Clinical presentation of hyperthyroidism in a large representative sample of outpatients in France: relationships with age, aetiology and hormonal parameters.

OBJECTIVE: Signs and symptoms of thyrotoxicosis are not specific, and thyroid function tests are frequently prescribed to recognize such thyroid dysfunction. Ultrasensitive assays of thyroid-stimulating hormone (TSH) allow early diagnosis and identification of mild hyperthyroidism (generally designed as 'subclinical'). The aim of this study was to re-evaluate the clinical picture of thyrotoxicosis in the context of the current large utilization of ultrasensitive TSH assays. DESIGN: Prospective descriptive cohort. METHODS: Clinical presentation of 1572 patients with a recent (<3 months) diagnosis of thyrotoxicosis recruited by a large representative sample of 263 French endocrinologists was studied using two questionnaires (one at inclusion and the second after 3 months) concerning symptoms, hormonal evaluation and treatment. RESULTS: A total of 1240 (78·9%) patients were women, mean age 48 ± 17 years. Subclinical hyperthyroidism (SCHT) was present in 86 patients (10·4%). Symptoms of thyrotoxicosis were in decreasing frequency order: palpitations, weakness, heat-related signs and disturbed sleep. A total of 64·9% of patients had lost weight. Signs and symptoms were more frequent in Graves' disease, in young patients, and were partially related to biochemical severity. Symptoms were less frequent in elderly patients except for cardiac manifestations (atrial fibrillation). Most patients with SCHT had one or several signs or symptoms of thyrotoxicosis. CONCLUSION: This study confirms that elderly patients have less symptoms of thyrotoxicosis than younger subjects but are at increased risk of cardiac complications. Our results show that most patients with 'subclinical' HT have in fact signs or symptoms of thyrotoxicosis.

Survival of patients managed in France for duodenal neuroendocrine tumors (D-NET): a 20-year multicenter cohort study from the GTE group: a cohort study.

INTRODUCTION: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival. METHODS: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group. RESULTS: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P <0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous ( P =0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade ( P =0.977) and location ( P =0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion ( P =0.387). CONCLUSION: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours.

Short-term very low-calorie diet in obese females improves the haemostatic balance through the reduction of leptin levels, PAI-1 concentrations and a diminished release of platelet and leukocyte-derived microparticles.

BACKGROUND: In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth. OBJECTIVES: In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage. METHODS: Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays. RESULTS: A total of 24 obese females (39 ± 10 years) with a mean body mass index of 35 ± 4 kg m(-2) were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r=0.534; P=0.010) and at 90 days follow-up (r=0.487; P=0.021). At 90 days, weight reduction (-9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (-38%), procoagulant platelet-derived MPs (-43%), leukocyte-derived MPs (-28%) and leptin (-32%) levels. CONCLUSION: In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.

Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience.

OBJECTIVE: The aim of our study was to evaluate the diagnostic contribution of (18)F-fluoro-deoxyglucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) in patients with fever of unknown origin (FUO) or unexplained prolonged inflammatory syndrome (UPIS) in real life. PATIENTS AND METHODS: We performed a retrospective study including 14 patients with FUO or UPIS hospitalised in our institution (Strasbourg University Hospital, France) between January 2005 and July 2006. (18)F-FDG-PET/CT was considered helpful when abnormal results allowed an accurate diagnosis. RESULTS: (18)F-FDG-PET/CT was helpful in half the patients (7/14) for final diagnosis. A diagnosis was reached in 87.5% of the patients (7/8) with an abnormal (18)F-FDG-PET/CT but only in 50% of the patients (3/6) with a normal (18)F-FDG-PET/CT. Conventional chest and abdominal CT was performed in 13 patients before ordering (18)F-FDG-PET/CT. We considered that (18)F-FDG-PET/CT was essential to establish the final diagnosis in only 23% of the patients (3/13) since neither chest nor abdominal CT identified abnormalities consistent with the final diagnosis. However, among the three patients, two were diagnosed with large vessel vasculitis and one patient with local prosthetic infection. CONCLUSIONS: Our study supports the potential interest of (18)F-FDG-PET/CT in the diagnostic workup of FUO and UPIS as it helped establish a fine diagnosis in half of the cases. However, (18)F-FDG-PET/CT appeared to be essential to the final diagnosis in only 23% of the cases. In our opinion, this protocol should be performed as a second level test, especially when conventional CT is normal or is unable to discriminate between active and silent lesions.

