Treatment of primary aldosteronism is associated with a reduction in the severity of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is known to commonly co-exist with primary aldosteronism (PA), but it is unknown if treatment of PA improves sleep apnoea parameters in these patients. We therefore aimed to determine whether specific medical or surgical treatment of PA improves OSA, as measured by the apnoea-hypopnoea index (AHI). We recruited patients undergoing diagnostic workup for PA if they had symptoms suggestive of OSA. Patients with confirmed PA underwent polysomnography (PSG) at baseline and again at least 3 months after specific treatment for PA. Of 34 patients with PA, 7 (21%) had no evidence of OSA (AHI <5), 9 (26%) had mild (AHI ⩾5 and <15), 8 (24%) moderate (AHI ⩾15 and <30) and 10 (29%) severe OSA (AHI ⩾30). Body mass index tertile, neck circumference and 24 h urinary sodium correlated with the AHI. Twenty patients had repeat PSG performed after treatment for PA (mineralocorticoid receptor antagonists in 13 with bilateral PA and adrenalectomy in 7 with unilateral PA). In this group the median (s.d.) AHI reduced from 22.5 (14.7) to 12.3 (12.1) (P=0.02). Neck circumference reduced with PA treatment (41.6 vs 41.2 cm, P=0.012). OSA is common in patients with primary aldosteronism and may improve with specific therapy for this disease. Aldosterone and sodium-mediated fluid retention in the upper airways and neck region may be a potential mechanism for this relationship.

Salt, aldosterone and hypertension.

Clinical studies have shown that aldosterone and salt are independently related to hypertension, cardiovascular morbidity and mortality. More recently, studies in humans have demonstrated that, similarly to animals, endogenous aldosterone and dietary salt intake have not only separate, but also combined effects to accelerate target-organ deterioration. The aldosterone-salt interaction has important clinical implications, because combined effects of both can be minimized, if not avoided, by reducing salt intake. This interaction could also be interrupted by blocking the effects of aldosterone, with use of mineralocorticoid receptor antagonists, or by reducing aldosterone effects by adrenalectomy, in patients with aldosterone producing adenoma. Furthermore, aldosterone reduction or blockade may reduce salt appetite.

Factors affecting the aldosterone/renin ratio.

Although the aldosterone/renin ratio (ARR) is the most reliable screening test for primary aldo-steronism, false positives and negatives occur. Dietary salt restriction, concomitant malignant or renovascular hypertension, pregnancy and treatment with diuretics (including spironolactone), dihydropyridine calcium blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor antagonists can produce false negatives by stimulating renin. We recently reported selective serotonin reuptake inhibitors lower the ratio. Because potassium regulates aldosterone, uncorrected hypokalemia can lead to false negatives. Beta-blockers, alpha-methyldopa, clonidine, and nonsteroidal anti-inflammatory drugs suppress renin, raising the ARR with potential for false positives. False positives may occur in patients with renal dysfunction or advancing age. We recently showed that (1) females have higher ratios than males, and (2) false positive ratios can occur during the luteal menstrual phase and while taking an oral ethynylestradiol/drospirenone (but not implanted subdermal etonogestrel) contraceptive, but only if calculated using direct renin concentration and not plasma renin activity. Where feasible, diuretics should be ceased at least 6 weeks and other interfering medications at least 2 before ARR measurement, substituting noninterfering agents (e. g., verapamil slow-release±hydralazine and prazosin or doxazosin) were required. Hypokalemia should be corrected and a liberal salt diet encouraged. Collecting blood midmorning from seated patients following 2-4 h upright posture improves sensitivity. The ARR is a screening test only and should be repeated once or more before deciding whether to proceed to confirmatory suppression testing. Liquid chromatography-tandem mass spectrometry aldosterone assays represent a major advance towards addressing inaccuracies inherent in other available methods.

Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II.

