The efficacy of Barbed Sutures for Anterior Pharyngoplasty: technical aspects and preliminary results.

After the first experiences with the Barbed Sutures (BS) in sleep surgery, we present the Modular Barbed Anterior Pharyngoplasty (M.B.A.Ph.), a functional tenso-structural reconstruction of the soft palate, as a surgical solution for Obstructive Sleep Apnea (OSA) due to antero-posterior collapse at the drug induced sleep endoscopy (DISE) for snoring and mild-moderate OSA. The action of the BS is sustained over time by means of solid and stable tissue scarring. M.B.A.Ph. avoids palatal fibromuscular resection and minimize iatrogenic bleeding (bloodless surgery). The technique is described in detail and some preliminary results are presented.

Effectiveness of progesterone, cerclage and pessary for preventing preterm birth in singleton pregnancies: a systematic review and network meta-analysis.

BACKGROUND: Preterm birth (PTB) is the leading cause of infant death, but it is unclear which intervention is best to prevent it. OBJECTIVES: To compare progesterone, cerclage and pessary, determine their relative effects and rank them. SEARCH STRATEGY: We searched Medline, EMBASE, CINAHL, Cochrane CENTRAL and Web of Science (to April 2016), without restrictions, and screened references of previous reviews. SELECTION CRITERIA: We included randomised trials of progesterone, cerclage or pessary for preventing PTB in women with singleton pregnancies at risk as defined by each study. DATA COLLECTION AND ANALYSIS: We extracted data by duplicate using a piloted form and performed Bayesian random-effects network meta-analyses and pairwise meta-analyses. We rated evidence quality using GRADE, ranked interventions using SUCRA and calculated numbers needed to treat (NNT). MAIN RESULTS: We included 36 trials (9425 women; 25 low risk of bias trials). Progesterone ranked first or second for most outcomes, reducing PTB < 34 weeks [odds ratio (OR) 0.44; 95% credible interval (CrI) 0.22-0.79; NNT 9; low quality], <37 weeks (OR 0.58; 95% CrI 0.41-0.79; NNT 9; moderate quality), and neonatal death (OR 0.50; 95% CrI 0.28-0.85; NNT 35; high quality), compared with control, in women overall at risk. We found similar results in the subgroup with previous PTB, but only a reduction of PTB < 34 weeks in women with a short cervix. Pessary showed inconsistent benefit and cerclage did not reduce PTB < 37 or <34 weeks. CONCLUSIONS: Progesterone was the best intervention for preventing PTB in singleton pregnancies at risk, reducing PTB < 34 weeks, <37 weeks, neonatal demise and other sequelae. TWEETABLE ABSTRACT: Progesterone was better than cerclage and pessary to prevent preterm birth, neonatal death and more in network meta-analysis.

Preterm birth prevention in twin pregnancies with progesterone, pessary, or cerclage: a systematic review and meta-analysis.

BACKGROUND: About half of twin pregnancies deliver preterm, and it is unclear whether any intervention reduces this risk. OBJECTIVES: To assess the evidence for the effectiveness of progesterone, cerclage, and pessary in twin pregnancies. SEARCH STRATEGY: We searched Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and ISI Web of Science, without language restrictions, up to 25 January 2016. SELECTION CRITERIA: Randomised controlled trials of progesterone, cerclage, or pessary for preventing preterm birth in women with twin pregnancies, without symptoms of threatened preterm labour. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data using a piloted form. Study quality was appraised with the Cochrane Risk of Bias tool. We performed pairwise inverse variance random-effects meta-analyses. MAIN RESULTS: We included 23 trials (all but three were considered to have a low risk of bias) comprising 6626 women with twin pregnancies. None of the interventions significantly reduced the risk of preterm birth overall at <34 or <37 weeks of gestation, or neonatal death, our primary outcomes, compared to a control group. In women receiving vaginal progesterone, the relative risk (RR) of preterm birth <34 weeks of gestation was 0.82 (95% CI 0.64-1.05, seven studies, I2  36%), with a significant reduction in some key secondary outcomes, including very low birthweight (<1500 g, RR 0.71, 95% CI 0.52-0.98, four studies, I2  46%) and mechanical ventilation (RR 0.61, 95% CI 0.45-0.82, four studies, I2  22%). CONCLUSION: In twin gestations, although no overarching intervention was beneficial for the prevention of preterm birth and its sequelae, vaginal progesterone improved some important secondary outcomes. TWEETABLE ABSTRACT: Vaginal progesterone may be beneficial in twin pregnancies, but not 17-OHPC, cerclage, or pessary.