[Bayesian statistic: an approach fitted to clinic]. / La statistique bayésienne : une approche des statistiques adaptée à la clinique.

Bayesian statistic has known a growing success though quite limited. This is surprising since Bayes' theorem on which this paradigm relies is frequently used by the clinicians. There is a direct link between the routine diagnostic test and the Bayesian statistic. This link is the Bayes' theorem which allows one to compute positive and negative predictive values of a test. The principle of this theorem is extended to simple statistical situations as an introduction to Bayesian statistic. The conceptual simplicity of Bayesian statistic should make for a greater acceptance in the biomedical world.

[Cardiac manifestations of pheochromocytoma]. / Manifestations cardiaques des phéochromocytomes.

Pheochromocytoma is a rare cause of secondary hypertension which may have protean clinical presentations. Noteworthy, it may be revealed or complicated by cardiovascular symptoms such as arrythmia, cardiomyopathy, acute coronary syndrome and cardiogenic shock. These cardiac manifestations of pheochromocytoma may delay diagnosis and must be known in order to provide the best chance at early detection. In some cases pheochromocytoma may be associated to a large apical dyskinesia of the left ventricule apex, tako-tsubo-like which is a reversible acute myocardiopathy. These acute cardiologic manifestations appear to be induced by a toxic effect of elevated catecholamine levels.

[Value of left atrial dilation in the diagnosis of silent myocardial ischemia in diabetes mellitus patients]. / Facteurs prédictifs de l'existence d'une ischémie myocardique silencieuse chez le patient diabétique. Intérêt de l'évaluation de la surface de l'oreillette gauche.

BACKGROUND: Accelerated atherothrombosis is a common feature in diabetes mellitus patients (DM), which can be related to abnormalities in vascular cell apoptosis and activation leading to the release of procoagulant microparticles (MPs). In DM patients, we hypothesized that circulating levels of biomarkers involved in atherothrombosis processes as well as cardiac and carotid echocardiography variables could be useful in the detection of silent myocardial diagnosed by myocardial perfusion imaging. METHODS AND RESULTS: We investigated, in 55 patients with diabetes (mean age 62+/-10 years) and 15 nondiabetics (46+/-14 years) patients the prevalence of silent myocardial ischemia (SMI) detected by a treadmill exercise or dipyridamole (99m)Tc-sestamibi stress test. Echocardiographic and -carotid variables were obtained using standardized methods. Biomarkers assessing endothelial apoptosis or activation (CD31+-MPs, CD62+-MPs, VCAM-1), inflammatory status (CD11a +/- MPs, MCP-1, CRP), platelet activation (GPIb+/-MPs, CD40-L, P-selectin, GPV) ventricular stretch (BNP) were measured in the plasma. SMI was diagnosed in 23/55 (42%) diabetics patients and in 3/15 (20%) nondiabetics patients. Enhanced inflammatory status and leukocyte damage (CD11a+-MPs) were evidenced in diabetic patients. Within the diabetic population, biomarkers levels of atherothrombosis were not significantly associated to the detection of SMI. In multivariable analyses adjusted for LV hypertophy, left atrial surface (LA) remained independent predictor of silent myocardial ischemia (OR 4.14; IC [1.7-16.13]; P=0.039). CONCLUSIONS: In diabetes mellitus patients, LA surface independently predicted silent myocardial ischemia after adjustment for established echocardiographic, and inflammatory risk factors. This simple measure of LA dilation could be helpful in the identification of diabetes mellitus patients at heightened cardiovascular risk.

Subclinical haemorrhage in non-functional adenomas.

