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Introduction: Blood pressure (BP) regulation is a complex process involving several factors, among which water-sodium balance holds a prominent place. Arginin-vasopressin (AVP), a key player in water metabolism, has been evoked in hypertension development since the 1980s, but, to date, the matter is still controversial. Hyaluronic acid metabolism has been reported to be involved in renal water management, and AVP appears to increase hyaluronidase activity resulting in decreased high-molecular-weight hyaluronan content in the renal interstitium, facilitating water reabsorption in collecting ducts. Hence, our aim was to evaluate urinary hyaluronidase activity in response to an oral water load in hypertensive patients (HT, n=21) compared to normotensive subjects with (NT+, n=36) and without (NT-, n=29) a family history of hypertension, and to study its association with BP and AVP system activation, expressed by serum copeptin levels and urine Aquaporin 2 (AQP2)/creatinine ratio., Methods: Eighty-six Caucasian men were studied. Water load test consisted in oral administration of 15-20 ml of water/kg body weight over 40-45 min. BP, heart rate, serum copeptin, urine hyaluronidase activity and AQP2 were monitored for 4 hours., Results: In response to water drinking, BP raised in all groups with a peak at 20-40 min. Baseline levels of serum copeptin, urinary hyaluronidase activity and AQP2/creatinine ratio were similar among groups and all decreased after water load, reaching their nadir at 120 min and then gradually recovering to baseline values. Significantly, a blunted reduction in serum copeptin, urinary hyaluronidase activity and AQP2/creatinine ratio was observed in NT+ compared to NT- subjects. A strong positive correlation was also found between urinary hyaluronidase activity and AQP2/creatinine ratio, and, although limited to the NT- group, both parameters were positively associated with systolic BP., Discussion: Our results demonstrate for the first time the existence in men of a close association between urinary hyaluronidase activity and vasopressinergic system and suggest that NT+ subjects have a reduced ability to respond to water loading possibly contributing to the blood volume expansion involved in early-stage hypertension. Considering these data, AVP could play a central role in BP regulation by affecting water metabolism through both hyaluronidase activity and AQP2 channel expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Calvi, Bongrani, Verzicco, Figus, Vicini, Coghi, Montanari and Cabassi.)

Background: Physical symptoms play an important role in late-life depression and may contribute to residual symptomatology after antidepressant treatment. In this exploratory study, we examined the role of specific bodily dimensions including movement, respiratory functions, fear of falling, cognition, and physical weakness in older people with depression., Methods: Clinically stable older patients with major depression within a Psychiatric Consultation-Liaison program for Primary Care underwent comprehensive assessment of depressive symptoms, instrumental movement analysis, dyspnea, weakness, activity limitations, cognitive function, and fear of falling. Network analysis was performed to explore the unique adjusted associations between clinical dimensions., Results: Sadness was associated with worse turning and walking ability and movement transitions from walking to sitting, as well as with worse general cognitive abilities. Sadness was also connected with dyspnea, while neurovegetative depressive burden was connected with activity limitations., Discussion: Limitations of motor and cognitive function, dyspnea, and weakness may contribute to the persistence of residual symptoms of late-life depression.

Background: Hypotensive susceptibility in hypertensive patients could facilitate orthostatic hypotension, syncope and fall. The aim of this study was to identify incidence, clinical form, complications and risk factors for non-cardiac syncope in a cohort of hypertensive patients., Methods: This is an observational, case-controlled, retrospective study carried out on 168 patients, evaluated at the Hypertension Center of the University Hospital of Parma (Italy). Based on the presence of episodes of syncope during the six months prior to enrolment, we identified cases and controls and then we compared them to personal data, comorbidities, current drug regimens, presence of orthostatic hypotension, office and ambulatory blood pressure monitoring (ABPM) blood pressure (BP) values., Results: In patients with previous syncopal episodes (29.8% of total), we more frequently found female gender, comorbidities associated with autonomic dysfunction, diuretics and non-CV drugs potentially associated with hypotension in their current drug regimen, orthostatic hypotension and lower office and ABPM BP values., Conclusions: To identify hypertensive patients at higher risk for syncope and falls, physicians should focus on comorbidities and current drug regimens, systematically perform an active standing test to identify orthostatic hypotension, employ ABPM to compare BP values with the pre-established target and highlight systolic BP drops and abnormalities suggesting concomitant autonomic dysfunction. The modulation of antihypertensive therapy is an effective tool to counteract the risk of non-cardiac syncope, with possible trauma or other negative influences.

Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739)., Competing Interests: This work was supported by the Marie Ingalls Cardiovascular Research Career Development Award in honor of Dr Alexander Schirger, Mayo Clinic CV Circulatory Program Award, and Scientist Development Award of the American Heart Association 16SDG29930003 (to Dr Cannone); Postdoctoral Fellowship 903661 (to Dr Ma) from the American Heart Association; and grants R01HL134668 and R01HL136340 (to Dr Burnett) from the National Heart, Lung and Blood Institute. Dr Burnett is the inventor of MANP, which the Mayo Clinic has licensed to E-STAR BIO TECH. All other authors have reported that they have no relationships relevant to the contents in this paper to disclose., (© 2024 The Authors.)

Objective: There is still uncertainty about the management of patients with pheochromocytoma-induced cardiogenic shock (PICS). This study aims to investigate the clinical presentation, management, and outcome of patients with PICS., Methods: We collected, retrospectively, the data of 18 patients without previously known pheochromocytoma admitted to 8 European hospitals with a diagnosis of PICS., Results: Among the 18 patients with a median age of 50 years (Q1-Q3: 40-61), 50% were men. The main clinical features at presentation were pulmonary congestion (83%) and cyclic fluctuation of hypertension peaks and hypotension (72%). Echocardiography showed a median left ventricular ejection fraction (LVEF) of 25% (Q1-Q3: 15-33.5) with an atypical- Takotsubo (TTS) pattern in 50%. Inotropes/vasopressors were started in all patients and temporary mechanical circulatory support (t-MCS) was required in 11 (61%) patients. All patients underwent surgical removal of the pheochromocytoma; 4 patients (22%) were operated on while under t-MCS. The median LVEF was estimated at 55% at discharge. Only one patient required heart transplantation (5.5%), and all patients were alive at a median follow-up of 679 days., Conclusions: PICS should be suspected in case of a CS with severe cyclic blood pressure fluctuation and rapid hemodynamic deterioration, associated with increased inflammatory markers or in case of TTS progressing to CS, particularly if an atypical TTS echocardiographic pattern is revealed. T-MCS should be considered in the most severe cases. The main challenge is to stabilize the patient, with medical therapy or with t-MCS, since it remains a reversible cause of CS with a low mortality rate., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The effects of excitability, refractoriness, and impulse conduction have been independently related to enhanced arrhythmias in the aged myocardium in experimental and clinical studies. However, their combined arrhythmic effects in the elderly are not yet completely understood. Hence, the aim of the present work is to relate relevant cardiac electrophysiological parameters to enhanced arrhythmia vulnerability in the in vivo senescent heart. We used multiple-lead epicardial potential mapping in control (9-month-old) and aged (24-month-old) rat hearts. Cardiac excitability and refractoriness were evaluated at numerous epicardial test sites by means of the strength-duration curve and effective refractory period, respectively. During sinus rhythm, durations of electrogram intervals and waves were prolonged in the senescent heart, compared with control, demonstrating a latency in tissue activation and recovery. During ventricular pacing, cardiac excitability, effective refractory period, and dispersion of refractoriness increased in the aged animal. This scenario was accompanied by impairment of impulse propagation. Moreover, both spontaneous and induced arrhythmias were increased in senescent cardiac tissue. Histopathological evaluation of aged heart specimens revealed connective tissue deposition and perinuclear myocytolysis in the atria, while scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium. This work suggests that enhanced arrhythmogenesis in the elderly is a multifactorial process due to the joint increase in excitability and dispersion of refractoriness in association with enhanced conduction inhomogeneity. The knowledge of these electrophysiological changes will possibly contribute to improved prevention of the age-associated increase in cardiac arrhythmias., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (prehypertensive phase) to SHR's 28-30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28-30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Verzicco, Tedeschi, Graiani, Bongrani, Carnevali, Dancelli, Zappa, Mattei, Bovino, Cavazzini, Rocco, Calvi, Palladini, Volpi, Cannone, Coghi, Borghetti and Cabassi.)

