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Background: Sarcopenia, the age-related loss of muscle mass [defined as appendicular LBM/Height2 (aLBM/ht2) below peak value by>1SD], strength and function, is a major contributing factor to frailty in the elderly. MK-0773 is a selective androgen receptor modulator designed to improve muscle function while minimizing effects on other tissues., Objectives: The primary objective of this study was to demonstrate an improvement in muscle strength and lean body mass (LBM) in sarcopenic frail elderly women treated with MK-0773 relative to placebo., Design: This was a randomized, double-blind, parallel-arm, placebo-controlled, multicenter, 6-month study. Participants were randomized in a 1:1 ratio to receive either MK-0773 50mg b.i.d. or placebo; all participants received Vitamin D and protein supplementation., Setting: General community., Participants: 170 Women aged ≥65 with sarcopenia and moderate physical dysfunction., Measurements: Dual energy X-ray absorptiometry, muscle strength and power, physical performance measures., Results: Participants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269). Both groups showed significant improvement from baseline at Month 6 in physical performance measures, but there were no statistically significant differences between participants receiving MK-0773 and placebo. A greater number of participants experienced elevated transaminases in the MK-0773 group vs. placebo, which resolved after discontinuation of study therapy. MK-0773 was generally well-tolerated with no evidence of androgenization., Conclusions: The MK-0773-induced increase in LBM did not translate to improvement in strength or function vs. placebo. The improvement of strength and physical function in the placebo group could be at least partly attributed to protein and vitamin D supplementation.

Objective: To evaluate the effects of two different doses of etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively., Research Design and Methods: In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or etoricoxib administered 90 min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (n = 144), etoricoxib 90 mg/day (n = 142), or etoricoxib 120 mg/day (n = 144). Average Pain Intensity at Rest over days 1-3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1-3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1-3., Clinical Trial Registration: This trial is registered on www.clinicaltrials.gov (NCT00788710)., Results: The least squares (LS) means (95% CI) for the primary endpoint were 3.26 (2.96, 3.55); 2.46 (2.16, 2.76); and 2.40 (2.11, 2.69) for placebo, etoricoxib 90 mg, and etoricoxib 120 mg, respectively, significantly different for both etoricoxib doses versus placebo (p < 0.001). Patients on etoricoxib 90 mg and 120 mg required ~30% less morphine per day than those on placebo (p < 0.001), which led to more rapid bowel recovery in the active treatment groups by ~10 hours vs. placebo. A greater proportion of patients on etoricoxib (10-30% greater than placebo) achieved mild levels of pain with movement, defined as pain ≤3/10., Limitations: A key limitation for this study was that movement-evoked pain measurements were not designated as primary endpoints., Conclusion: In patients undergoing total abdominal hysterectomy, etoricoxib 90 mg and 120 mg dosed preoperatively and then continued postoperatively significantly reduces both resting and movement-related pain, as well as reduced opioid (morphine) consumption that led to more rapid bowel recovery.

Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death., (Copyright © 2011 American Medical Directors Association. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the validity, sensitivity to change, and responsiveness of 3 self-report and 4 performance-based measures of physical function: activity measure for postacute care (AM-PAC) Physical Mobility and Personal Care scales, the Medical Outcomes Study 36-Item Short Form Health Survey Physical Function scale (SF-36 PF), the Physical Functional Performance test (PFP-10), the Short Physical Performance Battery (SPPB), a 4-meter gait speed, and the six-minute walk test (6MWT)., Design: A prospective observational study of patients after a hip fracture. Assessments were performed at baseline and 12 weeks postenrollment., Setting: Inpatient and outpatient rehabilitation facilities in Norway, the United Kingdom, Sweden, Israel, Germany, the United States, Denmark, and Spain., Participants: A sample of study participants (N=108) who had a hip fracture., Interventions: Not applicable., Main Outcome Measures: Assessments of validity (known-groups, concurrent, construct, and predictive), sensitivity to change (effect size, standardized response mean [SRM], SE of measure, minimal detectable change (MDC), and responsiveness (optimal operating cut-points and area under the curve) between baseline and 12-week follow-up., Results: All physical function measures achieved comparably acceptable levels of validity. Odds ratios in predicting patient Global Assessment of Improvement at 12 weeks were as follows: AM-PAC Physical Mobility scale, 5.3; AM-PAC Personal Care scale, 3.6; SF-36 PF, 4.3; SPPB, 2.0; PFP-10, 2.5; gait speed, 1.9; and 6MWT, 2.4. Effect sizes and SRM exceeded 1 SD for all 7 measures. Percent of patients who exceeded the MDC(90) at week 12 were as follows: AM-PAC Physical Mobility scale, 90%; AM-PAC Personal Care scale, 74%; SF-36 PF, 66%; SPPB, 36%; PFP-10, 75%; gait speed, 69%; and 6MWT, 75%. When evaluating responsiveness using the area under receiver operating curves for each measure, all measures had acceptable responsiveness, and no pattern emerged of superior responsiveness depending on the type of measure used., Conclusions: Findings reveal that the validity, sensitivity, and responsiveness of self-report measures of physical function are comparable to performance-based measures in a sample of patients followed after fracturing a hip. From a psychometric perspective, either type of functional measure would be suitable for use in clinical trials where improvement in function is an endpoint of interest. The selection of the most appropriate type of functional measure as the primary endpoint for a clinical trial will depend on other factors, such as the measure's feasibility or the strength of the association between the hypothesized mechanism of action of the study intervention and a functional outcome measure.

