Transcripts for the acetylcholine receptor and acetylcholine esterase show distribution differences in cultured chick muscle cells.

In situ hybridization of chick cultured muscle cells using exonic DNA probes for both AChR alpha-sub-unit and the catalytic subunit of AChE, revealed major differences in the distribution of label both over nuclei and in their surrounding cytoplasm, although some overlap in these distributions exists. For the AChR alpha-subunit there is a highly skewed distribution of labeled nuclei, with 35% of the nuclei being relatively inactive (less than 0.25 times the mean label) and approximately 10% being very heavily labeled (greater than 2.5 times the mean label). In contrast the nuclei labeled with the exonic probe for the AChE transcripts had a more Gaussian distribution, yet with some slight skewness in the direction of a few heavily labeled nuclei. There was also a difference in the cytoplasmic distribution of the label. The AChR alpha-subunit mRNA was mainly within 4 microns of labeled nuclei while the AChE mRNA was more widely distributed throughout the cytoplasm, possibly within a 10 microns rim around labeled nuclei. An intronic probe for the AChE gave the identical distribution of nuclear label to that of the exonic probe (but without any cytoplasmic label). In addition, calibration of the technique indicated that per myotube the AChE transcript is about sixfold more abundant than the AChR alpha-subunit transcript.

Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor.

For Ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl:protein transferase (FPTase). Inhibitors of FPTase have therefore been developed as potential anticancer agents. These compounds reverse many of the malignant phenotypes of Ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice. Furthermore, the FPTase inhibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice. Although these data support the further development of FTIs, it should be noted that Ki-ras is the ras gene most frequently mutated in human cancers. Moreover, Ki-RasB binds more tightly to FPTase than either Ha- or N-Ras, and thus higher concentrations of FTIs that are competitive with the protein substrate may be required to inhibit Ki-Ras processing. Given the unique biochemical and biological features of Ki-RasB, it is important to evaluate the efficacy of FTIs or any other modulator of oncogenic Ras function in model systems expressing this Ras oncoprotein. We have developed strains of transgenic mice carrying the human Ki-rasB cDNA with an activating mutation (G12V) under the control of the MMTV enhancer/promoter. The predominant pathological feature that develops in these mice is the stochastic appearance of mammary adenocarcinomas. High levels of the Ki-rasB transgene RNA are detected in these tumors. Treatment of MMTV-Ki-rasB mice with L-744,832 caused inhibition of tumor growth in the absence of systemic toxicity. Although FPTase activity was inhibited in tumors from the treated mice, unprocessed Ki-RasB was not detected. These results demonstrate the utility of the MMTV-Ki-rasB transgenic mice for testing potential anticancer agents. Additionally, the data suggest that although the FTI L-744,832 can inhibit tumor growth in this model, Ki-Ras may not be the sole mediator of the biological effects of the FTI.

Marijuana consumption and tolerance to physiological and subjective effects.

The relation between marijuana consumption and the development of tolerance was investigated during a 31-day study. Volunteers with a history of moderate or heavy marijuana use were given access to one-gram (2.1% delta9 tetrahydrocannabinol [THC]) marijuana cigarettes during a 21-day smoking period. Both groups tended to increase consumption during this time. Heavy users averaged 5.7 cigarettes per day and indicated a progressive decline in ratings of intoxication and duration of pulse rate effect. Moderate users averaged 3.2 cigarettes per day but showed no changes in either of these reactions during this time. Results suggested that tolerance does not develop to the two most reliable indexes of marijuana intoxication unless heavy doses of delta9 THC are self-administered repeatedly. Also, the tendency to increase consumption during this time is not necessarily associated with the development of tolerance.

Plasma lipid changes after supplementation with beta-glucan fiber from yeast.