Background: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature., Methods/results: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention., Conclusions: We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features., (© 2022. The Author(s).)

The human right ventricle is barely monitored during open-chest surgery due to the absence of intraoperative imaging techniques capable of elaborating its complex function. Accordingly, artificial intelligence could not be adopted for this specific task. We recently proposed a video-based approach for the real-time evaluation of the epicardial kinematics to support medical decisions. Here, we employed two supervised machine learning algorithms based on our technique to predict the patients' outcomes before chest closure. Videos of the beating hearts were acquired before and after pulmonary valve replacement in twelve Tetralogy of Fallot patients and recordings were properly labeled as the "unhealthy" and "healthy" classes. We extracted frequency-domain-related features to train different supervised machine learning models and selected their best characteristics via 10-fold cross-validation and optimization processes. Decision surfaces were built to classify two additional patients having good and unfavorable clinical outcomes. The k-nearest neighbors and support vector machine showed the highest prediction accuracy; the patients' class was identified with a true positive rate ≥95% and the decision surfaces correctly classified the additional patients in the "healthy" (good outcome) or "unhealthy" (unfavorable outcome) classes. We demonstrated that classifiers employed with our video-based technique may aid cardiac surgeons in decision making before chest closure.

Purpose: Pheochromocytoma, a catecholamine-secreting tumour leading to neurological and cardiovascular life-threatening conditions through hypertension crisis, occurs in 0.1-0.5% of hypertensive patients, but it is extremely rare in pregnancy (0.0018-0.006%). Some classes of drugs, even commonly used in pregnancy, can trigger catecholamine secretion, precipitating the clinical situation., Materials and Methods and Results: We report a 33-year-old woman, gravida 2 para 1, with previous mild hypertension, was admitted to the emergency room, at 28 2/7 weeks of gestation due to headache, tachycardia and severe arterial hypertension (220/120 mm Hg) triggered by the antiemetic metoclopramide used for a week because of nausea. In the emergency room, a paradoxical rise in blood pressure followed intravenous labetalol infusion was observed. Both metoclopramide and labetalol-triggered hypertensive crisis raised the suspicion of an undiagnosed pheochromocytoma. Diagnostic work-up showed elevated normetanephrine urinary excretion ​​and a right adrenal pheochromocytoma by abdominal magnetic resonance imaging. Oral alpha-1 and beta-1-adrenergic antagonist and calcium-channel blocker were started. At 33-weeks of gestation, she underwent a caesarean section giving birth to a female child. Seven weeks later she underwent a video-laparoscopic right adrenalectomy which normalised her blood pressure., Conclusions: Both metoclopramide, a selective dopamine type-2 receptor antagonist and partial agonist of 5-hydroxytryptamine 4 receptor, and labetalol, a non-selective β-adrenoreceptor-blocker with weak α1-adrenergic antagonism, exacerbated an acute hypertensive crisis revealing an unrecognised pheochromocytoma in a pregnant patient. Careful attention to potential drug-triggered catecholamine crises and especially early recognition of pheochromocytomas, are mandatory in hypertensive pregnant women. A missed or delayed diagnosis could result in catastrophic results affecting foetal and maternal outcomes.

Individuals suffering from depressive disorders display a greater incidence of hypertension compared with the general population, despite reports of the association between depression and hypotension. This phenomenon may depend, at least in part, on the use of antidepressant drugs, which may influence blood pressure through different effects on adrenergic and serotoninergic pathways, as well as on histaminergic, dopaminergic, and cholinergic systems. This review summarizes extant literature on the effect of antidepressant drugs on blood pressure. Selective serotonin reuptake inhibitors are characterized by limited effects on autonomic system activity and a lower impact on blood pressure. Thus, they represent the safest class-particularly among elderly and cardiovascular patients. Serotonin-norepinephrine reuptake inhibitors, particularly venlafaxine, carry a greater risk of hypertension, possibly related to greater effects on the sympathetic nervous system. The norepinephrine reuptake inhibitor reboxetine is considered a safe option because of its neutral effects on blood pressure in long-term studies, even if both hypotensive and hypertensive effects are reported. The dopamine-norepinephrine reuptake inhibitor bupropion can lead to blood pressure increases, usually at high doses, but may also cause orthostatic hypotension, especially in patients with cardiovascular diseases. The norepinephrine-serotonin modulators, mirtazapine and mianserin, have minimal effects on blood pressure but may rarely lead to orthostatic hypotension and falls. These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone. Agomelatine, the only melatonergic antidepressant drug, may also have limited effects on blood pressure. Tricyclic antidepressants have been associated with increases in blood pressure, as well as orthostatic hypotension, particularly imipramine. Oral monoamine-oxidase inhibitors, less frequently skin patch formulations, have been associated with orthostatic hypotension or, conversely, with hypertensive crisis due to ingestion of tyramine-containing food (i.e., cheese reaction). Lastly, a hypertensive crisis may complicate antidepressant treatment as a part of the serotonin syndrome, also including neuromuscular, cognitive, and autonomic dysfunctions. Clinicians treating depressive patients should carefully consider their blood pressure status and cardiovascular comorbidities because of the effects of antidepressant drugs on blood pressure profiles and potential interactions with antihypertensive treatments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Calvi, Fischetti, Verzicco, Belvederi Murri, Zanetidou, Volpi, Coghi, Tedeschi, Amore and Cabassi.)

