Revisiting Cushing Syndrome, Milder Forms Are Now a Common Occurrence: A Single-Center Cohort of 76 Subjects.

OBJECTIVE: Guidelines recommend initiating testing for Cushing syndrome (CS) based on strong clinical suspicion. Our recent experience suggests the absence of classical stigmata in the majority of patients with CS. We aimed to confirm this premise by revisiting the clinical features of this syndrome in a modern series of patients from a single center. METHODS: Computerized records of subjects with CS diagnosed at Tel Aviv Sourasky Medical Center between 2000 and 2018 were reviewed. A Cushing inventory score, including all clinical components of the syndrome, was computed for each subject. Data were compared between the subtypes and evaluated in light of those in the literature. RESULTS: Of the 76 subjects with CS (60 women/16 men), 49 (64.5%) had Cushing disease; 16 (21.1%), adrenal adenoma; 7 (9.2%), adrenocortical carcinoma; and 4 (5.3%), ectopic adrenocorticotropic hormone secretion. In only 15 of 74 cases (20.3%), clinical suspicion of CS led to testing. Catabolic signs of CS were present in less than 30% of cases. The most common symptom was weight gain (52/67, 77.6%), and the most common comorbidity was hypertension (47/76, 61.8%). There were no differences in the Cushing inventory score between the subtypes. Signs, symptoms, and comorbidities were all significantly less common than in the classical syndrome. CONCLUSIONS: Modern-day CS presents with subtler features than in the past. Initiating a testing cascade solely based on a strong clinical suspicion may lead to underdiagnosis of milder cases. A concerted effort to devise cost-efficient testing for CS in the current era is needed.

The effect of circuit resistance training, empagliflozin or "vegeterranean diet" on physical and metabolic function in older subjects with type 2 diabetes: a study protocol for a randomized control trial (CEV-65 trial).

BACKGROUND: Treatment of the older diabetic individual comprises a therapeutic challenge. Currently little scientific evidence exists depicting the best approach to type 2 diabetes treatment in this growing sub-population of patients. The purpose of this study is to assess the effects of a modified plant-based Mediterranean diet ("vegeterranean" diet), circuit resistance training (CRT) and empagliflozin, separately or in combination, on body composition and physical function in older subjects with type 2 diabetes. The rationale for this study is to assess three interventions associated with a negative energy/caloric balance (increased caloric use in exercise, caloric restriction in the "vegeterranean" diet and caloric wasting by glycosuria with empagliflozin), their interaction and effect on body composition and physical function. METHODS: One hundred and twenty men and women ≥65 years of age with type 2 diabetes, and low levels of physical activity will be randomized (1:1:1 manner, gender stratified) for 10 weeks to one of 3 parallel arms: CRT consisting of 3 home sessions/week; ad-libitum plant-based Mediterranean diet (limited consumption of eggs, dairy and fish, avoidance of red meat and poultry) or empagliflozin 10 mg/day. After 10 weeks CRT will be added to the empagliflozin and diet arms for an additional 10 weeks. Allocation concealment and blinding of primary outcome assessors will be implemented. Efficacy will be determined by assessment of lean body mass, body weight, frailty and functional status, sarcopenia, HbA1c and quality of life questionnaires. Safety will be evaluated by routine monitoring of adverse events. This study was approved by the Tel-Aviv Sourasky Medical Center Institutional Review Board. DISCUSSION: The combination and comparison of these diverse interventions to metabolic control may lead to better understanding of their mechanism of action with potential clinical implications in older individuals. Also, this study will provide evidence of the effectiveness of these interventions on delaying the progression from diabetes to sarcopenia and/or frailty. TRIAL REGISTRATION: ClinicalTrials.gov PRS: NCT03560375 . Last registration date (last update): 06/06/2018. The trial was a-priori registered before actual recruitment of subjects.

Liver and Steroid Hormones-Can a Touch of p53 Make a Difference?

