Metabolic alterations produced by cigarette smoke in rat lung and liver, and their modulation by oral N-acetylcysteine.

Male Sprague-Dawley rats were exposed whole-body to the mainstream smoke produced by a commercial filter cigarette for 8 consecutive days, accounting for a cumulative exposure to the smoke of 75 cigarettes. Liver and lung S12 fractions were used in the Salmonella mutagenicity test in order to assess either the decrease of potency of a direct-acting mutagen (sodium dichromate) or the metabolic activation of promutagens, including cigarette smoke itself and its condensate, benzo[a]pyrene and its 7,8-diol, the aromatic amine 2-aminofluorene, and the heterocyclic amine 3-amino-1-methyl-5H-pyrido(4,3)indole. Moreover, individual biochemical parameters were measured in the liver and lung of the same rats and, in the case of cytochrome P-450-dependent monooxygenases, also in the heart of untreated or Aroclor-treated rats. The monitored biochemical parameters included aryl hydrocarbon (benzo[a]pyrene) hydroxylase and ethoxyresorufin deethylase in microsomal fractions, epoxide (benzo[a]pyrene-4,5-oxide) hydrolase in both microsomal and cytosolic fractions, glutathione (GSH) and GSH S-transferase in the cytosol. Exposure to cigarette smoke resulted in a number of significant metabolic changes, as compared to sham-exposed rats. The most pronounced alterations consisted in a 2.6-fold induction of aryl hydrocarbon hydroxylase in the lung and 8-fold induction of ethoxyresorufin deethylase in the liver, and in a marked stimulation of the liver metabolic activation of all promutagens. The last effect was inhibited by the oral administration of the chemopreventive agent N-acetylcysteine. On the whole, there was a poor correlation between the monitored biochemical and mutagenicity endpoints.(ABSTRACT TRUNCATED AT 250 WORDS)


Benomyl-induced aneuploidy in mouse oocytes.

Benomyl (methyl-1-[butylcarbamoyl]-2-benzimidazole carbamate) is a plant fungicide which acts by inhibiting tubulin polymerization. It is also a carcinogen and a teratogen. A substantial number of reports consistently show that benomyl inhibits cellular division and induces numerical chromosome changes in somatic cells, while results from standard genotoxicity assays which measure mutations and structural chromosome aberrations are conflicting. To define further the genotoxic effects of benomyl and to demonstrate the utility of the in vivo mouse oocyte assay for detecting chemicals which induce numerical chromosome changes, we investigated the ability of benomyl to induce numerical and structural chromosome aberrations in mouse oocytes. Superovulated female ICR mice were administered benomyl by oral gavage and oocytes were collected 17 h later. The proportions (and percentages) of hyperploid oocytes were 1/309(0.3), 6/155(3.9), 38/229(16.6), 46/130(35.4), 60/215 (27.9), 42/143(29.4) for control, 500, 1000, 1500, 1750 and 2000 mg/kg respectively. No increase in structural aberrations was observed. These results demonstrate that benomyl specifically induces numerical chromosome changes in mouse oocytes.


Ricin and lentil lectin-affinity chromatography reveals oligosaccharide heterogeneity of thyrotropin secreted by 12 human pituitary tumors.

Some patients with thyrotropin (TSH)-producing pituitary tumors are more hyperthyroid than others despite similar TSH levels in serum, suggesting that qualitatively different TSH molecules with differing bioactivities may be secreted by different tumors. We used ricin and lentil lectin-affinity chromatography to test whether the TSH oligosaccharides varied among 12 patients with TSH-producing tumors. We found that each tumor secreted heterogeneous isoforms of TSH that differed in their extents of exposed galactose (Gal) residues, and their degrees of sialylation and core fucosylation. These biochemical parameters also varied markedly for TSH secreted by different tumors. Isoforms appeared to reflect poor sialyltransferase activity in two tumors and efficient sialyltransferase in the remainder. TSH secreted by tumors was more fucosylated than TSH secreted by control euthyroid persons. There was an inverse relationship between the sialylation and fucosylation of tumor TSH. No simple relationship between TSH oligosaccharide structures and bioactivity was evident, although mixtures of isoforms having the least and most sialylated TSH seemed to be the most bioactive clinically. In three patients from whom serum and medium TSH were both available, TSH in serum was more sialylated than TSH secreted by the tumor in vitro, perhaps reflecting slow clearance of sialylated isoforms from the circulation. Core fucosylation of serum TSH was less than that of medium TSH. These data prove that human tumors secrete TSH with heterogeneous oligosaccharide structures.


The pathobiochemistry of uremia and hyperargininemia further demonstrates a metabolic relationship between urea and guanidinosuccinic acid.

To better understand the biosynthesis of guanidinosuccinic acid, we determined urea, arginine, and guanidinosuccinic acid levels in nondialyzed uremic and hyperargininemic patients. These substances were also determined during several years of therapy in one hyperarginiemic patient. Interrelationships of guanidinosuccinic acid levels with their corresponding urea and arginine levels were assessed by linear correlation studies. In uremic patients, a significant positive linear correlation (r = .821, p less than .001) was found between serum urea and guanidinosuccinic acid levels A significant positive linear correlation was also found between serum urea levels and urinary guanidinosuccinic acid levels (r = .828, P less than .001), but not between serum arginine levels and urinary guanidinosuccinic acid levels in hyperargininemic patients. In the intrahyperargininemic patient study, a similar significant positive correlation was found between serum urea levels and the corresponding urinary guanidinosuccinic acid levels (r = .866, P less than .001); the correlation between serum arginine levels and the corresponding urinary guanidinosuccinic acid levels was smaller. The presented analytical findings in uremic and hyperargininemic patients clearly demonstrate a metabolic relationship between urea and guanidinosuccinic acid.


No significant effect of vitamin E deficiency or supplementation on collagen-linked fluorescence in skin of diabetic rats.

It is speculated that oxidative stress in vivo may have some influence on advanced, nonenzymatic, glycosylation end products. However, this has not been demonstrated yet. We assessed changes in collagen-linked fluorescence in the skin of nondiabetic and streptozotocin-induced diabetic rats fed three different diets for 4 weeks that could modify oxidative stress: vitamin E-deficient (D), vitamin E-supplemented (S), and control (C). The serum lipid peroxide level expressed as thiobarbituric acid (TBA) activity in diabetic rats on the S diet (9.6 +/- 1.0 [SE] nmol/L/mL) was significantly (P less than .01) lower than that in rats on the D diet (111.4 +/- 22.4), and similar to that in nondiabetic rats on the C diet (12.4 +/- 2.2). The collagen-linked fluorescence level was significantly (P less than .01) higher in diabetic rats than in nondiabetic rats, which corresponded to the serum glucose and glycosylated hemoglobin levels. However, there were no significant differences in the fluorescence levels among three groups classified by three different diets in both nondiabetic and diabetic rats (21.7 +/- 1.7 arbitrary U/mg collagen for D, 22.3 +/- 2.0 for C, and 22.8 +/- 2.5 for S in nondiabetic rats v 41.2 +/- 4.1 for D, 40.1 +/- 4.7 for C, and 39.3 +/- 3.5 for S in diabetic rats), despite significant changes in serum lipid peroxide levels. Consequently, there were no significant changes found in collagen-linked fluorescence levels in diabetic rats wherein oxidative stress was modified by vitamin E deficiency and supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)


Increased protein turnover in obese women.

Some previous studies have indicated that rates of proteolysis and protein synthesis are greater in obese than in lean subjects, whereas others have not supported this finding. In the present study, we have measured postabsorptive protein turnover in a large group (n = 24) of obese women to establish more conclusively whether obese women have higher rates of protein turnover than lean women (n = 12), and to determine whether obese subjects with the greatest abdominal fat accumulation or those with the most severe insulin resistance (as determined by oral glucose tolerance testing) have the highest rates of protein turnover. Leucine appearance rate (Ra) was used as an index of whole-body proteolysis, and the fraction of Ra not oxidized was used as an index of whole-body protein synthesis. Leu Ra, oxidation, and incorporation into protein after an overnight fast were approximately 25% greater in obese than in lean women, and were approximately 10% to 15% greater after dividing by lean body mass (LBM) or adjusting for LBM by analysis of covariance. Among obese women, the degree of obesity (over the range of 30% to 47% fat) was not a significant determinant of protein turnover, nor were degree of insulin resistance, visceral fat accumulation (determined by magnetic resonance imaging [MRI]), or subcutaneous abdominal fat accumulation (also determined by MRI). However, the women with the highest rates of protein turnover also had higher waist to hip circumference ratios (WHR). We conclude that even moderate obesity is associated with increased protein turnover, and that this effect is not completely explained by the higher LBM in obese subjects.


Benefit from hypocaloric diet in obese men depends on the extent of weight-loss regarding cholesterol, and on a simultaneous change in body fat distribution regarding insulin sensitivity and glucose tolerance.

Obesity and an android body fat distribution are related to metabolic disorders. We investigated the interdependences between metabolism, overweight, and body fat distribution in 40 moderately obese men before and after weight-loss. Correlations between metabolic parameters and body mass index (BMI) or waist to hip ratio (WHR) were much weaker in this exclusively obese population than in subjects of all weight categories, but the association between BMI and glucose tolerance (r = -.46, P less than .01) increased significantly after weight-loss. The improvement of metabolic parameters was much stronger in men who achieved normal weight (BMI less than 27 kg/m2) than in those who remained obese (BMI greater than 30 kg/m2, P less than .05). The WHR decreased during the diet (P less than .001), and this decrease and the extent of weight-loss were significantly correlated to an increase in insulin sensitivity (r = -.41, P less than .01) and a decrease in glucose area after an oral glucose load (r = .34, P less than .05). The decrease in apolipoprotein B, total cholesterol, and low-density lipoprotein (LDL) cholesterol was significantly correlated only to the extent of weight-loss (r = .34, .31, and .39, respectively; P less than .05). We conclude that it is best to reach normal weight for the normalization of metabolic aberrations. The reduction of cholesterol appears to be dependent on the extent of weight-loss, while the improvement in insulin sensitivity and glucose tolerance apparently is related to both the extent of weight-loss and to a change toward a less android body fat distribution.


