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The prevalence of obesity continues to escalate in the USA; however, there is no consensus regarding the optimal therapy for obesity. For the vast majority of severely obese patients, conventional medical therapies (i.e., diet, exercise, behavioral counseling) often fail over the long term. Existing pharmacotherapy adjunctive to behavioral therapy has limited effectiveness and an imperfect safety record. In contrast, bariatric surgery has a high degree of weight loss efficacy, yet only a small fraction of the qualifying obese population undergoes these procedures because of the associated perioperative risks and potential late complications. In addition, the role of bariatric surgery is unclear in certain patient populations, such as patients with lower body mass index (BMI, 30-35 kg/m(2)), the high-risk super-super obese patients (BMI > 60), the morbidly obese adolescent, and obese patients requiring weight reduction in preparation for other procedures, such as orthopedic, transplant, or vascular surgeries. In these circumstances, there is a need for an effective but less invasive treatment to bridge the gap between medical and surgical therapy. This review examines current treatment outcomes, identifies prominent areas of unmet clinical needs, and provides an overview of two minimally invasive "temporary procedures for weight loss" that may eventually address some of the unmet needs in obesity management.

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OBJECTIVE: Topical fat reduction from the thigh in women using aminophylline cream has been demonstrated, but the local fat reduction in other body areas or in men by lowering the local lipolytic threshold has not been demonstrated. This study is designed to test the hypothesis that aminophylline cream application to the waist will reduce waist circumference compared with a control. RESEARCH METHODS AND PROCEDURES: Fifty men and women who are 21-65 years of age with a BMI greater than 27 kg/m(2) and a waist to hip ratio > or =average were randomized in a 1 : 1 ratio to 0.5% aminophylline cream to the waist twice a day or no treatment to the waist. All subjects were instructed to follow a 1200 kcal balanced diet, participate in a walking program and return biweekly to encourage compliance. A theophylline level was drawn monthly, and the waist, BMI and waist to hip ratio were remeasured at 12 weeks. RESULTS: At week 12, there was a significant reduction in BMI from baseline that was not different between the groups. The reduction in waist circumference was 11 +/- 1.0 cm in the aminophylline cream group and 5.0 +/- 0.6 cm in the control group (p < 0.001). The reduction in waist circumference was significant for both women and men, but the women lost significantly more waist girth. The waist to hip ratio, a measure of fat distribution, declined. Aminophylline levels were undetectable, and there were no adverse events. DISCUSSION: Aminophylline cream offers a safe and effective method for cosmetic local fat reduction from the waist.

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OBJECTIVE: To determine if an herbal dietary supplement for weight loss increases metabolism. DESIGN: Measurement of peak oxygen consumption in response to the supplement followed by a double-blind placebo-controlled crossover measurement of oxygen consumption in response to the supplement. SETTING: The study was conducted in an academic research clinic. SUBJECTS: Ten obese females (aged 41 +/- 4 years [body mass index (BMI)] 33.3 +/- 2.6 kg/m2) participated in the peak oxygen consumption test; six of these females participated in the crossover trial. INTERVENTIONS AND OUTCOME MEASURES: Peak oxygen consumption was measured for 45 minutes after taking two herbal dietary supplement capsules orally, each containing the equivalent of 10 mg of caffeine and 5 mg of ephedrine. The crossover trial measured oxygen consumption for 45 minutes after taking two herbal dietary supplement capsules or two placebo capsules orally. RESULTS: The herbal dietary supplement increased peak oxygen consumption 0.178 +/- 0.03 (SEM) kcal/min (8.01 +/- 1.35 kcal/min expressed over 45 minutes) above baseline (p < 0.0001), and 2.0 +/- 0.56 kcal/min over 45 minutes compared to placebo (p < 0.006). CONCLUSIONS: The herbal dietary supplement increased oxygen consumption when taken according to the package directions. The significance of this rise for weight loss requires further research.

