mesangial cells are largely unknown. Since rat mesangial cells generate a matrix metalloproteinase 2 (MMP-2) that specifically degrades collagen type IV, the effects of prostaglandin E2 (PGE2) on transcription, steady-state mRNA levels, extracellular enzyme activity and protein concentration of this proteinase were evaluated. Mesangial cells (MC) were incubated with PGE2 (2 microM) for different time-periods (1 to 48 hr), and steady-state mRNA levels of MMP-2 were determined by Northern blotting. PGE2 increased MMP-2 mRNA levels beginning at one hour of incubation and remained elevated up to 24 hours. Nuclear run off experiments revealed that the PGE2-induced increase in mRNA expression for MMP-2 is due to stimulated gene transcription. Western blot analysis and zymography revealed that MMP-2 protein production and enzyme activity was also enhanced by PGE2. The cAMP analogue 8-bromo-cAMP increased MMP-2 mRNA levels, suggesting that PGE2-induced generation of intracellular cAMP plays a role in MMP-2 induction in MC. These studies demonstrate that PGE2 stimulates the transcription, protein formation and enzyme activity of MMP-2 in cultured rat MC. This effect may contribute to the prostaglandin mediated reduction of extracellular collagen deposition in glomerulonephritis.

We investigated 267 infants and children aged 9 days to 16.8 years to study the spontaneous otoacoustic emission (SOAE) data prevalence, number per ear, level and frequency as a function of growth. Dependence on age, gender and ear side was statistically analyzed using the method of generalized estimation equations. Except in the 1st year of life, SOAE prevalence per ear and SOAE number per ear decreased significantly with increasing age. Both SOAE parameters were significantly higher in female than in male subjects, with gender difference of SOAE prevalence per ear being more distinct in the 1st year of life. Although a clear ear side effect on SOAE prevalence per ear could already be seen in ears of female children in this age group, only SOAE number per ear was significantly higher in right ears than in left ears from the 1st year of life on. Except in the first 12 months, SOAE level and SOAE frequency decreased significantly with increasing age. Neither a significant gender difference nor a significant ear side difference could be determined. Our results found in infancy and childhood are discussed within the framework of the current literature.

The y chain of human fibrinogen has been shown to be heterogeneous; three forms of various sizes are normally present in plasma. To further characterize the two less prevalent elongated variants, we have purified the three forms of the y chain, isolated unique tryptic fragments, and sequenced the variant portions of each chain. The intermediate-sized form (ysV) has a sequence identical to the longest variant (Y57.5) from residue Val408 to Pro-423, which is the C terminus of the Vss chain. The t 7.5chain extends an additional four amino acids. The C-terminal amino acid sequence and corresponding nucleotide sequence of the yss chain show marked similarity with an elongated y-chain variant of rat fibrinogen. In addition, a remarkable similarity in both amino acid and nucleotide sequence was noted between the human yss chain and the C-terminal extension in human and bovine Aa chains of fibrinogen, which are encoded by the cDNA but are posttranslationally cleaved and are not found in plasma. The findings suggest an evolutionary conservation in this Cterminal amino acid sequence found in both the fibrinogen Aa and y chains in several species.The y chain of normal human plasma fibrinogen is heterogeneous in size due to variation in the C-terminal amino acid sequence. Francis et al. (1) found an apparently larger y-chain variant using NaDodSO4/polyacrylamide gel electrophoresis and suggested it was due to an elongated Cterminal amino acid sequence based on the pattern ofplasmic degradation. Wolfenstein-Todel and Mosesson (2) also isolated the larger variant and established its identity as the previously described chain variant termed y'. Determination of the amino acid sequence of the unique C-terminal tryptic fragment of the larger variant indicated that the terminal 4 amino acids of the smaller, more prevalent y chain were absent and were replaced by a 20-amino acid sequence in the larger form (3). The form (Y55) § functioned normally in crosslinking, and its difference in size was not due to a variation in sialic acid content (5). In the present report, we describe unique C-terminal tryptic fragments for each of the three y chains and report the amino acid sequences that characterize the two elongated forms. METHODSFibrinogen Chromatography. Chromatography of human fibrinogen (grade L, Kabi, Stockholm) was performed on DEAE-Sephacel by using a combined pH and ionic strength gradient as described previously (6, 7) after removal of plasminogen by lysine-Sepharose chromatography (8). Three peaks containing fibrinogen with different y-chain content were eluted. Peak A had only y50 chains , peak B had equal amounts of V5o and 'Y5, and peak C had equal amounts of lso and y57. (5). Fibronectin, which also eluted in peak B, was removed by using a column of Sepharose 4B to which gelatin was bound by the cyanogen bromide method (9).Purification of Fibrinogen Polypeptide Chains. After Scarboxymethylation (5, 10), fibrinogen was dissolved in 0.01 M sodium phosphate/0.01 M Tris/8 M urea, and the solution was adjusted to...