Competition for transport of amino acids into rat heart: effect of competitors on protein synthesis and degradation.

Transport of the neutral amino acids, 2-(methylamino)isobutyrate (MeAIB) and Phe, was examined in isolated rat hearts perfused by the Langendorff method. Hearts were perfused by recirculating for various time periods buffer containing [14C]-MeAIB or [14C]-Phe plus desired additions. Uptake of MeAIB was linear for approximately 30 minutes; Phe uptake was linear for a maximum of 5 minutes, and reached a steady state after 15 minutes. Km and Vmax for MeAIB were 1.1 +/- 0.03 mmol/L and 37.7 +/- 0.4 pmol/microL intracellular fluid (ICF)/min; values for Phe were 1.8 +/- 0.02 mmol/L and 364 +/- 5 pmol/microL ICF/minute. Uptake of MeAIB (0.2 mmol/L) was reduced 95% in the presence of Ser (10 mmol/L), and less severely by large neutral amino acids ([LNAA], 10 mmol/L) such as Phe and Leu (by 46% and 54%, respectively). Uptake of Phe (0.2 mmol/L) was reduced by LNAA such as Val, Leu, and Ile (by 51%, 78%, and 81%, respectively), or by commercial preparations used in parenteral nutrition, eg, Travasol or Travasol plus extra branched-chain amino acids (BCAA) (Branchamin); Ser had little effect (8% reduction). Insulin in the perfusion medium increased the fractional rate of protein synthesis. Individual BCAA at physiological concentrations (0.2 mmol/L) did not alter the rate of protein synthesis. Branchamin or Travasol plus Branchamin also had no effect on the rate of protein synthesis in heart, but did depress the rate of degradation. These studies suggest that amino acid transport into heart may be affected by normal levels of plasma amino acids, whereas protein synthesis is not.


Pulsatile hormone secretion during severe sepsis: accuracy of different blood sampling regimens.

The metabolic response to sepsis is dependent on the hormonal status. However, reported plasma hormone levels vary widely among studies. The persistence of pulsatile secretion, as occurs normally, may explain the observed variability. To study whether pulsatile hormone secretion persists during sepsis and how it affects assessment of the hormonal status from single measurements, we measured growth hormone (GH), prolactin, cortisol, insulin, and C-peptide at 20-minute intervals for 24 hours in eight consecutive patients with severe sepsis. Twenty-four-hour averages (mean +/- SD) were 3.3 +/- 2.5 ng/mL for GH, 640 +/- 461 nmol/L for cortisol, 18.2 +/- 4.8 mU/L for insulin, and 3.4 +/- 2.9 U/L for C-peptide, at a pulse frequency between 3.3 +/- 2.7 for C-peptide and 10.2 +/- 3.4 for insulin, and an increase of the maximal value in a pulse above the preceding nadir of 131% +/- 13% for cortisol and 376% +/- 386% for GH, as assessed with Cluster analysis. Prolactin levels were below the detection limit in all but one patient, probably due to the administration of dopamine. To determine the accuracy of less frequent blood sampling regimens, we simulated different sampling strategies and compared them with the 24-hour averages. The accuracy of single samples proved inadequate for all hormones. Sampling every 20 minutes for periods of 4, 8, or 12 hours improved accuracy, but intermittent sampling every 1, 2, 4, or 6 hours during a 24-hour period yielded even more accurate results.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of endurance training on energy intake, norepinephrine kinetics, and metabolic rate in older individuals.

The role of physical activity in the regulation of energy intake in older persons is presently unclear. We therefore examined the influence of endurance training on voluntary energy intake and the associated changes in resting metabolic rate (RMR) and norepinephrine (NE) kinetics in seven healthy (six men, one woman) older individuals (69.4 +/- 2.2 years) under supervised living conditions. Energy intake was measured by covert assessment in a clinical research environment during: (1) a 10-day inpatient control period (no exercise); (2) a 10-day light exercise period (150 kcal per session, 3 times/wk); and (3) a 10-day moderate exercise period (300 kcal per session, 3 times/wk). RMR was determined after all three periods, and NE kinetics were assessed before and after training by infusions of tritiated NE ([3H]-NE). No significant change in energy intake was found between the control (2,378 +/- 130 kcal/d) and light exercise (2,449 +/- 104 kcal/d) periods, whereas energy intake increased 17% (P less than .01) during moderate exercise (2,785 +/- 161 kcal/d). Changes in RMR paralleled those of energy intake, as no differences were noted in RMR after control (1.03 +/- 0.12 kcal/min) and light exercise periods (1.04 +/- 0.12 kcal/min), but RMR increased 9% (1.13 +/- 0.14 kcal/min, P less than .01) after moderate endurance training, despite no changes in body composition.(ABSTRACT TRUNCATED AT 250 WORDS)


Malnutrition-related polyunsaturated fatty acid changes in plasma lipid fractions of cirrhotic patients.

Cirrhotic patients have both impaired liver function and nutritional derangement. In fact, the prevalence of protein-energy malnutrition (PEM) is very high in these patients. The aim of the present study was to elucidate whether the nutritional status in cirrhosis could be an additional factor that would affect levels of plasma lipids. Plasma lipid phosphorus, cholesterol, and triglycerides (TG), and fatty acid profiles in plasma and plasma fractions were determined in 50 healthy subjects and 92 patients with liver cirrhosis. The cirrhotic patients were prospectively included in three groups according to the result of nutritional assessment: group 1 (n = 38), acceptable nutritional status (including well-nourished and mildly malnourished patients); group 2 (n = 29), moderate PEM; and group 3 (n = 25), severe PEM. The main findings of this study were that the decrease in plasma cholesterol and linoleic, dihomo-gamma-linolenic, and arachidonic acid levels of cirrhotic patients was related to the degree of PEM. Cholesteryl esters (CE) appeared to be the most sensitive indicator of lipid changes in cirrhosis. We consider that the role of malnutrition in the changes observed for polyunsaturated fatty acid (PUFA) profiles in plasma lipids of cirrhotic patients may be of major importance, since severe malnourished subjects exhibited the lowest levels of those compounds. Dietary supplementation of both essential fatty acids (EFA) and long-chain PUFA in adequate amounts to the cirrhotic patient might be of importance in the management of the disease.


Individual regulation of different hepatocellular functions during sepsis.

The purpose of this study was to test the hypothesis that different hepatocellular functions are regulated individually during sepsis. This was done by simultaneously measuring bile production, release of liver transaminases, and synthesis of secreted proteins in perfused livers from control and septic rats. Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham-operated. After 16 hours, livers were perfused in situ, and bile flow, synthesis rates of albumin and alpha 1-acid glycoprotein (a major acute-phase protein in rats), and release of glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) into perfusate were determined. Within the same livers, sepsis resulted in a 54% increase in the synthesis of alpha 1-acid glycoprotein and approximately 30% inhibition of albumin synthesis concomitant with 50% lower bile flow. The concentrations of GOT and GPT in the perfusate increased slightly during the experiments, both when control and septic livers were perfused. The maintained tissue levels of adenosine triphosphate (ATP) and the uptake of Evans blue dye by less than 1% of the hepatocytes, although a late test of viability, suggest that both control and septic livers remained viable during perfusion. The results are consistent with the concept that different hepatocellular functions are individually regulated during sepsis. Thus, impairment of certain hepatocellular functions does not necessarily imply generalized liver failure.


Differential metabolic responses to tumor necrosis factor with increase in age.

Previous studies have shown varied responses to the effects of tumor necrosis factor (TNF) on glucose and lipid metabolism. To elucidate possible causes for this variation, the present study compared sequential changes in plasma glucose, lactic acid, triglyceride (TG), free fatty acids (FFA), and plasma insulin levels in 1.5- and 16-month-old, normal, fed, male rats, 1 to 6 hours after different doses of intravenous (IV) TNF. In addition, assessment was made of TNF injected intraperitoneally (IP) in precannulated and intact young (1.5 months) rats and of the dose-response (0.25 to 50 micrograms/100 g rat) and the sensitivity to insulin in intact rats. Finally, the metabolic responses and changes in serum insulin and corticosterone concentration after IP TNF were compared in 1.5-, 5-, and 16-month-old rats. Data show that metabolic responses vary with increase in age and experimental conditions. Dose-dependent decreases in plasma glucose (1.4 to 3.9 mumol/mL) and elevations in lactic acid (0.8 to 3.0 mumol/mL) were greater in 1.5- versus 16-month-old rats, were delayed in cannulated rats, and were preceded by hyperglycemia following larger IV doses. Plasma TG levels were elevated after TNF in all groups except precannulated rats, and also showed differences with age. In young rats, the elevation in TG peaked 2 hours after IP injection with return to baseline and was preceded by an elevation in FFA levels. In older rats, which were hypertriglyceridemic at base line, the elevation in TG by TNF occurred by suppressing the decrease in TG of controls, was not accompanied by an increase in FFA levels, was sustained for 5 hours, and was of greater magnitude than in young rats. Significant changes in plasma insulin did not occur in young and older rats after IV TNF. However, young rats had a significant decrease (P less than .02) in plasma insulin and an elevation in corticosterone levels after IP TNF, whereas older rats exhibited an increase in plasma insulin (P less than .02) and a comparable elevation in plasma corticosterone. Young rats also showed an increase in plasma insulin following IP TNF when hypoglycemia was prevented by the infusion of glucose. However, when insulin levels were held comparable (2.4 ng/mL), glucose uptake was enhanced (P less than .05) compared with controls. These findings indicate that mobilization of energy substrates occurs during the initial exposure to TNF, which is altered by the nutritional state of the rats and the dose and route of administration.(ABSTRACT TRUNCATED AT 400 WORDS)


Enhanced glutamine and glucose metabolism in cultured rat splenocytes stimulated by phorbol myristate acetate plus ionomycin.