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OBJECTIVE: Phenylpropanolamine (PPA) and benzocaine are non-prescription medications approved for treating obesity. The dose of PPA for weight loss is 75 mg/day. PPA has the same chemical similarity to pseudoephedrine that amphetamine has to methamphetamine. Because benzocaine causes weight loss by altering taste and PPA by central appetite suppression, they may induce additional weight loss when combined. These studies explore the safety and efficacy of low-dose PPA, pseudoephedrine, and PPA with benzocaine in causing weight loss. RESEARCH METHODS AND PROCEDURES: Study 1 compared PPA 12.5 mg tid with 25 mg tid and placebo in a 6-week trial in 108 obese subjects. Study 2 compared pseudoephedrine 120 mg/day and a placebo in a 12-week trial with 72 obese subjects. Study 3 compared 4 groups of 20 obese subjects using PPA 75 mg/day, benzocaine gum 96 mg/day, PPA with benzocaine gum, and a placebo over 12 weeks. RESULTS: Both doses of PPA gave twice the weight loss of placebo, but the difference did not reach statistical significance. Pseudoephedrine was no different than placebo in inducing weight loss. The PPA with benzocaine group had more adverse events than the benzocaine group (p = 0.03), the placebo group (p = 0.03), or the PPA group (p = 0.09) without additional weight loss. DISCUSSION: We conclude that further studies with low-dose PPA for weight loss are indicated, that pseudoephedrine is not effective for weight loss, and that adding benzocaine to phenylpropanolamine increases adverse effects without increasing weight loss.

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BACKGROUND: Hypercortisolemia is frequently observed in major depression but its pathophysiologic significance is unknown. In patients in whom hypercortisolism contributes to depressive symptomatology, antiglucocorticoid agents should have antidepressant effects. METHODS: Twenty medication-free depressed patients (eight of whom were hypercortisolemic and twelve of whom were not) received either the cortisol biosynthesis inhibitor, ketoconazole (400-800 mg/d p.o.) or placebo for 4 weeks in a double-blind manner, and behavioral ratings were performed weekly. RESULTS: Ketoconazole, compared to placebo, was associated with improvements in depression ratings in the hypercortisolemic, but not in the non-hypercortisolemic patients. The hormonal changes seen (decreased dehydroepiandrosterone and testosterone levels and increased pregnenolone and pregnenolone-sulfate levels) are consistent with enzymatic blockade of C17,20-lyase, 11-hydroxylase, and 17-hydroxylase. Ketoconazole was generally well tolerated with no occurrence of significant side effects or laboratory abnormalities. CONCLUSIONS: This small-scale double-blind study suggests that antiglucocorticoids have antidepressant activity in hypercortisolemic depressed patients. The data are consistent with a causal role of adrenocortical dysfunction in some depressed patients and suggest the need for larger-scale trials.

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Erdheim-Chester (EC) disease belongs to the group of lipoid granulomatosis. Symmetric sclerosis of the meta- and diaphysis of long tubular bones are pathognomonic radiologic changes. Additionally, other skeletal segments can be affected. Extraskeletal manifestations can occur in almost all organs; lungs, pericardium, retroperitoneum, skin, and orbita play particularly important roles. The last case of 38 cases of Erdheim-Chester disease with an extraordinary mediastinal and perirenal involvement is described. For the second time following the initial description by Chester, an axial skeletal pattern of eburnated vertebra is shown.

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In utero ethanol exposure decreases the prenatal testosterone (T) surge in male rats. To determine the functional significance of this suppression, we measured sex behavior in adult litter representatives of pregnant rats that were administered a fortified liquid diet containing 35% ethanol-derived calories from day 15 of gestation through parturition. Control dams were pair-fed an isocaloric liquid diet with the ethanol calories replaced by sucrose. Results from the behavioral studies showed that gonadally intact fetal alcohol-exposed (FAE) males exhibited little masculine sex behavior in the first of four weekly sessions. However, their behavior in the subsequent three tests was indistinguishable from pair-fed controls. Lordosis quotients in the same males following castration and estrogen and progesterone treatment were under 10%. In castrated FAE females, no effects of prenatal ethanol exposure were observed in masculine behaviors following androgen replacement or feminine sex behaviors following estrogen and progesterone replacement. Additional studies measured the duration of prenatal ethanol exposure necessary to inhibit the prenatal T surge in order to determine whether the inhibition was due to a direct effect of the drug. Results revealed an inhibition of the surge in males exposed to ethanol from days 14 through 20 of pregnancy, days 14 through 16 of pregnancy, or days 17 through 20 of pregnancy. A normal surge of T was observed on days 18-19 of gestation in control fetuses. These findings indicate that ethanol does not have to be present in blood at the time of the surge to have an inhibitory effect. They also reveal that the surge can be inhibited with as little as 24-36 h of ethanol exposure prior to its normal appearance on day 18 of gestation. In spite of this inhibition of the prenatal T surge, the behavioral results indicate that normal masculinization and defeminization of sex behavior occurs in FAE males exposed to ethanol after the beginning of the period of differentiation of the hypothalamus and testes.

