Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines

The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.     

Activation of transducin guanosine triphosphatase by two proteins of the RGS family

RGS proteins (regulators of G protein signaling) constitute a newly appreciated group of negative regulators of G protein signaling. Several members of this group stimulate the guanosine triphosphatase (GTPase) activity of various G protein alpha-subunits, including the photoreceptor G protein, transducin. In photoreceptor cells transducin GTPase is known to be substantially accelerated by the coordinated action of the gamma-subunit of its effector enzyme, cGMP phosphodiesterase (PDE gamma), and another yet unidentified membrane-associated protein factor. Here we test the possibility that this factor belongs to the RGS family of GTPase stimulators. We report a detailed kinetic analysis of transducin GTPase activation by two members of the RGS family, RGS4 and G alpha interacting protein (GAIP). RGS4, being at least 5-fold more potent than GAIP, stimulates the rate of transducin GTPase by 2 orders of magnitude. Neither RGS4 nor GAIP requires PDE gamma for activating transducin. Rather, PDE gamma causes a partial reversal of transducin GTPase activation by RGS proteins. The effect of PDE gamma is based on a decreased apparent affinity of RGS for the alpha-subunit of transducin. Our observations indicate that GTPase activity of transducin can be activated by at least two distinct mechanisms, one based on the action of RGS proteins alone and another involving the cooperative action of the effector enzyme and another protein.     

Beta-1-integrin expression in adult acute lymphoblastic leukemia: possible relationship with the stem cell antigen CD34

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.     

Benzodiazepine receptors in the post-mortem brain of suicide victims and schizophrenic subjects

To examine the role of benzodiazepine (BZ) receptors in suicide and schizophrenia, we determined BZ receptors in post-mortem brain (Brodmann's area 10) obtained from suicide victims, schizophrenic patients, and control subjects using [3H]RO15-1788 as the radioligand. The maximum number of binding sites (Bmax) of BZ receptors in the cortex of suicide victims was significantly higher compared with controls, but this increase was mainly due to those suicide victims who died by violent means and whose Bmax was significantly higher than of those who died by non-violent means or control subjects. In schizophrenic patients, Bmax was not significantly different from that of control subjects. When the schizophrenic subjects were separated into two groups, those on neuroleptics and those off neuroleptics for at least 12 months, however, the mean Bmax of BZ receptors in the prefrontal cortex in post-mortem brain obtained from schizophrenic patients on neuroleptics was significantly lower than Bmax in drug-free schizophrenic patients or normal controls. There were no significant differences among groups in values of the apparent dissociation constant (KD) of [3H]RO15-1788 binding. These results suggest that BZ receptors are up-regulated in the cortex of suicide victims, specifically those who used violent means, and that neuroleptic treatment may result in decreased central BZ receptor binding in the cortex of schizophrenic patients. Thus, the method of suicide and previous exposure to neuroleptics should be considered in the interpretation of data on BZ receptors.     

Comparison of an extraconal block with a retrobulbar-facial block combination for ocular surgery. A safe alternative technique to the combination of retrobulbar block and facial nerve block

Four hundred and eight consecutive patients scheduled for cataract surgery under local anaesthesia were randomly allocated to one of two types of regional anaesthesia. One group was given the standard retrobulbar block combined with a facial nerve block of the O'Brien type, and the second group was given a modified peribulbar block. Results indicate that it is possible to achieve a high degree of reliability, within a relatively short time, from the modified peribulbar block without the major complications associated with retrobulbar block.     

Metabolic efficiency during arm and leg exercise at the same relative intensities

This study was conducted to compare gross efficiency (GE), net efficiency (NE), work efficiency (WE), and delta efficiency (DE) between arm crank and cycle exercise at the same relative intensities. Eight college-aged males underwent two experimental trials presented in a randomized counterbalanced order. During each trial subjects performed three intermittent 7-min exercise bouts separated by 10-min rest intervals on an arm or semirecumbent leg ergometer. The power outputs for the three bouts of arm crank or cycle exercise corresponded to 50, 60, and 70% of the mode-specific VO2peak. GE, NE, and WE were determined as the ratio of Kcal.min-1 equivalent of power output to Kcal.min-1 of total energy expended, energy expended above rest and energy expended above unloaded exercise, respectively. DE was determined as the ratio of the increment of Kcal.min-1 of power output above the previous lower intensity to the increment of kcal.min-1 of total energy expended above the previous lower intensity. GE and NE did not differ between arm crank and cycle exercises. However, WE was lower (P < 0.05) during arm crank than cycle exercise at 50, 60, and 70% VO2peak. DE was also lower (P < 0.05) during arm crank than cycle exercise at delta 50-60 and at delta 60-70% VO2peak. It is concluded metabolic efficiency as determined by work and delta efficiency indices was lower during arm crank compared with cycle exercise at the same relative intensities. These findings add to the understanding of the difference in metabolic efficiency between upper and lower body exercise.     

Synthesis of indolylalkoxyiminoalkylcarboxylates as leukotriene biosynthesis inhibitors

A series of substituted indolylalkoxyiminoalkylcarboxylates were found to be potent leukotriene biosynthesis inhibitors. The structure-activity relationships were investigated. Representative potent inhibitors identified were the quinolyl 3a (A-86885) and pyridyl 3b (A-86886) congeners with in vitro IC50s of 21 and 9 nM and in vivo leukotriene inhibition in the rat with oral ED50s of 0.9 and 1.7 mg/kg, respectively.     

Overdose among youth in Bahrain: psycho-social characteristics, contact with helping agencies and problems

The in vitro minimal inhibitory concentrations (MIC) and minimal bactericidal concentration (MBC) of roxithromycin and erythromycin against Actinobacillus actinomycetemcomitans were evaluated. Sixty-seven different A. actinomycetemcomitans isolated from periodontal pockets of 101 subjects with different forms of early-onset and adult periodontitis and three reference strains of A. actinomycetemcomitans (ATCC 29522, ATCC 29523, and NCTC 9710) were included in this study. Erythromycin showed poor in vitro activity against A. actinomycetemcomitans; roxithromycin, on the contrary, exhibited good in vitro activity. Moreover, roxithromycin showed the best in vitro antimicrobial activity against 17 serotype a and 12 serotype c subpopulations of A. actinomycetemcomitans; against 38 serotype b subpopulation of A. actinomycetemcomitans, roxithromycin was consistently active. Roxithromycin exhibited MBC values usually equal to, or one-fold higher than MIC values. All the MBC values of erythromycin were three- to four-fold higher than the respective MIC result. Since roxithromycin is characterized by high concentrations in serum and good penetration and diffusion into gingival tissue, it could be expected to pass into the gingival crevicular fluid at levels sufficiently high to inhibit A. actinomycetemcomitans in vivo. These data indicate that roxithromycin might be a potential candidate for therapeutic trials in patients with A. actinomycetemcomitans-associated periodontitis.