The pore scale mechanisms and network scale transient pattern of the immiscible displacement of a shear-thinning nonwetting oil phase (NWP) by a Newtonian wetting aqueous phase (WP) are investigated. Visualization imbibition experiments are performed on transparent glass-etched pore networks at a constant unfavorable viscosity ratio and varying values of the capillary number (Ca), and equilibrium contact angle (theta(e)). Dispersions of ozokerite in paraffin oil are used as the shear-thinning NWP, and aqueous solutions of PEG colored with methylene blue are used as the Newtonian WP. At high Ca values, the tip splitting and lateral spreading of WP viscous fingers are suppressed; at intermediate Ca values, the primary viscous fingers expand laterally with the growth of smaller capillary fingers; at low Ca values, network spanning clusters of capillary fingers separated by hydraulically conductive noninvaded zones of NWP arise. The spatial distribution of the mobility of shear-thinning NWP over the pore network is very broad. Pore network regions of low NWP mobility are invaded through a precursor advancement/swelling mechanism even at relatively high Ca and theta(e) values; this mechanism leads to irregular interfacial configurations and retention of a substantial amount of NWP along pore walls; it becomes the dominant mechanism in displacements performed at low Ca and theta(e) values. The residual NWP saturation increases and the end WP relative permeability decreases as Ca increases and both become more sensitive to this parameter as the shear-thinning behavior strengthens. The shear-thinning NWP is primarily entrapped in individual pores of the network rather than in clusters of pores bypassed by the WP. At relatively high flow rates, the amplitude of the variations of pressure drop, caused by fluid redistribution in the pore network, increase with shear-thinning strengthening, whereas at low flow rates, the motion of stable and unstable menisci in pores is reflected in strong pressure drop fluctuations.

Background: Individuals with acute infections experience a range of symptoms including fatigue, malaise, muscle aches, and difficulties with concentration and memory that are usually self-limited. This cluster of symptoms is otherwise, similar to those that characterize chronic fatigue syndrome (CFS). The goal of the present study was to evaluate the cognitive and psychological functioning of CFS patients and normal controls (NCs) when they both were experiencing acute influenza-like symptoms. To induce influenza-like symptoms, we administered interleukin-6 (IL-6), a cytokine that temporarily activates the acute phase immunological and endocrine responses., Methods: Nineteen patients who met the 1994 International CFS Study Group Criteria and ten normal controls (NCs) completed routine clinical evaluations, neuropsychological tests of short-term memory, selective attention, and executive control, and self-ratings of somatic symptoms and psychological mood before, shortly following, and 1 day after IL-6 administration., Results: CFS patients consistently reported more somatic symptoms, even when both groups perceived that they were ill. Both groups somatic symptoms increased during the IL-6 challenge, but the CFS patients symptoms increased more rapidly than controls. In general, the CFS patients performed similarly to NCs on the cognitive measures before, during, and after the IL-6. In contrast to predictions, IL-6 provocation did not impair the cognitive performance of either CFS patients or NCs., Conclusions: The IL-6 provocation exacerbated the patients self-reported symptoms but did not reveal notable cognitive impairments between patients and controls during cytokine-induced acute influenza-like symptoms.

Chronic insomnia, by far the most commonly encountered sleep disorder in medical practice, is characterized by difficulty falling or staying asleep at night and increased fatigue during the day. Interleukin-6 (IL-6) and tumor necrosis factor (TNF) are fatigue-inducing cytokines, and the daytime secretion of IL-6 is negatively influenced by the quantity and quality of the previous night's sleep. We hypothesize that the poor quality of insomniacs' sleep is associated with a hypersecretion of these 2 cytokines during the daytime, which, in turn, correlates with the fatigue experienced by these patients. Eleven young insomniacs (6 men and 5 women) and 11 (8 men and 3 women) age- and body mass index (BMI)-matched healthy controls participated in the study. Subjects were recorded in the sleep laboratory for 4 consecutive nights and serial 24-hour plasma measures of IL-6 and TNF were obtained during the 4th day. Insomniacs compared to controls slept poorly (sleep latency and wake were increased, whereas percentage sleep time was decreased during baseline nights, all P <.05). The mean 24-hour IL-6 and TNF secretions were not different between insomniacs and controls. However, the difference in the change (increase) of IL-6 plasma levels from midafternoon (2 PM) to evening (9 PM) between insomniacs and controls was significant (P <.01). Furthermore, cosinor analysis showed a significant shift of the major peak of IL-6 secretion from nighttime (4 AM) to evening (7 PM) in insomniacs compared to controls (P <.05). Also, while TNF secretion in controls showed a distinct circadian rhythm with a peak close and prior to the offset of sleep (P <.05), such a rhythm was not present in insomniacs. Finally, daytime secretion of TNF in insomniacs was characterized by a regular rhythm of 4 hours (P <.05); such a distinct periodicity was not present in controls. We conclude that chronic insomnia is associated with a shift of IL-6 and TNF secretion from nighttime to daytime, which may explain the daytime fatigue and performance decrements associated with this disorder. The daytime shift of IL-6 and TNF secretion, combined with a 24-hour hypersecretion of cortisol, an arousal hormone, may explain the insomniacs' daytime fatigue and difficulty falling asleep., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Objective: To elucidate the hormonal regulation of interleukin-6 (IL-6) production by human adipose tissue and its relation to leptin., Design: In vitro study. Human adipocytes were incubated with dexamethasone (with or without RU486), norepinephrine and epinephrine (with or without propranolol), or insulin., Measurements: IL-6 and leptin secretion by human adipocytes., Results: A gradual increase in IL-6 secretion by adipocytes during differentiation was observed. A positive correlation was found between basal IL-6 release and both glycerol 3-phosphate dehydrogenase activity--a marker of adipocyte differentiation-and leptin release. Dexamethasone decreased IL-6 secretion and increased leptin secretion in a dose-dependent manner. Both catecholamines increased IL-6 and leptin secretion. The effects of dexamethasone and catecholamines on IL-6 and leptin were abrogated by RU486 and propranolol, respectively. Incubation with insulin resulted in a dose-dependent stimulation of IL-6 and leptin secretion., Conclusions: IL-6 is produced by human adipocytes and is a potential marker of adipocyte differentiation. Furthermore it is a hormonally regulated cytokine, suppressed by glucocorticoids, and stimulated by catecholamines and insulin in physiological concentrations.