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Animal and clinical studies suggest that lead exposure disrupts the hypothalamic-pituitary axis. To define more precisely the toxic action of lead on the hypothalamic-pituitary unit, a series of in vivo and in vitro experiments were performed. The first experiment was designed to determine whether lead exposure exerts an inhibitory effect on GnRH secretion as reflected by an enhanced inhibition of luteinizing hormone (LH) secretion in response to the tyrosine hydroxylase inhibitor methyl-p-tyrosine (AMPT). In the control animals, the AMPT dose had no significant effect on LH secretion, whereas LH fell significantly in the lead-treated animals. In experiments designed to evaluate the effects of lead exposure on the pattern of pulsatile release of gonadotropins castrated control and lead-dosed animals were cannulated, and serial blood sampling was performed. Baseline LH and follicle-stimulating hormone values were not statistically different between the control and lead-treated group. There were no significant differences noted in pulsatile patterns when the data were analyzed as groups. Pituitary cells harvested from lead-treated animals released significantly more LH that did the control animals. These data are consistent with the hypothesis that the signals between the hypothalamus and pituitary gland are disrupted by lead exposure in the intact animal. However, the lead-exposed castrated rat's hypothalamic-pituitary unit is able to adapt to the toxic effects of lead.

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A cross-sectional survey was made in 56 exceptionally healthy males, ranging in age from 20 to 84 years. Measurements were made of selected steroidal components and peptidic hormones in blood serum, and cognitive and physical tests were performed. Of those blood serum variables that gave highly significant negative correlations with age (r > -0.6), bioavailable testosterone (BT), dehydroepiandrosterone sulfate (DHEAS), and the ratio of insulin-like growth factor 1 (IGF-1) to growth hormone (GH) showed a stepwise pattern of age-related changes most closely resembling those of the age steps themselves. Of these, BT correlated best with significantly age-correlated cognitive and physical measures. Because DHEAS correlated well with BT and considerably less well than BT with the cognitive and physical measures, it seems likely that BT and/or substances to which BT gives rise in tissues play a more direct role in whatever processes are rate-limiting in the functions measured and that DHEAS relates more indirectly to these functions. The high correlation of IGF-1/GH with age, its relatively low correlation with BT, and the patterns of correlations of IGF-1/GH and BT with significantly age-correlated cognitive and physical measures suggest that the GH-IGF-1 axis and BT play independent roles in affecting these functions. Serial determinations made after oral ingestion of pregnenolone and data from the literature suggest there is interdependence of steroid metabolic systems with those operational in control of interrelations in the GH-IGF-1 axis. Longitudinal concurrent measurements of serum levels of BT, DHEAS, and IGF-1/GH together with detailed studies of their correlations with age-correlated functional measures may be useful in detecting early age-related dysregulations and may be helpful in devising ameliorative approaches.

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Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

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A patient underwent elective removal of a phaeochromocytoma producing extremely high plasma concentrations of catecholamines. The new volatile agent, desflurane, was incorporated, in varying concentrations, into the general anaesthetic regimen.

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We investigated the effect of calorie and protein content of very-low-calorie diets for weight loss upon myocardial electrical activity. Patients were followed on very low calorie diets for up to 20 weeks. Study No. 1 had 16 obese patients (4 men and 12 women). Study No. 2 had 113 obese women. Both study groups were consecutive samples with patients who had BMI > 30. In Study No. 1 patients were given 400 kcal/d with 50 gm of protein and 45 gm of carbohydrates over 12 weeks. In Study No. 2 patients were given either Metabolic Nutrition Program (MNP) which contained 600 kcal/d with 70 gm protein and 70 gm carbohydrates, or Optifast-70 which contained 420 kcal/d with 70 gm protein and 32 gm carbohydrates, for up to 20 weeks. Electrocardiograms were obtained at baseline and during the third month in Study No. 1, and monthly in Study No. 2. The sum of the voltage in leads I+II+III and the length of the QT interval were derived from the electrocardiograms. In Study No. 1 the QRS voltage decreased from 2.77 +/- .18 mv to 2.45 +/- .17 mv (p < .02). Patients lost 18.1 kg +/- 4 kg and the QT interval remained unchanged. In Study No. 2 at 20 weeks the QRS voltage decreased on Optifast-70 (p < .001) in comparison to MNP, in which the QRS voltage remained unchanged. Patients on Optifast-70 lost 17.5 +/- .53 kg, patients on MNP lost 18.5 +/- .66 kg and the QT interval in both groups remained unchanged. The formula diets tested of less than 600 kcal/d were associated with a decrease in electrocardiographic voltage.