Familial hyperaldosteronism type II (FH-II) is an inherited form of hyperaldosteronism associated with hypertension in most patients. The mutations that cause FH-II are unknown, but linkage analysis has mapped them to chromosome 7p22. As FH-II is clinically indistinguishable from sporadic primary aldosteronism, a common and treatable condition, unravelling the cause of FH-II has important implications for these sporadic cases. To investigate whether FH-II is caused by large deletions or insertions, we examined the virtual karyotype of four pairs of affected and unaffected individuals using high-density bead chips. We also sequenced the coding regions of five 7p22 candidate genes that were prioritized because of their putative role in cell growth. We found no evidence of single-nucleotide polymorphism (SNP) copy number variation between pairs, and from the widest gap on the chip, chromosome 7p22 deletions or insertions exceeding ∼50 kb in these pedigrees can be excluded. We found 15 SNPs (two of which were novel), but none of them were non-synonymous and segregated with the disease in the FH-II pedigrees. We have been able to exclude large genomic deletions or insertions at 7p22 and refine the candidate gene list for this locus, but the mutations causing FH-II remain elusive.

Unilateral adrenalectomy improves urinary protein excretion but does not abolish its relationship to sodium excretion in patients with aldosterone-producing adenoma.

Experimental and human data suggest that adverse cardiovascular (CV) and renal effects of aldosterone excess are dependent on concomitant dietary salt intake. Increased urinary protein (Uprot) is an early sign of nephropathy independently associated with CV risk. We have previously reported a positive association between Uprot and urinary sodium (UNa) in patients with hyperaldosteronism, but not in patients with normal aldosterone levels. We aimed to determine whether Uprot is related to UNa in patients with aldosterone-producing adenoma (APA) and whether the degree of Uprot and strength of this relationship is reduced following correction of hyperaldosteronism. Subjects with APA (n=24) underwent measurement of 24 h Uprot and UNa before and after unilateral adrenalectomy (follow-up 15.0±11.9 months). Following surgery, mean clinic systolic blood pressure fell (150.4±18.2 vs 134.5±14.5 mm Hg, P=0.0008), despite a reduction in number of antihypertensive medications, and Uprot (211.2±101.6 vs 106.0±41.8 mg per day, P<0.0001) decreased. There was a positive correlation between Uprot and UNa both before (r=0.5477, P=0.0056) and after (r=0.5097, P=0.0109) adrenalectomy. Changes in UNa independently predicted Uprot reduction (P=0.0189). These findings suggest that both aldosterone levels and dietary salt contribute to renal damage, and that once glomerular damage occurs it is not completely resolved following correction of hyperaldosteronism. Our study suggests that treatment strategies based on reduction of aldosterone effects, by adrenalectomy or mineralocorticoid receptor blockade, in conjunction with low-salt diet would provide additional target-organ protection in patients with primary aldosteronism.

Examination of chromosome 7p22 candidate genes RBaK, PMS2 and GNA12 in familial hyperaldosteronism type II.

1. There are two types of familial hyperaldosteronism (FH): FH-I and FH-II. FH-I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH-II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We previously reported linkage of FH-II to a approximately 5 Mb region on chromosome 7p22. We subsequently reported finding no causative mutations in the retinoblastoma-associated Kruppel-associated box gene (RBaK), a candidate at 7p22 involved in tumorigenesis and cell cycle control. 2. In the current study we investigated RBaK regulatory regions and two other candidate genes: postmeiotic segregation increased 2 (PMS2, involved in DNA mismatch repair and tumour predisposition) and guanine nucleotide-binding protein alpha-12 (GNA12, a transforming oncogene). 3. The GNA12 and PMS2 genes were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from a large 7p22-linked FH-II family (family 1). No mutations were found. 4. The RBaK and PMS2 distal promoters were sequenced to -2150 bp from the transcription start site for RBaK and-2800 bp for PMS2. Five unreported single nucleotide polymorphisms (SNPs) were found in subjects A1, A2 but not in U1 or U2; A(-2031 bp)T, T(-2030 bp)G, G(-834 bp)C, C(-821 bp)G in RBaK and A(-876 bp)G in PMS2. Additional affected and unaffected subjects from family 1 and from two other 7p22-linked FH-II families and 58 unrelated normotensive control subjects were genotyped for these SNPs. 5. The five novel SNPs were found to be present in a significant proportion of normotensive controls. The four RBaK promoter SNPs were found to be in linkage disequilibrium in the normal population. The RBaK promoter (-)2031T/2030G/834C/821T allele was found to be in linkage disequilibrium with the causative mutation in FH-II family 1, but not in families 2 and 3. The PMS2 promoter (-)876G allele was also found to be linked to affected phenotypes in family 1. 6. The RBaK and PMS2 promoter SNPs alter the binding sites for several transcription factors. Although present in the normal population, it is possible that the RBaK (-)2031T/2030G/834C/821T and PMS2 (-)876G alleles may have functional roles contributing to the FH-II phenotype in family 1.