The essential oil of leaves and peel from the Cretan variety Zambetakis (Citrus limon) was obtained by steam distillation with a Clevenger apparatus. The essential oil was subjected to GC-MS analysis, and 35 substances were identified. The main component in both essential oils was limonene. beta-Pinene, myrcene, neral, geranial, neryl acetate, geranyl acetate, and beta-caryophyllene have been identified in the leaf oil. The peel oil contained gamma-terpinene, beta-pinene, myrcene, neral, and geranial. The quantification of volatile substances was based on the internal standard method, using octyl acetate as internal standard, and expressed in milligrams per kilogram of the essential oil. The high contents of neral and geranial were indicative of the high quality of both essential oils. The aroma profile and quantitative variations among the essential oil components were measured at six different time intervals over a period of greater than one year. Differences between the components of lemon leaves and peel were observed.

Purpose: To describe the imaging findings in the adrenal glands of 12 patients with adrenocorticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH)., Materials and Methods: Computed tomographic (CT) and magnetic resonance (MR) imaging findings in the adrenal glands were reviewed retrospectively in 12 patients (three men, nine women) with ACTH-independent Cushing syndrome and with bilateral nonpigmented multinodular adrenal hyperplasia. The results of pituitary MR imaging, adrenal scintigraphy, and petrosal sampling were available in nine, five, and six patients, respectively. Eleven patients underwent bilateral and one patient underwent unilateral adrenalectomy., Results: Eleven patients had enlarged multinodular adrenal glands: Nodules were 0.1-5.5 cm. The combined weight of both adrenal specimens for the 11 bilateral adrenalectomy specimens was 28-297 g, with a mean weight of 122 g. Glands were hypointense compared with the liver on T1-weighted images and were hyperintense on T2-weighted images. Pituitary MR imaging findings were negative in nine of nine patients. Iodomethylnorcholesterol scintigraphy showed bilateral uptake in four of five patients. Petrosal sinus sampling revealed no petrosal-to-peripheral ACTH gradients before corticotropin-releasing hormone (CRH) stimulation in six of six patients, but three patients had gradients after CRH stimulation. After undergoing bilateral or unilateral adrenalectomy, all patients were cured., Conclusion: AIMAH is a rare cause of ACTH-independent Cushing syndrome, with characteristic CT findings of massively enlarged multinodular adrenal glands. Bilateral adrenalectomy is indicated on the basis of clinical and CT findings.

Objective: There is currently no optimal test to screen for endogenous Cushing's syndrome (CS) in children. Traditional 24-hour urine or midnight serum cortisol values may be difficult to obtain or elevated by venipuncture stress. We hypothesized that salivary cortisol measurement is a reliable way to screen for CS in children., Study Design: Sixty-seven children (5-17 years) were studied: 24 obese volunteers, 29 non-obese volunteers, and 14 children with CS. Saliva was obtained at 7:30 AM, bedtime, and midnight for measurement of free cortisol by radioimmunoassay., Results: Salivary cortisol was detectable in all morning and evening samples from patients with CS but was frequently undetectable in healthy children at bedtime (66%) and at midnight (90%). With cut points that excluded healthy children, a midnight salivary cortisol value of 7.5 nmol/L (0.27 microg/dL) identified 13 of 14 patients with CS, whereas a bedtime value >27.6 nmol/L (1 microg/dL) detected CS in 5 of 6 patients. The diagnostic accuracies of midnight salivary cortisol and urinary free cortisol per square meter were the same (93%)., Conclusion: Salivary cortisol measurement at bedtime or midnight rules out CS in nearly all cases. Nighttime salivary cortisol sampling is thus a simple, accurate way to screen for hypercortisolism in children.