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42 patients with known malignancy and vertebral compressions underwent MRI. Sagittal T1-weighted spin-echo images pre and post Gd-DTPA, out of phase long TR gradient-echo images (GE) and short T1 inversion recovery images (STIR) were obtained at 1.0 T. The results were confirmed by histology (6/42) or clinical data (28/42) and follow up MRI studies (8/42). In 39 of 42 cases a correct differentiation between osteoporotic and tumorous vertebral compression fractures was possible by quantification and correlation of SE and GE signal intensities. Gd-DTPA did not improve differential diagnosis, since both tumour infiltration and bone marrow oedema in acute compression fracture showed comparable enhancement. STIR-sequences were most sensitive for pathology but unspecific due to a comparable amount of water in tumour tissue and bone marrow oedema. Susceptibility-induced signal reduction in GE images and morphologic criteria proved to be most reliable for differentiation of benign and tumour-related fractures. In the rare cases of single and nearly complete vertebral compressions with complete loss of bone marrow, differentiation with MRI was not possible.

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Sprague-Dawley dams from Harlan Ind. (Indianapolis, IN) were administered a fortified ethanol liquid diet containing 35% ethanol derived calories for two weeks (E-2) beginning on day 7 or one week (E-1) beginning on day 13 of gestation and continuing through parturition. Control dams were pair-fed an isocaloric liquid diet containing no ethanol during these periods or remained on lab chow and water. E-2 dams consumed an average of 13.52 g ethanol/kg bwt during the first week of exposure (days 8-14) and 12.50 g ethanol/kg bwt the second week (days 14-20). E-1 dams consumed significantly less than E-2 dams during the second week (9.75 g/kg; p < 0.0001). Although the lower consumption in E-1 dams led to a significant decrease in maternal weight gained during the few days of pregnancy compared to E-2 dams, birthweights of E-1 offspring were significantly heavier than those of E-2 offspring (p < 0.05). No effect of ethanol was detected on anogenital distance at birth in either sex. Puberty was delayed in female offspring of both E-1 and E-2 dams (p < 0.01) as measured by age of vaginal opening. These data suggest that the primary teratogenic actions of ethanol in the rat on fetal growth, as well as delayed puberty in females, occur in the last week of gestation. In adult E-2 males, testis weight was significantly heavier than all other groups when indexed to body weight. No effect of prenatal ethanol exposure was observed on the indexed weights of prostate, epididymis, or seminal vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

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Several adrenergically active drugs have been shown to prevent the masculinizing and/or defeminizing effects of testosterone on brain sexual differentiation. We examined the ability of the neuronal norepinephrine uptake blocker, cocaine, to produce similar effects. The ability of cocaine to inhibit sex steroid incorporation into the hypothalamus during a critical period for sexual differentiation of the brain was examined in females treated at birth with testosterone. Sixty minutes after administration, cocaine was observed to inhibit both testosterone and estradiol incorporation into the hypothalamus by approximately 50%. Long-term consequences of prenatal cocaine exposure were studied by injecting Sprague-Dawley dams twice daily with 3, 10 or 30 mg/kg of cocaine hydrochloride on days 15 through 20 of gestation and examining the offspring. In adulthood, cocaine-exposed males, but not females were found to exhibit significantly less marking behavior than controls. Cocaine-exposed males in the 10 mg/kg group tested for sex behavior exhibited demasculinization in some aspects of the behaviors tested. Measurement of plasma hormone levels in this group revealed elevated levels of plasma LH, but normal levels of FSH and testosterone. No differences were observed in cocaine-exposed males with respect to sex organ or adrenal weights, but thymus was approximately 25% smaller compared to control males at 80 days of age. In a separate experiment, dams were treated with 3 mg/kg of cocaine twice daily from days 15 through 21 of gestation and half of the male pups received additional injections twice a day for the first 5 days postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)

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Pregnant Sprague-Dawley rats were administered a liquid alcohol diet (35% ethanol-derived calories), a pair-fed isocaloric diet, or dry food pellets beginning on Day 14 of gestation and continuing until parturition. Testosterone levels in male fetuses were measured on Days 17 through 20 of gestation. The normal surge of testosterone on Days 18 and 19 was present in controls, but notably absent in male fetuses exposed to alcohol. Light microscopic examination of the testes at birth revealed a reduction in the number of leydig cells in the alcohol exposed group and the presence of a large number of vacuoles in the seminiferous tubules. In vitro studies of fetal testes at 18 and 22 days of gestation revealed that this in utero alcohol exposure regimen produced a marked insensitivity to rat LH (10 ng/ml) stimulation of testosterone secretion compared to controls. The response to ethanol (160 mg/dl) in alcohol exposed testes was characterized by a long-lasting suppression of testosterone compared to a large increase observed in control testes. No differences in anogenital distance were observed among the groups. Together, these data may explain some of the long-term feminizing and demasculinizing effects on reproductive and nonreproductive sexually dimorphic behaviors observed in adult males prenatally exposed to alcohol.

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