Metabolism of glutamine and glucose was studied in normal rat splenocytes cultured for 48 hours in the presence and absence of a mixture of the mitogens, phorbol myristate acetate (PMA) + ionomycin (Iono). 3H-Thymidine uptake by splenocytes was stimulated more than 500-fold by PMA + Iono. After culture, cells were incubated for 2 hours in the presence of either 2 mmol/L [U-14C]glutamine +/- 5 mmol/L glucose or 5 mmol/L [U-14C]glucose +/- 2 mmol/L glutamine in Krebs-Ringer HEPES buffer. Glutamine was metabolized mainly to ammonia, glutamate, aspartate, and CO2, and these products were all increased (P less than .01) by twofold to 2.5-fold in stimulated cells. Glucose was metabolized mainly to lactate and, to a lesser extent, to pyruvate and CO2. Lactate production from glucose was increased (P less than .01) by 2.4-fold in stimulated cells, without changes in pyruvate or CO2 production. In unstimulated, cultured splenocytes, glutamine was not quantitatively as important as glucose in the provision of adenosine triphosphate (ATP), as calculated on the basis of measured metabolites. However, in stimulated cells, glutamine became a much more important energy substrate, providing similar amounts of ATP to those from glucose. The oxidation of glutamine via the Krebs cycle was the major pathway for glutamine-derived ATP production, while lactate production from glucose accounted for the major part of glucose-derived ATP in PMA+Iono-stimulated splenocytes. Thus, we suggest glutamine plays a dual metabolic role in these cells, as both an important fuel and an essential source of carbon and nitrogen precursors for biosynthetic processes.(ABSTRACT TRUNCATED AT 250 WORDS)


Gastroenteropancreatic endocrine tumors: effect of Sandostatin on tumor growth. The German Sandostatin Study Group.

One hundred fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumors entered a prospective multicenter trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumors, and five with other endocrine GEP tumors) to determine the efficacy of 200 micrograms Sandostatin three times a day in the control of tumor growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a "negative" selection of patients included in the trial and suggesting that Sandostatin cannot prevent disease progress when it is far advanced. In the evaluation of 68 patients monitored for at least 3 months, partial regression was observed in 4.4%, stable disease in 50%, and tumor progression in 45%. However, an initially favorable response frequently occurred with a decrease in response later: 54.4% at 3 months to 38% at 12 months for the whole group of patients. Proven inhibition of tumor growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumor growth in patients with metastatic endocrine GEP tumors. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.


Pharmacodynamic effects of Sandostatin in the gastrointestinal tract.

Somatostatin (SST) is widely distributed throughout the human gastrointestinal system. There, it is found in neurons and fibers of both the submucosal and myenteric plexus and the pancreas, and also in the D cells of the stomach, gut, and pancreatic islets. Whereas in the intestinal nervous system, duodenum, and pancreas, somatostatin-14 (SST-14) appears to be the predominant molecular form, the endocrine-type D cells of the intestine primarily contain somatostatin-28 (SST-28). SST peptides may act very differently at different sites, as hormones, paracrine substances, or neurotransmitters. Because of this complexity of action, very little is known about the physiological effects of SST in the gastrointestinal tract. In contrast, the pharmacological actions of natural synthetic SST have been thoroughly studied and have given rise to many therapeutic applications. Octreotide, an analogue with a longer half-life and higher potency, has greatly facilitated the clinical application of SST. This review deals with the pharmacological effects of octreotide on different gastrointestinal functions. The SST analogue exerts a long-lasting inhibitory action on gastric acid, pancreatic enzyme, bicarbonate secretion, and on bile flow. It also inhibits stimulated intestinal secretion, ie, the release of neuropeptides from the gut and pancreas. It can also prolong orocecum transit time and prevent gallbladder contraction. It inhibits absorption of nutrients and exerts inhibitory effects on splanchnic hemodynamics. It is because of these actions that SST has attracted so much attention in the treatment of different gastrointestinal disorders.


The role of Sandostatin in acromegaly.

Long-acting somatostatin analogues are extensively used for the treatment of acromegalic patients who have not been cured by surgery or for whom surgery is contraindicated or hazardous. Such an analogue, Sandostatin, has been approved for this indication in various countries and to date an overall review is feasible. From the literature and our experience, clinical response of acromegaly is attained in 60% to 70%, with mainly a reduction in headaches, arthralgias, and acral growth. Hormonal response, evaluated on plasma growth hormone (GH) levels, is observed in more than 80% of the patients. In 36% to 45% of the patients, plasma GH levels are reduced to near-normal values, and in 50% of the patients, the percentage of reduction is greater than 50% of pretreatment values. The major source of concern is the occurrence of gallstones during the treatment; its frequency is evaluated differently. From the largest well-documented series, we retain a percentage of 12.5% of newly occurring cholelithiasis and in most cases they remain asymptomatic. Tumor shrinkage is minor in most cases.


Long-term efficacy and tolerability of octreotide treatment in acromegaly.

Twenty-five acromegalic patients were studied during 6 years of treatment with octreotide, with a particular focus on the following parameters: (1) Administration schedule: in 10 patients, continuous subcutaneous (SC) octreotide infusion was compared with injections of octreotide at three dose levels (100, 250, and 1,500 micrograms/24 h) and was found to induce a greater and less-fluctuating 24-hour growth hormone (GH) suppression. (2) Carbohydrate tolerance: average 24-hour blood glucose levels were unaffected by octreotide, regardless of administration schedule. Oral carbohydrate tolerance and intravenous (IV) glucose tolerance were unaffected by continuous octreotide infusion. However, octreotide injection given shortly before the tests reduced carbohydrate tolerance. (3) Thyroid function: octreotide and somatostatin acutely reduce the response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH). After a few days of treatment, it was demonstrated that octreotide slightly inhibits iodothyronine deiodination and induces a transient reduction in serum triiodothyronine (T3), rapidly compensated for by a persistent slight elevation of serum TSH. (4) Fat absorption was estimated as 24-hour fecal fat content and found to be in the same high-normal range before and after octreotide treatment. Vitamin K and D absorption were unaffected by octreotide. The incidence of gallstone formation was not greater than in the general Danish population, possibly due to the schedule used for octreotide injections. (5) Foot volume was regularly estimated and found to decrease with time, on average by 12% during the first 18 months.(ABSTRACT TRUNCATED AT 250 WORDS)


Presurgical octreotide treatment in acromegaly.

The aim of this study was to determine the role of octreotide administration in acromegalic patients as a preparation for selective adenomectomy using transsphenoidal route. Octreotide was administered for 3 to 6 weeks before surgery in 12 patients and for 4 to 39 months in 25 patients. The clinical response was judged as excellent or good in 10 of 12 patients from group I and in 23 of 25 patients from group II. Marked reduction (ie, greater than 50% of initial values) in serum growth hormone (GH) levels was seen in all patients, with levels to less than 5 micrograms/L in 68% of patients and less than 2 micrograms/L in 27%. Insulin-like growth factor 1 (IGF-1) levels decreased to within normal limits in half the cases. During long-term treatment, an escape phenomenon could be seen. Varying degrees of tumor shrinkage were seen in more than 50% of cases. During surgery, with regard to the relative ease or difficulty in removing the tumor, the consistency of the tumor and the separation of normal from pathological tissue, no significant difference was observed between patients given octreotide and those from control series. Morphological changes in adenomatous tissue were rather small. The surgical outcome was similar in the pretreated series as in the control series, except in enclosed adenomas, which showed a tendency to a higher success rate. Since octreotide improves both the clinical condition and hormonal parameters and induces varying degrees of tumor shrinkage, it is potentially useful as an adjunct to surgery. Morphological data suggest that octreotide exercises a functional inhibitory effect on GH release.


Treatment of thyroid-stimulating hormone-secreting adenomas with octreotide.

From data collected in the literature, the effects of octreotide therapy in 37 patients with thyroid-stimulating hormone (TSH)-secreting adenomas who received short-term (1 to 2 weeks, n = 23) and long-term treatment (3 to 36 months) are reviewed. In 20 of 21 patients studied, short-term administration of octreotide (50 or 100 micrograms subcutaneously [SC] produced a 25% to 100% (mean +/- SD, 55.3% +/- 29%) decrease in TSH levels, with the nadir being obtained between the third and sixth hour following injection. After 1 to 2 weeks therapy with 50 to 100 micrograms twice or three times a day, 21 of 23 patients studied demonstrated a 66% (+/- 30%) decrease in TSH levels and 14 of 16 showed a 64% (+/- 27%) decrease in alpha-subunit levels. In approximately two thirds of the patients, the response was better than after short-term administration. The effect of octreotide on clinical and biological thyroid status was significant in all patients studied. After 1 week or 1 month of treatment, thyroid hormone levels were reduced in all patients and were normalized in 78%. Response to therapy was similar whether TSH secretion was pure or mixed (growth hormone [GH]-TSH adenomas). Fourteen patients received long-term treatment (3 to 36 months; mean, 12 +/- 10) with daily doses ranging from 200 to 1,500 micrograms. The response was better than or similar to that with short-term treatment. An escape occurred in TSH levels in two patients and in thyroid hormone levels in three patients, leading to an adjustment of dose or frequency of injection.(ABSTRACT TRUNCATED AT 250 WORDS)


Octreotide and diabetes: theoretical and experimental aspects.

Diabetes is characterized by paradoxical hypersomatotropinemia and hyperglucagonemia. The latter appears to enhance the tendency in imperfect metabolic control to reduce nitrogen balance, and the former appears to accelerate the deterioration of carbohydrate and lipid metabolism, and also to induce peripheral insulin resistance and hyperinsulinemia. In addition to direct metabolic effects, increasing evidence points to an association between hypersomatotropinemia and a number of metabolically dependent, characteristic functional abnormalities linked to the development of late diabetic manifestations. These include increased capillary fragility, lipid and hemostatic aberrations, tissue hyperperfusion, including increased cardiac output and renal plasma flow, and kidney hypertrophy. In theory, octreotide's actions could reduce these aberrations, and, in fact, this has been confirmed in recent experimental trials.


