Increased F-18 FDG intestinal uptake in diabetic patients on metformin: a matched case-control analysis.

PURPOSE: A matched case-control study was performed to assess the relationship between metformin use and the degree of F-18 fluorodeoxyglucose (FDG) bowel activity in diabetic patients. MATERIALS AND METHODS: Seventy-seven diabetic patients referred to our department for a positron emission tomography/computed tomography study, including 45 on metformin, were compared with nondiabetic controls matched for sex, age, and body mass index. Positron emission tomography studies were obtained in a standard manner and reviewed in a blinded fashion. F-18 FDG uptake in the GI tract was evaluated quantitatively using maximal standardized uptake values and visually using a previously published semiquantitative scale. RESULTS: F-18 FDG uptake in small and large bowel was significantly increased in metformin patients compared with nondiabetic controls both visually and quantitatively (all P < 0.0001), as well as compared with nonmetformin patients with diabetes. Control sites (liver, fat, muscle) showed similar uptake. Multiple regression analysis confirmed that metformin was the variable most strongly associated with bowel uptake. CONCLUSION: Physiologic accumulation of F-18 FDG in bowel is increased in diabetic patients maintained on metformin.

Complications of tracheal and thoracic surgery: the role of multisection helical CT and computerized reformations.

Helical computed tomography (CT) has an important role in the evaluation of a wide range of congenital and acquired thoracic abnormalities. The development of advanced computerized reformations enables the generation of bronchographic and bronchoscopic images of the tracheobronchial tree, as well as angiographic images of pulmonary arteries and veins. Additionally, it provides coronal and sagittal reconstruction imaging of parenchymal abnormalities. This information is obtained by a 20-30s procedure on a typical single channel system, which makes helical CT an optimal technique for the evaluation of patients undergoing major upper airways and thoracic interventions. The recent introduction of multisection CT scanners allows faster imaging of patients with thinner collimation, thus improving spatial resolution along the longitudinal (z) axis of the patient along with reduction of motion artefacts. This article demonstrates the use of dual and quad-section helical CT in the postoperative evaluation of patients undergoing laryngo-tracheal and thoracic interventions, including laryngoplasty, tracheal endoscopic laser ablation, lobectomy, pneumonectomy, lung transplantation, sleeve resection, pulmonary angioplasty, and pulmonary artery thromboendarterectomy. Emphasis is given to the additive value of using computerized reformations over axial images, especially for delineation of complex postoperative anatomical details in the tracheobronchial tree and pulmonary vasculature.

Prevalence of the juxtaphrenic peak after upper lobectomy.

OBJECTIVE: The purpose of this study was to determine the prevalence of the juxtaphrenic peak after upper lobectomy in a large number of consecutive patients. MATERIALS AND METHODS: Available chest radiographs of 172 of 199 sequential patients who had undergone upper lobectomy in a university hospital were evaluated for the presence of a juxtaphrenic peak. The study included 98 cases with right upper lobectomy and 74 with left upper lobectomy. Radiographs were grouped in three postoperative periods: period I, within 7 days after lobectomy (n = 142); period II, between 8 and 30 days (n = 113); and period III, 31 days or more after lobectomy (n = 101). Four experienced radiologists in consensus determined the prevalence of the "juxtaphrenic peak sign," in relation to age, sex, side of lobectomy, positioning (erect or supine), presence of juxtadiaphragmatic abnormalities, and time interval since surgery. RESULTS: The prevalence of the juxtaphrenic peak sign gradually increased from 40.6% in period I to 71.9% in period III after right upper lobectomy (p < 0.01), and from 19% to 47.7%, respectively, after left upper lobectomy (p < 0.01). Its overall prevalence was significantly higher after right upper lobectomy (58.2%) than after left upper lobectomy (40.5%) (p = 0.02), and on erect chest films (51.4%) than on supine ones (28.9%). CONCLUSION: The prevalence of the juxtaphrenic peak sign increases gradually during the weeks following lobectomy. It is more frequent on erect films and after right upper lobectomy. The juxtaphrenic peak may serve as an additional useful radiologic sign suggesting upper lobectomy.

Aryloxy substituted N-arylpiperazinones as dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I.

A series of aryloxy substituted piperazinones with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to have potent inhibitory activity in vitro and are promising agents for the inhibition of Ki-Ras signaling.

Oxo-piperazine derivatives of N-arylpiperazinones as inhibitors of farnesyltransferase.

The evaluation of SAR associated with the insertion of carbonyl groups at various positions of N-arylpiperazinone farnesyltransferase inhibitors is described herein. 1-Aryl-2,3-diketopiperazine derivatives exhibited the best balance of potency and pharmacokinetic profile relative to the parent 1-aryl-2-piperazinones.

High-performance liquid chromatography/mass spectrometry characterization of Ki4B-Ras in PSN-1 cells treated with the prenyltransferase inhibitor L-778,123.