AIM: The prevalence and risk factors of subclinical haemorrhage on non-functional adenomas (NFA) remain controversial. The primary aim of our study was to assess the incidence of subclinical haemorrhage (SH) and the secondary objectives were to evaluate the risk factors of SH and the impact of SH on pituitary function at diagnosis. PATIENTS AND METHODS: This retrospective transversal analysis included 95 patients between January 2012 and December 2014. The patients included in this series were all adults (>18 years of age), who presented a non-functional adenoma confirmed by an endocrinological evaluation and on dedicated MRI pituitary imaging. Sixty-four patients were eligible for this study. Subclinical haemorrhage was defined by the presence of haemorrhage within pituitary adenoma confirmed by pituitary MRI with no clinical symptoms. A senior neuroradiologist blinded to the diagnosis reviewed all MRI. The population was prospectively divided into two groups based on MRI results (SH group vs. group control) to determine risk factors. RESULTS: SH was diagnosed in 22 patients (34.38%). No risk factors (age, sex, tumor size, chronic hypertension, diabetes mellitus, malignant disease, the use of anticoagulation or antithrombotic medication or Cabergoline treatment) were involved as regards the SH. At the diagnosis, pituitary deficiency was statistically significantly more frequent in the SH group (45.45%) than in the control group (19.04%) (P=0.04). CONCLUSION: The SH within NFA was observed in 34.38% of cases without an association of risk factors.

Circulating procoagulant microparticles in obesity.

AIM: Obesity is a risk factor for cardiovascular diseases and venous thromboembolism. Circulating procoagulant microparticles (MP) have been described in various clinical situations associated with thrombosis and in diabetic patients. The aim of this preliminary study was to evaluate the presence of MP in obese patients without any other vascular risk factor in particular diabetes. METHODS: Fifty-eight obese women <50 year-old without other cardiovascular risk factors were recruited from a single out-patient nutrition clinic. They were compared to 45 age-matched healthy normal weight controls. Main outcome was MP levels in patients and controls. Relationships between MP concentrations and parameters reflecting insulin resistance in patients were also studied. RESULTS: Obese patients were 33.3 +/- 1.2 years old and had a mean BMI of 42.4 +/- 0.9 kg/m2. There vas a greater proportion of smokers in the obese group (34.5 vs 15.6%). Mean MP levels were markedly higher in obese patients compared to controls (10.6 +/- 0.5 vs 3.2 +/- 0.3 nMPSeq, P < 0.001). There was no difference in MP concentrations between smokers and non smokers. In the obese group, there was a negative correlation between MP and BMI (r = -0.265, P < 0.05) but no relationship could be established between MP concentrations and markers of insulin resistance. CONCLUSION: This increase in circulating MP levels reflects cell activation and could account for the increased risk of thrombotic complications in obesity. Further studies are ongoing to explore the relationships between MP levels and coagulation markers and to assess the effect of weight reduction.

[Is subclinical hypothyroidism a cardiovascular risk factor?]. / L'hypothyroïdie fruste est-elle un facteur de risque cardiovasculaire?

OBJECTIVES: Subclinical hypothyroidism defined by the presence of elevated TSH levels but normal free T4 level is a common situation. Its consequences on health are yet on debate and the interest of a precocious treatment remains surrounded by controversy. KEY POINTS: The relationship between subclinical hypothyroidism and cardiovascular disease has been evaluated by several cross-sectional and longitudinal studies. Subclinical hypothyroidism has direct but subtle effects on the heart function, on the peripheral vascular resistance, and is associated with a mild elevation of LDL-cholesterol levels; all abnormalities may be partly reversed by a thyroxine supplementation. Data of the literature give insufficient evidence as to whether subclinical hypothyroidism is an independent cardiovascular risk factor. However treatment of subjects with TSH levels up or near to 10 mU/l would probably be beneficial in the prevention of cardiovascular disease. FUTURE PROSPECTS: Based on observational and interventional studies there are some arguments on the benefit of euthyroidism restoration only in patients with TSH levels superior to 10 mU/l.

An unusual pituitary stalk lesion: What is the place of surgery?

BACKGROUND: Sellar and suprasellar primary melanocytic tumors are exceptional occurrences. Besides the difficulty of differential diagnosis between a primary and secondary lesion, treatment of these pathologies is still unclear and controversial. CASE REPORT: We describe the case of a 36-year-old woman with no relevant previous medical history who presented with 1 month history of diabetes insipidus, blurred vision and generalized weakness; a brain MRI disclosed an atypical pituitary stalk lesion; initially the tumor was biopsied through an endonasal endoscopic approach that revealed a melanocytic tumor; the patient was afterwards managed by a second stage extended endonasal endoscopic approach achieving a subtotal tumor removal. The overall survival was of 14 months due to the multidisciplinary management including surgery, radio and chemotherapy. CONCLUSION: If a biopsy is essential to deal with these invasive lesions, treatment including surgical resection should be part of a multidisciplinary approach.