Preliminary results with Sandostatin nasal powder in acromegalic patients.

This report details the first half of a double-blind, crossover sequence (Latin square) study of local and hormonal effects of nasally insufflated Sandostatin compared with those of subcutaneously injected Sandostatin. Nine of the planned 16 patients have been studied. They received a single application of 0.5, 1.0, and 2.0 mg Sandostatin as nasal powder and 0.1 mg by subcutaneous (SC) injection. The results indicate that absorption from the nasal epithelium occurs after approximately 10 minutes and comprises approximately 20% of the dose administered. This indicates that peak serum Sandostatin values occur very rapidly, ie, 10 minutes after application. After approximately 2 hours, the serum disappearance rates are similar to those obtained after SC injection. The suppressive effect on serum growth hormone (GH) levels is equal with the two forms of application and suggests that future clinical treatment with an intranasal application of 0.5 mg thrice daily is feasible. No side effects were noted apart from an immediate swelling of nasal mucosa, which receded gradually over the following 2 hours. This was either unnoticed or considered insignificant by the patients and will probably be deemed harmless by the rhinologist in eventual long-term clinical trials.


Effects of the somatostatin analogue, octreotide, in polycystic ovary syndrome.

In view of the association of hyperinsulinemia with elevated luteinizing hormone (LH) levels and hyperandrogenism in polycystic ovary syndrome (PCOS), the effect of octreotide was investigated in women with PCOS. Twelve amenorrheic women were treated with 100 micrograms octreotide twice a day for 7 days; 13 infertile women unresponsive to clomiphene citrate were treated either with octreotide (100 micrograms twice a day from day 1 of the menstrual cycle until corpus luteum formation) in addition to human menopausal gonadotropins (HMG) or with HMG alone. Octreotide significantly reduced the 4-hour integrated LH concentrations. LH pulse amplitude and nadir concentrations, and LH, testosterone, androstenedione, and estradiol responses to a gonadotropin-releasing hormone (GnRH) analogue in amenorrheic PCOS women. Octreotide treatment also resulted in a more "appropriate" hormonal milieu at the time of human chorionic gonadotropin (HCG) injection in the infertile women, with LH and testosterone levels being reduced while follicle-stimulating hormone (FSH) levels increased. Orderly follicular growth occurred, with one or two mature follicles being present at the time of HCG injection in cycles in which octreotide was given together with HMG. There were no cases of hyperstimulation, even in women who had previously hyperstimulated after HMG alone. Octreotide thus inhibits LH and androgen secretion and may improve ovulatory performance in infertile women with PCOS.


Proceedings of the discussion, "Tolerability and safety of Sandostatin".

Side effects of octreotide may be local, biochemical, gastroenterological, or endocrinological. Local pain at the injection site occurs frequently, but rarely lasts more than 15 minutes and often resolves with continued therapy and may be improved if the vial is warmed prior to injection. No long-term hematological or biochemical abnormalities have been described. Despite initial diarrhea in some patients, no change in circulating fat-soluble vitamins has been consistently reported. Antibodies to octreotide have been described, but are rare. Abdominal pain or diarrhea can occur at the beginning of therapy. These symptoms rarely persist and are minimal if the injections are timed between meals, but this may increase the incidence of gallstones. Gallstones occur with increased frequency. Gastritis has been described as being an invariable consequence of long-term treatment with octreotide. We have found the incidence to be increased in patients on octreotide, but this is not invariable. Hypoglycemia may be exacerbated in some patients with insulinoma because of glucagon suppression. Small numbers of patients on octreotide for acromegaly have developed hypoglycemic. Conversely, carbohydrate tolerance may temporarily worsen because of insulin suppression and rarely oral hypoglycemia drug therapy may become necessary. Most frequently, carbohydrate tolerance does not deteriorate. In some patients with acromegaly, pituitary tumor size may continue to increase despite continued therapy. Last, there is the theoretical risk of addiction to a compound which may act through opiate receptors and considerably alleviates headache in some patients with pituitary tumor. Overall, despite the multiplicity of theoretical side effects, the majority of patients tolerate octreotide well, with no serious untoward effects.


Proceedings of the workshop, "Practical approaches to the diagnosis and treatment of acromegaly".

Practical approaches to the management of acromegaly are discussed. The roles of surgery, radiotherapy, and medical treatment with oral dopamine agonists such as bromocriptine or the long-acting somatostatin analogue octreotide given subcutaneously are reviewed. Most cases need surgery, but cure is rare in patients with macroadenomas, although common with microadenomas. Radiotherapy should be considered in surgical failures, but takes several years to be effective. Medical treatment with octreotide is effective in the majority, for whom it represents a major advance, but it needs to be administered subcutaneously and the development of gallstones and gastritis in long-term treatment are problems. Bromocriptine is usually less effective, but occasionally still plays a role in the therapeutic program. Combinations of the different modalities are usually required in the management of acromegalic patients.


Potential indications for octreotide in endocrinology.

Treatment with Sandostatin is established in acromegaly, thyroid-stimulating hormone (TSH)-producing pituitary, and endocrine-active gastroenteropancreatic tumors. Potential indications include ectopic hormone syndromes, medullary thyroid carcinomas, pituitary resistance to thyroid hormones, tall stature children, diabetes mellitus and diabetic complications, polycystic ovary syndrome, and Graves' ophthalmopathy. Particularly in the ectopic growth hormone-releasing hormone (GHRH) syndrome, Sandostatin is unequivocally effective and, in the ectopic corticotropin syndrome selected cases can be treated successfully with Sandostatin, leading to marked clinical improvement. In many of the above situations, only subgroups show a response to Sandostatin, which may be identified by scintigraphy with labeled Sandostatin. This pertains also to Graves' ophthalmopathy, for which Sandostatin may be particularly promising and where positive and negative Sandostatin scans have been demonstrated. However, for all these potential indications, larger, well-studied series are needed, before definitive conclusions can be drawn.


Thermodynamics of ligand-nucleic acid interactions.

Ligand-and protein-DNA equilibria are extremely sensitive to solution conditions (e.g., salt, temperature, and pH), and, in general, the effects of different solution variables are interdependent (i.e., linked). As a result, an assessment of the basis for the stability and specificity of ligand-or protein-DNA interactions requires quantitative studies of these interactions as a function of a range of solution variables. Many of the most dramatic effects on the stability of these interactions result from changes in the entropy of the system, caused by the preferential interaction of small molecules, principally ions which are released into solution on complex formation. A determination of the contributions of these entropy changes to the stability and specificity of protein-and ligand-DNA interactions requires thermodynamic approaches and cannot be assessed from structural studies alone.


Automatic verification of radiation field shape using digital portal images.

Two computer methods for matching digital line drawings have been tested for automatic on-line verification of the radiation field shape during radiotherapy. This work is part of a research program aiming at automated inspection of on-line acquired digital portal images. Both methods, moment normalization and point distance minimization, compare the field edge detected in the portal image with the intended field edge and the beam shaping devices marked in the simulator image. Tests showed that the methods should be used together. First, shape deviations in the detected field edge are classified quickly, in less than a second (25 MHz 386 + 387 PC), as large (e.g., missing blocks) or small (e.g., shifts of a few mm) by moment normalization. Then the portal image is mapped to the simulator image by field edge alignment with a translation and magnification obtained from moment normalization and a rotation from point distance minimization. The mapped portal image and the simulator image juxtaposed on a monitor screen for visual inspection. Finally, the small field shape deviations are detected by an analysis of the relationship between the radiation field shape and the positioning of field shaping devices using point distance minimization.


Charge-coupled device detector: performance considerations and potential for small-field mammographic imaging applications.

The physical characteristics of a charge-coupled device (CCD) image detector were evaluated, as well as its potential as a digital imaging device for small field mammographic applications such as preoperative needle localization. The detection system is based on a 2048 x 2048 pixel CCD operated in 1024 x 1024 mode. The CCD was optically coupled to an intensifying screen via a lens, without intermediate intensification. The thermal noise was suppressed to 0.15 electrons pixel-1s-1 by cooling the CCD with liquid nitrogen. The dominant source of noise was attributed to the on-chip amplifier during the readout process that was performed at 50,000 pixels s-1. The measured readout noise level was 15 electrons per pixel. The low-noise characteristics of this CCD prototype detector produced encouraging results under conditions simulating mammography, with a signal level close to one electron per pixel for each detected x ray. The mean glandular dose to the breast, based on the entrance exposure measured from a standard mammographic phantom would be 1.52 mGy (152 mrad). The ultimate spatial resolution of the system was approximately 8 cycles/mm but it was limited to about 5 cycles/mm when operated in the 1024 x 1024 imaging mode. Other physical characteristics of the system such as optical coupling efficiency, exposure response, and signal-to-noise ratio were evaluated. The results of this study suggest that the use of a scientific-grade CCD allows for very good low-contrast discrimination and moderate spatial resolution under conditions simulating mammography, but the current prototype is limited to a 9 x 9-cm2 field of view.(ABSTRACT TRUNCATED AT 250 WORDS)


Precision in quantitative CT: impact of x-ray dose and matrix size.

A study was performed to determine whether recommended technique factors for postprocessing dual-energy (DE) quantitative computed tomography are optimum in terms of precision and x-ray dose. In particular, possible dose reduction as a result of an upgrade of the CT scanner to more efficient detectors was explored. Series of images of an anthropomorphic phantom containing a human vertebra, a tissue-simulating lumbar simulator with various marrow inserts, and a polyethylene cylinder were generated. Recommended DE x-ray technique factors as well as factors resulting in about two times, one-half, and one-fourth the x-ray dose were employed. The effects of reconstruction with different matrix sizes was studied. Standard deviations of the CT numbers within regions of interest in individual images (noise) and standard deviations of mean CT numbers, single-energy (SE), and DE measurements for series of images (reproducibilities) were computed. It was found that the low-energy component of the DE technique was optimum, but the high-energy component could be reduced by a factor of 2 with negligible loss in precision. This translates into a dose reduction of 36% relative to the recommended DE technique. Vertebral inhomogeneities were responsible for more than 65% of the standard deviations in individual images of the vertebra even at the lowest doses. For all of the techniques, the noise in images of all objects decreased as the x-ray dose increased and as the matrix size decreased. Reproducibility of mean values, however, did not necessarily improve, and aberrant results such as improvement in reproducibility with a reduction in dose were sometimes observed. It is hypothesized that this may be due to variations in the actual kVp for each image in a series.


