prolonged serum levels exceeding 8-10 ,ug/ml. In cases 1 and 2 the immediate and dramatic changes occurred with levels greater than this. In case 3 lesser changes occurred even though the serum levels were in the "safe" range. The basal turn of the cochlea seems most vulnerable to both immediate and delayed effects, both of which may produce the dissociated pattern of AP response that is well recognised in high-tone sensory deafness of whatever cause.10The speed of onset of the observed effect suggests a direct action at a site in the cochlea, involving a temporary metabolic block-for example, interference with an energy requiring process or blocking of transport of cations across cell membranes. There is experimental and clinical evidence to show that aminoglycosides interfere with calcium metabolism (probably by binding).21-14 In the lateral line organ of the fish they may block potassium transport.15 Both these effects are rapid and may be reversed by administering the appropriate cation in solution. Other metabolic effects follow intoxication with aminoglycosides, although their speed of onset is not clearly established. Guinea-pigs treated with tobramycin sustain most outer hair cell damage in areas of the cochlea where there is the least amount and smallest granule size of glycogen-namely, the basal turn. The greatest oxygen consumption of the cochlea occurs in the basal turn, and is decreased by kanamycin.17 The adenosine triphosphatase hydrolysing system has been shown to be modified within the microstructures of the cochlea after the administration of aminoglycosides.'8 This may have an important effect on the function of the stria vascularis, which uses adenosine triphosphatase to support a sodium-potassium ion pump to maintain endolymphatic homoeostasis. The possibility that interference with protein synthesis caused of our observed changes is ruled out by their speed of onset.How our findings relate to long-term ototoxicity is not clear. Summary Two hundred and forty-three elderly people aged 60 to 96 years were questioned about their falls, and their sway was measured. For comparison sway was also measured in 63 younger subjects. Sway increased with age and was higher in women at all ages. There was no difference in sway between those with no history of falls and those who fell only because of tripping. In both sexes sway was significantly increased in people who fell because of loss of balance and in women whose falls were due to giddiness,

High expression of epidermal growth factor receptor (EGFR) is found in a variety of solid tumors, including colorectal cancer. EGFR has been identified as a rational target for anticancer therapy. Curcumin, the yellow pigment of turmeric in curry, has received attention as a promising dietary supplement for cancer prevention and treatment. We recently reported that curcumin inhibited the growth of human colon cancer-derived Moser cells by suppressing gene expression of cyclinD1 and EGFR. The aim of the present study was to explore the molecular mechanisms underlying curcumin inhibition of gene expression of EGFR in colon cancer cells. The generality of the inhibitory effect of curcumin on gene expression of EGFR was verified in other human colon cancer-derived cell lines, including Caco-2 and HT-29 cells. Promoter deletion assays and sitedirected mutageneses identified a binding site for the transcription factor early growth response-1 (Egr-1) in egfr promoter as a putative curcumin response element in regulating the promoter activity of the gene in Moser cells. Electrophoretic mobility shift assays demonstrated that curcumin significantly reduced the DNA-binding activity of the transcription factor Egr-1 to the curcumin response element. In addition, curcumin reduced the trans-activation activity of Egr-1 by suppressing egr-1 gene expression, which required interruption of the ERK signal pathway and reduction of the level of phosphorylation of Elk-1 and its activity. Taken together, our results demonstrated that curcumin inhibited human colon cancer cell growth by suppressing gene expression of EGFR through reducing the trans-activation activity of Egr-1. These results provided novel insights into the mechanisms of curcumin inhibition of colon cancer cell growth and potential therapeutic strategies for treatment of colon cancer.

These pilot data quantified the effects of surgical procedures most commonly combined to treat MPL. We hope to use these measurements to correlate surgical treatment with functional outcome and postoperative occurrence of luxation.

LFS and TPLO remain good options for stabilizing stifles with CrCL injury with all dogs showing significant functional improvement. This study does not support the superiority of either surgical technique.

One hundred fifty-seven mandibular fractures in 105 dogs occurred most frequently in male dogs less than 1 year of age. Automobile trauma was the most common cause. Fractures in the premolar region were significantly more frequent than fractures in other regions, and 113 fractures (72%) were open. One hundred forty-two fractures were stabilized, with tape muzzles being the most common method. Postoperative complications, the most common being dental malocclusion, occurred in 53 fractures (34%). Acceptable cosmetic and functional results were achieved in 89 dogs (85%). Fractures in the rostral portion of the mandible had shorter average time to clinical union than other mandibular fractures. Average time to clinical union for fractures in the caudal portions of the mandible was longer than that currently reported.

