More than 20 different cDNA clones encoding DNA-damage-inducible transcripts in rodent cells have recently been isolated by hybridization subtraction (A. J. Fornace, Jr., I. Alamo, Jr., and M. C. Hollander, Proc. Natl. Acad. Sci. USA 85:8800-8804, 1988). In most cells, one effect of DNA damage is the transient inhibition of DNA synthesis and cell growth. We now show that five of our clones encode transcripts that are increased by other growth cessation signals: growth arrest by serum reduction, medium depletion, contact inhibition, or a 24-h exposure to hydroxyurea. The genes coding for these transcripts have been designated gadd (growth arrest and DNA damage inducible). Two of the gadd cDNA clones were found to hybridize at high stringency to transcripts from human cells that were induced after growth cessation signals or treatment with DNA-damaging agents, which indicates that these responses have been conserved during mammalian evolution. In contrast to results with growth-arrested cells that still had the capacity to grow after removal of the growth arrest conditions, no induction occurred in HL60 cells when growth arrest was produced by terminal differentiation, indicating that only certain kinds of growth cessation signals induce these genes. All of our experiments suggest that the gadd genes are coordinately regulated: the kinetics of induction for all five transcripts were similar; in addition, overexpression of gadd genes was found in homozygous deletion c14CoS/c14CoS mice that are missing a small portion of chromosome 7, suggesting that a trans-acting factor encoded by a gene in this deleted portion is a negative effector of the gadd genes. The gadd genes may represent part of a novel regulatory pathway involved in the negative control of mammalian cell growth.
Introduction The optic nerve sheath diameter (ONSD) may be increased in brain-injured patients, especially children, with intracranial hypertension. We investigated whether measurements of ONSD correlated with simultaneous noninvasive and invasive measurements of the intracranial pressure (ICP) in brain-injured adults.
The current study reveals that anterior cruciate ligament deficiency can cause reorganization of the central nervous system, suggesting that such an injury might be regarded as a neurophysiologic dysfunction, not a simple peripheral musculoskeletal injury. This evidence could explain clinical symptoms that accompany this type of injury and lead to severe dysfunction. Understanding the pattern of brain activation after a peripheral joint injury such as anterior cruciate ligament injury lead to new standards in rehabilitation and motor control learning with a wide application in a number of clinical and research areas (eg, surgical procedures, patient re-education, athletic training, etc).
The effect of ionizing radiation on the expression of two DNA-damage-inducible genes, designated gadd45 and gaddl53, was examined in cultured human cells. These genes have previously been shown to be strongly and coordinately induced by UV radiation and alkylating agents in human and hamster cells. We found that the gadd45 but not the gaddl53 gene is strongly induced by X rays in human cells. The level of gadd45 mRNA increased rapidly after X rays at doses as low as 2 Gy. After 20 Gy of X rays, gadd45 induction, as measured by increased amounts of mRNA, was similar to that produced by the most effective dose of the alkylating agent methyl methanesulfonate. No induction was seen after treatment of either human or hamster cells with 12-O-tetradecanoylphorbol-13-acetate, a known activator of protein kinase C (PKC). Therefore, gadd45 represents the only known mammalian X-ray-responsive gene whose induction is not mediated by PKC. However, induction was blocked by the protein kinase inhibitor H7, indicating that induction is mediated by some other kinase(s). Sequence analysis of human and hamster cDNA clones demonstrated that this gene has been highly conserved and encodes a novel 165-amino-acid polypeptide which is 96% identical in the two species. This gene was localized to the short arm of human chromosome 1 between p12 and p34. When induction in lymphoblast lines from four normal individuals was compared with that in lines from four patients with ataxia telangiectasia, induction by X rays ofgadd45 mRNA was less in the cell lines from this cancer-prone radiosensitive disorder. Our results provide evidence for the existence of an X-ray stress response in human cells which is independent of PKC and which is abnormal in ataxia telangiectasia.There is increasing evidence that ionizing radiation can induce specific genes in mammalian and other eucaryotic cells. Such genes may have functions like those in procaryotes, in which genes encoding protective functions, such as DNA repair processes, can be induced (39). Prior treatment with a low dose of X rays induces a transient (usually small) protection, manifested as an increased survival or as a reduction in chromosomal damage, against a second, higher dose in human lymphocytes (25), Chinese hamster cells (12), and insect cells (15). These protective effects are blocked by inhibitors of protein (12) and RNA synthesis (15), indicating that such processes may be mediated by the induction of particular genes. The finding that certain proteins increase in abundance after X irradiation of human cells also provides evidence for X-ray-inducible genes (2). Recently, tumor necrosis factor a (TNF) mRNA has been reported to increase in human sarcoma cells after ionizing radiation (9). TNF has a role in a variety of cellular processes, including the acute-phase response and inflammation (1), and thus its induction probably represents a general response to cell injury rather than a specific response to X rays or other DNA-damaging agents. Transcription from the long terminal repeat o...
Enlargement of the optic nerve sheath has been described in patients with raised intracranial pressure (ICP), thereby serving as one of its indicators. Optic nerve sonography offers rapid bedside assessment of the optic nerve sheath diameter and has recently been introduced for the non-invasive detection of raised ICP, particularly in patients with severe brain injury. This review explains the pathophysiology of optic nerve sheath enlargement as a result of intracranial hypertension, describes the technique and clinical use of optic nerve sonography, and summarises the studies which have tested this modality in the non-invasive evaluation of ICP.
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