Signal and noise in modulation transfer function determinations using the slit, wire, and edge techniques.

The modulation transfer function (MTF) of an idealized imaging system can be determined from the Fourier transform of the system's line-spread function (LSF). Three techniques of experimentally determining the LSF require imaging either a slit, wire, or edge. In this paper, these three techniques are modeled theoretically to determine the noise in the calculated MTFs as a function of spatial frequency resulting from both quantum fluctuations and stochastic detector noise. The techniques are compared using the signal-to-noise ratio (SNR) in the MTF, defined as the ratio of the MTF value to the standard deviation in an ensemble of MTF determinations from independent measurements. It is shown that for a specified photon fluence, the edge method MTF has the highest SNR at low spatial frequencies, while that of the slit method is superior at high frequencies. The wire method SNR is always inferior to that of the slit technique. This suggests that the edge method is preferable for measuring parameters such as the low-frequency drop, and the slit method is preferable for determining high-frequency response. The cross-over frequency at which the slit and edge methods are equal (f(e)) for quantum-noise limited systems is a function of the slit width and the length over which the LSF is measured. For detector-noise limited systems, f(e) is dependent on the slit width only. The SNR in all but the quantum-noise limited slit method can therefore be increased by decreasing the length over which the LSF is measured, smoothing the tails of the LSF, or by fitting the tails to an analytic expression.


A multiple projection method for digital tomosynthesis.

A new method of optimized efficiency for the retrospective reconstruction of tomograms is presented. The method has been developed for use with isocentric fluoroscopic units and is capable of performing digital tomosynthesis of anatomical planes of user selected orientation and distance from the isocenter. Optimization of efficiency has been achieved by segmenting the reconstruction process into discrete transformations that are specific to groups of pixels, rather than performing pixel by pixel operations. These involve a number of projections of the acquired image matrices as well as parallel translations and summing. Application of this method has resulted in a significant reduction of computing time. The proposed algorithm has been experimentally tested on a radiotherapy simulator unit with the use of a phantom and the obtained results are reported and discussed.


Selection of fat-equivalent materials in postprocessing dual-energy quantitative CT.

Postprocessing dual-energy QCT is supposed to be able to predict the bone mineral more accurately than single-energy QCT. In addition, the fat content in the vertebral body can be determined. To this aim, some methods include fat-equivalent materials in the calibration device. However, the choice of an appropriate fat-equivalent material is difficult. To solve this selection problem, a method has been developed in which the x-ray interactions of tissue are characterized by three energy-independent parameters. For five different known constituents of anatomical fat, fat-equivalent materials are evaluated. It is shown that it is not possible to find one fat-equivalent material for all anatomical fat compositions. For this reason, the influence of a mismatch between the characterization parameters of anatomical fat compositions and fat-equivalent materials has been evaluated. It is shown that a mismatch in tissue characterization parameters can result in deviations of 10% in the bone mineral content and more than 300% in the estimated fat contents.


Nonlinear filters applied on computerized axial tomography: theory and phantom images.

New nonlinear image processing techniques, in particular smoothing based on the understanding of the image, may create computerized tomography (CT) images of good quality using less radiation. Such techniques may be applied before the reconstruction and particularly after it. Current CT scanners use strong linear low-pass filters applied to the CT projections, reducing noise but also deteriorating the resolution of the image. The method in this study was to apply a weak low-pass filter on the projections, to perform the reconstruction, and only then to apply a nonlinear filter on the image. Various kinds of nonlinear filters were investigated based on the fact that the image is approximately piecewise constant. The filters were applied with many values of several parameters and the effects on the spatial resolution and the noise reduction were evaluated. The signal-to-noise ratio of a high-contrast phantom image processed were compared with the nonlinear filter, with the SNR of the phantom images obtained with the built-in CT linear filters in two scanning modes, the normal and the ultra high resolution modes. It was found that the nonlinear filters improve the SNR of the image, compared to the built-in filters, about three times for the normal mode and twice for the UHR scanning mode. The most successful filter on low-contrast phantom image was applied and it also seems to lead to promising results. These results seem to show that applying nonlinear filters on CT images might lead to better image quality than using the current linear filters.(ABSTRACT TRUNCATED AT 250 WORDS)


X-ray imaging using amorphous selenium: determination of x-ray sensitivity by pulse height spectroscopy.

There is a renewed interest in the application of photoconductors especially amorphous selenium (a-Se) to x-ray imaging. A new method for evaluating W +/-, the energy absorption necessary to release an electron-hole pair in a-Se is described. All previous methods used for the evaluation of the x-ray sensitivity of a-Se measure a change in surface potential on a charged plate due to irradiation by x rays. This results in a measurement of W +/- and other factors in combination. These factors include the energy absorbed from the spectrum of irradiating x rays and the a-Se layer capacitance. Such indirect methods are prone to error. A direct method for the evaluation of W +/-, which is based on the pulse height spectra resulting from the absorption of individual monoenergetic x-ray photons in a-Se, has been developed.


Evaluating the spatial resolution performance of a time-resolved optical imaging system.

An imaging system is being developed as a possible means of screening for breast cancer using harmless doses of visible or near-infrared radiation. This system produces transmission images of highly scattering objects by recording and discriminating between the times-of-flight of transmitted photons. Experiments have been performed to evaluate the likely spatial resolution performance of such a system. This involved measuring the edge profile produced by an opaque mask embedded in a highly scattering medium, and evaluating the spatial resolution as a function of the period of time over which transmitted light was integrated. The results suggest that a resolution of a few millimeters is achievable with a system with a temporal resolution of about 10 ps.


Direct digitization of optical images using a photostimulable phosphor system.

The authors describe a method for directly digitizing optical images with a photostimulable phosphor (PSP) system. A PSP plate is initially charged with an exposure to a uniform x-ray field, and is then exposed to an optical image which discharges the plate in relation to the amount of incident light. Two applications were investigated: a contact-print technique for digitizing film radiographs, and a projection technique for digitizing transparent objects such as histology slides. Spatial uniformity was found to be adequate, and linearity of optical density response was excellent from 0.0-2.9 o.d. after look-up table correction. Spatial frequency response was degraded with the optical technique relative to the x-ray imaging properties of the plates, but was restorable by Fourier filtering. Image noise following spatial enhancement was satisfactory at intermediate to high optical densities using a high-resolution PSP plate, but was somewhat degraded at low densities.


The effect of intrinsic attenuation correction methods on the stationarity of the 3-D modulation transfer function of SPECT.

The application of stationary restoration techniques to SPECT images assumes that the modulation transfer function (MTF) of the imaging system is shift invariant. It was hypothesized that using intrinsic attenuation correction (i.e., methods which explicitly invert the exponential radon transform) would yield a three-dimensional (3-D) MTF which varies less with position within the transverse slices than the combined conjugate view two-dimensional (2-D) MTF varies with depth. Thus the assumption of shift invariance would become less of an approximation for 3-D post- than for 2-D pre-reconstruction restoration filtering. SPECT acquisitions were obtained from point sources located at various positions in three differently shaped, water-filled phantoms. The data were reconstructed with intrinsic attenuation correction, and 3-D MTFs were calculated. Four different intrinsic attenuation correction methods were compared: (1) exponentially weighted backprojection, (2) a modified exponentially weighted backprojection as described by Tanaka et al. [Phys. Med. Biol. 29, 1489-1500 (1984)], (3) a Fourier domain technique as described by Bellini et al. [IEEE Trans. ASSP 27, 213-218 (1979)], and (4) the circular harmonic transform (CHT) method as described by Hawkins et al. [IEEE Trans. Med. Imag. 7, 135-148 (1988)]. The dependence of the 3-D MTF obtained with these methods, on point source location within an attenuator, and on shape of the attenuator, was studied. These 3-D MTFs were compared to: (1) those MTFs obtained with no attenuation correction, and (2) the depth dependence of the arithmetic mean combined conjugate view 2-D MTFs.(ABSTRACT TRUNCATED AT 250 WORDS)


Human exposure to 4.0-Tesla magnetic fields in a whole-body scanner.

Details are given for the design, construction, properties, and performance of a large, highly homogeneous magnet designed to permit whole-body magnetic resonance imaging and spectroscopy at 4 T. The magnet has an inductance of 1289 H and a stored energy of 33.4 MJ at rated field. The health of a group of 11 volunteers who had varying degrees of exposure to this field was followed over a 12-month period and no change that could be associated with this exposure was detected. A mild level of sensory experiences, apparently associated with motion within the field of the magnet, was reported by some of the volunteers during some of their exposures. A questionnaire regarding sensory effects associated with magnetic resonance scanners and possibly caused by the static magnetic field of these instruments, was given to nine respondents who had experience within both 1.5-T scanners and this 4-T scanner and to another group of 24 respondents who had experience only within 1.5-T scanners. For the sensations of vertigo, nausea, and metallic taste there was statistically significant (p less than 0.05) evidence for a field-dependent effect that was greater at 4 T. In addition, there was evidence for motion-induced magnetophosphenes caused by motion of the eyes within the static field. These results indicate the practicality of experimental whole-body body scanners operating at 4 T and the possibility of mild sensory effects in humans associated with motion within a static magnetic field. The results also indicate the likelihood of a wide margin of safety for the exposure of noncompromised patients to the static fields of conventional magnetic resonance scanners operated at 1.5 to 2 T and below.


Mapping of the radio frequency magnetic field with a MR snapshot FLASH technique.