Topical hyaluronic acid in rhinitis medicamentosa: could our perspective be changed?

This study was designed to prospectively evaluate the role of nebulized hyaluronic acid (HA) administered for 10 days as treatment for patients with rhinitis medicamentosa (RM). RM is a pathological condition of the nasal mucosa induced by prolonged, excessive or improper use of topical decongestants. It is characterized by persistent nasal congestion that can lead the patient to increase the frequency of application and the quantity of the substance being applied, resulting in dependence on topical nasal decongestants. Twenty-five patients were treated with HA nebulized via Spray-sol twice a day for 10-days (T1) (HA Spray-sol treatment group). Subsequently, after 3 days of washout, patients were treated with physiological saline nebulized via Spray-sol twice a day for 10 days. (T2) (saline Spray-sol treatment group). The HA Spray-sol treatment group (tp) significantly improved visual analogue scale (VAS) scores (T0=6.25±1.64 vs T1=3.91±1.30; p less than 0.05), whereas there was no statistically significant difference in the saline Spray-sol treatment group (tp) (p>0.05), results confirmed by the anterior active rhinomanometry (AAR) data (HA Spray-sol tp T0=1.193±0.83 vs T1=0.44±0.25, p less than 0.05; saline Spray-sol tp (p>0.05). An improvement in the Global Rhinitis Score (GRS) was recorded in both groups (T0=15.37±5.16 vs T1=5.54±3.23, p less than 0.05; saline Spray-sol tp T0=15.37±5.16 vs T2=10. 7±5.43; p less than 0.05). Both groups showed a significant reduction in mucosal oedema and nasal secretions. Patients treated with HA Spray-sol reduced or even eliminated (11/25 patients) the use of topical decongestant within 10 days of treatment with HA. The results of this study suggest nebulized topical 9-mg sodium hyaluronate plays a pivotal role in the management of RM.

The efficacy of topical hyaluronan in rhinosinusitis: a systematic review.

Rhinosinusitis is one of the most common inflammatory conditions of the nasal cavity and paranasal sinuses and is one of the most common causes of absence from work and for visits to the family doctor. The treatment strategy in both acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) is to reduce the severity of the symptoms, minimize the duration of the disease and prevent complications. Topical therapy has become an important tool in otolaryngologists’ armamentarium for rhinosinusitis treatment. Recently, topical hyaluronic acid (HA), the major component of many extracellular matrices that promotes tissue healing, including activation and moderation of the inflammatory responses, cell proliferation, migration and angiogenesis, has been proposed for ARS and CRS adjuvant tool. The aim of the study is to systematically review the published literature regarding all the therapeutic effects of HA on the ARS and CRS. Relevant published studies were found in PubMed, Google Scholar and Ovid, using a combined keyword search or medical subject headings. At the end of our study selection process, 5 relevant publications were included: 2 of them investigated the potential role of HA in reducing symptoms and preventing exacerbations of CRS in adult population, two of them in paediatric patients affected by upper respiratory tract infections and one of them in cystic fibrosis patients with bacterial rhinopharyngitis. Data deriving from the present review of 5 clinical studies showed that the use of topical HA represents a relevant therapeutic advance in rhinosinusitis to minimize symptoms and prevent reacutization with a significant improvement of their quality of life, as it avoids systemic side effects and increases local drug activity. Further studies on larger populations and with new specific nebulization devices for upper airway are needed to confirm these encouraging results.

Post-operative nebulized sodium hyaluronate versus spray after functional endoscopic sinus surgery for chronic rhinosinusitis.

