Effects of short- and long-term changes in auditory feedback on vowel and sibilant contrasts.

PURPOSE: To assess the effects of short- and long-term changes in auditory feedback on vowel and sibilant contrasts and to evaluate hypotheses arising from a model of speech motor planning. METHOD: The perception and production of vowel and sibilant contrasts were measured in 8 postlingually deafened adults prior to activation of their cochlear implant speech processors, 1 month postactivation, and 1 year postactivation. Measures were taken postactivation both with and without auditory feedback. Contrast measures were also made for a group of speakers with reportedly normal hearing speaking with masked and unmasked auditory feedback. RESULTS: Vowel and sibilant contrasts, measured in the absence of auditory feedback after 1 month of prosthesis use, were diminished compared with their values measured before prosthesis. Contrasts measured in the absence of auditory feedback after 1 year's experience with the prosthesis were increased compared with their values after 1 month's experience. In both time samples, contrasts were enhanced when auditory feedback was restored. CONCLUSION: The provision of prosthetic hearing to postlingually deafened adults impaired their phonemic contrasts at first, as their auditory feedback had novel characteristics. Once auditory feedback became recalibrated with prosthesis use, it could, in turn, revise feedforward commands that control the contrasts in its absence.     

Injuries and muscle soreness during the one repetition maximum assessment in a cardiac rehabilitation population

BACKGROUND: Strength training (ST) may be beneficial for preservation of lean tissue, increasing bone mineral content, decreasing falls, and enhancing quality of life. Strength training is becoming an appropriate mode of exercise for cardiac rehabilitation (CR) patients. One method for determining optimal exercise intensity for safe and effective ST requires one repetition maximum (1RM) testing. Clinicians may be reluctant to perform 1RM testing in CR patients because of potential muscle soreness/injury and adverse hemodynamic responses in deconditioned patients. The purpose of this investigation was to perform 1RM testing in CR patients and determine muscle soreness/injury rate. METHODS: Seventy-four CR patients stratified by risk (low n = 30, intermediate n = 21, high n = 23) and sex (males = 55, females = 19) participated. Subject's ages ranged from 39 to 76 years and time from procedure ranged from 19 days to 2 years. No patient had ever undergone 1RM testing. The method of Kraemer and Fry was used to assess 1RM. High-risk patients' heart rates/rhythms and blood pressures were monitored. Patients were evaluated for occurrence of muscle soreness/injury immediately after 1RM testing and on days 2 and 7 using a soreness scale developed by Shaw et al. Muscle soreness/injury was considered significant if a patient reported altering or stopping physical activities. RESULTS: No injury or significant muscle soreness occurred as a result of 1RM testing. No abnormal heart rate/rhythm or blood pressure responses occurred in high-risk patients. CONCLUSIONS: Results indicate that with proper technique, 1RM testing may be performed in CR patients without injury or significant muscle soreness.     

Inhibitors of receptor protein kinases

Inhibitors of receptor protein kinases were the subject of numerous abstracts across several sections of the meeting, and the results reported emphasized the rapid progress in this field, with several new compounds reported to be in clinical trial.     

Cytotoxicity and DNA interaction of the enantiomers of 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indo- line (amino-seco-CI-TMI).

The enantiomers of the previously reported racemic 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl] indoline (amino-seco-CI-TMI) were prepared via resolution of a precursor by chiral HPLC. The only detectable product isolated from reaction of the racemic compound with calf thymus DNA, followed by thermal cleavage, was shown by mass spectrometry and two-dimensional NMR spectroscopy to be the adenine N3 adduct. Polyacrylamide gel electrophoresis assays with the racemate and with each enantiomer also showed adenine to be the only site of alkylation. While the racemic amino compound exhibited sequence selectivity identical to that of the previously characterized phenol analogue, the enantiomers exhibited distinctly different sequence selectivities, allowing the (+) enantiomer to be assigned the "natural" S configuration. The (+)-(S) enantiomer is 3-fold more cytotoxic than the (-)-(R) enantiomer (IC(50) values of 240 and 700 nM, respectively, in AA8 cells, after exposure for 4 h).     

Tirapazamine: a bioreductive anticancer drug that exploits tumour hypoxia

Tirapazamine is the second clinical anticancer drug (after porfiromycin) that functions primarily as a hypoxia-selective cytotoxin. Hypoxic cells in tumours are relatively resistant to radiotherapy and to some forms of chemotherapy and are also biologically aggressive, thus representing an important target population in oncology. Tirapazamine undergoes metabolism by reductases to form a transient oxidising radical that can be efficiently scavenged by molecular oxygen in normal tissues to re-form the parent compound. In the absence of oxygen, the oxidising radical abstracts a proton from DNA to form DNA radicals, largely at C4' on the ribose ring. Tirapazamine can also oxidise such DNA radicals to cytotoxic DNA strand breaks. It therefore shows substantial selective cytotoxicity for anoxic cells in culture (typically approximately 100-fold more potent than under oxic conditions) and for the hypoxic subfraction of cells in tumours. Preclinical studies showed enhanced activity of combinations of tirapazamine with radiation (to kill oxygenated cells) and with conventional cytotoxics, especially cisplatin (probably through inhibition of repair of cisplatin DNA cross-links in hypoxic cells). Phase II and III clinical studies of tirapazamine and cisplatin in malignant melanoma and non-small cell lung cancer suggest that the combination is more active than cisplatin alone and preliminary results with advanced squamous cell carcinomas of the head and neck indicate that tirapazamine may enhance the activity of cisplatin with fractionated radiotherapy.     

Role of DNA minor groove alkylation and DNA cross-linking in the cytotoxicity of polybenzamide mustards

Interstrand DNA cross-links have been considered essential to the activity of current clinical DNA-alkylating antitumour drugs, which generally alkylate in the major groove. However, the relationship between cross-linking adducts located in the minor groove of DNA with cytotoxicity and antitumour activity has not been extensively investigated. Previous studies have shown that cross-linking ability is not correlated with cytotoxicity in a novel series of polybenzamide-linked nitrogen mustard compounds which alkylate DNA at adenines in the minor groove. In the present study the nature of these cross-linking adducts was explored for a related pair of compounds which are both highly effective cross-linkers but which differ in antitumour potential. Both of these drugs effectively interact with adenines in the minor groove, although their sequence specificity differs. However, the cross-linking event was not inhibited by pre-treatment with Hoechst 33258, although this pre-treatment effectively prevented adenine alkylation. The primary cross-links detected may thus represent guanine N7 alkylations in the major groove. Whether minor groove cross-linking adducts can be formed is uncertain, since the effect of background guanine N7 alkylation may complicate analysis. The cytotoxicity of the polybenzamides may therefore be related to other factors such as their interaction with cellular repair systems.