Background Fibromuscolar dysplasia (FMD) is an idiopathic, non-atherosclerotic and non-inflammatory stenotic lesion of renal arteries causing renovascular hypertension up-regulating renin-angiotensin-aldosterone system. Case report: A 18-year-old man was referred to our Hypertension Center (Clinica e Terapia Medica) for the recent onset of hypertension, poorly controlled on calcium channel blockers, already associated to electrocardiographic and echocardiography signs of left ventricular hypertrophy and significant albuminuria (728 mg/24 h). An increased plasma renin activity (PRA), aldosterone level and a mild hypokalemia raised the suspicion of renovascular hypertension. Abdominal CT and MRI angiography showed mild kidneys asymmetry and a tubular stenosis of the right renal artery in its mid-distal portion close to renal hilum. Radionuclide renal scintigraphy documented a kidneys asymmetry of separated glomerular filtration rate. Renal FMD was diagnosed based on patient age and the absence of cardiovascular risk factors for atherosclerosis. Patient successfully underwent right renal angioplasty giving a rapid normalization of blood pressure levels without antihypertensive drugs. Plasma aldosterone and PRA rapidly normalized as well as serum potassium levels. Six months after angioplasty echocardiography showed a regression of left ventricular hypertrophy and the patient albumin urine excretion became normal (14 mg/24 h). Conclusions FMD can cause renovascular hypertension associated to organ damage such myocardial hypertrophy and albuminuria through mechanisms dependent but also independent from blood pressure levels. Renal angioplasty turned off renin-angiotensin-aldosterone overactivity allowing the cure the hypertension and a surprisingly rapid reverse of myocardial hypertrophy and of excess of albumin urine excretion not only dependent on blood pressure normalization.

Background: Pheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP)., Clinical Case: A 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on 68 GaDOTA-octreotate positron emission tomography. Metastasis in lumbar region and lung were present. Both chromogranin A and VIP levels were high (more than10 times the normal value) with slightly elevated urine normetanephrine and metanephrine excretion. Right adrenalectomy was performed and a somatostatin analogue therapy with lanreotide started. Immunostaining showed chromogranin A and VIP co-expression, with weak somatostatin-receptor-2A positivity. In two months, patient clinical conditions deteriorated with severe WDHA and multiple liver and lung metastasis. Metabolic acidosis and hypokalemia worsened, leading to hemodynamic shock and exitus., Conclusions: A rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Negro, Verzicco, Tedeschi, Campanini, Zanelli, Negri, Farnetti, Nicoli, Palladini, Santi, Cunzi, Calvi, Coghi, Gerra, Volpi, Graiani and Cabassi.)

Motivation: Diverse applications-particularly in tumour subtyping-have demonstrated the importance of integrative clustering techniques for combining information from multiple data sources. Cluster Of Clusters Analysis (COCA) is one such approach that has been widely applied in the context of tumour subtyping. However, the properties of COCA have never been systematically explored, and its robustness to the inclusion of noisy datasets is unclear., Results: We rigorously benchmark COCA, and present Kernel Learning Integrative Clustering (KLIC) as an alternative strategy. KLIC frames the challenge of combining clustering structures as a multiple kernel learning problem, in which different datasets each provide a weighted contribution to the final clustering. This allows the contribution of noisy datasets to be down-weighted relative to more informative datasets. We compare the performances of KLIC and COCA in a variety of situations through simulation studies. We also present the output of KLIC and COCA in real data applications to cancer subtyping and transcriptional module discovery., Availability and Implementation: R packages klic and coca are available on the Comprehensive R Archive Network., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press.)

The role of mitochondria in cardiac tissue is of utmost importance due to the dynamic nature of the heart and its energetic demands, necessary to assure its proper beating function. Recently, other important mitochondrial roles have been discovered, namely its contribution to intracellular calcium handling in normal and pathological myocardium. Novel investigations support the fact that during the progression toward heart failure, mitochondrial calcium machinery is compromised due to its morphological, structural and biochemical modifications resulting in facilitated arrhythmogenesis and heart failure development. The interaction between mitochondria and sarcomere directly affect cardiomyocyte excitation-contraction and is also involved in mechano-transduction through the cytoskeletal proteins that tether together the mitochondria and the sarcoplasmic reticulum. The focus of this review is to briefly elucidate the role of mitochondria as (mechano) sensors in the heart., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review., (© 2020 The authors.)

The use of antineoplastic drugs has a central role in treatment of patients affected by cancer but is often associated with numerous electrolyte derangements which, in many cases, could represent life-threatening conditions. In fact, while several anti-cancer agents can interfere with kidney function leading to acute kidney injury, proteinuria, and hypertension, in many cases alterations of electrolyte tubular handling and water balance occur. This review summarizes the mechanisms underlying the disturbances of sodium, potassium, magnesium, calcium, and phosphate metabolism during anti-cancer treatment. Platinum compounds are associated with sodium, potassium, and magnesium derangements while alkylating agents and Vinca alkaloids with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Novel anti-neoplastic agents, such as targeted therapies (monoclonal antibodies, tyrosine kinase inhibitors, immunomodulators, mammalian target of rapamycin), can induce SIADH-related hyponatremia and, less frequently, urinary sodium loss. The blockade of epidermal growth factor receptor (EGFR) by anti-EGFR antibodies can result in clinically significant magnesium and potassium losses. Finally, the tumor lysis syndrome is associated with hyperphosphatemia, hypocalcemia and hyperkalemia, all of which represent serious complications of chemotherapy. Thus, clinicians should be aware of these side effects of antineoplastic drugs, in order to set out preventive measures and start appropriate treatments., (Copyright © 2020 Verzicco, Regolisti, Quaini, Bocchi, Brusasco, Ferrari, Passeri, Cannone, Coghi, Fiaccadori, Vignali, Volpi and Cabassi.)

Background: Posterior reversible encephalopathy (PRES) is a rare syndrome characterized by headache, confusion, seizures, visual changes and white matter edema at radiological imaging. Its pathophysiology is not clarified and different causes, including uncontrolled hypertension, eclampsia, chemotherapy and hypomagnesemia have been suggested., Case Report: A woman affected by stage IV breast cancer with lower extremity deep vein thrombosis treated with low-molecular-weight-heparin, currently in therapy with Palbociclib/Fulvestrant (antiCDK4 and 6/estrogen receptor antagonist) but previously treated with several other chemotherapy lines (including VEGF inhibitor bevacizumab), was admitted to our Internal Medicine department because of ascites and abdominal pain. She was treated with diuretics (and paracentesis). Recently (six-month earlier) a pan-encephalic radiotherapy was done because of brain and skull metastasis. Among blood tests, low serum levels of hypomagnesemia were observed. She developed PRES that rapidly progressed to lethargy, unresponsiveness till coma without changes in blood pressure. Magnetic Resonance Imaging study showed bilateral parieto-occipital edema and a thrombosis of left transverse and sigmoid sinuses. Anti-edema therapy, intravenous supplementation of magnesium and decoagulation were started, with complete and rapid recovery (within 18 hours) of clinical and radiologic changes., Conclusions: PRES diagnosis was based on the rapid clinical recovery after antiedema treatment and magnesium supplementation. Low magnesium level related to both diuretic and Fulvestrant/Palbociclib therapies and recent radiotherapy can represent potential mechanisms favouring PRES development. The previous bevacizumab treatment may also be involved as a PRES predisposing factor. The concomitant occurrence of cerebral thrombosis can have precipitated the clinical situation.

Excessive or inappropriate use of non-steroidal anti-inflammatory drugs can affect cardiovascular and renal function. Non-steroidal anti-inflammatory drugs, both non-selective and selective cyclooxygenase 2 inhibitors, are among the most widely used drugs, especially in the elderly, with multiple comorbidities. Exposition to a polypharmacy burden represents a favourable substrate for the onset of non-steroidal anti-inflammatory drug-induced deleterious effects. Cardiovascular and renal issues concerning the occurrence of myocardial infarction, atrial fibrillation, heart failure and arterial hypertension, as well as acute or chronic kidney damage, become critical for clinicians in their daily practice. We discuss current available knowledge regarding prostanoid physiology in vascular, cardiac and renal systems, pointing out potential negative non-steroidal anti-inflammatory drug-related issues in clinical practice.

