TFEB inhibition induces melanoma shut-down by blocking the cell cycle and rewiring metabolism.

Melanomas are characterised by accelerated cell proliferation and metabolic reprogramming resulting from the contemporary dysregulation of the MAPK pathway, glycolysis and the tricarboxylic acid (TCA) cycle. Here, we suggest that the oncogenic transcription factor EB (TFEB), a key regulator of lysosomal biogenesis and function, controls melanoma tumour growth through a transcriptional programme targeting ERK1/2 activity and glucose, glutamine and cholesterol metabolism. Mechanistically, TFEB binds and negatively regulates the promoter of DUSP-1, which dephosphorylates ERK1/2. In melanoma cells, TFEB silencing correlates with ERK1/2 dephosphorylation at the activation-related p-Thr185 and p-Tyr187 residues. The decreased ERK1/2 activity synergises with TFEB control of CDK4 expression, resulting in cell proliferation blockade. Simultaneously, TFEB rewires metabolism, influencing glycolysis, glucose and glutamine uptake, and cholesterol synthesis. In TFEB-silenced melanoma cells, cholesterol synthesis is impaired, and the uptake of glucose and glutamine is inhibited, leading to a reduction in glycolysis, glutaminolysis and oxidative phosphorylation. Moreover, the reduction in TFEB level induces reverses TCA cycle, leading to fatty acid production. A syngeneic BRAFV600E melanoma model recapitulated the in vitro study results, showing that TFEB silencing sustains the reduction in tumour growth, increase in DUSP-1 level and inhibition of ERK1/2 action, suggesting a pivotal role for TFEB in maintaining proliferative melanoma cell behaviour and the operational metabolic pathways necessary for meeting the high energy demands of melanoma cells.

Sacubitril/valsartan for heart failure with reduced left ventricular ejection fraction : A retrospective cohort study.

BACKGROUND: The combination drug sacubitril/valsartan was reported to be superior to enalapril in reducing all-cause death, cardiovascular mortality, and heart failure (HF) hospitalizations in patients with cardiac insufficiency and reduced left ventricular ejection fraction (HFREF) with NYHA class II-IV. METHODS: Our retrospective cohort study aimed to assess the effects of sacubitril/valsartan in addition to a beta-blocker and mineral receptor antagonist (MRA) in a group of HFREF patients with NYHA class II-III HF vs. conventional therapy (ACE inhibitor or angiotensin II receptor blocker added to a beta-blocker plus an MRA) administered to a control group of HFREF patients with comparable clinical features. In both groups, treatment was supplemented by a loop diuretic, usually furosemide, at variable doses. The primary outcomes were all-cause death and HF hospitalizations. Safety outcomes were symptomatic hypotension, angioedema, hyperkalemia, and worsening renal function. RESULTS: Mortality at 6 months was 6.8% in patients taking sacubitril/valsartan vs. 34% in those on conventional therapy (odds ratio [OR] = 0.14; 95% CI: 0.04-0.49). Moreover, there was a 4.5% rate of HF hospitalizations in the sacubitril/valsartan group vs. 59% in the control group (OR = 0.03; 95% CI: 0.01-0.14). Safety outcomes were comparable in the two groups, although hypotension (systolic blood pressure < 100 mm Hg) was found in 15.9% of patients in the sacubitril/valsartan group vs. 5.7% in the control group (OR = 3.14; 95% CI: 0.94-10.55). CONCLUSION: Sacubitril/valsartan offered strong protection against all-cause death and HF hospitalizations at 6 months without any significant side effects. To validate this efficacious molecule, further postmarketing observational studies, focusing mainly on hypotension and angioedema are warranted.

In HFREF patients, sacubitril/valsartan, given at relatively low doses, does not lead to increased mortality or hospitalization : A retrospective cohort study.