[The significance of circulating microparticles in physiology, inflammatory and thrombotic diseases]. / Les microparticules circulantes: rôles physiologiques et implications dans les maladies inflammatoires et thrombotiques.

BACKGROUND: In multicellular organisms, apoptosis and subsequent microparticle shedding play a key role in homeostasis. Having long been considered as << cellular dust >>, microparticles released in biological fluids upon cell activation or apoptosis appear as multifunctional bioeffectors involved in the modulation of key functions including immunity, inflammation, hemostasis and thrombosis, angiogenesis. MP constitute reliable markers of vascular damage, accessible to biological detection whilst the cells they originate from remain sequestered in tissues or are promptly submitted to phagocytosis. RECENT FINDINGS: MP modulate biological functions of target cells through the transfer of cytoplasmic content, lipids and membrane receptors. The pharmacological modulation of circulating levels of microparticles could be of particular interest in thrombotic or inflammatory diseases, cancer or hemophilia. CONCLUSION: MP can now be viewed not only as a hallmark of cell damage but also as a true biological tool.

[Cellular mechanisms of thyroid hormone action]. / Mécanismes d'action cellulaire des hormones thyroïdiennes.

KEY POINTS: Thyroid hormones affect cardiac myocytes as well as the smooth muscle and endothelial cells of the vascular wall. Free 3,53'-L-triiodothyronine (FT3) and its specific nuclear receptor modulate the transcription of various proteins, principally those involved in the myocyte contractile apparatus (myosin heavy chains), and the regulation of intracellular calcium flux (sarcoplasmic reticulum Ca2+ATPase). Thyroid hormones also have non-genomic effects that work rapidly, complement the effects described above, and are related to alterations in the properties of many channels and membrane receptors, especially in the sinoatrial mode. Thyroid hormones also affect the smooth muscle and endothelial cells of the vascular walls and reduce systemic vascular resistance. These effects on cardiac and vascular cells globally explain the cardiac manifestations (especially the inotropic and chronotropic effects) observed during dysthyroidism, particularly in hyperthyroidism where they are often in the forefront (positive inotropic and chronotropic effects).

[Cardiac consequences of clinical dysthyroidism. Pathophysiological, clinical, and epidemiologic data]. / Répercussions cardiaques des dysthyroïdies avérées. Données physiopathologiques, cliniques et épidémiologiques.

KEY POINTS: Thyroid hormones affect the vascular system, including the diastolic and systolic functioning of the heart. Resting heart rate increases early in hyperthyroidism (cardiac contractility expands due to improved ventricular loading and decreased systemic vascular resistance). Paradoxically, these hemodynamic alterations progressively reduce cardiac performance on effort (changes in diastolic, then systolic functioning) and finally at rest (modification in ventricular loading following tachycardia or atrial fibrillation), especially in cases of underlying heart disease (in the elderly). Hypothyroidism has an inverse hemodynamic effect and is less noisy, usually limited to relative bradycardia. The morbidity and mortality associated with hypothyroidism are apparently related to the atherogenic and prothrombotic vascular modifications that follow thyroid hormone deficiency, whereas heart failure and particularly atrial fibrillation and its thromboembolic complications are the primary consequences of hyperthyroidism. In both cases, return to normal thyroid levels corrects the cardiac abnormalities caused by the dysthyroidism. Dysthyroidism (hypo- or hyperthyroidism) occurs in 10 to 20% of the patients treated with amiodarone for arrhythmia. Because of its potential seriousness, some clinical or laboratory tests are necessary before initiating treatment, and specific clinical surveillance should be scheduled, including laboratory tests.

[Cardiac consequences of subclinical dysthyroidism. Experimental, clinical, and epidemiologic data]. / Répercussions cardiaques des dysthyroïdies frustes. Données expérimentales, cliniques et épidémiologiques.