Cellular transformation by Ras oncoproteins requires the posttranslation modification of farnesylation in a reaction catalyzed by farnesyl protein transferase (FPTase). Thus, inhibitors of FPTase have been developed as potential anticancer agents. However, recent studies with selective inhibitors of FPTase have shown that Ki4B-Ras retains its ability to transform cells by undergoing alternative prenylation by the related geranylgeranyl protein transferase I (GGPTase-I) in human tumor cells. We have developed a high-performance liquid chromatography/mass spectrometry assay for the detection and quantitation of the different processing states of Ki4B-Ras isolated from PSN-1 cells (a human pancreatic cell line with an activating Gly12 to Arg mutation) treated with the prenyltransferase inhibitor, L-778,123. Recently tested in the clinic, L-778,123 is a potent inhibitor of FPTase (in vitro IC50 = 2 nM) with some activity against GGPTase-I (in vitro IC50 = 98 nM). We find primarily farnesylated-Ki4B-Ras in vehicle-treated PSN-1 cells, a mixture of farnesylated- and geranylgeranylated-Ki4B-Ras in cells treated with nanomolar concentrations of L-778,123, and a mixture of unprocessed, farnesylated, and geranylgeranylated-Ki4B-Ras in cells treated with micromolar concentrations of compound. Of importance, this technique does not require metabolic labeling and may be used as a pharmacodynamic assay for Ki4B-Ras processing in mouse models.

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.

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.

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.

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.

Hysterosalpingography with a balloon catheter versus a metal cannula: a prospective, randomized, blinded comparative study.

A prospective, randomized, blinded study was conducted to compare the use of a balloon catheter for performing hysterosalpingography (HSG) with the use of a traditional metal cannula. Sixty-one consecutive women who underwent HSG for evaluation of infertility were prospectively randomized to undergo the procedure with either a metal cannula (n = 31) or the balloon catheter (n = 30). The HSG procedure was identical in both groups. HSG using the balloon catheter, compared to the metal cannula, required significantly less fluoroscopic time (57.4 +/- 17.6 versus 75.6 +/- 40.5 s), smaller amounts of contrast medium (7.8 +/- 3.9 versus 20.1 +/- 15.8 ml), produced less pain (3.8 +/- 2.0 versus 5.6 +/- 2; on a scale of 1-10), and was easier for the physician to perform (8.8 +/- 1.1 versus 6.4 +/- 1.9; on a scale of 1-10) (P < 0.01). Eight patients (13%) were diagnosed as having proximal tubal occlusion. It was possible to offer an immediate transcervical tubal catheterization for further diagnosis and treatment of the occlusion only to the five patients with this condition from the balloon catheter group. We conclude that the balloon catheter is superior to the traditional metal cannula for performing HSG. Furthermore, if proximal tubal occlusion is diagnosed, an immediate selective salpingography and transcervical tubal catheterization can be performed without the need to replace the cannula or to reschedule the patient.

Transgene-coded chimeric proteins as reporters of intracellular proteolysis: starvation-induced catabolism of a lacZ fusion protein in muscle cells of Caenorhabditis elegans.

The product of an integrated transgene provides a convenient and cell-specific reporter of intracellular protein catabolism in 103 muscle cells of the nematode Caenorhabditis elegans. The transgene is an in-frame fusion of a 5'-region of the C. elegans unc-54 (muscle myosin heavy-chain) gene to the lacZ gene of Escherichia coli [Fire and Waterston (1989): EMBO J 8:3419-3428], encoding a 146-kDa fusion polypeptide that forms active beta-galactosidase tetramers. The protein is stable in vivo in well-fed animals, but upon removal of the food source it is inactivated exponentially (t1/2 = 17 h) following an initial lag of 8 h. The same rate constant (but no lag) is observed in animals starved in the presence of cycloheximide, implying that inactivation is catalyzed by pre-existing proteases. Both the 146-kDa fusion polypeptide (t1/2 = 13 h) and a major 116-kDa intermediate (t1/2 = 7 h) undergo exponential physical degradation after a lag of 8 h. Degradation is thus paradoxically faster than inactivation, and a number of characteristic immunoreactive degradation intermediates, some less than one-third the size of the parent polypeptide, are found in affinity-purified (active) protein. Some of these intermediates are conjugated to ubiquitin. We infer that the initial proteolytic cleavages occur in the cytosol, possibly by a ubiquitin-mediated proteolytic pathway and do not necessarily inactivate the fusion protein tetramer.

Diagnostic imaging management in Manitoba: 1995-2000.

As part of a 5-year imaging management plan being developed for the single insurance carrier in Manitoba, the radiologic utilization for the province was reviewed. For the fiscal year 1993 (April 1, 1992, through March 31, 1993), 1,056,694 imaging studies were performed in a total patient population of 1,133,117 in 81 hospitals and 39 offices in which 648 units of equipment were operated by 773.4 full-time personnel at a cost of $100,302,812 ($75,227,109 in U.S. dollars). The skin dose for the total population for the year was 40,112 Gy, compared with 35,513 Gy in 1979. Since 1979, there has been a 9% increase in the number of radiologic examinations (from 972,426 examinations), a greater need for more personnel to conduct ultrasound, mammography, computed tomography, and magnetic resonance imaging examinations, and striking costs escalation (from $25,082,500 to $100,302,812). Reduction of total funding for imaging services will be possible only if the medical service infrastructure and physician behavior are altered, since imaging is a support service. Hospital services must be integrated and the infrastructure reduced, and physicians must adhere to guidelines and practice protocols for requesting consultations.

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.

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.

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.