INTRODUCTION: In heart failure with reduced left ventricular ejection fraction (HFREF) patients, the dosage of sacubitril/valsartan is modulated according to a gradual increase regimen. Nevertheless, if patients exhibit tolerability problems, a provisional reduction of the dose of sacubitril/valsartan or even its interruption are recommended. MATERIAL AND METHODS: This study provides estimates of respective proportions of patients receiving minimum or intermediate doses of sacubitril/valsartan. In addition, a comparison was made to detect possible differences regarding all-cause mortality and heart failure hospitalization in patients treated with the recommended optimum dose compared to those receiving submaximum maintenance doses of sacubitril/valsartan. RESULTS: Patients treated with sacubitril/valsartan in addition to beta-blocker and mineralocorticoid receptor blocker were 68. Among them, 20 patients (29.4%), were identified as having clinical features that were contraindications to the administration of sacubitril/valsartan at full dose. The subsequent decision was to maintain an intermediate dose in 11 patients and to reduce the dose to the minimum level allowed, i.e., 24 mg/26 mg twice daily in nine patients. After a median follow-up of 5.25 months, no differences were found concerning the risk of all-cause death by comparing patients treated with reduced versus those subjected to target doses of sacubitril/valsartan (odds ratio [OR] = 1.666; 95% confidence interval [CI] = 0.256-10.823; p = 0.6266). Patients taking reduced doses had a similar risk of heart failure hospitalizations when compared to patients treated with the target dose (OR = 0.789; 95% CI: 0.077-8.0808; p = 1.00). CONCLUSION: During a median follow-up of 5.25 months, in the group of patients who had proven to be intolerant to the maximum dose of sacubitril/valsartan, use of reduced doses of the drug did not result in increased all-cause mortality or heart failure hospitalization compared to patients treated with sacubitril/valsartan at the target dose.

Cognitive performance of patients with chronic heart failure on sacubitril/valsartan : A retrospective cohort study.

BACKGROUND: Sacubitril, a neprilysin inhibitor in the combination molecule sacubitril/valsartan, slows down degradation of endogenous natriuretic peptides, thereby enhancing their beneficial cardiovascular effects. However, sacubitril might also promote neuronal dysfunction and cognitive impairment in patients with chronic heart failure (CHF) treated with sacubitril/valsartan, due to possible neprilysin inhibition at the level of Central Nervous System. METHODS: A retrospective cohort study was undertaken to detect the effects exerted by sacubitril/valsartan on cognitive function in CHF patients. The patients' clinical data were examined for information provided in the Mini-Mental State Examination (MMSE), which was routinely administered during clinical visits at two centers from 15 March to 31 October 2017. Patients in the sacubitril/valsartan group had a clinical history of at least 3 months of continuous sacubitril/valsartan administration. The control group comprised CHF patients on conventional therapy not taking sacubitril/valsartan. In the between-group comparison, patients were matched for mean age, educational level, sex, NYHA class, and comorbidities. In the present retrospective study only patients in NYHA class II-III were enrolled. RESULTS: The mean MMSE score was 22.72 ± 2.68 (mean ± standard deviation [SD]) in the sacubitril/valsartan group (n = 51 patients) vs. 21.96 ± 2.73 (mean ± SD) in the control group (n = 51; p = 0.1572, independent samples t-test). Thus, a similar mild-to-moderate impairment in cognitive performance was found in the comparison between the two groups. CONCLUSION: In our study, we did not find any evidence of the alleged harmful influence of sacubitril/valsartan on cognitive function. Patients taking sacubitril/valsartan for at least 3 months had similar mean MMSE scores to control subjects.

Platypnea-orthodeoxia syndrome : Orthostatic dyspnea and possible pathophysiological substrates.

Platypnea-orthodeoxia syndrome (POS) is a rare disorder characterized by the emergence of a right-to-left shunt at the intracardiac or intrapulmonary level. The clinical picture is distinguished by shortness of breath that worsens on standing due to an accentuation of oxygen desaturation, and instead improves, at least partly, in the recumbent position. In this article we present a brief review of the pathophysiology of POS, as well as its clinical picture, diagnostic assessment, and preferential therapeutic options. Pathophysiological issues that are still not completely understood or much debated are outlined. The currently accepted pathophysiological concepts are presented and a summary of the main diagnostic and therapeutic tools is provided.