We prospectively evaluated the efficacy of nebulized Hyaluronic Acid (HA) as an adjuvant treatment to hasten the improvement of nasal respiration and to minimize patients’ discomfort in the postoperative functional endoscopic sinus surgery (FESS) for chronic rhino-sinusitis (CRS). We enrolled 33 CRS adult patients who underwent endoscopic functional sinus surgery. They were randomly assigned into two groups: Spray-Sol group (18 patients) with HA nebulized with a new nasal device named Spray-Sol and Spray group (15 patients) with a HA nebulized with a common spray. Both groups were treated twice daily for 4 weeks. CRS questionnaire, Visual analogic scale (VAS) and nasal endoscopy were used to assess the outcomes of the treatments during the 1st month of follow up. The mean VAS score of the Spray-Sol group at 2 weeks was significantly lower than the Spray group (5.2±2.1 vs 10.5±3.7; p less than 0.05). The VAS score remained significantly lower in the Spray-Sol group also at the 4 weeks (2.9±0.8 vs 6.1±3.4; p less than 0.05). The CRS score was significantly better at week 2 and 4 in both groups in comparison with baseline values, with better results in the Spray-Sol group. Since the first visit the Spray-Sol group also showed significantly lower crusts, edema and secretions than the Spray group (p less than 0.05). The compliance to treatment was similar in both groups. The results of this prospective study suggest a role nebulized of HA through new device (Spray-sol) as a supportive treatment for faster improvement of nasal respiration, also minimizing patient discomfort, promoting nasal mucosa healing in postoperative FESS for CRS.

A specific DNA methylation profile correlates with a high risk of disease progression in stage I classical (Alibert-Bazin type) mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma; in its classical presentation it evolves slowly, but it can have an aggressive course in a subset of patients. OBJECTIVES: To investigate the impact of epigenetic mechanisms on the progression of early stage MF. METHODS: We analysed DNA methylation at 12 different loci and long interspersed nucleotide elements-1 (LINE-1), as a surrogate marker of global methylation, on tissue samples from 41 patients with stage I MF followed up for at least 12 years or until disease progression. The methylation profiles were also analysed in two T-cell lymphoma cell lines and correlated with gene expression. RESULTS: The selected loci were methylated in a tumour-specific manner; concomitant hypermethylation of at least four loci was more frequent in cases progressing within 1-3 and 3-6 years than in late-progressive or non-progressive cases. LINE-1 methylation was significantly lower in rapidly progressive MF at 3 years (61%, P < 0·001) than in those at 12 years (67%). PPARG, SOCS1 and NEUROG1 methylation showed remarkable differences among the prognostic groups, but only PPARG was a significant predictor of disease progression within 6 years, after adjustment for patients' age or gender. Strikingly, a methylation profile similar to progressive cases was found in highly proliferative Sézary-derived HUT78 cells but not in MF-derived HUT102 cells. Exposure to a DNA demethylating agent restored sensitivity to apoptosis and cell cycle arrest. CONCLUSIONS: Epigenetic silencing of specific biomarkers can predict the risk of disease progression in early-stage MF, providing insights into its pathogenesis, prognosis and therapy.

LH, progesterone, and TSH can stimulate aldosterone in vitro: a study on normal adrenal cortex and aldosterone producing adenoma.

Endocrine factors different from ACTH or angiotensin II can stimulate aldosterone secretion and have a role in the pathophysiology of hyperaldosteronism. Aldosterone may increase in luteotropic/progestogenic and in hypothyroid states; LH and, occasionally, TSH receptors have been detected in normal adrenal cortex and aldosterone-producing adenoma. The aim of the study was to compare adrenal contents of LH and TSH receptors between normal cortex and aldosterone-producing adenoma and to evaluate the ability of LH, its product progesterone, and TSH to stimulate aldosterone secretion in vitro from primary adrenocortical cells. Surgical aldosterone-producing adenoma fragments from 19 patients and adrenal cortex fragments from 10 kidney donors were used for Western blotting and cell cultures. LH (n=26), TSH (n=19) and progesterone (n=8) receptor proteins were investigated; LH receptor-mRNA was also tested in 8 samples. Aldosterone responses in vitro to LH, progesterone, and TSH stimulation were assayed. LH and TSH receptors were more expressed in adenoma than normal cortex (p<0.01, p<0.05, respectively); progesterone receptor was observed in 6/8 samples. Aldosterone increased after in vitro stimulation with LH (5/12 adenoma, 1/7 normal cells), progesterone (4/5 adenoma, 5/6 normal cells), and TSH (3/5 adenoma and 3/5 normal cells). LH and TSH receptors were more expressed in aldosterone producing adenoma than normal adrenal cortex. LH, progesterone, and TSH can stimulate aldosterone in vitro. Similar mechanisms could participate in vivo in the aldosterone increase in lutheotropic, progestogenic, or hypothyroid states and may exist in both normal adrenal cortex and adenoma in responsive individuals.

Long-term remodeling of rat pial microcirculation after transient middle cerebral artery occlusion and reperfusion.