BACKGROUND: Dietary fiber has been shown to improve blood lipids. OBJECTIVE: The purpose of this study was to evaluate the effect on serum lipids of a yeast-derived beta-glucan fiber in 15 free-living, obese, hypercholesterolemic men. DESIGN: After a 3-wk period in which subjects ate their usual diet, 15 g fiber/d was added to the diet for 8 wk and then stopped for 4 wk. Plasma lipids were measured weekly during baseline and at week 7 and 8 of fiber consumption, and again at week 12. RESULTS: Compared with baseline, fiber consumption significantly reduced plasma total cholesterol (by 8% at week 7 and 6% at week 8; P < 0.05 using Bonferroni correction); week 12 values did not differ from baseline. No significant differences were noted between baseline LDL cholesterol and values at weeks 7, 8, or 12 when comparing individual groups by using Bonferroni correction, even though the overall one-way analysis of variance with repeated measures was highly significant (P < 0.001). LDL-cholesterol concentrations did decline by 8% at week 8 compared with baseline. There was a significant effect of diet on plasma HDL-cholesterol concentrations (P < 0.005 by one-way ANOVA with repeated measures). However, a group difference was observed only between baseline and week 12 (16% increase; P < 0.05 by Bonferroni correction). Triacylglycerol concentrations did not change. CONCLUSIONS: The yeast-derived beta-glucan fiber significantly lowered total cholesterol concentrations and was well tolerated; HDL-cholesterol concentrations rose, but only 4 wk after the fiber was stopped.

Effects of adinazolam on plasma catecholamine, heart rate and blood pressure responses in stressed and non-stressed rats.

Adinazolam (ADI) is a new benzodiazepine with anxiolytic and antidepressant properties. To assess its effects on the acute stress response, rats were given a single intraperitoneal injection of 2.5 or 5.0 mg/kg of ADI and stressed for 1 hr by restraint. Neither dose of ADI had any effect on heart rate, blood pressure or norepinephrine (NE) and epinephrine (EP) in plasma in the resting rats. In the stressed animal, 2.5 and 5.0 mg/kg of ADI did not affect stress-induced increases in heart rate or blood pressure but both significantly reduced the stress-induced increases in plasma NE and EP. During certain stressful experiences in patients with abnormally-increased sympathetic drive, ADI may be therapeutically useful in reducing high levels of catecholamines.

Reference range determination: the problem of small sample sizes.

The process of developing and validating a quantitative test includes determination of a reference range. Traditionally this has been taken as the mean +/- 2 standard deviations for a random sampling from a reference population. However, this method fails to recognize the substantial variability in the sample mean and standard deviation for the small sample sizes frequently encountered in nuclear medicine. A new approach, which involves calculating confidence intervals for the upper and lower bounds of the traditionally defined range, recognizes three ranges of values: normal, indeterminate, and abnormal. The principles of this approach are illustrated using differential renal function in twelve renal transplant donors. The 99mTc-DTPA differential uptake between 1 and 2 min gave a traditionally-defined single-kidney range of 50% +/- 8%, whereas with our method the normal range would be 50% +/- 6% with indeterminate ranges of 37%-44% and 56%-63%. These values are consistent with the wide variation in reference ranges reported in the literature, and suggest that much of this variability may be a statistical artifact resulting from inadequate sample sizes. A nomogram has been derived that permits the power of the reference range determination to be easily calculated from the sample size. Analysis of the effect of sample size on the accuracy of the upper and lower bounds of the reference range is advocated whenever small reference populations are used.

Effect of exercise supplementation on dipyridamole thallium-201 image quality.

To determine the effect of different types of exercise supplementation on dipyridamole thallium image quality, 78 patients were prospectively randomized to one of three protocols: dipyridamole infusion alone, dipyridamole supplemented with isometric handgrip, and dipyridamole with low-level treadmill exercise. Heart-to-lung, heart-to-liver, and heart-to-adjacent infradiaphragmatic activity ratios were generated from anterior images acquired immediately following the test. Additionally, heart-to-total infradiaphragmatic activity was graded semiquantitatively. Results showed a significantly higher ratio of heart to subdiaphragmatic activity in the treadmill group as compared with dipyridamole alone (p less than 0.001) and dipyridamole supplemented with isometric handgrip exercise (p less than 0.001). No significant difference was observed between patients receiving the dipyridamole infusion, and dipyridamole supplemented with isometric handgrip exercise. We conclude that low-level treadmill exercise supplementation of dipyridamole infusion is an effective means of improving image quality. Supplementation with isometric handgrip does not improve image quality over dipyridamole alone.

Quantification of walking exercise required for improvement of dipyridamole thallium-201 image quality.