[Neurological and neuropsychological comparison between subjects with learning disorder and those suffering from learning difficulties when eeg abnormalities are detected at pediatric age]. / Confronto neurologico e neuropsicologico tra soggetti affetti da disturb specifico dell'apprendimento "puro" e soggetti con disturb dell;apprendimento in presenza di anomalie elettroencefalografiche, in età pediatrica.

AIM: The objective of the study is to compare data and investigate the points of overlap between the two clinical conditions. The hypothesis is to observe a similar cognitive and neuropsychological profile in LD children and subjects with electroencephalogram (EEG) abnormalities. METHODS: The present study consists of a descriptive analysis of 35 children who have been tested for suspected learning disorder (LD). The diagnostic protocol includes a detailed cognitive and neuropsychological evaluation, as well as logopedic and neuropsychomotor assessment. Children carried neurological visit, EEG in waking and encephalic nuclear magnetic resonance (NMR). In this study, anamnestic data and the results of some of the neuropsychological tests were administrated to children and subsequently were analyzed. Depending on EEG report (positive or negative), subjects were split in two subsample: subjects with "pure" LD and subjects who showed significant paroxysmal abnormalities at the EEG. RESULTS: This comparison shows that the profile of the two subsamples matches for many aspects. The only statistically significant differences are the increased impairment of meta-phonological skills and reading speed in children with EEG abnormalities. On the other hand, children with "pure" LD are inclined to manifest more frequently difficulties in highly-modularized processes, such as counting. CONCLUSION: In conclusion, the substantial overlap of the two profiles causes a reflection about the difficulty in making differential diagnosis in children who show a suspected LD, in absence of an accurate neurophysiological and neuroradiological investigation. The study did not find out useful markers to select subjects who should carry EEG and encephalic NMR. Our team established to keep EEG in waking in the diagnostic protocol, for all children with LD diagnosis. Only in case of abnormalities at the track, we prescribed EEG in sleeping and encephalic NMR.

Hypertonic saline plus i.v. furosemide improve renal safety profile and clinical outcomes in acute decompensated heart failure: A meta-analysis of the literature.

BACKGROUND: In advanced congestive heart failure (CHF), intravenous (i.v.) inotropic agents, i.v. diuretics, ultrafiltration, and hemodialysis have been shown to not yield better clinical outcomes. In this scenario, the simultaneous administration of hypertonic saline solution (HSS) and furosemide may offer a more effective therapeutic option with a good safety profile. METHODS: Therefore, a meta-analysis was performed to compare combined therapy, consisting of i.v. furosemide plus concomitant administration of HSS, with i.v. furosemide alone for acute decompensated heart failure (ADHF). The outcomes we chose were all-cause mortality, risk of re-hospitalization for ADHF, length of hospital stay, weight loss, and variation of serum creatinine. RESULTS: Based on five randomized controlled trials (RCTs) involving 1,032 patients treated with i.v. HSS plus furosemide vs. 1,032 patients treated with i.v. furosemide alone, a decrease in all-cause mortality in patients treated with HSS plus furosemide was proven [RR = 0.57; 95 % confidence interval (CI) = 0.44-0.74, p = 0.0003]. Likewise, combined therapy with HSS plus furosemide was shown to be associated with a reduced risk of ADHF-related re-hospitalization (RR = 0.51; 95 % CI = 0.35-0.75, p = 0.001). Besides, combined therapy with HSS plus furosemide was found to be associated with a reduced length of hospital stay (p = 0.0002), greater weight loss (p < 0.00001), and better preservation of renal function (p < 0.00001). CONCLUSION: HSS as an adjunct to i.v. furosemide for diuretic-resistant CHF patients led to a better renal safety profile and improved clinical endpoints such as mortality and heart failure-related hospitalizations.

Cardiovascular risk associated with celecoxib or etoricoxib: a meta-analysis of randomized controlled trials which adopted comparison with placebo or naproxen.