A fast method to measure the radio frequency magnetic field intensity distribution during magnetic resonance examinations within objects or patients is proposed. Using a snapshot FLASH sequence, several images are obtained with different transmitter amplitudes for the single prepulse prior to the imaging sequence. The signal intensity at each pixel within a selected slice is diminished by this prepulse, unless the pulse angle is 0 degrees or a multiple of 360 degrees. This condition can be used to measure that transmitter amplitude Umax for each pixel which causes an excitation of 360 degrees by the prepulse. The values of Umax can be visualized in an image and are inversely proportional to the radio frequency magnetic field strength at each position within the image. The method can also be used for in-vivo measurements, where it may be difficult to realize prepulses with sufficient high flip angles. In these cases, signal corresponding to a 180 degree prepulse can be used for calculating Umax.


A diffusion theory model of spatially resolved, steady-state diffuse reflectance for the noninvasive determination of tissue optical properties in vivo.

A model based upon steady-state diffusion theory which describes the radial dependence of diffuse reflectance of light from tissues is developed. This model incorporates a photon dipole source in order to satisfy the tissue boundary conditions and is suitable for either refractive index matched or mismatched surfaces. The predictions of the model were compared with Monte Carlo simulations as well as experimental measurements made with tissue simulating phantoms. The model describes the reflectance data accurately to radial distances as small as 0.5 mm when compared to Monte Carlo simulations and agrees with experimental measurements to distances as small as 1 mm. A nonlinear least-squares fitting procedure has been used to determine the tissue optical properties from the radial reflectance data in both phantoms and tissues in vivo. The optical properties derived for the phantoms are within 5%-10% of those determined by other established techniques. The in vivo values are also consistent with those reported by other investigators.


A pseudo-Poisson noise model for simulation of positron emission tomographic projection data.

Although radioactive decay obeys Poisson statistics, because of the corrections that are applied to the projection data prior to reconstruction, the noise in positron emission tomography (PET) projections does not follow a Poisson distribution. Use of Poisson noise when simulating PET projections in order to test the performance of reconstruction and processing techniques is therefore not appropriate. The magnitude of PET projection noise was observed to be as much as 10 to 100 times greater than Poisson noise in some instances. A quadratic function was found to fit the relationship between noise power spectral density and total projection count. The coefficients of the quadratic function were determined for projections of different tracer distributions and types. Using these observations, a method of simulating PET projections was developed based on a pseudo-Poisson noise model. Projections simulated according to this method are good approximations to real projection data and take into account the characteristics of individual PET cameras and particular tracer distributions. Such simulated projections have been valuable in predicting the performance of reconstruction algorithms. This approach can also be applied to single photon emission tomography.


Calibration of parallel-plate chambers: resolution of several problems by using Monte Carlo calculations.

For five commonly used parallel-plate ion chambers, Monte Carlo calculations are presented of the wall attenuation and scatter correction factors (Kwall = Awall-1 or katt-1) and the correction for nonhomogeneous composition of the chamber (Kcomp or related to km). The chambers are assumed to have 0.5 g/cm2 buildup caps made of the predominant material in each chamber. These correction factors are needed if air-kerma calibration factors are used to deduce the chamber's cavity-gas calibration factor, Ngas. The scatter from the material around the cavity more than compensates for the attenuation in the front wall and hence Kwall values are less than unity. The corrections for the nonhomogeneous composition can be significant. Thin collectors or insulators behind the collecting volume can have a major effect because electron backscattering depends strongly on material. The calculations agree well with experimental data and explain previous results that had not been understood. Calculations for different buildup caps predict trends in chamber in-air responses, which go in the opposite direction to the km values for homogeneous chambers of the same materials. It is argued that Pwall, the wall correction factor for photon-beam measurements in-phantom is, to first order, the same correction factor as Kcomp, calculated for a buildup cap of the same material as the phantom material and the initial assumption that the wall material is made of the same material. Hence, Pwall can also be significantly different from unity. Recommended values of kmkatt or the equivalent Ngas/Nx, and Pwall (in 60Co beams) are presented for the 5 chambers. These values treat the Exradin P11, Markus and Holt parallel-plate chambers as homogeneous in construction whereas the values for the NACP and Capintec PS-033 chambers demonstrate that the chambers are distinctly nonhomogeneous.


An analysis of equivalent fields for electron beam central-axis dose calculations.

The concepts of the equivalent square or circular field have long been used in dose calculations for photon beams. These concepts allow data measured for square or circular fields to be extended to calculate, for example, the percentage depth doses or output factors of rectangular or irregular fields. It has been pointed out in the past that an electron beam equivalent field dimension varies with depth and, thus, will have questionable utility. As the equivalent square and circle have proven to be useful in photon beam dose calculations, the work described in this paper has sought to analyze conditions under which equivalent fields may be useful for electron beam dose calculations. Equivalent square field dimensions and circular field radii are derived using the Fermi-Eyges theory and are compared to a number of approximate equivalent fields that have been applied to electron dose calculations. Calculations are also compared with measurements presented in the literature. It is shown that the accuracy of an electron dose calculation using these approximate equivalent fields diminishes with a decreasing degree of lateral scatter equilibrium at the central axis and only becomes accurate once equilibrium is established. As the central-axis dose under this latter condition is in any event independent of field shape or size, the equivalent field approach becomes unnecessary. Because of this and other restrictions discussed, it is concluded that the equivalent fields analyzed here should not be used for electron beam dose calculations.


A convolution method for calculating 10-MV x-ray primary and scatter dose including electron contamination dose.

This paper has improved some of the weak points appearing in a previous article [A. Iwasaki, Med. Phys. 17, 203-211 (1990)] dealing with the calculation of 10-MV x-ray primary and scatter dose. The main improved points are as follows: (i) A pair of new functional equations expressing the primary dose spread array has been yielded. Consequently, the accuracy of the primary dose calculation both in the aluminum layer and in the soft tissue layer beyond the aluminum has been improved. (ii) A new functional equation expressing the backscatter factor has been developed. It has been utilized in the differential backscatter factor equation. Consequently, the calculated scatter dose spread array has been improved. (iii) A method of calculating the dose due to electron contamination has been introduced. With respect to the primary dose, the primary plus scatter dose, and the primary plus scatter plus electron contamination dose, it has been shown how the depth of maximum dose (dmax) varies with field size.


Higher energy: is it necessary, is it worth the cost for radiation oncology?

The physical characteristics of the interactions of megavoltage photons and electrons with matter provide distinct advantages, relative to low-energy (orthovoltage) x rays, that lead to better radiation dose distributions in patients. Use of these high-energy radiations has resulted in better patient care, which has been reflected in improved radiation treatment outcome in recent years. But, as the desire for higher energy radiation beams increases, it becomes important to determine whether the physical characteristics that make megavoltage beams beneficial continue to provide a net advantage. It is demonstrated that, in fact, there is an energy range from 4 to 15 MV for photons and 4 to 20 MeV for electrons that is optimally suited for the treatment of cancer in humans. Radiation beams that exceed these maximum energies were found to add no advantage. This is because the costs (price of unit, installation, maintenance, shielding for neutron and photons) are not justified by either improved physical characteristics of the radiation (penetration, skin sparing, dose distribution) or treatment outcome. In fact, for photon beams some physical characteristics result in less desirable dose distributions, less accurate dosimetry, and increased safety problems as the energy increases for example, increasingly diffuse beam edges, loss of electron equilibrium, uncertainty in dose perturbations at interfaces, increased neutron contamination, and potential for higher personnel dose. The special features that make electron beams useful at lower energies, for example, skin sparing and small penetration, are lost at high energies. These physical factors are analyzed together with the economic factors related to radiation therapy patient care using megavoltage beams.


Photon spectral characteristics of a new double-walled iodine-125 source.

The photon spectral characteristics of a recently designed Iodine-125 source have been measured. The source has a physical length of 5 mm and a diameter of 0.8 mm. A thin tungsten filament coated with radioactive Iodine-125 is used as a radiographic marker and is encapsulated in a double wall titanium shell of uniform thickness all around. The photon spectral characteristics, measured with an intrinsic germanium (Ge) detector coupled to a multichannel analyzer, reveal that the seed emits the 27.4-keV K alpha and 31.4-keV K beta x rays and 35.5-keV gamma photons from the decay of Iodine-125. Because of their low energy, the tungsten x rays are not observed in the spectrum. The anisotropy of the radiation fluence for each of the above-mentioned photon energies was measured in planes containing the seed short and long axes. The 4 pi-averaged anisotropy factor for the total radiation fluence, i.e., sum of the above three photon energies is 0.92. The photon intensity radiated along the seed long axis is approximately equal to the intensity in the seed transverse direction due to the absence of end welds. The new Iodine-125 source is characterized by good radiographic visualization, greater structural strength due to double wall encapsulation design, and emission of more isotropic Iodine-125 photon spectrum.


Clinically relevant optimization of 3-D conformal treatments.

In this paper a method of computer-aided optimization of 3-D conformal treatment plans is presented which incorporates models to predict the clinical consequences of resulting dose distributions. Even though these models are simplistic, it is submitted that their intelligent use leads to treatment plans which indicate lower normal tissue complications and higher tumor control. Dose distribution data, biological models, and observed normal tissue and tumor response data are used to compute tumor control and normal tissue complication probabilities for each of the critical normal structures encountered in a treatment plan. These quantities are combined into a single score using an objective function which incorporates the importance of each end point as assessed by the physician. Using the "simulated annealing" method of optimization, the beam weights are adjusted to maximize the score. Additional constraints are applied to ensure consistency of the results of optimization with the judgment of the physician. These optimization methods have been applied to conformal treatment plans consisting of multiple fixed fields with conformal field shaping. The results indicate that the methods presented have considerable potential.


Optimization of brachytherapy dose distributions by simulated annealing.