Objective: To determine whether deficient activity of the hypothalamic corticotropin-releasing hormone (CRH) neuron, which stimulates the hypothalamic-pituitary-adrenal (HPA) axis and the central control nuclei of the sympathetic nervous system and inhibits ascending pain pathways, may be pathogenic in patients with fibromyalgia (FM)., Methods: We administered interleukin-6 (IL-6; 3 microg/kg of body weight subcutaneously), a cytokine capable of stimulating hypothalamic CRH release, and measured plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and catecholamines and their metabolites and precursors. Thirteen female FM patients and 8 age- and body mass index-matched female controls were studied. The diagnosis of FM was made according to American College of Rheumatology criteria. Tender points were quantitated by pressure algometry. All subjects had HPA axis studies. Seven FM patients and 7 controls also had catecholamine measurements., Results: After IL-6 injection, delayed ACTH release was evident in the FM patients, with peak levels at 96.9 +/- 6.0 minutes (mean +/- SEM; control peak 68.6 +/- 10.3 minutes; P = 0.02). Plasma cortisol responses to IL-6 did not differ significantly between patients and controls. Basal norepinephrine (NE) levels were higher in the FM patients than in the controls. While a small, although not significant, rise in NE levels occurred after IL-6 injection in the controls, NE levels dramatically increased over basal levels in the FM patients between 60 and 180 minutes after IL-6 injection. Both peak NE levels (mean +/- SEM 537.6 +/- 82.3 versus 254.3 +/- 41.6 pg/ml; P = 0.0001) and time-integrated NE responses (93.2 +/- 16.6 pg/ml x minutes(-3) versus 52.2 +/- 5.7 pg/ml x minutes(-3); P = 0.038) were greater in FM patients than in controls. Heart rate was increased by IL-6 injection in FM patients and controls, but rose to significantly higher levels in the FM patients from 30 minutes to 180 minutes after IL-6 injection (P < 0.03)., Conclusion: Exaggerated NE responses and heart rate increases, as well as delayed ACTH release, were observed among female FM patients compared with age-matched female controls. Delayed ACTH release after IL-6 administration in FM is consistent with a defect in hypothalamic CRH neuronal function. Exaggerated NE release may reflect abnormal regulation of the sympathetic nervous system, perhaps secondary to chronically deficient hypothalamic CRH. The excessive heart rate response after IL-6 injection in FM patients may be unrelated to the increase in NE, or it may reflect an alteration in the sensitivity of cardiac beta-adrenoceptors to NE. These responses to a physiologic stressor support the notion that FM may represent a primary disorder of the stress system.

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-alpha and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-alpha and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.

Inflammatory cytokines are soluble mediators of immune function that also regulate intermediate metabolism and several endocrine axes. To examine the effects of interleukin-6 (IL-6), the main circulating cytokine, on the hypothalamic-pituitary-testicular axis in men, we performed dose-response studies of recombinant human IL-6 (rHuIL-6) in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 microg/kg body weight) were injected subcutaneously into 15 healthy male volunteers (3 at each dose) in the morning. We measured the circulating levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone binding globulin (SHBG) at baseline and then at 24 h, 48 h, and 7 days after the IL-6 injection. LH and FSH levels were also measured half-hourly for the first 4 h after the IL-6 injection. All IL-6 doses were tolerated well and produced no significant adverse effects. Mean peak plasma IL-6 levels achieved after IL-6 administration were 8 +/- 1, 22 +/- 5, 65 +/- 22, 290 +/- 38, and 4050 +/- 149 pg/ml, respectively for the five doses. We observed no significant changes in plasma testosterone levels after the two smaller IL-6 doses. The three higher IL-6 doses, however, caused significant decreases in testosterone levels by 24 h, which persisted at 48 h and returned to baseline by 7 days. The higher testosterone suppression was after the 3.0 microg/kg dose, making the dose-response curve bell-shaped. There also appeared to be small but not significant increases in LH levels after the three higher IL-6 doses, which were not acute and seemed to follow temporally the testosterone decreases. The concurrent plasma levels of FSH and SHBG were not appreciably affected by any IL-6 dose. In conclusion, subcutaneous IL-6 administration, which caused acute elevations in circulating IL-6 levels of a similar magnitude to those observed in severe inflammatory and noninflammatory stress, induced prolonged suppression in testosterone levels in healthy men without apparent changes in gonadotropin levels. This suggests that IL-6 might induce persistent testicular resistance to LH action or suppression of Leydig cell steroidogenesis or both, with potential adverse effects on male reproductive function.

Background: Primary pigmented nodular adrenocortical disease causes the Cushing syndrome in children and young adults and is most frequently associated with the Carney complex., Objective: To evaluate diagnostic tests for primary pigmented nodular adrenocortical disease., Design: Retrospective cohort study., Setting: Tertiary care center., Patients: 21 patients with primary pigmented nodular adrenocortical disease. The control groups consisted of 9 patients with macronodular adrenocortical disease and 15 patients with primary unilateral adrenocortical disease (single adenomas)., Measurements: Clinical characteristics, radiologic imaging, and a 6-day Liddle test with determination of urinary free cortisol and 17-hydroxycorticosteroid excretion., Results: Adrenal imaging and other tests were of limited value for the diagnosis of primary pigmented nodular adrenocortical disease. The Liddle test, however, distinguished patients with this disorder from those with other primary adrenocortical lesions. An increase of 50% or more in urinary free cortisol levels on day 6 of the Liddle test identified 9 of 13 patients (69.2% [95% CI, 46.6% to 91.8%]) with primary pigmented nodular adrenocortical disease, excluded all patients with macronodular adrenocortical disease, and was present in only 3 of the 15 patients with single adrenocortical adenomas (20% [CI, 0% to 40.2%]). An increase in urinary free cortisol excretion of 100% or more on day 6 of the Liddle test identified only patients with primary pigmented nodular adrenocortical disease., Conclusions: Patients with primary pigmented nodular adrenocortical disease responded to dexamethasone with a paradoxical increase in glucocorticoid excretion during the Liddle test. This feature distinguishes such patients from those who have the Cushing syndrome caused by other primary adrenal disorders and may lead to timely detection of the Carney complex (a potentially fatal disorder) in asymptomatic patients.