AIM: The present meta-analysis attempted to assess whether an unfavourable cardiovascular risk profile could be identified in the case of two COX2 selective inhibitors (COXIBs), namely celecoxib and etoricoxib. Based on the data from the literature, our meta-analysis aimed to assess the probability of major cardiovascular events reported with the use of celecoxib or etoricoxib and compare this with the results seen in patients assigned to the placebo group. Furthermore, the risk of cardiovascular events found by using celecoxib or etoricoxib was also compared with that associated with the use of naproxen, a nonselective non-steroidal anti-inflammatory drug (NSAID) chosen as our reference drug. METHODS: The studies had to be randomized controlled trials with at least 4-week duration. Studies were included if they compared celecoxib or etoricoxib against placebo or naproxen. Moreover, the selected studies had to have determined the risk, odds or incidence of myocardial infarction, stroke or cardiovascular death. For the comparisons versus placebo, the endpoints of interest were "serious vascular events", "non-fatal myocardial infarction", "non-fatal stroke" and "death from cardiovascular causes", whereas "myocardial infarction" and "stroke" were the endpoints of interest concerning the comparison versus naproxen. RESULTS: From the evaluation of 41 studies comparing celecoxib with placebo, we found a significantly higher incidence of serious vascular events in the celecoxib group compared to controls treated with placebo (rate ratio 1.598, 95% CI: 1.048 to 2.438; P=0.029). Furthermore, in patients allocated to treatment with celecoxib, we found an incidence rate of non-fatal acute myocardial infarction that was three times higher compared with the placebo group (rate ratio 3.074, 95% CI: 1.375-6.873, P=0.006). In contrast, we did not find any significant difference with regard to the incidence of nonfatal stroke and that of death from cardiovascular causes by comparing celecoxib and placebo. In addition, by examining cardiovascular outcomes that emerged from the 17 trials which compared etoricoxib with placebo, it was not possible to demonstrate statistically significant differences in incidence for each of the explored endpoints. With regard to the comparison of each coxib with the non-selective COX2 inhibitor naproxen, we did not find any significant difference for either the odds of myocardial infarction or that of stroke. CONCLUSION: On the basis of our meta-analysis, we can state that symptomatic benefits induced by the prolonged administration of celecoxib may be partially invalidated by a concomitant increase in vascular risk, particularly the increased risk of myocardial infarction found in celecoxib-treated patients, compared to controls taking placebo. In contrast, treatment with etoricoxib proved not to result in an increased risk of serious vascular events when compared with both the placebo and naproxen. Our meta-analysis also denotes that the alternative to COXIBs, represented by naproxen, does not show significant benefit in terms of reduced cardiovascular risk. Therefore, considering that the increase in incidence rate of cardiovascular events associated with treatment with celecoxib is small in absolute terms, it is reasonable to state that celecoxib is still a drug whose benefits outweigh the potential adverse effects on the cardiovascular system.

Efficacy and safety assessment of isolated ultrafiltration compared to intravenous diuretics for acutely decompensated heart failure: a systematic review with meta-analysis.

AIM: Intravenous diuretics at relatively high doses are currently used for treating acute decompensated heart failure (ADHF). However, the existence of harmful side effects diuretic-related, such as electrolyte abnormalities, symptomatic hypotension and marked neuro-hormonal activation have led researchers to implement alternative therapeutic tools such as isolated ultrafiltration (IUF). METHODS: Our study aimed to compare intravenous diuretics vs. IUF as regards their respective efficacy and safety in ADHF patients through systematic review and meta-analysis of data derived from relevant randomized controlled trials. RESULTS: 6 studies grouping a total of 477 patients were included in the systematic review. By contrast, data from only three studies were pooled for the meta-analysis, because of different adopted outcomes or marked dissimilarities in the data presentation . Weight loss at 48 h was greater in IUF group compared to the diuretics group [weighted mean difference (WMD)=1.77 kg; 95%CI: 1.18-2.36 kg; P<0.001)]. Similarly, greater fluid loss at 48 h was found in IUF group in comparison with diuretics group (WMD=1.2 liters; 95%CI: 0.73-1.67 liters; P< 0.001). In contrast, the probability of exhibiting worsening renal function (WRF), i.e., increase in serum creatinine > 0.3 mg/dl at 48 hours, was similar to the one found in the diuretics group (OR=1.33; 95% CI: 0.81-2.16 P=0.26). CONCLUSION: On the basis of this meta-analysis, IUF induced greater weight loss and larger fluid removal compared to iv diuretics in ADHF patients, whereas the probability of developing WRF was not significantly different in the comparison between iv diuretics and IUF.

