Dietary obesity in the rat induces endothelial dysfunction without causing insulin resistance: a possible role for triacylglycerols.

Impaired arterial vasorelaxation, due primarily to endothelial dysfunction, is associated with obesity. To clarify the relationship with insulin resistance and other metabolic disturbances, we studied endothelial-dependent and -independent vascular responses in rats with dietary-induced obesity. Dietary-obese rats had significantly higher body weights (10-32%; P<0.001) and fat-pad masses (220-280%; P<0.001) than lean controls, together with raised plasma levels of triacylglycerols (15-80%; P<0.001), non-esterified fatty acids (13-38%; P<0.05) and leptin (85-180%; P<0.001). However, measures of insulin sensitivity (including the hyperinsulinaemic-euglycaemic clamp in a parallel experiment) were comparable with those in controls. Contractions induced in mesenteric arteries by noradrenaline (0.5-8 micromol/l) were comparable in lean and obese groups, but vasorelaxation in noradrenaline-preconstricted arteries was markedly reduced in dietary-obese rats of both sexes. Concentration-response curves to endothelium-dependent vasorelaxants (acetylcholine, A23187 and insulin) showed significant reductions in maximal relaxation (20-95% less than in leans; P<0.001) and significant rightward shifts in EC(40) (concentration giving 40% of maximal response) (P<0.01). Relaxation in response to the direct NO donor, sodium nitroprusside, showed a lesser impairment (12%; P<0.01) in dietary-obese rats. Maximal relaxation to acetylcholine was correlated inversely in both sexes with fat-pad mass (r(2)=0.37, P<0.05) and plasma triacylglycerols (r(2)=0.51, P<0.01), and with leptin in males only (r(2)=0.35, P<0.05). Independent determinants of acetylcholine-induced relaxation were fat mass and plasma triacylglycerols; plasma insulin and insulin sensitivity had no effect. Dietary-induced obesity severely impaired arterial relaxation in both sexes, particularly at the endothelial level. This is not attributable to insulin resistance, but may be related to moderate hypertriglyceridaemia.

Troglitazone corrects metabolic changes but not vascular dysfunction in dietary-obese rats.

Insulin resistance has been attributed to the defect in vascular function associated with obesity, type 2 diabetes and dyslipidaemia. We have investigated vascular effects of chronic (3-week) administration of troglitazone on female Wistar rats with moderate dietary obesity. Compared with lean controls, untreated obese rats had significantly higher body weights, fat pad masses, plasma triglycerides, free fatty acids and leptin levels (for all P < 0.01). These metabolic changes were corrected by troglitazone treatment. In mesenteric arteries, responses to noradrenaline or KCl were similar in all groups. However, in noradrenaline-preconstricted arteries, vasorelaxations to acetylcholine and insulin were significantly (50-60% less than in lean, P < 0.001) attenuated in both untreated and troglitazone-treated obese rats. Relaxations to sodium nitroprusside showed similar but lesser impairment in both untreated and troglitazone-treated obese animals. Our data show that although troglitazone markedly improved obesity-induced metabolic changes, it failed to correct vascular dysfunction associated with obesity in female Wistar rats.

Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation.

Peroxisome proliferator-activated receptor (PPAR)-alpha agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-alpha activation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-gamma activation. Three-week high fat-fed male Wistar rats were untreated or treated with the specific PPAR-alpha agonist WY14643 or the PPAR-gamma agonist pioglitazone (both 3 mg x kg(-1) x day(-1)) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides (-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%) and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced whole-body insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulin-mediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P = 0.001) and with plasma triglyceride levels (r = -0.77, P < 0.001). We conclude that even though WY14643 and pioglitazone, representing PPAR-alpha and PPAR-gamma activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat-fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation.

Vasorelaxant effects of oestradiols on guinea pigs: a role for gender differences.

Various studies have shown vasorelaxation properties for 17alpha- and 17beta-oestradiol. Here, we studied the effects of gender difference as well as oestrous cycle on oestradiol-induced vasorelaxation in mesenteric arteries from male and female guinea-pigs and in main uterine arteries from female guinea-pigs in vitro. Both 17alpha- and 17beta-oestradiol (0.5-20 micromol L-1) induced concentration-dependent relaxation of both mesenteric and uterine arteries preconstricted with either noradrenaline (NA; 10 micromol L-1) or KCl (125 mmol L-1) from both day-7 and day-15 female guinea-pigs. 17beta-oestradiol was more potent in relaxing arteries precontracted with NA than those pretreated with KCl, while 17alpha-oestradiol was more effective in relaxing those arteries precontracted with KCl. In mesenteric arteries from male animals, 17alpha-oestradiol was significantly (P < 0.001) more potent on arteries precontracted with NA than KCl, an effect opposite to that seen on arteries from female animals. However, both 17alpha- and 17beta-oestradiol were more potent in relaxing arteries from male animals compared with their female counterparts. These data indicate a possible role for gender differences in the vascular effects of oestradiols.