Background: Mutations of genes related to Krebs cycle enzymes, kinases or to pseudohypoxic signaling pathways, including Von-Hippel-Lindau (VHL) and transmembrane-protein-127 predispose to pheochromocytoma and paraganglioma development. Homozygous loss of function mutation of VHL (VHL 598C>T) gene can associate with polycythemia because of an altered hypoxia sensing., Patient: A 19-year-old normotensive man presented with headache, fatigue associated with severe erythrocytosis (hematocrit 76%), high hemoglobin (25.3 g/dl) in normoxic condition. Bone marrow biopsy showed marked hyperplasia of erythroid series. The Janus kinase 2 (V617F) mutation was absent. Abdominal computed tomography scan showed a 8-mm left adrenal pheochromocytoma with tracer uptake on GaDOTA-octreotate PET. Twenty-four-hour urinary metanephrine excretion was slightly increased, while normetanephrine, 3-methoxytyramine were normal. Adrenal veins sampling showed high left-side erythropoietin secretion., Results: Next-generation sequencing genetic analysis evidenced two concurrent heterozygous mutation of VHL598C>T and of transmembrane-protein-127 c.268G>A. Left side adrenalectomy improved symptoms, erythrocytosis, hemoglobin, and erythropoietin circulating levels. Adrenal histologic sections showed a pheochromocytoma with extensive immunostaining for erythropoietin, but also coexpression of chromogranin A, a marker of chromaffin tissue., Conclusion: Congenital polycythemia was clinically diagnosed, mimicking Chuvash polycythemia. Chuvash polycythemia is an autosomal recessive disorder that usually harbors a homozygous mutation of VHL598C>T but not predispose to pheochromocytoma development; in contrast our patient showed for the first time that the concurrent heterozygous VHL and TMEM mutations, resulted in a clinical phenotype of a normotensive patient with polycythemia due to erythropoietin-secreting pheochromocytoma that improved after adrenalectomy.

Treatment guidelines for patients with schizophrenia recommend evaluating their risk of physical comorbidities, especially since these patients are known to have decreased life expectancy due to comorbidities. Therefore, to the authors' knowledge, this is the first national survey conducted to investigate how Italian psychiatrists deal with the risk of physical comorbidities and sexual dysfunction in patients with schizophrenia. A sample of 750 psychiatrists completed an ad hoc online survey investigating their decision making about performing blood tests, clinical and instrumental examinations, and scheduling follow-up appointments in relation to the different phases of the illness and possible pharmacological side effects. Compared to patients in therapeutic continuation, those diagnosed for the first time and those who received a therapeutic change were visited more frequently (every 15 to 17 days vs. every 40 days, respectively), and were more regularly prescribed blood tests and instrumental examinations (every 4.2 to 4.4 months vs. every 9 months, respectively). There was a high interest in the surveillance of cardiometabolic risk. In 54% of patients, prolactin testing was not requested before starting an antipsychotic. In terms of specialist referrals, only 5% of surveyed psychiatrists "never" sought for additional counseling. There was little attention given to sexual functioning assessment based on the survey results about patients' daily life and with regard to deciding to prescribe additional examinations. In fact, only up to 3% of psychiatrists reported assessing sexual functioning using specific psychometric tests. In summary, Italian psychiatrists describes themselves as careful healthcare providers for the physical illnesses of patients with schizophrenia but with several shortcomings. For instance, clinical attention toward patients' sexual and reproductive healthcare needs remains a challenge. Psychiatrists should take the lead for the integrated education, assessment, and care of medical needs of their patients with mental illness. Based on the results of this survey, the authors also believe that a future challenge for the management of patients with mental illness will be the classification of patients based on their risk of comorbidities, to help ensure optimal healthcare provision for those at greater risk of other illnesses., (Copyright © 2019 Monteleone, Amore, Cabassi, Clerici, Fagiolini, Girardi, Jannini, Maina, Rossi, Vita and Siracusano.)

Atrial natriuretic peptide (ANP) is a cardiac hormone with pleiotropic cardiovascular and metabolic properties including vasodilation, natriuresis and suppression of the renin-angiotensin-aldosterone system. Moreover, ANP induces lipolysis, lipid oxidation, adipocyte browning and ameliorates insulin sensitivity. Studies on ANP genetic variants revealed that subjects with higher ANP plasma levels have lower cardio-metabolic risk. In vivo and in humans, augmenting the ANP pathway has been shown to exert cardiovascular therapeutic actions while ameliorating the metabolic profile. MANP is a novel designer ANP-based peptide with greater and more sustained biological actions than ANP in animal models. Recent studies also demonstrated that MANP lowers blood pressure and inhibits aldosterone in hypertensive subjects whereas cardiometabolic properties of MANP are currently tested in an on-going clinical study in hypertension and metabolic syndrome. Evidence from in vitro, in vivo and in human studies support the concept that ANP and related pathway represent an optimal target for a comprehensive approach to cardiometabolic disease., Competing Interests: Mayo Clinic has licensed MANP to Zumbro Discovery; John C. Burnett Jr. is Co-Founder of Zumbro Discovery and holds equity.

Background: Physical exercise is increasingly recognized as a treatment for major depression, even among older patients. However, it is still unknown which depressive symptoms exercise affects most, (e.g. somatic vs. affective) and the timing of its effects. Thus, the aim of this study was to examine the changes of depressive symptoms after treatment with exercise., Methods: We analyzed data from the SEEDS study, a trial comparing the antidepressant effectiveness of sertraline (S) and sertraline plus exercise (S+EX). Exercise was delivered thrice weekly in small groups and monitored by heart rate meters. Patients with late life depression (n=121) were assessed at baseline, 4, 8, 12 and 24 weeks with the Hamilton Depression Scale. Scores of affective, vegetative, anxiety and agitation/insight factors were analyzed using Multilevel Growth Curve Models and sensitivity analyses (multiple imputation)., Results: Compared with the S group, patients in the S+EX group displayed significantly greater improvements of the affective symptom dimension (total effect size = 0.79) with largest changes in the first 4 weeks and last 12 weeks. Improvements were mainly driven by depressed mood and psychomotor retardation., Limitations: Sample size; lack of an exercise only treatment arm CONCLUSIONS: Adding exercise to antidepressant drug treatment may offer significant advantages over affective symptoms of depression, rather than somatic symptoms or other dimensions of depression. Compared with standard antidepressant treatment, clinical advantages should be expected both at an early (first 4 weeks) and later stage (after 12 weeks)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Dyspnea is one of the most frequent causes of admission in Internal Medicine wards, leading to a sizeable utilization of medical resources., Study Design and Methods: The role of bedside lung ultrasound (LUS) was evaluated in 130 consecutive patients (age: 81±9years), in whom blindly collected LUS results were compared with data obtained by clinical examination, medical history, blood analysis, and chest X-ray. Dyspnea etiology was classified as "cardiac" (n=80), "respiratory" (n=36) or "mixed" (n=14), according to the discharge diagnosis (congestive heart failure either alone [n=80] or associated with pneumonia [n=14], pneumonia [n=24], and obstructive disventilatory syndrome [n=12]). An 8-window LUS protocol was applied to evaluate B-line distribution, "interstitial syndrome" pattern, pleural effusion and images of static or dynamic air bronchogram/focal parenchymal consolidation., Results: The presence of a generalized "interstitial syndrome" at the initial LUS evaluation allowed to discriminate "cardiac" from "pulmonary" Dyspnea with high sensitivity (93.75%; confidence intervals: 86.01%-97.94%) and specificity (86.11%; 70.50%-95.33%). Positive and negative predictive values were 93.76% (86.03%-97.94%) and 86.09% (70.47%-95.32%), respectively. Moreover, LUS diagnostic accuracy for the diagnosis of pneumonia was not inferior to that of chest X-ray., Conclusions: Bedside LUS evaluation contributes with high sensitivity and specificity to the differential diagnosis of Dyspnea. This holds true not only in the emergency setting, but also in the sub-acute Internal Medicine arena. A wider use of this portable technique in our wards is warranted., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The heart consists of millions of cells, namely cardiomyocytes, which are highly organized in terms of structure and function, at both macroscale and microscale levels. Such meticulous organization is imperative for assuring the physiological pump-function of the heart. One of the key players for the electrical and mechanical synchronization and contraction is the calcium ion via the well-known calcium-induced calcium release process. In cardiovascular diseases, the structural organization is lost, resulting in morphological, electrical, and metabolic remodeling owing the imbalance of the calcium handling and promoting heart failure and arrhythmias. Recently, attention has been focused on the role of mitochondria, which seem to jeopardize these events by misbalancing the calcium processes. In this review, we highlight our recent findings, especially the role of mitochondria (dys)function in failing cardiomyocytes with respect to the calcium machinery., Competing Interests: The authors declare no conflict of interest.

Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 μg·kg -1 ·min -1 N G -nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP ( P < 0.005 vs. baseline), -10% GFR, -20% RBF, -49% UNaV ( P < 0.001), and +120% U8-iso-PGF2αV ( P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME ( P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (-6%), RBF (-12%), and UNaV (-34%) were blunted vs. PL + l-NAME and LOS + l-NAME ( P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability., (Copyright © 2017 the American Physiological Society.)

Background: Acute kidney injury (AKI) following major heart surgery (MHS) is associated with early decrease in renal blood flow and worsened prognosis. Doppler-derived renal resistive index (RRI), which reflects renal vascular resistance, may predict the development of AKI in patients undergoing MHS., Methods: We studied 60 consecutive patients (mean age 69.5 years, range 30-88, 41 males) undergoing MHS. We measured RRI, both at the renal sinus and intraparenchymally, by transesophageal echo-Doppler ultrasound (TE-ED us ) at anesthesia induction and at the end of surgery in all patients. Additionally, we measured RRI by external transparietal echo-Doppler ultrasound (TP-ED us ) at the following time points: anesthesia induction, end of surgery, 4 and 24 h from cardiopulmonary bypass (CPB) start. We also measured serum neutrophil gelatinase associated lipocalin (NGAL) at the same time points., Results: AKI [serum creatinine (sCr) increase ≥0.3 mg/dl vs. baseline within 72 h] developed in 23/60 (38.3 %) patients, with two requiring dialysis. Systemic hemodynamic parameters were similar in the patients who developed AKI (AKI+) and in those who did not (AKI-). Intraparenchymal RRI at end-surgery was significantly higher in AKI+ compared to AKI- patients, both at TE-ED us and TP-ED us (TE-ED us mean difference, p = 0.004; TP-ED us mean difference, p = 0.013; difference between TE-ED us and TP-ED us results, p = 0.066), although the predictive performance was limited with both methods (area under the curve [AUC] of the receiver-operator characteristics: 0.71 and 0.70 for TE-ED us and TP-ED us , respectively). Serum NGAL values were higher in AKI + than in AKI- patients (anesthesia induction, p = 0.037; end-surgery, p = 0.007; 4 h from CPB start, p = 0.093; 24 h from CPB start, p = 0.024. However, combining RRI with serum NGAL at end-surgery did not provide a clear-cut advantage in predicting AKI., Conclusions: In patients undergoing MHS, increased echo-Doppler ultrasound-derived RRI at end-surgery is significantly associated with the risk of AKI, but has limited practical utility for identifying the patients who will develop AKI.

The cardiomyocytes populating the 'working myocardium' are highly organized and such organization ranges from macroscale (e.g. the geometrical rod shape) to microscale (dyad/t-tubules) domains. This meticulous level of organization is imperative for assuring the normal and physiological pump-function of the heart. In the pathological cardiac tissue, the domains-related architecture is partially lost, resulting in morphological, electrical and metabolic remodeling and promoting cardiovascular diseases including heart failure and arrhythmias. Indeed, arrhythmogenesis during heart failure is a major clinical problem. Arrhythmias have been extensively studied from an electrical etiology, but only recently, physiologists and scientists have focused their attention on cellular and subcellular mechanosensors. We and others have investigated whether the nanoscale mechanosensitive properties of cardiomyocytes from failing hearts have a bearing upon the initiation of abnormal electrical activity. This chapter highlights the recent findings in the field, especially the role of mitochondria function and alignment in failing cardiomyocytes interrogated via nanomechanical stimuli.