Possible role of BNP for an early diagnosis of asymptomatic left ventricular dysfunction: a retrospective study.

AIM: The use of haematochemical markers of intra-ventricular myocardial strain, known as B-type natriuretic peptides, has been proposed as an initial diagnostic step for early screening programs targeting asymptomatic left ventricular dysfunction (ALVD) in populations of subjects at risk. METHODS: The diagnostic accuracy of BNP for the identification of ALVD was assessed by adopting Doppler echocardiography supplemented by Doppler Tissue Imaging (DTI) as the gold standard method. For this purpose, a retrospective analysis of the medical records of patients judged at risk of ALVD, mostly hypertensive and/or diabetic patients, was carried out. For admission into the study, at least one determination of plasma BNP and one Doppler echocardiographic assessment complemented by DTI were required for each patient. Systolic ALVD was diagnosed in the presence of left ventricular ejection fraction(LVEF) of <50 %. Diastolic ALVD was assessed according to the recommendations of the American Society of Echocardiography using two-dimensional Doppler echocardiography and TDI. Thus, in the presence of LVEF of ≥50%, concomitant findings of lateral mitral annular e' velocity <10 cm/s and septal mitral annular e' velocity <8 cm/s with left atrial volume index ≥34 ml/m2 were required to substantiate a diagnosis of diastolic ALVD . It was subsequently graded by measuring the ratio of early (E) to late (A) transmitral flow velocity (E/A ratio), mitral deceleration time and E/average e' ratio. Several Receiver Operating Characteristic (ROC) curves were built in the entire study population as well as in some subsets, to identify the BNP values exhibiting the best profile of sensitivity, specificity and positive and negative likelihood ratios with respect to ALVD. RESULTS: Among 88 patients at risk enrolled on the whole, 33 cases (37.5%) of mild diastolic ALVD and 10 cases (11.4%) of moderate-to-severe diastolic ALVD were found. No cases of systolic ALVD were detected. The ROC plots for the diagnostic accuracy of serum BNP in early detection of ALVD in the entire cohort of patients at risk of heart failure showed an area under the curve of 0.761 [standard error=0.0523; P<0.0001 ] . Moreover, among the various BNP values located across the ROC curve, an optimal cut-off value of 156 pg/ml was found (sensitivity=83.7%; specificity=46.7%; positive likelihood ratio=1.57; negative likelihood ratio=0.35). Conversely, a value of 290 pg/ml was shown to be more specific at the cost of a remarkable loss in sensitivity (sensitivity=53.5%;specificity=95.5%; positive likelihood ratio=12; negative likelihood ratio=0.5). CONCLUSION: The sensitivity of BNP in the identification of patients with ALVD by adopting a cut-off of 156 pg/ml was equal to 83.7%, which is in keeping with the literature values. In case of programs targeted to ALVD screening, the choice of adopting a relatively low threshold value for BNP seems to comply with the goal of enhancing sensitivity , so as to exclude from the echocardiography the individuals found negative at BNP assay and thereby reduce the number of unnecessary echocardiographic examinations in individuals with low probability of having ALVD.

Hepatorenal syndrome and type 1 and 2 cardiorenal syndromes: distinct competing medical therapies applied to a similar background of vasomotor reactive nephropathy.