The liver is the main metabolic organ in the body, serving as a significant hormonal secretory gland and functioning to maintain hormone balance and homeostasis. Steroid hormones regulate various biological pathways, mainly in the reproductive system and in many metabolic processes. The liver, as well as steroid hormones, contribute significantly, through functional intertwine, to homeostasis maintenance, and proper responses during stress. Malfunction of either has a significant impact on the other and may lead to severe liver diseases as well as to several endocrine syndromes. Thus, the regulation on liver functions as on steroid hormones levels and activities is well-controlled. p53, the well-known tumor suppressor gene, was recently found to regulate metabolism and general homeostasis processes, particularly within the liver. Moreover, p53 was shown to be involved in steroid hormones regulation. In this review, we discuss the bi-directional regulation of the liver and the steroid hormones pointing to p53 as a novel regulator in this axis. A comprehensive understanding of the molecular mechanisms of this axis may help to prevent and treat related disease, especially with the increasing exposure of the population to environmental steroid hormones and steroid hormone-based medication.

Human sex hormone-binding globulin does not provide metabolic protection against diet-induced obesity and dysglycemia in mice.

BACKGROUND: Sex hormone-binding globulin (SHBG) is the main transporter of sex hormones in most vertebrates. Low SHBG levels have been linked to increased risk for diabetes and metabolic syndrome. Polymorphisms of the SHBG gene linked to low SHBG protein levels also strongly predicted increased risk of type 2 diabetes, thus raising the possibility that SHBG may play a role in the pathogenesis of insulin resistance and diabetes. AIM: To examine whether expression of human SHBG in mice may ameliorate the development of diabetes and metabolic syndrome in response to a high-fat diet (HFD). METHODS: Transgene mice expressing a human SHBG transgene (SHBG+) (N = 10/11; males/females) and their wild type littermates (N = 12/8; males/females) were fed HFD for 4.5 months. RESULTS: HFD induced comparable obesity in control and SHBG+ mice. Male transgenes had higher muscle mass after 2-3.5 months HFD (0.43 ± 0.028 (n = 4) vs 0.38 ± 0.053 g (n = 7), P = 0.05). Fasting blood glucose, as well as insulin or HOMA-IR, was not different in transgenic vs wild-type males after 4-5 months HFD. Female transgenes had higher fasting glucose (152 ± 29 (n = 7) vs 115 ± 27 mg/dL, P = 0.01 (n = 8)), but mean insulin and HOMA-IR were not different. Likewise, insulin tolerance test and intra-peritoneal glucose tolerance test (GTT) were not different. Finally, SHBG+ mice were not different from controls in terms of liver enzymes, serum triglyceride levels and blood pressure. CONCLUSION: In mice with diet-induced obesity, human SHBG did not protect against development of obesity or dysglycemia.

Arterial properties in acromegaly: relation to disease activity and associated cardiovascular risk factors.

PURPOSE: Acromegaly is associated with increased cardiovascular morbidity and mortality when inadequately treated, which may be secondary to associated comorbidities or to direct IGF-1 effects on the cardiovascular system. By using a control group carefully matched for traditional cardiovascular risk factors, we aimed to assess the direct contribution of disease activity and IGF-1 levels to arterial damage as assessed by measurements of arterial stiffness and endothelial function. METHODS: Twenty-nine subjects with acromegaly (11 males, 52 ± 14 year; 15 active acromegaly) and 24 matched controls underwent evaluation of large and small artery compliance using applanation tonometry, pulse wave velocity (PWV), augmentation index (Alx), carotid ultrasonography intima-media thickness, (IMT) and flow-mediated dilatation (FMD). RESULTS: IGF-1 expressed as times the upper limit of the normal range (x ULN) was 2.2 ± 1.1 in patients with active disease versus 0.7 ± 0.2 in patients in remission. Irrespective of disease activity, FMD was lower in patients with acromegaly than in control subjects, (3.4 ± 2.7 % in active acromegaly, 4.4 ± 3.3 % in controlled acromegaly and 7.5 ± 3.8 % in controls; p = 0.004). There were no significant differences in PWV, Alx, and IMT between groups. A positive correlation was found between IGF-1× ULN and IMT (r = 0.4; P = 0.02). Asymmetric dimethylarginine (ADMA), a novel cardiovascular risk factor, was positively correlated to arterial stiffness (r = 0.46; p = 0.017) and negatively with small vessel compliance (r = -0.44, p = 0.02). CONCLUSIONS: Patients with acromegaly have significantly impaired endothelial function as assessed by FMD, but other tested vascular parameters were similar to a control group that was adequately matched for cardiovascular risk factors.

Effect of cyclic, low dose pyrimethamine treatment in patients with Late Onset Tay Sachs: an open label, extended pilot study.

BACKGROUND: Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of ß-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. METHODS: In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). RESULTS: HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. CONCLUSIONS: Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.

