Cecilia Mattsson

Primary aldosteronism: diagnostic and treatment strategies

Primary aldosteronism is caused by bilateral idiopathic hyperplasia in approximately two-thirds of cases and aldosterone-producing adenoma in one-third. Most patients with primary aldosteronism are normokalemic. In the clinical setting of normokalemic hypertension, patients who have resistant hypertension and hypertensive patients with a family history atypical for polygenic hypertension should be tested for primary aldosteronism. The ratio of plasma aldosterone concentration to plasma renin activity has been generally accepted as a first-line case-finding test. If a patient has an increased ratio, autonomous aldosterone production must be confirmed with an aldosterone suppression test. Once primary aldosteronism is confirmed, the subtype needs to be determined to guide treatment. The initial test in subtype evaluation is CT imaging of the adrenal glands. If surgical treatment is considered, adrenal vein sampling is the most accurate method for distinguishing between unilateral and bilateral adrenal aldosterone production. Optimal treatment for aldosterone-producing adenoma or unilateral hyperplasia is unilateral laparoscopic adrenalectomy. The idiopathic bilateral hyperplasia and glucocorticoid-remediable aldosteronism subtypes should be treated pharmacologically. All patients treated pharmacologically should receive a mineralocorticoid receptor antagonist, a drug type that has been shown to block the toxic effects of aldosterone on nonepithelial tissues.

Myringosclerosis Caused by Increased Oxygen Concentration in Traumatized Tympanic Membranes Experimental Study

The purpose of this study was to elucidate possible relationships between the oxygen concentration of the middle ear cavity and the development of myringosclerosis. Three groups of rats with myringotomized tympanic membranes were exposed to different oxygen concentrations of 10%, 15%, and 40%, respectively, for 1 week. A fourth group was kept in ambient air. Two other groups of rats with myringotomized and intubated tympanic membranes were exposed to oxygen concentrations of 10% and 40%, respectively, for the same period of time. Otomicroscopically, all hyperoxic animals had more numerous myringosclerotic lesions compared with the ambient air group, and also displayed a pronounced hyperplasia of the keratinizing epithelium around the perforation border. By contrast, the hypoxic animals showed less pronounced myringosclerotic lesions or even completely lacked them. It is inferred that an increased oxygen concentration in the middle ear cavity will increase the likelihood of myringosclerotic deposits. The mechanism involved could be related to the formation of oxygen radicals.

Application of Oxygen Free Radical Scavengers to Diminish the Occurrence of Myringosclerosis

The present study was designed to establish whether or not an increased production of oxygen-derived free radicals is involved in the causation of myringosclerosis. Sclerotic lesions in the tympanic membrane were experimentally elicited by keeping rats with perforated tympanic membranes in an atmosphere containing roughly 40% oxygen. The animals were treated daily with a solution containing either copper zinc-supcroxide dismutase plus catalase, deferoxamine, or copper sulfate plus iron chloride, applied to the traumatized area. After 1 week the extension of myringosclerotic plaques was determined otomicroscopically. The pars tensa and pars flaccida were then dissected free and prepared for light microscopic studies. The results showed that treatment with copper zinc-superoxide dismutase plus catalase and deferoxamine inhibited or reduced the development of myringosclerosis, whereas die ears treated with copper sulfate plus iron chloride appeared unaffected. Consequently, the findings support the hypothesis that the formation of oxygen free radicals contributes significantly to the development of myringosclerosis.

Combined Receptor Antagonist Stimulation of the Hypothalamic-Pituitary-Adrenal Axis Test Identifies Impaired Negative Feedback Sensitivity to Cortisol in Obese Men

CONTEXT Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline, and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR). OBJECTIVE The objective of the study was to use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity. DESIGN This was a double-blind, placebo-controlled, randomized, crossover study. SETTING The study was conducted at a clinical research facility. PARTICIPANTS Participants included 15 lean (body mass index 22.0 +/- 1.6 kg/m(2)) and 16 overweight/obese (body mass index 30.1 +/- 3.5 kg/m(2)) men. INTERVENTION Subjects attended on four occasions for blood and saliva sampling every 30 min between 1800 and 2200 h. At 1100 and 1600 h before visits, subjects took 200 mg spironolactone, 400 mg RU38486, 200 mg spironolactone + 400 mg RU38486, or placebo orally. MAIN OUTCOME MEASURES Serum cortisol levels after drug or placebo were measured. RESULTS Cortisol levels did not differ between lean and obese after placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by less than 50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, more so in lean than obese men [2.9- (0.3) vs. 2.2 (0.3)-fold elevation, P = 0.002]. CONCLUSIONS Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.