The authors summarize some current views regarding the pharmacologic therapies of hepatorenal and cardiorenal syndromes, respectively. A common pathogenetic background of the two edematous disorders is outlined, consisting in reduced effective blood arterial volume ­ due to the splanchnic vasodilation in the hepatorenal syndrome (HRS) and to the fall in cardiac output and the rise in central venous pressure in cardiorenal syndrome (CRS). In both diseases, arterial underfilling elicits multiple water- and sodium- retentive mechanisms, by activating sympathetic nervous system and stimulating both rennin-angiotensin-aldosterone and vasopressin systems. These neurohormonal adjustments subsequently concur to a vasomotor nephropathy which originates - as a same kind of vasoconstrictor reflex renal response ­ from the splanchnic vasodilation, in the case of liver cirrhosis, or from the fall in renal perfusion and filtration gradients in the case of cardiorenal syndrome. Despite these pathogenetic similarities, the renal insufficiency of HRS compared to that of CRS is treated using diametrically opposite approaches: actually withdrawal of diuretics and administration of vasoconstrictor agents is the first choice in the case of HRS, while CRS is tackled by forcing diuretic regimen and by continuing vasodilator treatment with ACE-inhibitors. The pros and cons of these strategies ­ which are still matter of debate among the physicians and researchers ­ are then succinctly presented and discussed.

B-type natriuretic peptide. Guided vs. conventional care in outpatients with chronic heart failure: a retrospective study.

AIM: It is not known whether therapy assisted by determinations of serum B-type natriuretic peptide (BNP) may improve the outcome for outpatients with chronic heart failure (CHF). METHODS: A retrospective case-control study was carried out, enrolling patients with acutely decompensated heart failure (ADHF) who were followed up for a mean period of four months. The patients who had died or had new episodes of ADHF were studied as the cases. For each case, one living patient who was free from ADHF-related re-hospitalisations was recruited as control. Cases and controls were also matched for some variables to minimise possible confounding. The possible role of BNP-guided therapy as a predictor of decreased risk of deaths or new hospitalisations related to heart failure was explored. RESULTS: Twenty-eight cases and 44 controls were enrolled. A fall in BNP on the fifth day after admission was found to be a predictor of a decreased risk of the composite endpoint "death or new hospitalisation, heart failure-related" (hazard ratio=0.1508; 95% CI: 0.049 to 0.463; P=0.001). On the other hand, low glomerular filtration rate at admission (<60 mL/min/1.73 m2) was associated with increased risk of the abovementioned endpoint (hazard ratio=7.1785; 95% CI: 1.574 to 32.725; P=0.0113). On the contrary, BNP-guided therapy was associated with a similar risk of death and/or CHF-related hospitalisation, compared to the conventional clinical approach. CONCLUSION: A fall in BNP ≥60% from baseline on the fifth day after admission was found to be associated with a favorable clinical outcome in outpatients with CHF after four months of follow-up, irrespective whether this finding had been detected in patients treated according to the BNP-guided therapy or in patients treated with conventional clinical criteria. However, among the outpatients with previous ADHF, a substantial improvement in cardiovascular event rates could not be demonstrated in those treated with BNP-guided therapy compared with those undergoing usual, symptom-guided treatment.

Cabergoline use and risk of fibrosis and insufficiency of cardiac valves. Meta-analysis of observational studies.