Hyperandrogenism is associated with earlier age of onset of idiopathic intracranial hypertension in women.

PURPOSE: Previous reports have connected between Idiopathic intracranial hypertension (IIH), obesity and different hormonal states. The aim of this study was to characterize the endocrine profile in women with IIH. METHODS: This is a data-based study of 51 IIH patients. We measured anthropometric parameters and assessed hormonal profile including cortisol, testosterone, bioavailable testosterone (BT), prolactin, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, insulin, aldosterone, estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Pearson or Spearman rank correlation for non-normally distributed variables were calculated to evaluate the relation among the anthropometric measurements: age, body mass index (BMI), waist and hip circumference and waist to hip ratio (WHR) with hormones levels. RESULTS: Seventy-eight percent of the cohort had WHR < 0.85 and 21.6% had a WHR > 0.85. Increased levels of testosterone, BT and androstenedione were all positively related to younger age of diagnosis in patient who are diagnosed after the age of 25 (R = -1.066, -0.845, -0.735, p < 0.001, =0.024, 0.019, respectively). No correlation was found between any of the analyzed hormones and the duration of the disease, WHR or BMI, except insulin, which was positively related to BMI (R = 0.461, p = 0.001). CONCLUSIONS: Increased levels of circulating androgens are associated with earlier age of onset of IIH in women.

Low achieved diastolic pressure in tightly controlled mid-older hypertensive subjects is associated with favorable arterial properties.

Low diastolic blood pressure (DBP) is commonly seen in well-controlled hypertensive subjects. We evaluated arterial properties in 53 hypertensive subjects with low on-treatment DBP (<70 mm Hg; LODP), 54 subjects with normal BP and spontaneously low DBP (SLDP), and 52 treated hypertensive subjects with DBP ≥70 mm Hg (HNDP). The two measures of large artery rigidity, pulse wave velocity and augmentation index, were similar in LODP and SLDP groups. In contrast, the HNDP group had higher PWV and the lowest large and small artery compliance in comparison with all other groups. Low on-treatment DBP is associated with favorable arterial properties in mid-older hypertensive patients.

Serum free cortisol as an ancillary tool in the interpretation of the low-dose 1-µg ACTH test.

OBJECTIVE: Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter-subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic-pituitary-adrenal (HPA) assessment in noncritically ill subjects is unknown. DESIGN, PATIENTS AND MEASUREMENTS: We performed the low-dose 1-µg ACTH test in 75 subjects referred for HPA evaluation. Serum TC was determined by a chemiluminescence method, and serum free cortisol was measured by the same method following equilibrium dialysis. In a subset of these patients, salivary cortisol was also measured. RESULTS: Mean fraction of free cortisol was 5·07 ± 4·08% (±SD; range 1·77-10·1%). Although no correlation was seen between TC and the fraction (%) of free serum cortisol, a positive correlation existed between baseline total and free cortisol (R = 0·539 P = 0·01), as well as between peak ACTH-stimulated total and free cortisol (R = 0·619; P = 0·01). There was no correlation between baseline salivary cortisol and serum free cortisol and between peak ACTH-stimulated salivary and serum free cortisol. Using the lowest attained peak serum free cortisol in subjects whose TC response to ACTH was normal (≥ 500 nM), the minimal 'pass' level for normal serum free cortisol response to 1 µg ACTH was set at 25·0 nM. Five of the 19 subjects showing subnormal TC response to 1 µg ACTH had normal serum free cortisol response. CONCLUSIONS: Discrepancies between the peak free and TC were noted mostly for subjects whose ACTH-stimulated TC peaked between 440 and 580 nm. At this range, the measurement of serum free cortisol allows further refinement of the assessment of borderline responses to 1-µg ACTH.

Pyrimethamine increases ß-hexosaminidase A activity in patients with Late Onset Tay Sachs.