Dipyridamole 201Tl imaging is an accepted diagnostic procedure for the evaluation of patients unable to perform adequate treadmill exercise, but is limited by high infradiaphragmatic activity. While recent studies have shown that the addition of exercise reduces this activity, the amount of exercise needed to effect such an improvement is uncertain. To prospectively evaluate the amount of walking exercise required to produce improvement in image quality, 120 patients were randomized to either a control group receiving dipyridamole alone, or to dipyridamole supplemented with one of four exercise protocols. Ratios of heart-to-liver and heart-to-adjacent infradiaphragmatic activity were generated from anterior images acquired immediately following the test. Heart-to-total infradiaphragmatic activity was also graded semiquantitatively. Results showed improved target-to-background ratios as well as semiquantitative assessment of image quality for dipyridamole supplemented with exercise as compared to dipyridamole alone. No difference was seen between walking in place and Bruce treadmill exercise at Stage 0 or 0.5. A trend towards higher values was seen with Bruce Stage 1 exercise supplementation, but this did not reach statistical significance. No significant complications occurred during the study. We conclude that 3 min of walking exercise is a safe and effective means of improving the quality of dipyridamole 201Tl images.

Nonpharmacologic and pharmacologic management of weight gain.

Obesity increases the risk of several serious health problems, including heart disease, type II diabetes mellitus, hypertension, and osteoarthritis. Patients taking certain psychotropic medications may gain a significant amount of weight (as much as a 5% increase in body weight within 1 to 2 months), placing them at risk for obesity. Body weight monitoring and prudent drug selection are the best approaches to preventing weight gain in patients taking psychotropic drugs. When weight gain (> 5% of initial body weight) is unavoidable, intervention counseling should begin. Nonpharmacologic measures for managing weight gain include a balanced deficit diet of 1000 calories and higher, depending on the patient's weight; 30 to 60 minutes of physical activity daily; and behavioral training to restrain excess caloric intake. Each of these measures requires a considerable commitment on the part of the patient and works best with support from the physician and weight-loss support groups. Drug therapy for weight loss is available (at present, sibutramine is the only approved appetite suppressant in the United States); however, for most patients already being treated with a psychotropic agent, the risks (such as drug interactions, adverse events, compliance problems) of adding an antiobesity agent probably outweigh the benefits. Surgical intervention for obesity should be reserved for morbidly obese patients whose disease is intractable to medical therapy.

Experimental analysis of the 'happy hour": effects of purchase price on alcohol consumption.

An experimental analogue of a discount drink policy known as the "happy hour" was used to study the effects of purchase price on drinking behavior. Male volunteers with a prior history of either casual (N=20) or heavy (N=14) drinking were given free access to beverage alcohol during a 20-day period. Approximately half the subjects could purchase alcohol under a single-price condition (50 cents/drink), while a matched group was given a price reduction daily (25 cents/drink) during a three-hour period in the afternoon. The results demonstrated that the afternoon price reduction significantly increased alcohol consumption in both casual and heavy drinkers. Reinstatement of the standard purchase price effectively suppressed drinking in both groups. The findings are discussed in terms of the theoretical and research implications of environmental influences on drinking.

Effects of marihuana use on body weight and caloric intake in humans.

Body weight and caloric intake were measured in a group of heavy and casual marihuana users prior to, during and following 21 days of marihuana smoking under research ward conditions. A group of control subjects were studied under identical conditions, but they did not smoke marihuana. Both heavy and casual marihuana users had a significant increase in caloric intake and gained weight during the marihuana smoking period. Heavy and casual users gained an average of 3.7 and 2.8 lbs respectively during the first 5 days of marihuana smoking. In contrast, control subjects gained only a small amount of weight (0.2 lbs) during the same time interval. Water retention did not appear to be a major factor in weight gain by the marihuana users. These findings are in agreement with both anecdotal reports and previous experimental data that marihuana use is associated with increased caloric intake and weight gain.

Proximity storage of surgical instruments in the operative field.

A new microsurgical instrument, the surgical pocket, is described, and its value for storing instruments in the surgical field during operation is discussed. Specific procedures for using the pocket in the field with the bipolar coagulator, suction irrigator, dissector, and scissors are presented. Proximity storage of microsurgical instruments reduces the surgeon's reliance upon other surgical personnel by allowing instrument transfers to be made without assistance. In addition, it reduces stress and fatigue for the surgeon by shortening the length of the operation and reducing eye strain by reducing the need to shift vision from the eyepieces of the microscope to the operating room and back each time an instrument is exchanged.

Intraoperative ultrasonography with a cystoscope for the biopsy of a deep-seated brain lesion: case study.