Objectives: Late-life major depression is associated with increased cardiovascular risk and impaired autonomic control of the heart, as evident from reduced heart rate variability (HRV). Moreover, antidepressant drug therapy also might be associated with further reductions of HRV. In the SEEDS study, we investigated whether sertraline associated with physical exercise protocols led to improvements of HRV, compared with antidepressant drug therapy alone., Design: Single-blind randomized controlled trial., Setting: Psychiatric consultation-liaison program for primary care., Participants: Patients aged 65-85 years with major depression, recruited from primary care., Interventions: Sertraline plus structured, tailored group physical exercise (S + EX) versus sertraline alone (S) for 24 weeks., Measurements: HRV indices (RR, percentage of NN intervals greater than 50 msec [pNN50], square root of the mean squared differences of successive NN intervals [RMSSD], standard deviation of heart rate [SDHR], standard deviation of the NN interval [SDNN], high-frequency band [HF], low-frequency band [LF], and their ratio [LF/HF]) were measured at baseline, week 12, and week 24. Psychiatric and medical assessments., Results: Participants displayed significant improvements of most HRV indices over time, irrespective of the group assignment (pNN50, RMSSD, SDHR, SDNN, HF, LF, and LF/HF). Moreover, patients in the S + EX group displayed greater increases of different HRV indices(RR, pNN50, RMSSD, SDHR, SDNN, HF, and LF) compared with those in the S group., Conclusions: The combination of structured physical exercise and sertraline might exert positive effects on the autonomic control of the heart among older patients with major depression., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Recent studies have highlighted the close relationship between the kidney and the gastrointestinal (GI) tract--frequently referred to as the kidney--gut axis--in patients with chronic kidney disease (CKD). In this regard, two important pathophysiological concepts have evolved: (i) production and accumulation of toxic end-products derived from increased bacterial fermentation of protein and other nitrogen-containing substances in the GI tract, (ii) translocation of endotoxins and live bacteria from gut lumen into the bloodstream, due to damage of the intestinal epithelial barrier and quantitative/qualitative alterations of the intestinal microbiota associated with the uraemic milieu. In both cases, these gut-centred alterations may have relevant systemic consequences in CKD patients, since they are able to trigger chronic inflammation, increase cardiovascular risk and worsen uraemic toxicity. The present review is thus focused on the kidney-gut axis in CKD, with special attention to the alterations of the intestinal barrier and the local microbiota (i.e. the collection of microorganisms living in a symbiotic coexistence with their host in the intestinal lumen) and their relationships to inflammation and uraemic toxicity in CKD. Moreover, we will summarize the most important clinical data suggesting the potential for nutritional modulation of gut-related inflammation and intestinal production of noxious by-products contributing to uraemic toxicity in CKD patients., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Hyponatremia is the most frequent electrolyte disorder in hospitalized patients and it is associated with unfavorable clinical outcomes as well as increased hospital costs. Its clinical presentation may be highly variable, ranging from asymptomaticity to neurologic emergencies with seizures or coma as signs of rapidly worsening cerebral edema. In these cases, prompt treatment is mandatory to avoid the patients death. On the other hand, in the case of gradual development of hyponatremia, it is imperative that its correction be also appropriately slow in order to avoid another neurological catastrophe, namely the osmotic demyelination syndrome. Whilst recent international guidelines and expert consensus agree on the approach to the treatment of acute severe and symptomatic hyponatremia, the recommendations on pharmacological therapy in chronic hyponatremia diverge, particularly as to the potential use of vasopressin antagonists. This review is aimed at summarizing essential aspects of epidemiology, pathophysiology and the diagnostic process of hyponatremia, to set the ground for a practical as well as evidence-based approach to treatment. As a guide through the discussion of the available evidence, a clinical case is presented in which the patients history and laboratory data are crucial for identifying the etiology of hyponatremia. The severe neurological signs at presentation justify an emergency treatment with hypertonic saline, as indicated. Subsequently, as the neurological emergency subsides, we discuss the need to revert the trend towards hypercorrection by an apparently counterintuitive approach, based in fact on sound pathophysiological grounds, with continuous infusion of hypotonic solutions and administration of desmopressin.

Rationale: Heart failure (HF) is accompanied by the development of an imbalance between oxygen- and nitric oxide-derived free radical production leading to protein nitration. Both chlorinating and peroxidase cycle of Myeloperoxidase (MPO) contribute to oxidative and nitrosative stress and are involved in tyrosine nitration of protein. Ceruloplasmin (Cp) has antioxidant function through its ferroxidase I (FeOxI) activity and has recently been proposed as a physiological defense mechanism against MPO inappropriate actions., Objective: We investigated the relationship between plasma MPO-related chlorinating activity, Cp and FeOxI, and nitrosative stress, inflammatory, neurohormonal, and nutritional biomarkers in HF patients., Methods and Results: In chronic HF patients (n = 81, 76 ± 9 years, NYHA Class II (26); Class III (29); Class IV (26)) and age-matched controls (n = 17, 75 ± 11 years, CTR), plasma MPO chlorinating activity, Cp, FeOxI, nitrated protein, free Malondialdehyde, BNP, norepinephrine, hsCRP, albumin, and prealbumin were measured. Plasma MPO chlorinating activity, Cp, BNP, norepinephrine, and hsCRP were increased in HF versus CTR. FeOxI, albumin, and prealbumin were decreased in HF. MPO-related chlorinating activity was positively related to Cp (r = 0.363, P < 0.001), nitrated protein, hsCRP, and BNP and inversely to albumin., Conclusions: Plasma MPO chlorinated activity is increased in elderly chronic HF patients and positively associated with Cp, inflammatory, neurohormonal, and nitrosative parameters suggesting a role in HF progression.

Colistin (CS) is a polymyxin with bactericidal activity, which is increasingly used in nosocomial infections associated with multidrug-resistant Gram-negative bacteria (MDR-GNB). Intravenous CS is usually administered as a less toxic pro-drug, i.e. colistin sodium methanesulfonate (CMS). In water-containing solutions, CMS undergoes a spontaneous hydrolysis to form a complex mixture of partially sulfomethylated derivatives and CS. Pharmacokinetic of CS is dependent on the route of administration, i.e. parenteral, intramuscular, nebulized, intrathecal/intraventricular. Renal toxicity is the most common adverse effect of CS treatment, as the drug is excreted primarily by the kidney and elevated levels of CS may further impair renal function, with a dose-dependent effect. Clinical manifestations of CS associated nephrotoxicity include acute kidney injury, proteinuria and tubular damage. Only few data are currently available on the effects of different renal replacement therapy modalities on CS pharmacokinetics. In patients undergoing the most efficient forms of renal replacement therapies, the extracorporeal clearance of CMS may result in a substantial removal of the antibiotic. Thus, in this setting, the recommended daily doses should be increased. Future studies should better explore CS pharmacokinetics in patients undergoing different modalities of renal replacement therapy.

Arginine vasopressin (AVP) plays a key role in many physiologic and pathologic processes. The most important stimulus for AVP release is a change in plasma osmolality. AVP is also involved in the response and adaptation to stress. Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps. Copeptin (CTproAVP), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of the AVP system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP represents AVP levels and its behavior represents changes in plasma osmolality, stress and various disease states, and shows some of the various physiologic and pathophysiologic conditions associated with increased or decreased AVP. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Autosomal polycystic kidney disease (ADPKD) patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance. A possibility raised by these clinical observations is that CTproAVP may serve to identify patients who could benefit from an intervention aimed at countering AVP.

Acute decompensated heart failure (ADHF) is the most common cause of cardiovascular hospitalization. The presentation is characterized by different clinical profiles due to various underlying causes, volume balance and tissue perfusion status. Currently, a variety of pharmacological therapies, including diuretics, beta-blockers, ACE-inhibitors, angiotensin receptor blockers and digoxin, are usually prescribed in order to treat chronic heart failure (HF) syndromes caused by left ventricular systolic dysfunction. Despite the large number of HF patients with frequent hospitalizations for decompensation, only a few studies have evaluated the management of oral chronic therapies in the clinical setting of ADHF. This article summarizes the information derived from the few published trials on this subject and a therapeutic approach is suggested with respect to the continuation, dose modification or suspension of oral medications., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background Severe hypokalemia, defined as serum potassium &lt; 2.5 mEq/L, may lead to neuromuscular, gastrointestinal, and ECG abnormalities. Neuromuscular consequences of hypokalemia include weakness, cramps, rarely paralysis, eventually progressing to rhabdomyolysis. Case presentation We report a case of a 4-year-old girl presenting carpopedal spasm and rhabdomyolysis due to severe hypokalemia associated to hypophosphatemia and hypovolemia. At one month of age she underwent an ileal resection because of a neonatal necrotizing enterocolitis, and a bowel resection at two years of age, because of sub-occlusive episodes. The child had frequent episodes of diarrhoea and was treated with oral white clay (kaolin) and a restrictive diet. Three days prior the admission to the hospital she had numerous episodes of watery diarrhoea. Laboratory tests revealed severe hypokalemia, hypophosphatemia, normal calcium levels associated with marked dehydration. An ECG demonstrated sinus bradycardia, ST-segment depression, T-wave flattening, U-wave, and long-QTc. Symmetric carpal and pedal spasms were observed. A marked rise of creatinine phosphokinase and myoglobin associated to cola colored urine was observed. Intravenous supplementation of potassium phosphate as well as adequate volume repletion led to an improvement of the clinical condition, to the disappearance of carpal and pedal spasms, to normalisation of ECG.  Conclusions Careful electrolytes and volume supplementation led to the correction of potential life-threatening arrhythmias and obtained a complete recovery from carpopedal spasm and rhabdomyolysis. Dietary restriction and pharmacological preparations as kaolin have to be administered with caution to treat diarrhea in children and particularly in those who may present other pre-existing risk factors.