An algorithm based on the method of simulated annealing is presented for optimizing brachy-therapy dose distributions. The algorithm accommodates either static configurations of multiple sources or single stepping sources, hence in principle can be used to optimize both low- and high-dose rate treatments delivered with remote afterloading equipment. Required inputs include the specification of target dose rates and dose rate limits, expressed in absolute or relative terms, at operator selected points near the treatment site. The influence of the dose rate limits can be adjusted continuously through the use of one or more penalty factors. The algorithm generates a set of integer weights, one for each available source position, which are interpreted in terms of configuration occupancy numbers for static source arrangements and relative dwell times for stepping sources. Application is made to several variations of a hypothetical low-dose rate vaginal vault planning problem involving one rectal and six applicator calculation points. The algorithm's performance for different source strengths, annealing schedules, target dose rates, dose rate limits, and values of a single penalty factor lambda was examined. With a simple annealing schedule and value of lambda = 25, the algorithm found solutions of high quality for all problem variants. The CPU time required for optimization on a Vax 11/750 computer ranged from 2 min for a single configuration to 25 min for a solution consisting of four configurations. These results support the use of simulated annealing for clinical planning of low dose rate vaginal treatments, and encourage investigation of other applications in brachytherapy.


A model for computer-controlled delivery of 3-D conformal treatments.

Three-dimensional conformal radiation treatments are highly complex and may comprise a large number of coplanar and noncoplanar beams, virtually all of which are shaped and may also employ arbitrary intensity modulation. The delivery of such treatments with conventional means is highly labor intensive and limited to a relatively small number of fields. A generalized model for a system that can deliver 3-D conformal treatments rapidly and safely using a computer-controlled treatment machine equipped with a multileaf collimator is presented. The model emphasizes the separation of tasks between an external computer programmed by the user institution and a control computer proprietary to the treatment machine manufacturer. The treatment scheme that is employed consists of a sequence of fixed fields, called segments, which are delivered in succession without human intervention. Settings for all segments, derived from a 3-D conformal treatment planning system, are downloaded by the external computer into the control computer of the treatment machine. During patient setup, the control computer enables the operator to step through computer-controlled setup of the segments without radiation to ensure the absence of collisions, and to allow the adjustment of setup parameters if necessary. The external computer verifies the treatment setup and permits the control computer to carry out the treatment segment by segment. Safety aspects of the model and anomalous situations which may arise are discussed.


Rapid dose calculations for stereotactic radiosurgery.

A three-dimensional dose calculation algorithm is described for stereotactic radiosurgery using multiple noncoplanar beam arcs. Precalculated dose libraries of 20-deg arc segments, or mini arcs, are stored in computer memory which permits rapid calculation of complete, high resolution, three-dimensional isodose distributions and dose volume histograms. Three-dimensional patient contours and target volumes are obtained from CT scans and angiographic x rays. Rapid dose calculations are made possible by the use of arc libraries and an improved algorithm for mapping beam doses to the dose calculation grid. This permits more flexibility in designing optimum treatment plans, as five-six complete plans can be generated in less than 1 h. Thus many possible treatment options can be tested in the 3-4-h time period typically available in stereotactic procedures between CT scanning and treatment.


Optimized dynamic rotation with wedges.

Dynamic rotation is a computer-controlled therapy technique utilizing an automated multileaf collimator in which the radiation beam shape changes dynamically as the treatment machine rotates about the patient so that at each instant the beam shape matches the projected shape of the target volume. In simple dynamic rotation, the dose rate remains constant during rotation. For optimized dynamic rotation, the dose rate is varied as a function of gantry angle. Optimum dose rate at each gantry angle is computed by linear programming. Wedges can be included in the optimized dynamic rotation therapy by using additional rotations. Simple and optimized dynamic rotation treatment plans, with and without wedges, for a pancreatic tumor have been compared using optimization cost function values, normal tissue complication probabilities, and positive difference statistic values. For planning purposes, a continuous rotation is approximated by static beams at a number of gantry angles equally spaced about the patient. In theory, the quality of optimized treatment planning solutions should improve as the number of static beams increases. The addition of wedges should further improve dose distributions. For the case studied, no significant improvements were seen for more than 36 beam angles. Open and wedged optimized dynamic rotations were better than simple dynamic rotation, but wedged optimized dynamic rotation showed no definitive improvement over open beam optimized dynamic rotation.


The feasibility of interstitial ultrasound hyperthermia.

One of the most promising ways to increase the efficacy of brachytherapy is to combine it with hyperthermia. In this paper, the feasibility of using ultrasound transducers as interstitial hyperthermia sources was investigated. The ultrasound output of eight cylindrical transducers (diameter 1 mm and length 25 mm) was studied. It was found that many of these transducers were able to generate between 2 and 3 W of acoustic energy at the frequency of 9.5 MHz. The ultrasound field emitted radially was well collimated and extended the full length of the transducer. In vitro perfused liver and kidney experiments showed that an array of four transducers placed in brachytherapy catheters up to a maximum spacing of 20 mm in a square pattern could induce therapeutic temperatures. Also, the effect of flow rate into the organs and catheter cooling were investigated. These results showed that interstitial ultrasound sources are potentially the most promising way of generating therapeutic temperatures through standard interstitial radiation therapy catheters.


[The leukemia-lymphoma syndrome with gastrointestinal involvement in childhood. A case report].

The gastrointestinal tract is an uncommon site of presentation for acute lymphoblastic leukemia in children. We report a child who developed a leukemia-lymphoma syndrome with central nervous system and gastrointestinal tract involvement at the diagnosis. The patient received an intensive combination chemotherapy and is currently off-therapy in continuous complete remission 29 months after the diagnosis.


Three-dimensional simulations of ferromagnetic implant hyperthermia.

A general three-dimensional planning program has been developed for hyperthermia treatments for cancer. In this study, the program is used to analyze the three-dimensional temperature distributions generated by interstitial ferromagnetic implants. An empirical power absorption formula developed by Haider for thermally self-regulating nickel-silicon ferromagnetic seeds has been used to calculate the seed power absorption as a function of seed temperature. By properly choosing the seed type (Curie point of seeds), and by using appropriate seed spacing, this heating modality can generate desirable three-dimensional temperature distributions for many different situations over a fairly large range of blood perfusion values. Detailed information regarding the choice of the Curie points of the seeds and the seed spacing for certain blood perfusions is also given as a quantitative guide for treatment planning.


[Follicular cysts of the mandible. The diagnostic problems].

The authors describe a case of follicular cyst of the jaw diagnosed in a male infant who was 2 years and 4 months old. The authors discuss recent advances in the classification of this disorder and the difficulties that arise in performing differential diagnosis; some peculiar features of the described case are discussed.


[Toxocariasis (visceral larva migrans). A report of a case in an adopted child].

A case of asymptomatic toxocariasis in a Brazilian adopted child with hypereosinophilia is described. The diagnosis is confirmed by measuring specific IgG antibodies anti-Toxocara and, in the light of growing adoptions of children coming from low standard of living extra-European countries, the authors note the importance of investigating also on those parasitosis until today rather infrequent in our country.


[The clinical use of dynamic EEG in childhood].

A-EEG is an important recent technologic innovation in EEG recording that facilitates long-term monitoring. The system consists of a miniature cassette tape recorder and a video play-back unit, which permits the taped EEG to be reviewed (Brain Spy CH24, Micromed). Because it is extremely lightweight and portable, the system permits unrestricted activity during recording. On the other hand, this predisposes the recording to more artifacts than are seen in routine recordings. We examined 103 patients, aged 3 months-24 years, between July 1988 and July 1990. Patients were divided into three groups: group 1 included 61 subjects with evidence of epilepsy and clinically definite seizures; group 2 included 29 patients with recurrent episodes that were not clearly epileptic (suspected "pseudo epileptic"); group 3 included 13 subjects with psychiatric disorders. We found that the clinical utility of A-EEG in epileptic children was: 1) obtain better clinical and EEG characterization and circadian distribution of seizures in 17 cases (28%); 2) quantify epileptiform generalized abnormalities and their variations during the sleep in 6 cases (10%); 3) verify the efficacy of specific drug treatment such as Bzd and ACTH in 12 cases (20%). The role of A-EEG in non-epileptic children with pseudoseizures was to establish the epileptic or non epileptic nature of some ictal events by detecting EEG seizure patterns in 11 cases (38%). As to regard the group 3, A-EEG has permitted to study sleep architecture and REM sleep measures, especially in depressed children compared to normal children. We discuss advantages, drawbacks and clinical applications of A-EEG in child neurology and psychiatry vs conventional EEG.


A study on the efficacy of digital enhancement of on-line portal images.

A novel method for evaluation of observer performance with portal images has been developed, in which the observer is required to identify and localize predefined anatomical landmarks in digital portal images. The method was employed to compare the spatial accuracy and decision time for landmark localization in unenhanced on-line portal images and images enhanced digitally by selective adaptive histogram modification. The results indicate that anatomical landmarks were more readily identified in the enhanced images, leading to significantly higher accuracy in landmark localization.


[The effects of l-dopa administration on the prolactin levels in short-stature subjects].

In this study, on the basis of the inhibiting action of l-dopa administration on prolactin (PRL) secretion, we evaluated in a number of short children the levels of PRL during the provocative stimuli test with l-dopa in order to identify an index able to give reliability to the test and to investigate whether some differences may exist among the subjects showing a different response in growth hormone (GH) secretion to l-dopa. We examined 76 subjects (44 boys and 32 girls) with chronological age from 4.5-15.17 years. The subjects, on the basis of the GH peaks during two provocative stimuli tests [l-dopa and insulin-induced hypoglycemia (IIH)], were subdivided into 3 groups: group 1 (n = 24) with both deficient responses (peak less than 10 ng/ml); group 2 (n = 28) with discordant responses and further subdivided into group 2a (n = 14) with normal responses to IIH and 2b (n = 14) with a normal response to l-dopa; group 3 (n = 24) with both normal responses. PRL levels peaked between times -20' (58 cases) and +20' (2 cases) whereas nadir occurred between +80' (4 cases) and +120 (48 cases) without any significant difference (p = ns) among the groups. PRL levels significantly decreased in all groups, also in those with a deficient response to l-dopa (1 and 2a); furthermore no significant correlation between PRL and GH levels was demonstrated. In conclusion, this study showed the importance of PRL evaluation during l-dopa test in order to give reliability to the test and did not demonstrate any difference in PRL levels among the examined groups of short children.