OBJECTIVE: To assess whether or not pyrimethamine (PMT) can be used to enhance ß-hexosaminidase A activity (HexA) in subjects with Late Onset Tay Sachs (LOTS), we studied the effect of incremental doses of PMT in vivo in 9 LOTS patients carrying the αG269S/c.1278insTACT mutations. METHODS: PMT treatment was initiated at a dose of 6.25 mg, increasing gradually up to a maximal allowable dose of 75 mg daily at 4-6 weeks intervals for a total of up 10 months. Mean patients' age was 37.9±16.1 yrs (range 20-67 years). RESULTS: Lymphocyte HexA activity rose in all subjects, peaking at 78±30% over baseline activity (mean±SD; range 36-114%). The optimal PMT dose varied considerably, averaging at 30±24.1 mg (range-6.25-75 mg, daily). Further increase in PMT beyond the optimal dose was associated with gradual loss of effect on lymphocyte HexA. Improvement in speech was seen within several weeks in 4 out of 9 subjects, mostly paralleling the initial increment in HexA. Mood stabilization was also perceived in 3 subjects, but this was more difficult to assess due to the concomitant use of psychotropic/mood stabilizing agents. Reversible decline in motor activity manifesting predominantly in more frequent falls was seen in 3 subjects when the PMT dose was increased beyond the peak effect generating dose. CONCLUSIONS: PMT therapy can increase HexA activity in LOTS in vivo. Optimal doses should be tailored individually to avoid loss of biochemical effects. Clear cut neurological and psychiatric effects are difficult to discern at this time, mostly due to short term study follow up and large inter-individual variability.

Cardiovascular risk factors and arterial rigidity are similar in asymptomatic normocalcemic and hypercalcemic primary hyperparathyroidism.

OBJECTIVE: It is still uncertain whether mild primary hyperparathyroidism (PHPT) carries the same risk for increased cardiovascular (CV) morbidity as the more severe symptomatic form. In recent years, the even more subtle normocalcemic (NC) variant is being increasingly recognized. We sought to compare the prevalence of CV risk factors in patients with NC- and hypercalcemic (HC)-PHPT, and to examine whether they differ on a battery of non-invasive vascular parameters. DESIGN/SUBJECTS/METHODS: A retrospective study of two cohorts of patients with PHPT in a referral center: 32 subjects with NC-PHPT and 81 subjects with HC-PHPT, compared for the presence of clinical and biochemical risk factors, and CV morbidity. Non-invasive parameters of arterial stiffness (augmentation index; pulse wave velocity; and vascular compliance indices, C1 and C2) were extracted from the data of gender- and age-matched subsets of these patients, and were related to those of a group of matched control subjects. RESULTS: Despite a similar prevalence of hypertension (approximately 62%), hyperlipidemia (approximately 30%), and impaired glucose metabolism in both PHPT groups, CV or cerebrovascular disease was more common in the HC-PHPT group (24.7 vs 3.1%, P=0.007). Arterial stiffness parameters did not differ in the three groups, and were unrelated to serum calcium or parathyroid hormone concentration. CONCLUSIONS: NC-PHPT and HC-PHPT subjects exhibit similar high rates of traditional CV risk factors, and have comparable indices of arterial stiffness. The lower clinical CV morbidity observed with NC-PHPT remains unexplained, and requires confirmation. Until then, the CV risk associated with NC-PHPT should not be underestimated.

Effect of testosterone replacement therapy on arterial stiffness in older hypogonadal men.

OBJECTIVE: To assess arterial stiffness in a cohort of hypogonadal males and to investigate the effect of testosterone replacement therapy on arterial properties in this specific group. DESIGN: Eighteen male patients with untreated acquired hypogonadism due to either adult-onset idiopathic hypogonadotropic hypogonadism (n=9) or pituitary tumor (n=9) and 12 age-, sex, and weight-matched eugonadal healthy controls were recruited for the study. Arterial properties, plasma glucose, lipid profile, total, and bioavailable testosterone (BT) levels were measured in fasting state. In the hypogonadal subjects, the effect of transdermal testosterone replacement therapy on arterial properties was studied by repeat noninvasive measurements at baseline, as well as 48 h and 90 days following the initiation of treatment. METHODS: Arterial stiffness was evaluated using applanation tonometry and pulse wave analysis by three different standard devices that assess various measures of arterial stiffness: pulse wave velocity (PWV), augmentation index (AIx), and large/small artery compliance (C1 and C2). RESULTS: Age- and blood pressure-adjusted PWV was significantly higher in hypogonadal men (8.90+/-2.29 vs 6.78+/-1.16 m/s in the control group; P=0.025). Testosterone therapy increased BT level from 2.01+/-1.04 to 4.68+/-2.43 and 7.83+/-6.2 nmol/l after 48 h and 3 months respectively (P=0.001). PWV decreased from 8.9+/-2.29 to 8.24+/-1.39 and 8.25+/-1.82 m/s after 48 h and 3 months of treatment respectively (P=0.03). CONCLUSIONS: Male hypogonadism is associated with increased PWV, which is rapidly but incompletely ameliorated by normalization of circulating testosterone levels.