Protein-energy malnutrition (PEW) is highly prevalent in patients with end-stage renal disease (ESRD) and is associated with a significant increase of the already high mortality and morbidity risk typical of this clinical setting. Since a key mechanism of PEW in ESRD is inadequate nutrient intake, oral nutritional supplements are extensively employed, and have been demonstrated to be highly effective in PEW prevention and treatment. Intradialytic parenteral nutrition (IDPN), i.e. the administration of nutrients through the extracorporeal circuit during hemodialysis, has also been proposed as a modality of nutritional support for patients with ESRD. However, even though metabolic/nutritional status is improved by this nutritional approach, the evidence linking IDPN to decreased hospitalization rate and lower mortality risk is still scant. The aim of the present paper is to review the role of IDPN as a modality of nutritional supplementation for ESRD patients on hemodialysis. To this end, quantitative and qualitative aspects, practical management, the indications, and limits of IDPN are discussed. On the basis of the available evidence, it is suggested that IDPN is a safe and efficacious modality of nutritional support in ESRD, and could represent an adjunctive strategy for patients with reduced spontaneous dietary intake when intensive dietetic counseling and oral supplementation have failed.

Rationale: Ceruloplasmin antioxidant function is mainly related to its ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite, whose production is increased in heart failure (HF), can affect ceruloplasmin antioxidant function through amino acid modification., Objective: We investigated the relationship between FeOxI and ceruloplasmin tyrosine and cysteine modification and explored in a cohort of patients with HF the potential clinical relevance of serum FeOxI., Methods and Results: In patients with chronic HF (n=96, 76 ± 9 years; New York Heart Association class, 2.9 ± 0.8) and age-matched controls (n=35), serum FeOxI, FeOxII, ceruloplasmin, nitrotyrosine-bound ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were measured, and the patients were followed up for 24 months. Ceruloplasmin, B-type natriuretic peptide, norepinephrine, and high-sensitivity C-reactive protein were increased in HF versus controls. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound ceruloplasmin (r, -0.305; P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared with middle-higher tertiles. FeOxI emerged as a mortality predictor (hazard ratio, 2.95; 95% confidence intervals [1.29-6.75]; P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, estimated glomerular filtration rate, and high-sensitivity C-reactive protein. In experimental settings, peroxynitrite incubation of serum samples and isolated purified ceruloplasmin reduced FeOxI activity while increasing ceruloplasmin tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented peroxynitrite-induced FeOxI drop, tyrosine nitration, and cysteine oxidation; flavonoid(-)-epicatechin, which prevented ceruloplasmin tyrosine nitration but not cysteine oxidation, partially impeded peroxynitrite-induced FeOxI drop., Conclusions: Reduced activity of serum FeOxI is associated with ceruloplasmin nitration and reduced survival in patients with HF. Both ceruloplasmin tyrosine nitration and cysteine thiol oxidation may be operant in vivo in peroxynitrite-induced FeOxI activity inhibition., (© 2014 American Heart Association, Inc.)

Body cell mass (BCM) is the metabolically active cell mass involved in O₂ consumption, CO₂ production and energy expenditure. BCM measurement has been suggested as a tool for the evaluation of nutritional status. Since BCM is closely related to energy expenditure, it could also represent a good reference value for the calculation of nutrient needs. In a recent issue of Critical Care, Ismael and colleagues used bioelectrical impedance analysis parameters and anthropometric variables to evaluate BCM in patients with acute kidney injury, before and after a hemodialysis session. The results of this study suggest that BCM is relatively insensitive to major body fluid shifts, a well known factor interfering with nutritional evaluation/monitoring and energy need calculations in the ICU. Thus, BCM seems to be a more 'stable' nutritional variable, as it is apparently less influenced by non-nutritional factors. The results of this paper emphasize the need to identify biologically sound parameters for nutritional status evaluation and energy need calculation in critically ill patients; in this regard, BCM could fulfill these expectations.

Optimal nutritional requirements and nutrient intake composition for patients with acute kidney injury is still a partially unresolved issue. Targeting nutritional support to the actual protein and energy needs improves the clinical outcome of critically ill patients. So far, very few data are currently available on this topic in acute kidney injury. In this specific clinical condition, the risk for under- and overfeeding may be increased by factors interfering on nutrient need estimation, such as rapidly changing body weight due to fluid balance variations, nutrient losses and hidden calorie sources from renal replacement therapy. Moreover, since acute kidney injury is now considered a kidney-centered inflammatory syndrome, the renoprotective role of specific pharmaconutrients with anti-inflammatory properties remains to be fully defined. This review is aimed at discussing recently published results concerning quantitative and qualitative aspects of the nutritional approach to acute kidney injury in critically ill patients.