OBJECTIVE: The aim of this study was to assess the in vivo structural and functional remodeling of pial arteriolar networks in the ischemic area of rats submitted to transient middle cerebral artery occlusion (MCAO) and different time intervals of reperfusion. METHODS AND RESULTS: Two closed cranial windows were implanted above the left and right parietal cortex to observe pial microcirculation by fluorescence microscopy. The geometric characteristics of pial arteriolar networks, permeability increase, leukocyte adhesion and capillary density were analyzed after 1 h or 1, 7, 14 or 28 days of reperfusion. MCAO and 1-hour reperfusion caused marked microvascular changes in pial networks. The necrotic core was devoid of vessels, while the penumbra area presented a few arterioles, capillaries and venules with severe neuronal damage. Penumbra microvascular permeability and leukocyte adhesion were pronounced. At 7 days of reperfusion, new pial arterioles were organized in anastomotic vessels, overlapping the ischemic core and in penetrating pial arterioles. Vascular remodeling caused different arteriolar rearrangement up to 28 days of reperfusion and animals gradually regained their motor and sensory functions. CONCLUSIONS: Transient MCAO-induced pial-network remodeling is characterized by arteriolar anastomotic arcades. Remodeling mechanisms appear to be accompanied by an increased expression of nitric oxide synthases.

A novel germline mutation in peroxisome proliferator-activated receptor gamma gene associated with large intestine polyp formation and dyslipidemia.

We report a novel PPARG germline mutation in a patient affected by colorectal cancer that replaces serine 289 with cysteine in the mature protein (S289C). The mutant has impaired transactivation potential and acts as dominant negative to the wild type receptor. In addition, it no longer restrains cell proliferation both in vitro and in vivo. Interestingly, the S289C mutant poorly activates target genes and interferes with the inflammatory pathway in tumor tissues and proximal normal mucosa. Consistently, only mutation carriers exhibit colonic lesions that can evolve to dysplastic polyps. The proband presented also dyslipidemia, hypertension and overweight, not associated to type 2 diabetes; of note, family members tested positive for the mutation and display only a dyslipidemic profile at variable penetrance with other biochemical parameters in the normal range. Finally, superimposing the mutation to the crystal structure of the ligand binding domain, the new Cys289 becomes so closely positioned to Cys285 to form an S-S bridge. This would reduce the depth of the ligand binding pocket and impede agonist positioning, explaining the biological effects and subcellular distribution of the mutant protein. This is the first PPARG germline mutation associated with dyslipidemia and colonic polyp formation that can progress to full-blown adenocarcinoma.

A 'chemical help' in middle-ear surgery? A systematic review on sodium 2-mercaptoethanesulfonate.

OBJECTIVE: Sodium 2-mercaptoethanesulfonate (Mesna) has been proposed as a chemical aid in any surgical procedure, including cholesteatoma surgery. This review investigated the benefits and safety of Mesna during surgical management of cholesteatoma and adhesive otitis media. METHOD: A systematic literature review was performed to identify clinical studies evaluating topical Mesna application during ear surgery (cholesteatoma or atelectasis). A qualitative analysis based on data extracted was conducted. RESULTS: From 27 articles, 5 retrospective studies were selected for a full analysis for a total of 607 patients (aged 5 to 72 years). Three studies evaluated cholesteatoma recidivism after Mesna application during cholesteatoma surgery, one study evaluated the surgical success rate of Mesna application for the treatment of atelectatic ears and adhesive otitis media, and one study evaluated potential ototoxicity of Mesna during cholesteatoma surgery. All the studies showed overall improvement in recurrence and residual cholesteatoma disease after Mesna application during surgery. Sensorineural hearing loss was not encountered after Mesna application. CONCLUSION: Mesna application in cholesteatoma surgery could represent a valid and safe support tool during surgical treatment carried out both with microscopy and endoscopy. More studies are required to confirm these promising results.

Minimally invasive surgery under local anaesthesia for chronic rhinosinusitis with nasal polyps: our experience in older adults.