Nontraumatic avascular necrosis (AVN) of the hip is commonly caused by exogenous glucocorticoid administration, whereas it has rarely been associated with endogenous hypercortisolism. We report a 30-yr-old woman with Cushing's disease whose presenting manifestation was early AVN of the hip. Although plain x-ray was negative, magnetic resonance imaging (MRI) of the hip showed stage 2 AVN. Her orthopedic disease was considered an emergency, and thus, it was treated with core decompression before the diagnosis of Cushing's syndrome (CS) was pursued further. The femur recovered fully, as demonstrated by her improved clinical picture and a subsequent MRI. AVN carries a poor prognosis, if not treated early. The diagnostic procedure of choice is MRI, because plain radiographs are falsely negative in early stages. This case illustrates that AVN can be the presenting manifestation of CS; to prevent irreversible effects on the femoral head, core decompression should not be delayed for the purpose of evaluation and treatment of CS.

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep.

Purpose: The study was undertaken to determine whether acute supplementation with zinc or vitamin E would modify neuroendocrine responses to physiologic stress., Methods: Specifically, the effects of exhaustive running on blood glucose, lactate, ACTH, cortisol, growth hormone, prolactin, catecholamine, and interleukin 6 (IL-6) concentrations were determined in 10 eumenorrheic runners after supplementation with zinc (25 mg), vitamin E (400 IU), or placebo. Subjects ran at 65-70% of their VO2max, to exhaustion, on a treadmill during the follicular phase of their menstrual cycles over three cycles., Results: There were no significant differences associated with supplementation for any of the hormonal and metabolic measures. Exercise, however, significantly (P<0.05) increased plasma lactate, ACTH, prolactin, and catecholamine concentrations, all of which peaked immediately after exercise (POST). Plasma cortisol concentrations were significantly (P<0.05) elevated at POST, and a further increase was noted 1 h after exercise. IL-6 concentrations rose linearly throughout exercise and reached peak values at POST. Exercise-induced changes were transient in that all measures returned to baseline within 24 h., Conclusions: Acute supplementation with zinc or vitamin E did not influence the effects of exhaustive running on metabolic and endocrine responses in women. The effects of chronic supplementation on neuroendocrine responses to exercise remain to be determined.

Interleukin-6 (IL-6) is produced in response to inflammatory and noninflammatory stress and acts as the principal regulator of the acute-phase protein response. IL-6 stimulates the hypothalamic-pituitary-adrenal axis and may be involved in the thyroid function abnormalities observed in nonthyroidal illness (NTI). This study examined the effects of single-dose IL-6 (3 microg/kg subcutaneously [s.c.]) in healthy human subjects: 19 received IL-6 and 13 received control saline injection. The dose of IL-6 was chosen on the basis of previous studies indicating that the peak IL-6 level after injection reaches concentrations observed with major stress such as abdominal surgery. Plasma levels of thyrotropin (TSH), free thyroxine (FT4), total T4, 3,5-3'-L-triiodothyronine (T3), 3,3'-5'-L-triiodothyronine or reverse T3 (rT3), and thyroxine-binding globulin (TBG) were measured over a 4-hour period and 24 hours after IL-6 injection. Plasma TSH levels were 27% lower 240 minutes after IL-6 relative to control levels (0.93 +/- 0.10 v 1.28 +/- 0.18 mIU/mL, P = .001), but recovered by 24 hours. Plasma FT4 was elevated at 240 minutes compared with the controls (1.16 +/- 0.04 v 1.03 +/- 0.03 ng/dL, P = .0002). T4 levels were also elevated at 240 minutes (7.8 +/- 0.36 v 7.05 +/- 0.37 microg/dL, P = .0003). TBG levels were not significantly changed at this time point. At 24 hours, T3 levels were 19% lower than the control values (87.6 +/- 5.1 v 108.5 +/- 5.4 ng/dL, P = .0002); plasma rT3 levels were elevated by 21% compared with control levels (30.6 +/- 1.7 v 24.3 +/- 1.3 ng/dL, P = .002), while FT4 levels returned to normal. The changes in T3/rT3 levels were reminiscent of the pattern observed in NTI that may be due to inhibition of type-1 5'-deiodinase. Cortisol levels were greatly elevated after IL-6 compared with control values; peak levels were observed 120 minutes after IL-6 injection (28.7 +/- 1.6 v 9.5 +/- 1.0 ng/dL, P < .0001). This elevation in cortisol may have contributed to the suppression of TSH levels and inhibition of type-1 5'-deiodinase activity. Alternatively, IL-6 may have suppressed TSH secretion via a direct suprapituitary action. The elevation of T4 and FT4 levels may have been due to inhibition of T4 degradation at the liver and/or by direct action of IL-6 on the thyroid gland. These findings demonstrate the potent effects of IL-6 on thyroid hormone metabolism in healthy individuals, and suggest that IL-6 may act directly or indirectly at two or more sites on thyroid hormone secretion and metabolism.