An intraoperative technique for deep brain biopsy is described. It features the use of an integrated surgical support system for the instruments and a rod that provides external topographical maintenance of the coordinates established ultrasonographically. A cystoscope, when supported mechanically by this system, permits multiple entries of the biopsy forceps to the lesion without further disturbance of the brain, as well as irrigation, coagulation, and visualization, if desired. When used in conjunction with real time intraoperative ultrasonography, the surgeon may view the entire procedure and be certain that the biopsy sample has been obtained from the lesion, major deep blood vessels have been avoided, and the biopsy site is stable after the procedure. The advantages of this technique include simplicity, low cost, accuracy, stability, and availability to every neurosurgeon in every hospital.

Cerebral aneurysm rupture during neurosurgery.

The author describes a technique providing mechanical rather than manual support to a suction tube for improved control of aneurysm hemorrhage during operation. This results in increased precision, fewer hand movements, reduced reliance upon other operating room personnel, decreased trauma to tissues as a result of multiple manipulations, reduced anxiety for the surgeon, and a shorter operating time.

Staircase concept of instrument placement in microsurgery.

A new technique of mechanical support for microinstruments of action (e.g., scissors and air turbine drills) is presented. The technique consists of attaching instruments to ball and cable retractor arms (Flexbars) and securing them to a framework around the operative site. By assigning functional levels for instrument and hand placement, surgical procedures are simplified and shortened. A brief comparison of self-retaining retractors and an evaluation of them in terms of this technique is also included.

Self-retaining retractor and handrest system for neurosurgery.

A system for self-retaining retraction that has also been used as part of a technique of dissection in microneurosurgery is described. Small, multiple (i.e., more than two) blades can be used easily with a positioning opportunity of 360 degrees of purchase and without the necessity of another surgeon. Hand tremor, which is not particularly during microsurgery, has been dealt with by the development of a system for stabilization by a handrest. The components of the system, its sequential assembly, and its use are described and illustrated.

Energy regulation in morbid obesity by multidisciplinary therapy.

Regulation of energy expenditure should be directed toward fat mobilization and oxidation with concomitant preservation of lean body mass. This requires a multidisciplinary approach. The key surgical component of a gastric bypass is a properly sized pouch and stoma outlet. Compliance with a diet of approximately 800 to 1200 kcal per day, limited to three small meals and two snacks is the desired result. Weight loss should average 10 to 15 pounds monthly when surgery is added to intense medical, nutritional, and behavior therapy to ensure that the weight is reduced to desirable levels.

Comparison of the discriminative stimulus properties of delta9-THC and psilocybin in rats.

Male albino rats were trained to respond differentially on the left or right lever in a 2-lever chamber on the basis of which drug had been given intra-peritoneally (IP) 30 min before experimentation. In 1 group 1.9 mg/kg of delta9-THC and control injections (vehicle) served as the discriminative stimuli associated with each lever and in another group the drug stimuli were 1.0 mg/kg of delta9-THC and 1.0 mg/kg of psilocybin. The results confirmed those of other experiments using different procedures; that delta9-THC can acquire discriminative control over responding. The fact that delta9-THC and psilocybin were also found to differentially control lever choice demonstrates that these 2 drugs probably produce discriminably different states in rats.

Intraperitoneal urine leak following renal transplant.

A 47-year-old man with chronic renal failure underwent renal transplantation. He remained anuric and was diagnosed with an intraperitoneal urine leak by Tc-99m MAG3 renal scintigraphy. The diagnosis was confirmed by imaging fluid withdrawn via the peritoneal dialysis catheter.

Diagnostic thyroid procedures and corresponding radiation doses in Manitoba: 1981-1985.

Data on nuclear medicine thyroid examinations performed in Manitoba (population 1 million) from 1981-1985 were collected, with more detailed demographic data obtained on 1,100 consecutive patients between June 1987 and January 1988. An average of 2,081 patients were examined per year, 81% female and 19% male, representing 8.4% of all nuclear medicine procedures. Typical administered activity and associated HE per patient were 238.0 MBq and 1.5 mSv for 99mTc, 7.4 MBq and 1.2 mSv for 123I, and 0.33 MBq and 3.9 mSv for 131I. Based on NCRP risk estimates with explicit corrections for age, sex, and radionuclide used, it is estimated that the rate of thyroid cancer induction is unlikely to exceed 0.56 y-1, of which about 10% would be fatal. This estimate is about a factor of 4 less than that generated using more generally applicable radiation protection risk estimates averaged over both sexes and all ages in the general population. The replacement of 131I with the present mix of radiotracers used for thyroid evaluation has resulted in a reduction of the estimated population detriment by a factor of 3.6.