OBJECTIVE: This paper aims to report our experience with a minimally invasive surgical procedure for the treatment of chronic rhinosinusitis with nasal polyps, performed in a day-surgery setting under local anaesthesia. METHODS: A retrospective study of 30 patients with chronic rhinosinusitis with nasal polyps was conducted. Sino-Nasal Outcome Test 22 and modified Lund-Kennedy scores were collected. Intra- and post-operative pain was evaluated using a 10-point visual analogue scale. RESULTS: The mean Sino-Nasal Outcome Test 22 score decreased from 41.8 ± 15.8 pre-operatively to 13.3 ± 9.5 post-operatively (p < 0.001). Accordingly, the mean endoscopic score decreased from 6.8 ± 1.8 to 0.2 ± 0.7 (p < 0.001). The mean intra-operative pain score was 2.9 ± 3.2, and 29 patients (96.7 per cent) reported no pain in the post-operative period (visual analogue scale score = 0). CONCLUSION: Our study confirms that minimally invasive surgery represents a safe, repeatable procedure that results in remarkable subjective and objective improvement, without intra- and post-operative pain or discomfort.

Antioxidants in the Diet and Cognitive Function: Which Role for the Mediterranean Life-style?

This review aims to focus on main antioxidants- abundantly contained in the diet- as well as of the whole Mediterranean diet and life-style and their relationship with cognitive function, especially critical in two phases of life, in children until adolescence and oldness. The role of emerging biochemical and molecular biomarkers as opportunity to estimate more accurately nutritional assumption and requirement, in terms of cognitive preservation and disease risk, will be also discussed. The cluster of factors within the Mediterranean pattern -which include not only nutritional, but also physical, social, and stimulating aspects- is still largely understudied as a whole, but it is proposed as attractive research area and tool for public health planning of prevention and intervention.

A reddish pulsatile mass beyond tympanic membrane: think before act.

We report a case of a 76-year-old man that referred to our hospital because of progressive mixed right hearing loss, aural fullness and pulsatile tinnitus synchronized with heart beats. Otoscopic examination revealed a reddish pulsatile mass beyond tympanic membrane. CT and MRI scans showed a class C glomus tumor. Anamnesis and a complete physical examination, with careful differential diagnosis, should be obtained to rule out highly vascularized middle ear lesion before any invasive procedure.

Breathing training on lower esophageal sphincter as a complementary treatment of gastroesophageal reflux disease (GERD): a systematic review.

OBJECTIVE: Gastroesophageal reflux disease (GERD) represents one of the most common gastrointestinal disorders, but is still a challenge to cure. Proton pump inhibitors (PPIs) are currently the GERD's standard treatment, although not successful in all patients; some concerns have been raised regarding their long term consumption. Recently, some studies showed the benefits of inspiratory muscle training in increasing the lower esophageal sphincter pressure in patients affected by GERD, thereby reducing their symptoms. MATERIALS AND METHODS: Relevant published studies were searched in Pubmed, Google Scholar, Ovid or Medical Subject Headings using the following keywords: "GERD" and physiotherapy", "GERD" and "exercise", "GERD" and "breathing", "GERD and "training". RESULTS: At the end of our selection process, four publications have been included for systematic review. All of them were prospective controlled studies, mainly based on the training of the diaphragm muscle. GERD symptoms, pH-manometry values and PPIs usage were assessed. CONCLUSIONS: Among the non-surgical, non-pharmacological treatment modalities, the breathing training on diaphragm could play an important role in selected patients to manage the symptoms of GERD.

The miR-27a-calreticulin axis affects drug-induced immunogenic cell death in human colorectal cancer cells.

Immunogenic cell death (ICD) evoked by chemotherapeutic agents implies emission of selected damage-associated molecular patterns (DAMP) such as cell surface exposure of calreticulin, secretion of ATP and HMGB1. We sought to verify whether miR-27a is implicated in ICD, having demonstrated that it directly targets calreticulin. To this goal, we exposed colorectal cancer cell lines, genetically modified to express high or low miR-27a levels, to two bona fide ICD inducers (mitoxantrone and oxaliplatin). Low miR-27a-expressing cells displayed more ecto-calreticulin on the cell surface and increased ATP and HMGB1 secretion than high miR-27a-expressing ones in time-course experiments upon drug exposure. A calreticulin target protector counteracted the miR-27a effects while specific siRNAs mimicked them, confirming the results reported. In addition, miR-27a negatively influenced the PERK-mediated route and the late PI3K-dependent secretory step of the unfolded protein response to endoplasmic reticulum stress, suggesting that miR-27a modulates the entire ICD program. Interestingly, upon chemotherapeutic exposure, low miR-27a levels associated with an earlier and stronger induction of apoptosis and with morphological and molecular features of autophagy. Remarkably, in ex vivo setting, under the same chemotherapeutic induction, the conditioned media from high miR-27a-expressing cells impeded dendritic cell maturation while increased the secretion of specific cytokines (interleukin (IL)-4, IL-6, IL-8) and negatively influenced CD4(+) T-cell interferon γ production and proliferation, all markers of a tumor immunoevasion strategy. In conclusion, we provide the first evidence that miR-27a impairs the cell response to drug-induced ICD through the regulatory axis with calreticulin.