The mechanism of resveratrol-induced vasorelaxation differs in the mesenteric resistance arteries of lean and obese rats.

Resveratrol has been shown to induce vasorelaxation. In this study, we investigated the mechanism(s) of resveratrol-induced vasorelaxation in resistance mesenteric arteries from male lean and dietary-induced obese rats. Compared with lean rats, arteries from dietary-obese rats showed significant (P<0.001) endothelial dysfunction, as indicated by a decrease (>20%) in maximal acetylcholine-induced vasorelaxation. Resveratrol (5-35 micromol/l) induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8 micromol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. There were no significant differences between the two groups, achieving a maximum relaxation of >95% at a concentration of 35 micromol/l. In noradrenaline-preconstricted arteries from lean rats, N(G)-nitro-L-arginine methyl ester (L-NAME; 100 and 300 micromol/l) caused a significant (P<0.01) concentration-dependent rightward shift in reseveratrol activity, with no effect on maximal responses. However, L-NAME (100 and 300 micromol/l) did not alter the effects of reseveratrol on arteries from dietary-obese rats, giving superimposed concentration-responses curves. Indomethacin was also ineffective in altering resveratrol activity in arteries from both lean and dietary-obese rats. In noradrenaline-precontracted arteries from dietary-obese rats, responses to resveratrol were not attenuated by endothelial denudation, indicating an action independent of the endothelium. This study indicates that: (a) the maximal effects of resveratrol on resistance arteries from lean and dietary-obese rats are not effected by endothelial dysfunction, and (b) the effects of resveratrol in lean animals (where endothelial function is not impaired), but not in dietary-obese rats, are mediated via NO.

Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female guinea-pigs.

Naturally occurring hydroxystilbenes have been shown to induce vasorelaxation. Here, we studied the mechanism of resveratrol-induced vasorelaxation in different types of blood vessels, namely mesenteric (resistance) and main uterine (conductance) arteries, from female guinea-pigs on day 7 and day 15 of the oestrous cycle. Resveratrol (5-70 micromol/l) induced concentration-dependent relaxation of both mesenteric and uterine arteries preconstricted with either noradrenaline (NA; 10 micromol/l) or KCl (125 mmol/l). Resveratrol was 2-fold more potent in inducing relaxation of mesenteric arteries than of uterine arteries. Its effects on uterine arteries from both day-7 and day-15 guinea-pigs were similar, irrespective of the constrictor used, but it was significantly (P<0.01) more potent in inducing relaxation of mesenteric arteries contracted with NA compared with those constricted with KCl. In day-7 arteries precontracted with NA, N(G)-nitro-L-arginine methyl ester (L-NAME; 10 micromol/l) had no effects on the time course of resveratrol-induced vasorelaxation in either mesenteric or uterine arteries. However, indomethacin (50 micromol/l) significantly (P<0.05) potentiated resveratrol's effect on mesenteric, but not uterine, arteries. Indomethacin had no effect on resveratrol-induced vasorelaxation of arteries contracted with KCl, whereas L-NAME significantly (P<0.05) reduced the effects of resveratrol on uterine, but not on mesenteric, arteries. In day-15 arteries, L-NAME significantly (P<0.01) attenuated the effects of resveratrol on mesenteric arteries contracted with NA. Indomethacin had no effect on resveratrol activity. This study indicates that: (a) the effect of resveratrol on resistance arteries is greater than that on conductance arteries; (b) the effects of resveratrol are not mediated via prostanoids, but NO may play a role; and (c) the stage of the oestrous cycle has no influence on resveratrol-induced vasorelaxation.

Effects of treatment for sound errors in apraxia of speech and aphasia.

This investigation was designed to examine the acquisition, generalization, and maintenance effects of a treatment for sound errors in speakers with co-occurring apraxia of speech and aphasia. Three speakers with chronic apraxia of speech and aphasia were studied in the context of a multiple baseline design across speakers and behaviors. Treatment combined the use of minimal contrast pairs with traditional sound production training techniques such as integral stimulation and articulatory placement cueing and was applied sequentially to sounds that were determined to be consistently in error before training. Results revealed increased correct sound productions for all speakers in trained and untrained words. Response generalization effects across sounds and stimulus generalization effects varied, but appeared to be limited for most speakers. Although positive maintenance effects were evidenced, some loss of treatment gains was noted following cessation of treatment.

Phrenic nerve reinnervation of the cat's larynx: a new technique with proven success.