[The use of ofloxacin in cystic fibrosis patients].

The new quinolones represent the latest possibility of specific oral antibiotic treatment of infections caused by gram-negative bacteria. Among the new quinolones, ciprofloxacin and ofloxacin are characterized by strong in vitro activity against most Pseudomonas species strains, favourable kinetic in body fluids, good tolerability and the possibility of oral administration. For these reasons they appear to be ideal antibiotics for long-term home therapy of chronic obstructive pulmonary disease in cystic fibrosis (CF). The efficacy of ciprofloxacin has been recently assessed. In this study, actual effectiveness of ofloxacin in long-term home antibiotic treatment of patients affected by CF was evaluated. The study was a no-blind cross-over study, designed to compare ofloxacin treatment with conventional oral antibiotic therapy. Young adult patients, who needed long-term antibiotic therapy and whom sputum culture were positive for sensitive strains, were randomly assigned to 2 groups. One group received ofloxacin, the other group was given a non-quinolone oral antibiotic, selected according to sputum culture sensitivity. Oral antibiotics were administered for 20 days, then a break of 10 days was allowed during which patients received nebulized aminoglucosides, usually tobramycin. After 3 months, therapies were rotated: the first group received a non-quinolone oral antibiotic and the second group received ofloxacin for another 3 months. The clinical score (according to Huang et al., see table I) and the lung function (FVC, FEV1, pulsed SaO2) were assessed in all the patients at the beginning and at the end of each three months period of oral antibiotic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Rapid health needs assessment following hurricane Andrew--Florida and Louisiana, 1992.

Following the impact phase of Hurricane Andrew in Florida (August 24) and Louisiana (August 26) (Figure 1), the primary objectives of the public health response have been to address the health and medical needs of residents in the storm-damaged areas and to provide data for relief interventions and decision-making. This report presents the combined findings from rapid health needs assessment surveys conducted by state health departments with CDC assistance 3-10 days postimpact.


Early childhood vaccination in two rural counties--Nebraska, 1991-1992.

The national vaccination objectives for the year 2000 include increasing coverage for the recommended primary vaccination series* among children aged less than 2 years to at least 90% and to vaccinate at least 95% of school-aged children (1). Although baseline data for these two goals have been obtained in numerous urban settings (2), similar baseline data from rural populations are limited. To determine the vaccination status of children in rural Nebraska, where 51% (812,000) of Nebraska's residents live, the Nebraska Department of Health, in collaboration with Hastings College, conducted a retrospective study of school-aged children in grades kindergarten through six in two rural counties during the 1991-92 school year. This report summarizes the study findings.


Update: International Task Force for Disease Eradication, 1992.

In 1988, the International Task Force for Disease Eradication (ITFDE) was formed to systematically evaluate the potential for global eradicability* of candidate diseases, identify specific barriers to their eradication that might be surmountable, and promote eradication efforts. In its first four meetings during 1988-1991, the ITFDE examined 15 infectious diseases and determined that four-dracunculiasis, poliomyelitis, mumps, and rubella-are good candidates for eradication (1,2). In its fifth meeting in March 1992, the ITFDE evaluated the potential eradicability of six other diseases (Table 1). The criteria used by the ITFDE to evaluate these diseases was provided previously (2). This report summarizes the results of the fifth meeting.


Tobacco, alcohol, and other drug use among high school students--United States, 1991.

In the United States, use of tobacco, alcohol, and other drugs is associated with the leading causes of morbidity and mortality (e.g., motor-vehicle crashes, homicide, suicide, and cancer [1]), with lower educational achievement, and with school dropout (2-5). This report presents self-reported data about the prevalence of tobacco, alcohol, marijuana, and cocaine use among students in grades 9-12 from two school-based components of the Youth Risk Behavior Surveillance System (6): 1) state and local Youth Risk Behavior Surveys (YRBSs) conducted by departments of education in 23 states and 10 cities during the spring of 1991 and 2) the national YRBS conducted during the same period.


Oscillations in glycolysis: multifactorial quantitative analysis in muscle extract.

A multifactorial quantitative analysis of oscillations in glycolysis was conducted in the postmicrosomal supernatant of rat muscle homogenates incubated in the presence of yeast hexokinase. Oscillations in adenine nucleotides, D-fructose 1,6-bisphosphate, triose phosphates, L-glycerol 3-phosphate, 3HOH generation from D-[5-3H]glucose, NADH and L-lactate production were documented. The occurrence of such oscillations were found to depend mainly on the balance between the consumption of ATP associated with the phosphorylation of D-glucose, as catalyzed by both yeast and muscle hexokinase, and the net production of ATP resulting from the further catabolism of D-fructose 6-phosphate, as initiated by activation of phosphofructokinase. The oscillatory pattern was suppressed in the presence of D-fructose 2,6-bisphosphate. It is proposed that the quantitative information gathered in this study may set the scene for further studies in extracts of cells other than myocytes, e.g. hepatocytes and pancreatic islet cells, in which no oscillation of glycolysis was so far observed.


Low density lipoprotein heterogeneity in spontaneously hypercholesterolemic pigs.

We previously described a strain of spontaneously hypercholesterolemic pigs carrying an apo-B allele termed Lpb5. Lpb5 pigs are heterogeneous with respect to the severity of their hypercholesterolemia. We have termed Lpb5 pigs with severe hypercholesterolemia Lpb 5.1 pigs, and those with moderate hypercholesterolemia Lpb 5.2, Lpb 5.1 animals have a dramatic increase in buoyant LDL relative to dense LDL, with a buoyant-to-dense LDL ratio of 2.2. In contrast, Lpb 5.2 and control pigs have buoyant-to-dense LDL ratios of 0.7 and 0.5 respectively. This ratio appears to be a stable characteristic of the Lpb 5.1 phenotype because sexually mature boars have a dramatic decrease in total plasma cholesterol concentration with no decrease in their ratio of buoyant-to-dense LDL. We have previously demonstrated a fourteen-fold overproduction of buoyant LDL in the Lpb 5.1 pigs, with very little conversion of dense LDL to buoyant LDL. In the current work, very low density lipoprotein (VLDL) turnover experiments were conducted to determine whether VLDL conversion to buoyant LDL was increased in the Lpb 5.1 pigs. VLDL conversion to buoyant LDL could not account for the increased production of buoyant LDL in Lpb 5.1 pigs. Thus, we cannot account for the increased production of buoyant LDL in the Lpb 5.1 pigs from any measurable plasma lipoprotein source. We have therefore termed this production of buoyant LDL in the Lpb 5.1 pigs direct buoyant LDL production.


Analysis of familial hypoalphalipoproteinemia syndromes.

Familial hypoalphalipoproteinemias (HA) are a heterogenous group of disorders characterized by various degrees of HDL deficiency. Differential diagnosis involves clinical and biochemical evaluation after intervention designed to correct known secondary causes of low HDL. Two specific HAs are discussed in this report: 1. primary isolated HA (PIHA) is a poorly characterized entity with an apparent autosomal dominant transmission and distinct abnormalities in the structure and function of HDL. 2. Lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes are caused by a number of different genetic defects that lead to at least two distinct clinical presentations i.e. familial LCAT deficiency and fish eye disease. PIHA is an example of a genetic disorder whose diagnosis would greatly be improved by the availability of molecular diagnostic tests. Conversely, the effect of the genetic heterogeneity of LCAT deficiency syndromes on diagnosis is best overcome by utilizing existing biochemical measurement of LCAT activity and the plasma cholesterol esterification rate.


Genetic aspects of susceptibility to obesity and related dyslipidemias.

Obesity has a multifactorial origin. However, although environmental variables undoubtedly play a role in the development of obesity, it is now clear that genetic variation is also involved in the determination of an individual's susceptibility to body fat accumulation. In addition, it is also widely accepted that obesity is not a single homogeneous phenotype. It is also heterogeneous regarding its causes and metabolic complications. The regional distribution of body fat appears to be an important correlate of the metabolic complications that have been related to obesity. Due to their higher accumulation of abdominal fat, men are generally more at risk for the metabolic complications of obesity than women whereas some obese women, with large gluteal-femoral adipose depots may have a cosmetic problem which may not necessarily require medical intervention. Several studies have been conducted to understand the mechanisms by which abdominal obesity is related to diabetes, hypertension and cardiovascular disease. It appears that the increased risk of abdominal obesity is the result of complex hormonal and metabolic interactions. Studies in genetic epidemiology have shown that both total body fatness and the regional distribution of body fat have a significant genetic component. Standardized intervention studies using an identical twin design have shown that individuals that have the same genetic background tend to show similar changes in body fat and in plasma lipoprotein levels when exposed to standardized caloric excess or energy restriction. Finally, although abdominal obesity is a significant risk factor for cardiovascular disease, not every abdominal obese subject will experience metabolic complications, suggesting that some obese individuals may be more susceptible than others. Variation in several genes relevant to lipid and lipoprotein metabolism may alter the relation of abdominal obesity to dyslipoproteinemias. Abdominal obesity should therefore be considered as a factor that exacerbates an individual's susceptibility to cardiovascular disease.


Molecular genetics of human lipoprotein lipase deficiency.

Lipoprotein lipase (LPL) hydrolysis the triglyceride core of circulating chylomicrons and very-low-density lipoprotein, and modulates the levels and lipid composition of low and high density lipoproteins. Worldwide, more than 20 mutations in the LPL gene have been identified in patients with familial LPL deficiency. Most of these mutations are clustered in the region encoded by exons 4, 5 and 6 which forms the proposed catalytic domain of LPL. In French Canadians who have the highest reported frequency for LPL deficiency, three common mutations in the LPL gene have been identified which account for approximately 97% of mutant genes in this group. Simple DNA-based tests for the detection of all these mutations have been developed for the screening for carriers of LPL deficiency. This will facilitate further studies of phenotypic expression in heterozygous carriers and assessment of the risk of atherosclerosis in these individuals.