Topical Ascorbic Acid Reduces Myringosclerosis in Perforated Tympanic Membranes a Study in the Rat

Myringosclerosis, a common finding after myringotomy, has been recently associated with an increased production of oxygen free radicals. Ascorbic acids proposed actions include collagen synthesis, antioxidation, and free radical scavenging. The effects of topical ascorbic acid on healing tympanic membranes were studied. Particular attention was given to detecting the presence of myringosclerosis. Twelve Sprague-Dawley rats were bilaterally myringotomized. Their ears were randomized into group A, which received topical ascorbic acid in Gelfoam, group B, which received topical saline solution in Gelfoam, and group C, which received no treatment. The tympanic membranes were harvested on day 13, after routine otomicroscopy. Under light microscopy, the connective tissue layer of the untouched side of the pars tensa was distinctly thicker in group A than in group B or group C. At this level, the extent of sclerotic lesions was significantly less in the ascorbic acid—treated group. It is inferred that topical ascorbic acid reduces the occurrence of myringosclerosis following tympanic membrane perforations in the rat.

Myringosclerosis Develops within 9 h of Myringotomy

The aim of the present experimental study was to elucidate the temporal development of myringosclerosis. Twenty-four Sprague-Dawley rats were myringotomized bilaterally. At 3, 6, 9, 12, 18, 24, 30, 36, 48, 60, 72 and 84 h after the myringotomy, 2 animals at each time were examined otomicroscopically and thereafter sacrificed. The pars flaccida and pars tensa were excised and prepared for light- and electron-microscopic studies. Otomicroscopically, myringosclerosis was visible in the pars tensa 24 h after myringotomy, whereas no sclerotic lesions were noted in the pars flaccida. Histologically, sclerotic lesions were present in the pars tensa and pars flaccida 9 and 12 h, respectively, after myringotomy. The pars flaccida responds promptly with an inflammatory reaction characterized by abundant macrophages. Myringosclerosis develops promptly after myringotomy and its establishment is related to an inflammatory reaction.

Tissue-Specific Increases in 11β-Hydroxysteroid Dehydrogenase Type 1 in Normal Weight Postmenopausal Women

With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11βHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11βHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11βHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5α-tetrahydrocortisol+5β-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11βHSD1 activity. Postmenopausal women had higher 11βHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11βHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11βHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.

Myringotomy : A prerequisite for the development of myringosclerosis?

Streptococcus pneumoniae was inoculated into the left middle‐ear cavity in two groups of rats, resulting in purulent otitis media. After 3 days, one group of infected animals and a third group of noninfected animals were subjected to left‐sided myringotomy. The tympanic membranes were examined both otomicroscopically and histologically 1 and 3 months later. On otomicroscopic examination the noninfected myringotomized animals had developed extensive myringosclerotic lesions, whereas only minimal sclerotic deposits were noted in the myringotomized animals with acute otitis media (AOM). On histologic examination both the noninfected myringotomized animals and the myringotomized animals with AOM were similar in the frequency and extension of sclerotic lesions in the tympanic membrane. The nonmyringotomized rats with AOM were free of sclerotic lesions, except for minor changes found in one animal.

Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling

The glucocorticoid activating enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1) is of major interest in obesity‐related morbidity. Alterations in tissue‐specific cortisol levels may influence lipogenetic and gluco/glyceroneogenetic pathways in fat and liver. We analyzed the expression and activity of 11βHSD1 as well as the expression of phosphoenolpyruvate carboxykinase (PEPCK), sterol regulatory element binding protein (SREBP), and fatty acid synthase (FAS) in adipose and liver and investigated putative associations between 11βHSD1 and energy metabolism genes. A total of 33 obese women (mean BMI 44.6) undergoing gastric bypass surgery were enrolled. Subcutaneous adipose tissue (SAT), omental fat (omental adipose tissue (OmAT)), and liver biopsies were collected during the surgery. 11βHSD1 gene expression was higher in SAT vs. OmAT (P = 0.013), whereas the activity was higher in OmAT (P = 0.009). The SAT 11βHSD1 correlated with waist circumference (P = 0.045) and was an independent predictor for the OmAT area in a linear regression model. Energy metabolism genes had AT depot–specific expression; higher leptin and SREBP in SAT than OmAT, but higher PEPCK in OmAT than SAT. The expression of 11βHSD1 correlated with PEPCK in both AT depots (P = 0.05 for SAT and P = 0.0001 for OmAT). Hepatic 11βHSD1 activity correlated negatively with abdominal adipose area (P = 0.002) and expression positively with PEPCK (P = 0.003). In human obesity, glucocorticoid regeneration in the SAT is associated with central fat accumulation indicating that the importance of this specific fat depot is underestimated. Central fat accumulation is negatively associated with hepatic 11βHSD1 activity. A disturbance in peripheral glucocorticoid metabolism is associated with changes in genes involved in fatty acid (FA) recycling in adipose tissue (AT).

Cognitive-behavioural stress management does not improve biological cardiovascular risk indicators in women with ischaemic heart disease : a randomized-controlled trial

Objectives.  Psychosocial factors, such as stress and vital exhaustion, are associated with an increased risk of cardiovascular events, and women report more psychosocial ill‐being after an acute myocardial infarction than men. We have earlier shown that a cognitive‐behavioural intervention in women with ischaemic heart disease (IHD) improved psychosocial well‐being. In the present study, we tested the hypothesis that the improvement in psychosocial well‐being is associated with an improvement in biochemical indicators of cardiovascular risk.