Reinnervation of the posterior cricoarytenoid muscle (PCA) should provide vocal cord abduction on inspiration, and passive adduction to enable phonation. Previous investigators have shown that reinnervation is possible, but results have not been clinically encouraging. When reinnervation was successful, the question remained whether it was provided by the transplanted nerve or by the ingrowth of adjacent nerves. In this study the phrenic nerve was transplanted directly into the PCA in a series of 12 cats. Fibrin glue was used to overcome nerve trauma and to prevent retraction of the nerve from the PCA. Laryngoscopy, electromyography, and retrograde labeling of the phrenic motoneurons provided evidence of functional reinnervation in 9 cats. Partial or complete failure in the remaining 3 was due to retraction of the nerve from the muscle. These results appear to justify trials of the procedure in humans.

Stapes surgery: subjective and objective results revisited.

In 1980 we presented a retrospective review of one surgeon's experience with stapes surgery. The results were disappointing both from the standpoint of hearing results and patient satisfaction. Because of those findings we modified both indications for surgery and our surgical technique. A second subjective and objective review was carried out between 1980 and 1992. We are pleased to report that both the subjective and objective findings are markedly improved, but there is still room for further improvement and our surgical technique will again be modified.

The cochlear implant: a comparison of single-channel and multichannel results.

We have performed 39 cochlear implants at St. Paul's Hospital since 1982. Fourteen patients received a House/3M implant and 23 patients received a total of 25 multichannel Nucleus implants. We present a comparison of subjective and objective results in seven patients who first received a single channel implant and were subsequently implanted with a multichannel device. We also report in detail results obtained by a 55-year-old man who received a House/3M implant and subsequently received bilateral Nucleus implants. Results in this patient demonstrate some factors that influence successful use of an implant.

Cochlear implants: update of the program at the University of British Columbia.

Since 1982, we have performed 26 cochlear implants at the University of British Columbia. The first 14 patients were implanted with the House/3M single-channel unit and the last 12 have been implanted with the Nucleus 22-channel unit. This paper reviews the methods used in patient selection and rehabilitation and compares the results obtained in patients using a single-channel with those using a multi-channel unit.

Facilitating generalized requesting behavior in Broca's aphasia: an experimental analysis of a generalization training procedure.

The effects of a generalization training procedure on requesting by 4 subjects with chronic Broca's aphasia were examined using a multiple baseline design across behaviors and subjects. Subjects were trained to request information on three topics sequentially. Generalization across topics and persons was assessed in weekly probe sessions consisting of 5-min conversational interactions with trainers and unfamiliar volunteers in a nontreatment setting. Results revealed generalization effects were greatest when trainers, as opposed to unfamiliar volunteers, served as conversational participants. Nevertheless, subjects' requests increased with all conversational participants to a level comparable to a normal comparison group assessed under conditions identical to the experimental probes. Social validation of treatment effects using a subjective evaluation procedure revealed significant improvement on the parameters of talkativeness, inquisitiveness, and conversational success.

Bilateral gustatory rhinorrhea following bilateral parotidectomy: a case report.

To the authors' knowledge, no cases of gustatory rhinorrhea following parotidectomy have been reported. A case is presented of a 28-year-old woman who underwent bilateral parotidectomies within a four-year period for congenital sialectasia and secondary infection. Both operations were complicated by Frey's syndrome and she also developed bilateral gustatory rhinorrhea. The successful management of this problem with bilateral vidian neurectomies and the refractory nature of her Frey's syndrome, finally controlled with tympanic neurectomies, are discussed.

Solubilization kinetics of a triglyceride/n-alkane mixture in a non-ionic surfactant solution.

The kinetics of solubilization in a non-ionic surfactant solution of pure n-hexadecane, pure triolein and a mixture of the two oils have been investigated. The rates were determined from observations of the dissolution of a single, microscopic droplet, using a drop-on-fibre technique. Conditions were such that negligible saturation of the micellar surfactant with solubilizate occurred. The rate of solubilization of each of the pure oils was found to be independent of time, hexadecane solubilization on a volume basis being about 8 times as rapid as that for triolein. The rate of solubilization of a mixture of the two oils, having a volume fraction 0.69 for triolein, was found to vary in the medium term, the rates apparently being steady both initially and (at a lower value) in the long term. These observations can be related quantitatively to the rates found for the pure oils.

Cochlear implant experience at the University of British Columbia.

The authors review their experience with 13 totally deaf patients implanted with the House/3M cochlear implant. The preoperative evaluation, operative procedure, postoperative rehabilitation and hearing results are presented.

Management of tinnitus: a practical approach.

This paper presents our experience with 500 patients with intractable tinnitus who were referred to our tinnitus clinic during the past 10 years. We propose a management plan based on identification and classification of three types of tinnitus. We describe what a tinnitus clinic adds to patient care, with emphasis on how these treatment methods can be utilized in office practice.