Stress and hypercaloric food are recognized risk factors for obesity, Metabolic Syndrome (MetS) and Type 2 Diabetes (T2D). Given the complexity of these metabolic processes and the unavailability of animal models, there is poor understanding of their underlying mechanisms. We established a model of chronic psychosocial stress in which subordinate mice are vulnerable to weight gain while dominant mice are resilient. Subordinate mice fed a standard diet showed marked hyperphagia, high leptin, low adiponectin, and dyslipidemia. Despite these molecular signatures of MetS and T2D, subordinate mice fed a standard diet were still euglycemic. We hypothesized that stress predisposes subordinate mice to develop T2D when synergizing with other risk factors. High fat diet aggravated dyslipidemia and the MetS thus causing a pre-diabetes-like state in subordinate mice. Contrary to subordinates, dominant mice were fully protected from stress-induced metabolic disorders when fed both a standard- and a high fat-diet. Dominant mice showed a hyperphagic response that was similar to subordinate but, unlike subordinates, showed a significant increase in VO2, VCO2, and respiratory exchange ratio when compared to control mice. Overall, we demonstrated a robust stress- and social status-dependent effect on the development of MetS and T2D and provided insights on the physiological mechanisms. Our results are reminiscent of the effect of the individual socioeconomic status on human health and provide an animal model to study the underlying molecular mechanisms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM., Methods: Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75±8years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition., Results: Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31-0.76) p=0.002) and cTnI (HR 2.03 CI: (1.20-3.45) p=0.009). In fact, with respect to BNP-added SHFM (Harrell's C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+0.021, p=0.033) and only a trend was observed for cTn I (+0.023, p=0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement-IDI) at 1-year (IDI: cTnI, p=0.002; prealbumin, p=0.020), 2-years (IDI: cTnI, p=0.018; prealbumin: p=0.006) and 3-years of follow-up (IDI: cTnI p=0.024; prealbumin: p=0.012)., Conclusions: Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Objectives: A simple anticoagulation protocol was developed for sustained low-efficiency dialysis (SLED) in patients with AKI, based on the use of anticoagulant citrate dextrose solution formulation A (ACD-A) and standard dialysis equipment. Patients' blood recalcification was obtained from calcium backtransport from dialysis fluid., Design, Setting, Participants, & Measurements: All patients treated with SLED (8- to 12-hour sessions) for AKI in four intensive care units of a university hospital were studied over a 30-month period, from May 1, 2008 to September 30, 2010. SLED interruptions and their causes, hemorrhagic complications, as well as coagulation parameters, ionized calcium, and blood citrate levels were recorded., Results: This study examined 807 SLED sessions in 116 patients (mean age of 69.7 years [SD 12.1]; mean Acute Physiology and Chronic Health Evaluation II score of 23.8 [4.6]). Major bleeding was observed in six patients (5.2% or 0.4 episodes/100 person-days follow-up while patients were on SLED treatment). Citrate accumulation never occurred, even in patients with liver dysfunction. Intravenous calcium for ionized hypocalcemia (< 3.6 mg/dl or < 0.9 mmol/L) was needed in 28 sessions (3.4%); in 8 of these 28 sessions (28.6%), low ionized calcium was already present before SLED start. In 92.6% of treatments, SLED was completed within the scheduled time (median 8 hours). Interruptions of SLED by impending/irreversible clotting were recorded in 19 sessions (2.4%). Blood return was complete in 98% of the cases. In-hospital mortality was 45 of 116 patients (38.8%)., Conclusions: This study protocol affords efficacious and safe anticoagulation of the SLED circuit, avoiding citrate accumulation and, in most patients, systematic calcium supplementation; it can be implemented with commercial citrate solutions, standard dialysis equipment, on-line produced dialysis fluid, and minimal laboratory monitoring.

The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 μg·kg⁻¹·min⁻¹ NG-nitro-L-arginine-methyl-ester (L-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM (P < 0.005). In the C group, PL + L-NAME caused declines in GFR (101 ± 3 to 90 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (931 ± 22 to 754 ± 31 ml·min⁻¹·1.73 m⁻²), and UNaV (158 ± 12 to 82 ± 18 μmol/min) and an increase in FF (0.19 ± 0.02 to 0.21 ± 02; P < 0.001), which were not influenced by LOS pretreatment (P > 0.05 for LOS + L-NAME-C vs. PL + l-NAME-C). In DM, PL + L-NAME resulted in exaggerated renal effects, with changes in GFR (128 ± 3 to 104 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (1,019 ± 27 to 699 ± 34 ml·min⁻¹·1.73 m⁻²), UNaV (150 ± 13 to 39 ± 14 μmol/min), and FF (0.22 ± 0.03 to 0.26 ± 0.02) that were significantly greater vs. PL + L-NAME-C (P < 0.005). LOS pretreatment blunted GFR, RBF, FF, and UNaV responses to L-NAME in DM (P < 0.005 vs. PL + L-NAME-DM), resulting in a response profile that was similar to PL + L-NAME and LOS + L-NAME in C (P > 0.05). Renal responses to L-NAME in uncomplicated, type 1 DM are exaggerated vs. C, consistent with an upregulation of NO bioactivity. LOS, without effects in C, prevents the accentuated actions of L-NAME in DM, thus indicating an augmented role for NO-RAS interactions in renal hemodynamic function in DM.

Background: Cerebral blood flow (CBF) decreases during intermittent hemodialysis (HD) in patients with acute kidney injury (AKI). Since cerebral hemodynamics may be impaired in liver cirrhosis (LC), this condition could aggravate cerebral hypoperfusion during HD in patients with AKI. We examined CBF during the first HD session in patients admitted for AKI, with or without LC., Methods: CBF was examined by measuring middle cerebral artery mean flow velocity (MCAmfv) with transcranial Doppler at baseline and at the end of the first 4-hour HD session in 11 patients with both AKI and LC (median age 69 years, range 40-87, 7 men). Eleven patients with AKI without LC (median age 77 years, range 69-92, 6 men) served as controls., Results: Median net ultrafiltration volume at the end of the HD session was slightly, albeit not significantly, smaller in the patients with LC than in those without (-0.25 kg [range 0.00 to -1.50] vs. -1.00 kg [range 0.00 to -2.00], p = 0.18). At end of HD session, median MCAmfv had decreased by -5.5 cm/s (range -41.3 to 9.9) in the patients with LC, and by -4.5 cm/s (range -11.0 to -2.5) in those without LC (p = 0.79). At end of HD session, the mean MCAmfv of the 2 groups, adjusted for baseline MCAmfv and net ultrafiltration volume, was 25.7 and 21.1 cm/s in AKI patients with and without LC, respectively (difference between groups: 4.6 cm/sec; 95% confidence interval, -3.8 to +13.0)., Conclusion: In patients with AKI, concomitant LC does not confer greater vulnerability to cerebral hypoperfusion during intermittent HD.

Protein-energy wasting is common in patients with acute kidney injury (AKI) and represents a major negative prognostic factor. Nutritional support as parenteral and/or enteral nutrition is frequently needed because the early phases of this are often a highly catabolic state, although the optimal nutritional requirements and nutrient intake composition remain a partially unresolved issue. Nutrient needs of patients with AKI are highly heterogeneous, depending on different pathogenetic mechanisms, catabolic rate, acute and chronic comorbidities, and renal replacement therapy (RRT) modalities. Thus, quantitative and qualitative aspects of nutrient intake should be frequently evaluated in this clinical setting to achieve better individualization of nutritional support, to integrate nutritional support with RRT, and to avoid under- and overfeeding. Moreover, AKI is now considered a kidney-centered inflammatory syndrome; indeed, recent experimental data indicate that specific nutrients with anti-inflammatory effects could play an important role in the prevention of renal function loss after an episode of AKI., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: The term 'kidney dysfunction' is increasingly used in cardiological literature to indicate different forms of impaired kidney function which can usually be grouped within the broad categories of Acute Kidney Injury (AKI) or Chronic Kidney Disease (CKD)., Methods: In this review, renal function parameters commonly utilized in patients with acutely decompensated heart failure are illustrated. Some concepts of definition and classification of renal dysfunction in this clinical setting are presented, on the basis of the most recent data in the literature. Aspects of epidemiology and limits of methodologies are explored, in addition to the correct interpretation of findings, and the impact and prognostic value of renal dysfunction within the context of heart failure will be discussed., Results: An impairment of kidney function is frequently observed in patients with heart failure, especially during the acutely decompensated phase (Acutely Decompensated Heart Failure or ADHF). Importantly, this complication may impact negatively on clinical outcomes, as well as directly affecting the choice of therapeutic approach, especially when congestive cardiac failure is present. New, recently proposed bio-markers are indicative of kidney injury and cannot be used to replace classical functional indexes., Conclusion: The evaluation of kidney function, together with the correct interpretation of the significance of clinical findings and the limitations of specific laboratory results, bears major methodological relevance for the care of patients with heart failure. At the present time, more extensive utilization of the new kidney injury bio-markers cannot be recommended in the care of patients with acute decompensated heart failure.