Sixty-one large dogs (weighing 22.7 kg or more) with cranial cruciate ligament ruptures (CCLRs) were treated with either fibular head transpositions (FHTs; n = 22 stifles), lateral fabellar sutures (LFSs; n = 39 stifles), or conservatively (CT; n = 11 stifles) with rest and aspirin. Based on owner evaluation, dogs treated with FHTs or CT did not perform as well as dogs treated with LFSs (p less than 0.05). There was no difference in owner evaluation scores for the dogs treated with FHTs or CT. Thirty dogs were reevaluated by investigators. No differences between treatment groups regarding age, sex, or time until diagnosis were noted. No differences in scores for lameness, stifle instability, or forceplate analysis among the treatment groups were observed. Degenerative joint disease progressed or remained severe regardless of treatment, based upon radiographic evidence.

The epidermal growth factor (EGF) receptor is the functional target of the mitogen EGF and the cellular homolog of the avian erythroblastosis virus erbB oncogene product. Regulation of expression of the proto-oncogene encoding the EGF receptor can be elucidated by studying the structure and function of the gene promoter outside the confines of the cell. Previously, we reported the isolation of the human EGF receptor gene promoter. The promoter is highly GC rich, contains no TATA or CAAT box, and has multiple transcription start sites. An Si nuclease-sensitive site has now been found 80 to 110 base pairs (bp) upstream from the maijor in vivo transcription initiation site. Two sets of direct repeat sequences were found in this area; both conform to the motif TCCTCCTCC. When deletion mutations were made in this region of the promoter by using either Bal 31 exonuclease or S1 nuclease, we found that in vivo activity dropped three-to fivefold, on the basis of transient-transfection analysis. Examination of nuclear protein binding to normal and mutated promoter DNAs by gel retardation analysis and DNase I footprinting revealed that two specific factors bind to the direct repeat region but cannot bind to the S1 nuclease-mutated promoter. One of the specific factors is the transcription factor Spl. The results suggest that these nuclear trans-acting factors interact with the S1 nuclease-sensitive region of the EGF receptor gene promoter and either directly or indirectly stimulate transcription.The epidermal growth factor (EGF) is a potent mitogen capable of stimulating protein and RNA synthesis, DNA replication, and, ultimately, cellular proliferation (5,19,30). It elicits these cellular responses by binding to the Nterminus of a 170-kilodalton cell surface glycoprotein, the EGF receptor. The receptor possesses a very active tyrosine kinase at its C-terminus and is capable of phosphorylating itself and other substrates upon EGF binding (4). By virtue of its extensive homology to the erbB oncogene product of the avian erythroblastosis virus, the EGF receptor is considered the cellular erbB proto-oncogene (7,33,47,53). This proto-oncogene has been found to be overexpressed and occasionally amplified in a variety of malignant cell types (6,27,31,37,38,54 Promoter regions of active genes are frequently hypersensitive to the endonucleases DNase I and S1 (10,29,50). This sensitivity is thought to be the result of changes in the structure of the active chromatin, possibly because of the differential dissociation of nucleosomes and local alteration in DNA superhelicity (29,50). Isolated eucaryotic promoter regions cloned into plasmid vectors maintain sensitivity to S1 nuclease, provided the plasmid is supercoiled (12,14,34,35,40,44,55 (#1) is designated by the bent arrow at position -258. Heavy arrows underscore the location of the four sequences making up two sets of direct repeats (designated A and B). The cross-hatched box marks the general region sensitive to Si nuclease. The underlined sequences are those deleted by S1 nuc...

A retrospective study was made of 75 mandibular fractures in 62 cats. Mandibular fractures comprised 14.5% of all fractures seen in 517 cats. Automobile trauma was the cause of injury in more than 50% of the cases. The mean age of patients was 29.5 months. Symphyseal fractures were most common (73.3%), followed by fractures of the body (16%), condyle (6.7%), and coronoid process (4%). Sixty-seven percent of the fractures were stabilized. Cerclage and interfragmentary wiring were the most common forms of fixation. Antibiotics were administered to 73.6% of the patients. Complications were reported in 24.5% of the cats. Malocclusion and soft tissue infections were the most frequent complications. Complications developed more commonly in cats with multiple or open fractures. Clinical union occurred by an average of 6 weeks (range, 3-12 weeks) for symphyseal fractures, 10 weeks (range, 8-16 weeks) for body fractures, 6 weeks for coronoid fractures, and 6 weeks (range, 4-8 weeks) for condylar fractures.