IL-12 and IL-10, respectively, stimulate Th1 and Th2 immune responses. The development of some allergic reactions, infections, and tumors are associated with excessive histamine production and a shift toward Th2 responses. Here we address the possibility that this association is causally linked, at least in part, to modulation of IL-12 and IL-10 production by histamine. We report that histamine dose-dependently inhibited the secretion of human IL-12 (p70) and increased the production of IL-10 in LPS-stimulated whole blood cultures. These effects of histamine were antagonized by cimetidine, an H2 receptor antagonist, but not by selective H1 and H3 receptor blockers, and were mimicked by an H2 receptor agonist. The effects of histamine on IL-12 and IL-10 secretion were independent of endogenous secretion of IL-10 or exogenous addition of IL-12, while Ro 20-1724, a phosphodiesterase inhibitor, potentiated the effects of histamine on IL-12 and IL-10 production, implicating cAMP in its actions. Similar modulatory effects of histamine on IL-12 and IL-10 production, which were reversed by the H2 antagonist cimetidine, were observed in PBMC and isolated monocytes stimulated by Staphylococcus aureus Cowan strain 1 and LPS, respectively. Thus, histamine, via stimulation of H2 receptors on peripheral monocytes and subsequent elevation of cAMP, suppresses IL-12 and stimulates IL-10 secretion, changes that may result in a shift of Th1/Th2 balance toward Th2-dominance. This may represent a novel mechanism by which excessive secretion of histamine potentiates Th2-mediated allergic reactions and contributes to the development of certain infections and tumors normally eliminated by Th1-dependent immune mechanisms.

Cushing's syndrome (CS) may be difficult to distinguish from pseudo-Cushing states (PCS) based on physical findings or urinary glucocorticoid excretion. As the lack of diurnal variation in serum cortisol is characteristic of CS, we studied whether diurnal cortisol determinations could discriminate CS from PCS. Two hundred and sixty-three patients were evaluated: 240 had CS, and 23 had PCS. Urine was collected for 24 h for measurement of cortisol and 17-hydroxycorticosteroids (17OHCS). Blood was drawn at 2300, 2330, 0000, 0030, and 0100 h and at 0600, 0630, 0700, 0730, and 0800 h the next morning for serum cortisol determination. The main outcome measure was the sensitivity of these parameters for the diagnosis of CS at 100% specificity. A midnight cortisol value greater than 7.5 microg/dL correctly identified 225 of 234 patients with CS and all PCS patients. This sensitivity (96%) was superior to that obtained for any other measure, including urinary cortisol (45%), 17OHCS (22%), any other individual cortisol time point (10-92%), the morning (23%) or the evening (93%) cortisol mean, and the ratio (11%) of morning to evening values. We conclude that at 100% specificity, a single serum cortisol value above 7.5 microg/dL at midnight discriminates CS from PCS with higher sensitivity than 24-h urinary cortisol or 17OHCS, or other individual or combined measures of serum cortisol.

Interleukin-6, an inflammatory cytokine, is characterized by pleiotropy and redundancy of action. Apart from its hematologic, immune, and hepatic effects, it has many endocrine and metabolic actions. Specifically, it is a potent stimulator of the hypothalamic-pituitary-adrenal axis and is under the tonic negative control of glucocorticoids. It acutely stimulates the secretion of growth hormone, inhibits thyroid-stimulating hormone secretion, and decreases serum lipid concentrations. Furthermore, it is secreted during stress and is positively controlled by catecholamines. Administration of interleukin-6 results in fever, anorexia, and fatigue. Elevated levels of circulating interleukin-6 have been seen in the steroid withdrawal syndrome and in the severe inflammatory, infectious, and traumatic states potentially associated with the inappropriate secretion of vasopressin. Levels of circulating interleukin-6 are also elevated in several inflammatory diseases, such as rheumatoid arthritis. Interleukin-6 is negatively controlled by estrogens and androgens, and it plays a central role in the pathogenesis of the osteoporosis seen in conditions characterized by increased bone resorption, such as sex-steroid deficiency and hyperparathyroidism. Overproduction of interleukin-6 may contribute to illness during aging and chronic stress. Finally, administration of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis.

Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of continued fasting, decreased slightly over time. By 60 min after the 3 higher IL-6 doses, however, the decline in fasting blood glucose was arrested, and glucose levels increased in a dose-dependent fashion. The concurrent levels of plasma insulin and C-peptide were not affected by any IL-6 dose. In contrast, IL-6 caused significant increases in plasma glucagon levels, which peaked between 120 and 150 min after the IL-6 injection. In conclusion, sc IL-6 administration induced dose-dependent increases in fasting blood glucose, probably by stimulating glucagon release and other counteregulatory hormones and/or by inducing peripheral resistance to insulin action.

To assess the association of the overall amount of rapid eye movement (REM) sleep and the activities of the hypothalamic-pituitary-adrenal axis and sympathetic system, we performed polysomnography and measured 24-h urinary free cortisol and catecholamine excretion in 21 healthy adults. After an adaptation night, each subject was recorded in the sleep laboratory for 3 consecutive nights while 24-h urine specimens were collected. Urinary free cortisol, epinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid levels were significantly and positively correlated with the average values of percent REM sleep (P < 0.05). There were no correlations between hormone values and REM latency, other variables of REM distribution, or REM density, an index of phasic activity during REM sleep. The positive correlations between stress system activity and REM sleep are consistent with hormonal and sleep alterations in melancholic depression, a state characterized by increased cortisol and catecholamine secretion.