Mycophenolate mofetil use is associated with decreased risk of late acute rejection in adult liver transplant recipients.

Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.

Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial.

UNLABELLED: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. RESULTS: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). CONCLUSION: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.

Addition of MMF to dual immunosuppression does not increase the risk of malignant short-term death after liver transplantation.

Immunosuppression is often incriminated for the increased risk of post-transplant malignancies. To examine whether triple- (MMF+Tacro+CS) versus dual-drug therapy (Tacro+CS) is associated with an increased incidence of malignancy, or death due to malignancy, data from a large registry of liver transplant recipients were analyzed. Data from adult primary liver recipients reported to the Scientific Registry of Transplant Recipients between June 1, 1995, and April 30, 2004, and recorded at transplant on triple-drug (n = 9180) or dual-drug (n = 10 099) therapy were included. Kaplan-Meier survival analysis showed no significant differences in death due to malignancy 4 years post-transplantation between the treatment groups. Multivariable analysis using Cox proportional hazard models confirmed no differences in risk of death due to malignancy between the groups (HR: 0.83, p = 0.107). Incidence of any post-transplant malignancy was also not significantly different. Older recipient age and cause of liver disease were significantly associated with an increased risk of malignancy-related death. These data utilizing relatively short follow-up suggest the addition of MMF to Tacro+CS at transplant is not associated with death due to malignancy, at least in the short term. Individual recipient factors appear to be important risk factors for malignancy-related death; elucidating these risk factors can assist in identifying who should be monitored most aggressively for post-transplant malignancies.

Daclizumab is associated with decreased rejection and improved patient survival in renal transplant recipients.

The present study investigated the safety of induction therapy with daclizumab (compared with no induction treatment), in adult renal transplant patients reported to the Scientific Registry of Transplant Recipients (SRTR) database between January 1, 1998 and July 27, 2003. Patients who were discharged from the hospital on mycophenolate mofetil, azathioprine, or sirolimus were divided into two groups: induction treatment with daclizumab (n = 8203) and no induction treatment (n = 25,368). Patient survival, death due to infection and death due to malignancy were evaluated at 1 and 3 yr post-transplantation. Rejection and graft survival were also examined. Kaplan-Meier and Cox regression models were used to evaluate outcomes. No significant differences were found between patients treated with daclizumab compared with patients who received no induction therapy for death due to infection or malignancy at 1 and 3 yr post-transplantation. Patients treated with daclizumab (compared with no induction treatment) had statistically significantly better survival rates at 1 (96.9% vs. 96.2%, p = 0.003) and 3 yr (92.4% vs. 91.4%, p = 0.004) although absolute differences were minimal. This was confirmed in the multivariable Cox regression analysis for patient death at 1 (HR = 0.77, p < 0.001) and 3 yr (HR = 0.83, p = 0.001) post-transplantation. Patients treated with daclizumab compared to no induction had lower rejection rates at 1 (13.1% vs. 17.3%, p < 0.001) and 3 yr post-transplantation (16.7% vs. 21.3%, p < 0.001). Cox regression confirmed a decreased risk for rejection at 1 (HR = 0.74, p < 0.001) and 3 yr (HR = 0.75, p < 0.001). Treatment with daclizumab was associated with reduced risk for graft loss at 1 (HR = 0.82, p < 0.001) and 3 years (HR = 0.86, p < 0.001). In conclusion, daclizumab was associated with a significantly reduced risk for rejection and graft loss compared with no induction treatment, and improved patient survival. In addition, daclizumab was not associated with an increase in risk of death due to infection or malignancy, when compared with no induction therapy. These findings demonstrate the short and long-term safety and efficacy of daclizumab in patients transplanted between January 1998 and July 2003.