BACKGROUND: Therapy with ergot-derivative dopamine agonists (ergot-DAs) is suspected to cause or promote the development of insufficiency and regurgitation in previously normal cardiac valves. Thus, we conducted a systematic review and meta-analysis of the literature to determine whether administration of cabergoline, i.e., an ergot-DA used to treat Parkinson's disease (PD) or hyperprolactinemia, is associated with an increased risk of valve regurgitation compared with pharmacological regimens not comprising ergot-DAs or with no therapy. METHODS: Observational studies were selected from the Pubmed and Embase databases. Studies had to have assessed the prevalence, odds, or risk of cardiac valve regurgitation in patients who underwent chronic treatment with cabergoline for PD or hyperprolactinemia compared with patients with the same diseases whose therapy did not include cabergoline or another ergot-DA. Separate meta-analyses were performed for PD and hyperprolactinemia patients. RESULTS: On the basis of five studies, 634 PD patients were taking cabergoline, while 9,120 PD patients were treated with dopa/dopamine decarboxylase inhibitor, alone or associated with a non-ergot DA. Valvular regurgitation of any degree - at one cardiac valve or more - was more frequent in PD patients who were taking cabergoline compared to those treated with a non-ergot DA agent or not treated with any dopamine agonist [adjusted (inverse variance: iv) odds ratio: 7.25 95 % CI: 3.71-14.18; p < 0.0001]. On the other hand, pooled data from seven studies showed that patients with hyperprolactinemia who were taking cabergoline (n = 444) exhibited significantly higher odds of mild- to-moderate tricuspid regurgitation compared to untreated controls (n = 954) [adjusted (iv) odds ratio: 1.92 95 % CI:1.34-2.73; p = 0.0003]. No significant differences in mitral or aortic valve regurgitation were detected between hyperprolactinemic patients taking cabergoline and controls. CONCLUSION: In PD patients, the risk of valvular regurgitation of any grade involving one or more cardiac valves was proven to be strongly associated with cabergoline treatment. Furthermore, based on our results, hyperprolactinemic patients taking cabergoline have an increased risk of mild-to-moderate tricuspid valve regurgitation.

In right or biventricular chronic heart failure addition of thiazides to loop diuretics to achieve a sequential blockade of the nephron is associated with increased risk of dilutional hyponatremia: results of a case-control study.

AIM: Chronic hyponatremia is frequently found in some syndromes characterized by widespread edema coupled to impairment in arterial effective circulating volume, such as congestive chronic heart failure (CHF). In this setting, it is unclear whether the hyponatremia itself makes this condition worse or whether it represents a simply marker of decompensation. The factors responsible for development of hyponatremia in CHF have not exhaustively been elucidated yet. The aim of this paper was to ascertain whether some laboratory, clinical and therapeutical factors are able to predict occurrence of hyponatremia in CHF patients. METHODS: A case-control study was carried out by recruiting 57 CHF patients, whose 19 characterized by hyponatremia (serum Na+<135 mEq/L) and 38 controls, matched for age, sex, etiology of CHF, time elapsed since beginning of both symptoms and diuretic therapy. Eligibility criteria included right or biventricular heart failure in NYHA class III, absence of hyponatremia at the first visit and therapy at enrollment with oral dose not less than 175 mg per week of furosemide or equivalent weekly dose of torsemide. Exclusion criteria were electrostimulation therapies (pace-maker or cardiac resynchronization therapy), documented episodes- one or more- of infective gastroenteritis or diarrhea and use of any drug influencing neuroendocrine mechanisms of arginin-vasopressin (AVP) secretion, such as opiates, tetracyclines, phenothiazines, lithium, serotonin selective reuptake inhibitors (SSRIs) etc. RESULTS: At univariate analysis, intensive intravenous (iv) therapy with furosemide (one or more courses), ascites, mixed regimen with thiazide diuretic plus furosemide, high (>3 ng/mL/h) plasma renin activity, serum creatinine ≥2,2 mg/dl and oligoanuria were shown to be associated with hyponatremia. At multivariate analysis a role of predictor of hyponatremia was maintained by combined therapy with thiazide diuretic plus furosemide (OR=35.68 95%CI: 2.83-449.37 P=0.0057) as well as by intensive iv furosemide therapy (OR=12.44 95%CI: 1.207-128.27 P=0.0342). CONCLUSION: Inhibition of free water clearance by thiazides may account for association found between their use and hyponatremia development in congestive CHF setting. Even though loop diuretics are known to promote free water excretion, in our experience hyponatremia might have been favored by iv furosemide high doses, because drop in effective circulating volume and further impairment in arterial underfilling due to overzealous iv loop diuretic administration are able to foster AVP non osmotic release, thereby leading to hemodilution hyponatremia.