Interleukin-6 (IL-6), the main circulating cytokine, is putatively a major mediator of the effects of the immune system on several endocrine axes and intermediate metabolism. We performed dose-response studies of recombinant human IL-6 on pituitary hormone secretion in 15 healthy male volunteers, using 5 single, escalating subcutaneous doses of IL-6 (0.1, 0.3, 1.0, 3.0 and 10.0 micrograms/kg body weight), each in 3 volunteers. We measured resting metabolic rate (RMR) with indirect calorimetry and plasma anterior pituitary hormones and vasopressin (AVP) at baseline and half-hourly over 4 h after the injection. All doses examined were tolerated well and produced no significant adverse effects. Dose-dependent RMR increases were observed in response to the 3.0- and 10.0-microgram/kg doses of IL-6, beginning at 60 min and slowly peaking between 180 and 240 min. Plasma adrenocorticotropic-hormone concentrations increased dramatically and dose-dependently in all the patients who received the 3.0- and 10.0-microgram/kg doses of IL-6, respectively, peaking to 150 and 255 pg/ml at 60 min, and slowly returning to normal by 4 h. Corresponding plasma cortisol levels peaked dose-dependently between 90 and 150 min, but remained elevated throughout the sampling period. In contrast, the growth hormone (GH) dose-response was bell-shaped, with maximum (approximately 100-fold) stimulation achieved by 3.0 micrograms/kg IL-6. Prolactin (PRL) showed a similar but less pronounced response pattern. Thyroid-stimulating hormone (TSH) dose-dependently and progressively decreased over the 240 min, while gonadotropins showed no clear-cut changes. In conclusion, subcutaneous IL-6 administration induced synchronized dose-dependent increases in the RMR and hypothalamic-pituitary-adrenal axis activity, suggesting that hypothalamic corticotropin-releasing hormone may mediate both of these functions in humans. IL-6 also acutely stimulated GH and PRL secretion and suppressed TSH secretion. The dose of 3.0 micrograms/kg could be used safely in the study of patients with disturbances of the hypothalamic-pituitary unit or of thermogenesis.

Excessive daytime sleepiness (EDS) and fatigue are frequent symptoms in the general population and the chief complaint of the majority of patients at Sleep Disorders Centers. There is evidence that the inflammatory cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and IL-6 are involved in physiological sleep regulation and that their administration to humans is associated with sleepiness and fatigue. To explore whether plasma levels of TNF alpha, IL-1beta, and IL-6 are elevated in patients with EDS, we measured morning plasma levels of TNF alpha, IL-1beta, and IL-6 in 12 sleep apneics, 11 narcoleptics, 8 idiopathic hypersomniacs, and 10 normal controls. TNF alpha was significantly elevated in sleep apneics and narcoleptics compared to that in normal controls (P < 0.001 and P = 0.001, respectively). Plasma IL-1beta concentrations were not different between sleep disorder patients and controls, whereas IL-6 was markedly and significantly elevated in sleep apneics compared to that in normal controls (P = 0.028). The primary factor influencing TNF alpha values was the degree of nocturnal sleep disturbance, whereas the primary determinant for IL-6 levels was the body mass index. Our findings suggest that TNF alpha and IL-6 might play a significant role in mediating sleepiness and fatigue in disorders of EDS in humans.

Interleukin-12 (IL-12) is a key inducer of differentiation of uncommitted T helper (TH) cells toward the TH1 phenotype, which regulates cellular immunity, whereas IL-10 inhibits TH1 functions and potentiates TH2-regulated responses (i.e., humoral immunity). To examine the potential effects of stress on TH1/TH2 balance, we studied the ability of three prototype stress hormones-dexamethasone (a synthetic glucocorticoid) and the catecholamines norepinephrine and epinephrine-to alter the production of IL-12 (p70) and IL-10 induced by bacterial lipopolysaccharide (LPS) in human whole blood. Dexamethasone inhibited LPS-induced bioactive IL-12 production in a dose-dependent fashion and at physiologically relevant concentrations; it had no effect on IL-10 secretion. The glucocorticoid-induced reduction of IL-12 production was antagonized by RU 486, a glucocorticoid-receptor antagonist, suggesting that it was mediated by the glucocorticoid receptor. Norepinephrine and epinephrine also suppressed IL-12 production in a dose-dependent fashion and at physiological concentrations; both catecholamines, however, dose-dependently increased the production of IL-10. The effects of either catecholamine on IL-12 or IL-10 secretion were blocked completely by propranolol, a beta-adrenoreceptor antagonist, indicating that they were mediated by the beta-adrenergic receptor. These findings suggest that the central nervous system may regulate IL-12 and IL-10 secretion and, hence, TH1/TH2 balance via the peripheral end-effectors of the stress system. Thus, stress may cause a selective suppression of TH1 functions and a shift toward a TH2 cytokine pattern rather than generalized TH suppression. The TH1-to-TH2 shift may be responsible for the stress-induced susceptibility of the organism to certain infections. Through the same or a reciprocal mechanism, states associated with chronic hyperactivity or hypoactivity of the stress system might influence the susceptibility of an individual to certain autoimmune, allergic, infectious, or neoplastic diseases.