Proteomic screening identifies calreticulin as a miR-27a direct target repressing MHC class I cell surface exposure in colorectal cancer.

Impairment of the immune response and aberrant expression of microRNAs are emerging hallmarks of tumour initiation/progression, in addition to driver gene mutations and epigenetic modifications. We performed a preliminary survey of independent adenoma and colorectal cancer (CRC) miRnoma data sets and, among the most dysregulated miRNAs, we selected miR-27a and disclosed that it is already upregulated in adenoma and further increases during the evolution to adenocarcinoma. To identify novel genes and pathways regulated by this miRNA, we employed a differential 2DE-DIGE proteome analysis. We showed that miR-27a modulates a group of proteins involved in MHC class I cell surface exposure and, mechanistically, demonstrated that calreticulin is a miR-27a direct target responsible for most downstream effects in epistasis experiments. In vitro miR-27a affected cell proliferation and angiogenesis; mouse xenografts of human CRC cell lines expressing different miR-27a levels confirmed the protein variations and recapitulated the cell growth and apoptosis effects. In vivo miR-27a inversely correlated with MHC class I molecules and calreticulin expression, CD8(+) T cells infiltration and cytotoxic activity (LAMP-1 exposure and perforin release). Tumours with high miR-27a, low calreticulin and CD8(+) T cells' infiltration were associated with distant metastasis and poor prognosis. Our data demonstrate that miR-27a acts as an oncomiRNA, represses MHC class I expression through calreticulin downregulation and affects tumour progression. These results may pave the way for better diagnosis, patient stratification and novel therapeutic approaches.

Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes.

Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.

Evidence that atrial natriuretic peptide tissue extraction is not changed by large increases in its plasma levels induced by pacing in humans.

Atrial natiurectic peptide (ANP) is a cardiac hormone with a very short plasma half-life, which plays an important role in a variety of clinical conditions associated with an increase in pressure and/or volume overload on the heart. The MCR of the hormone is considered to represent a stable parameter, reflecting the uptake and degradation rate of ANP by the periphery, only scarcely affected by rapid oscillations of circulating levels. To evaluate the extent to which MCR is affected by rapid and large variations of circulating levels of the hormone, we measured MCR in five patients with different degrees of myocardial function (from normal to severely impaired), in whom changes in ANP levels were induced by atrial and/or ventricular pacing. Cardiac output was simultaneously measured by thermodilution to calculate whole body extraction of ANP. During constant i.v. infusion of [125I]ANP, the hormone MCR was determined both under basal conditions (at tracer equilibration, 20-30 min after the start of infusion) and during atrial and ventricular pacing. Pacing maneuvers, begun 50 min after the start of infusion, induced a marked and rapid increase in endogenous plasma ANP values in all patients (on the average, 3,7-fold compared to basal values; range, 1.8-5.68), whereas corresponding values of [125I]ANP only minimally changed. The MCR of ANP (3.62 +/- 1.06 L/min, mean +/- SD) slightly decreased (by repeated measures ANOVA, P = 0.0458) during atrial and ventricular pacing procedures (3.35 +/- 1.03 and 3.15 +/- 0.74 L/min, respectively), reaching a mean value of 88.7 +/- 9.0% compared to basal. The small decrease in MCR could be almost completely ascribed to hemodynamic factors; indeed, basal cardiac output (5.76 +/- 1.70 L/min) was found, on the average, to be slightly decreased during atrial and ventricular pacing (5.28 +/- 1.46 and 5.16 +/- 1.33 L/min, respectively), and so whole body extraction of the hormone, measured before pacing (50.0 +/- 12%), remains stable throughout the study period (50.4 +/- 10.6% and 49.6 +/- 10% during atrial and ventricular pacing, respectively). Our findings demonstrate that degradative mechanisms involved in ANP clearance are not saturable at least for acute elevations of ANP plasma levels up to 3-5 times the basal level.