Daclizumab is associated with decreased rejection and no increased mortality in cardiac transplant patients receiving MMF, cyclosporine, and corticosteroids.

BACKGROUND: Sparse published data exist on outcomes in daclizumab-treated cardiac transplant patients. One trial observed an increased mortality risk 6 and 12 months posttransplant in patients receiving daclizumab plus mycophenolate mofetil (MMF), cyclosporine, and steroids. This study further investigates the safety profile of daclizumab with this same immunosuppressive regimen from a large registry. METHODS: Data obtained at hospital discharge on all adult cardiac transplants performed in the USA between January 1998 and October 2003 for patients receiving MMF plus cyclosporine and steroids were accessed from the Scientific Registry of Transplant Recipients. Patients were selected based on induction treatment: daclizumab (n = 684) or no induction (n = 2525). Outcomes were evaluated at 6 months, 12 months, and 3 years posttransplant. Univariate Kaplan-Meier and multivariate Cox models were used to evaluate the effect of treatment on outcomes. Patient survival and infectious death were the primary endpoints. Secondary endpoints included rejection within the first year posttransplant (acute rejection; AR) and total rejection episodes over time. The two treatment groups shared similar demographics and transplant procedure details. RESULTS: Daclizumab (vs no induction) patients had no increased risk of patient death nor infectious death. Daclizumab patients had a lower incidence of AR at 6 months (P = .005) and 12 months (P < .001); the adjusted risk for AR at 12 months (hazards ratio [HR] = 0.77; P = .89) and over 3 years (HR 0.83, P = .006) was also lower in daclizumab-treated patients. CONCLUSIONS: In cardiac transplant patients, daclizumab (vs no induction) does not result in increased mortality or infectious death, and is associated with a lower incidence of AR.

Emergency anaesthesia in a patient with Gordon's syndrome.

Gordon's syndrome is a rare condition characterized by hypertension and hyperkalemia despite normal renal glomerular function. We report the administration of an anaesthetic to one such patient for an urgent surgical procedure. The patient's serum potassium was only marginally raised at the outset of the procedure. During surgery the serum potassium rose significantly, but responded to conventional management. Hyperkalaemia is a specific electrolyte disturbance that has numerous implications for the administration of an anaesthetic. Most importantly, there is a danger that further acute elevations may occur, caused by the surgery, the anaesthetic, or the condition itself

African-American injection drug users: tensions and barriers in HIV/AIDS prevention.

This exploratory study utilized a focus group methodology to explore tensions and barriers in HIV/AIDS prevention among African-American injection drug users. Participants discussed HIV infection risks, national/community HIV prevention effectiveness, prevention barriers, ideas on barrier removal, and the tensions which exist between users and the larger African-American community. Recognizing the inevitability of continued drug use for many injectors, participants requested basic harm-reduction supplies including condoms, needle exchange programs, additional drug user treatment services, and the use of culturally- and gender-matched peer-led prevention and treatment outreach. Preliminary recommendations are made for consideration in HIV/AIDS prevention among African-American IDUs.

Familial hyperaldosteronism.

Primary aldosteronism (PAL) may be as much as ten times more common than has been traditionally thought, with most patients normokalemic. The study of familial varieties has facilitated a fuller appreciation of the nature and diversity of its clinical, biochemical, morphological and molecular aspects. In familial hyperaldosteronism type I (FH-I), glucocorticoid-remediable PAL is caused by inheritance of an ACTH-regulated, hybrid CYP11B1/CYP11B2 gene. Genetic testing has greatly facilitated diagnosis. Hypertension severity varies widely, demonstrating relationships with gender, affected parent's gender, urinary kallikrein level, degree of biochemical disturbance and hybrid gene crossover point position. Analyses of aldosterone/PRA/cortisol 'day-curves' have revealed that (1) the hybrid gene dominates over wild type CYP11B2 in terms of aldosterone regulation and (2) correction of hypertension in FH-I requires only partial suppression of ACTH, and much smaller glucocorticoid doses than those previously recommended. Familial hyperaldosteronism type II is not glucocorticoid-remediable, and is clinically, biochemically and morphologically indistinguishable from apparently sporadic PAL. In one informative family available for linkage analysis, FH-II does not segregate with either the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL and other curable or specifically treatable forms of hypertension.