In experimental animals, stress and catecholamines stimulate endogenous interleukin-6 (IL-6) secretion, whereas glucocorticoids inhibit it. To examine whether physical stress alters the secretion of IL-6 in humans, and to what extent this is correlated with catecholamines and modified by glucocorticoids, we performed high-intensity treadmill exercise test runs on 15 male volunteers, in a double-blind crossover design, after pretreatment with placebo, hydrocortisone, or dexamethasone. Plasma epinephrine and norepinephrine concentrations peaked 15 min after the start of exercise, whereas plasma IL-6 concentrations peaked twice, 15 min and 45 min after the onset of the test run. There was no difference in either the epinephrine or norepinephrine peaks among the three treatments, but the net area under the curve for IL-6 was smaller after hydrocortisone or dexamethasone than after placebo and smaller after dexamethasone than after hydrocortisone. A positive correlation was observed between peak plasma epinephrine or norepinephrine and IL-6 levels at 15 min. These findings suggest that IL-6 secretion is stimulated during exercise, possibly by catecholamines, whereas exogenous glucocorticoids attenuate this effect without affecting the catecholamine levels.

The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 are secreted at inflammatory sites in tandem and play a crucial role in the inflammatory and wound-healing processes. All three cytokines are potent activators of the hypothalamic-pituitary-adrenal axis, through which they restrain inflammation, whereas IL-6 itself plays a role in the termination of inflammation as well. To test the hypothesis that endogenous glucocorticoids exert a negative tonic effect on the secretion of these cytokines, we studied 17 patients with Cushing's disease and 2 patients with primary adrenal Cushing's syndrome before and after surgery. Plasma TNF alpha, IL-1 beta and IL-6 were measured before surgery, while the patients were hypercortisolemic; on postoperative day 4 or 5, when they were hypocortisolemic; and on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. During severe hypocortisolism, on postoperative day 4 or 5, plasma IL-6 levels rose significantly, compared to the preoperative values (P < 0.001). During the same interval, TNF alpha and IL-1 beta also rose, albeit to a lesser extent. Over the same interval, patients with severe hypocortisolism experienced temperature elevation, fatigue, somnolence, flu-like symptoms, and anorexia, symptoms that have been traditionally attributed to glucocorticoid deficiency; these were also experienced by subjects that received recombinant human IL-6. There was no postoperative increase in any of the cytokines studied in the patients who were not hypocortisolemic after surgery and who also lacked the corresponding symptomatology. Plasma IL-6 concentrations decreased significantly, albeit not to normal levels, in the hypocortisolemic group of patients on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. We conclude that the peripheral levels of IL-6 and to a lesser extent, those of TNF alpha and IL-1 beta are tonically inhibited by basal levels of glucocorticoids. The increased IL-6 production that occurs when cortisol levels fall might explain the symptomatology of acute glucocorticoid deficiency.

Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31 and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at theta = 0.03 for the marker CA-2 (odds in favor of linkage 10(6):1. The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias.

In the recent past, we have seen novel information on the bidirectional interactions between the endocrine and immune systems. Thus, the central nervous system, through the hypothalamic-pituitary-adrenal axis and the peripheral autonomic and sensory systems, influences the quantity and the quality of the immune and inflammatory reactions. The latter, on the other hand, regulates the activity of the endocrine system by influencing its central and peripheral components. The reciprocal effects of the two systems on each other are adaptive and help survival of the self and species. Dysregulation or chronic alterations of the endocrine system can, however, increase the susceptibility of individuals to various diseases or lead to frank pathologic states.

Excess endogenous glucocorticoid production, whether ACTH-dependent or ACTH-independent, results in the classic clinical and biochemical picture of Cushing's syndrome. The diagnosis requires demonstration of an increased cortisol secretion rate, best achieved using determination of urinary free cortisol as an index. In mild cases, distinction from the hypercortisolism of pseudo-Cushing states may prove difficult. If the physician is in doubt, a dexamethasone/CRH test should be performed. Primary adrenal Cushing's syndrome can be diagnosed on the basis of undetectable plasma ACTH and the results of adrenal imaging procedures. ACTH-dependent Cushing's syndrome can be differentiated using an oCRH test and imaging procedures. In the presence of a discrete pituitary lesion on imaging, a standard oCRH test with results consistent with such a lesion is sufficient to proceed to transsphenoidal surgery. In the absence of such a lesion or if the oCRH test is equivocal, simultaneous BIPSS with oCRH administration should be performed to distinguish between a pituitary or ectopic source. Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In the 5% of cases with Cushing's disease in whom transsphenoidal surgery fails and in the 5% of cases in whom the disease recurs, repeat transsphenoidal surgery or radiation therapy in association with mitotane treatment are reasonable alternatives. Bilateral adrenalectomy effectively cures hypercortisolism if resection of the ACTH-secreting tumour is unsuccessful and radiation/medical therapy fails.

As some patients with beta-thalassaemia manifested neurological signs, clinical and electrophysiological investigations were carried out on 53 thalassaemic patients and 29 healthy control subjects. Twenty per cent of the patients showed clinical and electrophysiological findings of a mild peripheral sensorimotor neuropathy, mainly of the lower limbs. The clinical symptoms were numbness, pins and needles sensations, muscular cramps, myalgia and muscle weakness. The electrophysiological abnormalities were manifested by decreased motor conduction velocity (MCV) and prolonged F-wave latencies of the tibial and the peroneal nerves. Borderline increase in the latencies of the sensory potentials of the median nerve was also observed. The electromyographic findings of the patients with diminished MCVs were compatible with a predominantly motor peripheral neuropathy. This neuropathy appears during the second and third decade of life.