Diastolic pressure in type 2 diabetes: can target systolic pressure be reached without "diastolic hypotension"?

The practicality of vigorous lowering of systolic pressure in diabetes to <130 mmHg remains uncertain. Baseline blood pressure data from several recent trials indicate that, in diabetic subjects, there is nearly a fourfold excess in systolic pressure (the difference between baseline pressure and target pressure) over diastolic pressure with respect to the recommended systolic/diastolic target pressure of <130/80 mmHg. Additionally, systolic pressure was 2-3 mmHg higher and diastolic pressure was 1-3 mmHg lower in diabetic hypertensive than in nondiabetic hypertensive individuals, which adds approximately 4 mmHg to pulse pressure and also to the difference between the excess systolic and excess diastolic pressure. We attempted to force (titrate both systolic and excess diastolic pressure) systolic and diastolic blood pressure to <130/85 mmHg based on Joint National Committee VI guidelines in the setting of a clinical practice in 257 diabetic patients. Although target systolic pressure was attained in a third of this cohort, in 57% of the patients, the attained diastolic pressure was

Hypoadiponectinemia as a marker of adipocyte dysfunction--part II: the functional significance of low adiponectin secretion.

Low adiponectin expression is common in obesity and is tightly linked to insulin resistance and fat mass expansion. Whereas normal adipocytes offer effective metabolic buffering through well-controlled release and uptake of free fatty acids on demand, adipocyte expansion induced by caloric excess and modulated by genetic, regional, and systemic factors elicits major unfavorable changes in fat cell phenotypes. Large, dysfunctional adipocytes show increased lipolysis and enhanced expression and secretion of proinflammatory and pro-oxidative cytokines. Low adiponectin secretion is a hallmark of impaired adipocyte function; its secretion is inhibited by cytokines such as tumor necrosis factor alpha, interleukin 6 and plasminogen activator inhibitor 1 and by high oxidative stress induced by increased fatty acids that activate nicotinamide adenine dinucleotide phosphate-oxidase. The ensuing hypoadiponectinemia may aggravate insulin resistance and facilitate the evolution of type 2 diabetes. Only massive weight loss allows true and sustained recovery of normal fat cell function as reflected by adiponectin secretion.

Absence of peroxisome proliferator-activated receptor-alpha abolishes hypertension and attenuates atherosclerosis in the Tsukuba hypertensive mouse.

Peroxisome proliferator-activated receptor-alpha is widely distributed in the vasculature where it is believed to exert pleiotropic antiatherogenic effects. Its role in the regulation of blood pressure is still unresolved; however, some evidence suggests that it may affect the renin-angiotensin system. We investigated its role in angiotensin II-induced hypertension in the Tsukuba hypertensive mouse (THM). This is a model of hypertension and atherosclerosis because of high angiotensin II and aldosterone levels as a result of the transgenic expression of the entire human renin-angiotensin system. Making the THM animals deficient in Peroxisome proliferator-activated receptor-alpha (THM/PPARKO) totally abolished hypertension and myocardial hypertrophy. This was accompanied by a reduction in plasma human active renin in THM/PPARKO mice compared with THM animals from 3525+/-128 mU/L to 1910+/-750 mU/L (P<0.05) and by a normalization of serum aldosterone (1.6+/-0.29 nmol/L versus 3.4+/-0.69 nmol/L; P=0.003). In the THM/PPARKO mice, the extent of atherosclerosis at the aortic sinus after a 12-week period on an atherogenic diet was decreased by >80%. In addition, the spontaneous formation of foam cells from peritoneal macrophages, a blood pressure-independent event, was reduced by 92% in the THM/PPARKO mice, suggesting protection from the usual oxidative stress in these animals, possibly because of lower prevailing angiotensin II levels. Finally, chronic fenofibrate treatment further elevated blood pressure in THM animals but not in THM/PPARKO animals. Taken together, these data indicate that peroxisome proliferator-activated receptor-alpha may regulate the renin-angiotensin system. They raise the possibility that its activation may aggravate hypertension and hasten atherosclerosis in the context of an activated renin-angiotensin system.