Primary aldosteronism: are we diagnosing and operating on too few patients?

Many cases of potentially curable primary aldosteronism are currently likely to be diagnosed as essential hypertension unless screening tests based on suppression of renin are carried out in all hypertensive patients. More than half of the patients with primary aldosteronism detected in this way have normal circulating potassium levels, so measurement of potassium is not enough to exclude primary aldosteronism. When primary aldosteronism is diagnosed, fewer than one-third of patients are suitable for surgery as initial treatment, but this still represents a significant percentage of hypertensive patients. After excluding glucocorticoid-suppressible primary aldosteronism, adrenal venous sampling is essential to detect unilateral production of aldosterone and diagnose angiotensin-responsive aldosterone-producing adenoma. One cannot rely on the computed tomography scan. If all hypertensive patients are screened for primary aldosteronism and the workup is continued methodically in those with a positive screening test, patients with unilateral overproduction of aldosterone who potentially can be cured surgically are not denied the possibility of cure.

Executive control of visual attention in dual-task situations.

A theory of executive control is presented that proposes that executive processes control subordinate processes by manipulating their parameters, reconfiguring them to respond in accord with the current task set. It adopts C. Bundesen's (1990) theory of visual attention (TVA) and R. M. Nosofsky and T. J. Palmeri's (1997) exemplar-based random walk (EBRW) as the theory of subordinate processes. It assumes that a task set is a set of TVA and EBRW parameters sufficient to perform a task and that set switching involves changing those parameters. The theory solves 2 computational problems that emerge in dual-task situations: the binding problem and the serial order problem. It can perform dual tasks in series or in parallel but prefers the serial strategy because it is faster and it solves the binding problem naturally. The theory accounts for concurrence cost, set-switching cost, crosstalk between tasks, and the modulation of crosstalk by task set.

Familial varieties of primary aldosteronism.

1. Improved approaches to screening and diagnosis have revealed primary aldosteronism (PAL) to be much more common than previously thought, with most patients normokalaemic. The spectrum of this disorder has been further broadened by the study of familial varieties. 2. Familial hyperaldosteronism type I (FH-I) is a glucocorticoid-remediable form of PAL caused by the inheritance of an adrenocorticotrophic hormone (ACTH)- regulated, hybrid CYP11B1/CYP11B2 gene. Diagnosis has been greatly facilitated by the advent of genetic testing. The severity of hypertension varies widely in FH-I, even among members of the same family, and has demonstrated relationships with gender, degree of biochemical disturbance and hybrid gene crossover point position. Hormone "day curve" studies show that the hybrid gene dominates over wild-type CYP11B2 in terms of aldosterone regulation. This may be due, in part, to a defect in wild-type CYP11B2-induced aldosterone production. Control of hypertension in FH-I requires only partial suppression of ACTH and much smaller glucocorticoid doses than previously recommended. 3. Familial hyperaldosteronism type II (FH-II) is not glucocorticoid remediable and is not associated with the hybrid gene mutation. Familial hyperaldosteronism type II is clinically, biochemically and morphologically indistinguishable from apparently non-familial PAL. Linkage studies in one informative family did not show segregation of FH-II with the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL.

A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22).

Familial hyperaldosteronism type II (FH-II) is caused by adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted in an autosomal dominant fashion. Unlike FH type I (FH-I), which results from fusion of the CYP11B1 and CYP11B2 genes, hyperaldosteronism in FH-II is not glucocorticoid remediable. A large family with FH-II was used for a genome wide search and its members were evaluated by measuring the aldosterone:renin ratio. In those with an increased ratio, FH-II was confirmed by fludrocortisone suppression testing. After excluding most of the genome, genetic linkage was identified with a maximum two point lod score of 3.26 at theta=0, between FH-II in this family and the polymorphic markers D7S511, D7S517, and GATA24F03 on chromosome 7, a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II; its molecular elucidation may provide further insight into the aetiology of primary aldosteronism.