KEY POINTS: Although the cardiovascular consequences of clinical or "overt" dysthyroidism are well known and treatment relatively well established, subclinical dysthyroidism remains a controversial topic, both regarding its cardiovascular effects and the best methods for its management. Subclinical hyperthyroidism is frequent among the elderly, usually associated with multinodular goiter. Although several epidemiologic studies have demonstrated that subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and high cardiovascular mortality, solid practical data on which management can be based are not currently available. The risks related to subclinical hypothyroidism appear essentially vascular but a conclusive assessment must await further epidemiologic surveys.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Low cholesterol concentrations in free-living elderly subjects: relations with dietary intake and nutritional status.

Hypocholesterolemia has been reported in epidemiologic studies to be associated with increased mortality from noncardiovascular causes. Low cholesterol concentrations have been reported in various pathologic conditions and in institutionalized elderly patients, and seem to be associated with poor outcome. The role of nutritional factors in the genesis of hypocholesterolemia was investigated in 380 free-living elderly subjects. Subjects in the lowest cholesterol quartile had lower free triidothyronine and prealbumin concentrations and a lower Folstein's score (a minimental test) than did those in the other quartiles. They did not differ from the other subjects for energy or nutrient intakes. Only 12 subjects (9 men and 3 women) had cholesterol concentrations < 3.62 mmol/L: the men had low free triidothyronine, free thyroxine, and prealbumin concentrations but normal energy and nutrient intakes, whereas the women differed from those with normal cholesterol concentrations for biological and nutritional data. These results indicate that low cholesterol concentration is a nonspecific feature of poor health status that is independent of nutrient or energy intake. The role of nutrient factors as a determinant of cholesterol concentration appears marginal in free-living elderly subjects.

Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption.

BACKGROUND: The standard treatment for cobalamin (vitamin B(12)) deficiency involves regular intramuscular cobalamin injection. It has been suggested that oral cobalamin therapy may be effective for treating patients who have food-cobalamin malabsorption. SUBJECTS AND METHODS: We prospectively studied 10 patients with cobalamin deficiency and well-established food-cobalamin malabsorption who received 3000 microg or 5000 microg of oral crystalline cyanocobalamin once a week for at least 3 months. Complete blood counts and serum cobalamin, homocysteine, and folate levels were determined at baseline and after 3 months of treatment. Patients were reexamined after 6 months. RESULTS: After 3 months of treatment, all patients had increased hemoglobin levels (mean increase, 1.9 g/dL; 95% confidence interval: 0.9 to 3.9 g/dL;P <0.01 compared with baseline) and decreased erythrocyte cell volume (mean decrease, 7.8 fL; 95% confidence interval: 0.9 to 16.5 fL;P<0.001). However, 2 patients had only minor, if any, responses. Serum cobalamin levels were increased in all 8 patients in whom it was measured. CONCLUSION: Our findings suggest that moderate doses of crystalline cyanocobalamin given orally may be an effective treatment for food-cobalamin malabsorption.

Twenty-four-hour profiles of plasma renin activity in relation to the sleep-wake cycle.

OBJECTIVE: To evaluate the relative contribution of sleep and the endogenous circadian rhythmicity in producing the 24-h variations in the plasma renin activity. METHODS: Ten normal young men were studied, under basal conditions with normal nocturnal sleep from 2300-0700 h and once after a night of total sleep deprivation followed by 8 h daytime sleep from 0700 to 1500 h. Plasma renin activity was measured every 10 min for 24 h and the profiles were analysed using the pulse detection program ULTRA. RESULTS: During the 8 h night-time sleep a significant increase in the mean plasma renin activity levels occurred compared with the subsequent 8-h waking periods. After the shift in the sleep period, a sleep-associated increase was clearly apparent during the daytime hours. The number of the amplitude of the oscillations, linked to the non-rapid eye movement-rapid eye movement sleep cycles, increased during sleep (at whatever time it occurred), and were dependent on the regularity and the length of the sleep cycles. In awake subjects the plasma renin activity generally fluctuated in a more damped and irregular manner, but occasionally the plasma renin activity oscillated at a regular periodicity with two dominant peaks centred around 100 and 50 min. CONCLUSION: These results demonstrate that the 24-h plasma renin activity variations are not circadian in nature but are related to sleep processes, which create the nycthemeral rhythm by increasing both the frequency and the amplitude of the oscillations.