Hypoadiponectinemia as a marker of adipocyte dysfunction -- Part I: the biology of adiponectin.

Adiponectin is the most abundantly secreted adipocyte-derived peptide hormone, possessing an array of antidiabetogenic and cardiovascular protective effects. Acting through 2 distinct membrane receptors, adiponectin receptors 1 and 2 (which utilize 5'-adenosine monophosphate-activated protein kinase phosphorylation, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha as key cell signaling elements), adiponectin increases hepatic and skeletal muscle sensitivity to insulin, enhances fatty acid oxidation, suppresses monocyte-endothelial interaction, supports endothelial cell growth, lowers blood pressure, and moderates adipose tissue growth. The secretion of adiponectin can be suppressed by adipose factors, which are turned on once fat cell mass increases, such as cytokines, adipose renin-angiotensin system, and increased oxidative stress. Inhibition of adiponectin secretion results in the loss of an array of mechanisms, which under normal conditions of fat cell homeostasis provide protection from insulin resistance, diabetes, and atherosclerosis.

Thyroid cysts: a new extra-adrenal site of aldosterone synthase expression and increased aldosterone content.

BACKGROUND: The rapid re-accumulation of fluid following aspiration of thyroid cystic lesions suggests that active transport of sodium and water may be involved in volume regulation of these lesions. In this study we address the possibility that aldosterone may take part in this process. SUBJECTS AND METHODS: Thirty-one patients (29 women and two men), with a mean age of 52.7 +/- 13.2 years (range: 27-77 years) underwent evaluation for thyroid nodules that had a sonographic cystic component. Cystic fluid obtained by FNA biopsy was sent for cytological examination and biochemical measurements. In 10 patients, material was collected for RNA extraction and determination of aldosterone synthase expression by RT-PCR amplification. RESULTS: All lesions were benign, cystic, colloid nodules. Cyst fluid aldosterone levels as measured by routine radioimmunoassay (RIA) were elevated above the normal plasma levels in all but five patients. Mean aldosterone levels were 27.1 +/- 22.9 ng/dl (SD) (range: 5.9-117.5 ng/dl). In contrast, cyst cortisol values were in the low, low normal serum range (6.2 +/- 2.9 microg/dl, range: 0.2-10.2 microg/dl). Sodium, chloride and potassium levels were 137 +/- 4.7 mEq/l, 98 +/- 5 mEq/l and 4.9 +/- 1.4 mEq/l, respectively. Plasma aldosterone levels were normal in all patients tested. To confirm these results, 12 samples were assayed after extraction and chromatography using a highly specific antibody. Cyst aldosterone levels in this group were elevated above the normal serum range in all but one patient (mean concentration: 24.5 +/- 14.6 ng/dl, range: 8.72-40.1 ng/dl). In this group, 18(OH)B levels were within the normal plasma range (12-55 ng/dl) in all but one patient (34.9 +/- 17 ng/dl). Furthermore, aldosterone synthase mRNA expression was found in aspirates of four of 10 patients. CONCLUSIONS: The increased aldosterone concentration and the presence of aldosterone synthase expression suggest that aldosterone may be locally produced and secreted in thyroid tissue. The pathophysiological implications of this finding remain to be established.

The 5 lipoxygenase system in the vasculature: emerging role in health and disease.

Activation of the 5 lipoygenase (5LO) system within the vascular bed requires the presence of several cell types with distinct transcellular cross-talk mechanisms, resulting in the generation of 5LO produced metabolites and increased expression of receptors for these metabolites in vascular cells. The key products in this system, the leukotriens LTB4, LTC4 and LTD4, are potent mediators of vascular inflammation initiated by white blood cells and sustained or propagated thereafter through amplified metabolite generation and direct effects in endothelial and vascular smooth muscle cells. Leukotrienes act to enhance cell permeability and increase oxidative stress, vascular smooth muscle cell migration and arterial tone. 5LO activation is highly regulated, and is apparently both model/species-specific and region-specific. 5LO activation is also linked to plaque progression, plaque stability, activation of matrix metalloproteinases, propensity to coronary and cerebrovascular events and the evolution of aortic aneurysms. Genetic variants in the 5LO activating protein are strongly linked to increased cardiovascular risk and may serve as useful markers for future therapy targeting down regulation of 5LO expression and activity as a means to combat cardiovascular disease.