In chronic heart failure with marked fluid retention, the i.v. high doses of loop diuretic are a predictor of aggravated renal dysfunction, especially in the set of heart failure with normal or only mildly impaired left ventricular systolic function.

AIM: In the presence of resistance to oral diuretics in chronic heart failure (CHF) patients with extreme hydrosaline retention, among the proposed therapeutic options the administration of high doses of loop diuretics - either intravenous (i.v.) boluses or i.v. continuous infusion - should first of all be considered. Nevertheless, the use of this therapy may lead to the risk of further aggravation of frequently coexisting renal dysfunction, especially when loop diuretics such as furosemide (FUR), torasemide etc. are administered at excessive doses leading to hypotension, hypoperfusion and/or relative dehydration in patients with decompensated CHF who could have benefit from intensive unloading therapy. The aim of this study was to identify the clinical and hematochemical markers which are able to predict a possible decline or rapid deterioration of renal function implying a rise in serum creatinine (Cr) >25% of its basal value, i.e. the so-called aggravated renal dysfunction (ARD), typically occurring during intensive unloading therapy with i.v. FUR or other loop diuretics, administered to CHF pts with extreme fluid retention. METHODS: The protocol of our case-control observational study established to enroll every CHF patient who was demonstrated to develop a rise in Cr suggestive of ARD at the end of i.v. diuretic therapy (VI-VIII day). For each case enrolled, 3 patients at least were selected as controls, matched for age, sex and time elapsed from the beginning of the signs and symptoms of CHF. For the prediction of the dependent variable, represented by ARD diuretic infusion-related, the following independent variables were considered: creatinine clearance (Cr clear) <60 mL/min, Cr clear expressed as a continuous variable (Cr clear continuous), daily dose of i.v. furosemide ≥ 125 mg, left ventricular ejection fraction (LVEF), CHF with normal (≥ 50%) LVEF (HFNEF), urinary sodium concentration (U Na+) ≥ 40 mEq/L, U Na+expressed as a continuous variable (U Na+ continuous), sodium fractional excretion (FE Na+) >2%, urine/plasma concentration ratios for creatinine (U/P cr) <10, for urea (U/P urea) <5 and for osmolality (U/P osmolal) <1.1, mean duration of the symptoms of CHF, history of pre-existing parenchymal renal disease . The values of U Na+, FE Na+, U/P Cr, U/P urea and U/P osmolal were measured after discontinuance of diuretic oral therapy for four days, before the onset of intensive i.v. diuretic administration, so as to identify the patients with pathological values of tubular renal function indexes, known to be not interpretable in the presence of diuretics, suggestive of possible preexisting anatomic renal damage (acute tubular necrosis prior to onset of iv diuretic therapy). RESULTS: Nineteen 19 CHF patients with ARD and 60 controls were enrolled. At univariable analysis, Cr clear <60 mL/min, Cr clear continuous, daily dose of iv furosemide ≥ 125 mg, LVEF, HFNEF, FE Na+>2%, Na+≥ 40 mEq/L and U Na+ continuous were shown to be associated with ARD. At multivariate analysis, the role of prognostic indicator of ARD was maintained by daily dose only of iv FUR ≥125 mg (OR: 7.2088 95% CI: 1.3096-39.6802 P=0.0232). By using the 2x2 contingency tables, a qualitative interaction was identified by crossing ARD ­ outcome variable - against dose of iv FUR ≥ 125 mg/day - exposure variable - and by subsequently stratifying by the HFNEF. Actually, a significant association with ARD was not present in any CHF patient with dilated left ventricle treated with high dosage of iv FUR, whereas a highly significant association with ARD was observed in HFNEF patients (OR: 72 95% CI: 6.601-785.2694 P=0.00001) who had experienced the same high iv fur dose. CONCLUSION: In CHF patients with widespread edema refractory to oral diuretic, ARD can be propitiated by high dosages of i.v. FUR, when not associated with other treatments to preserve the effective circulating volume and renal flow. The HFNEF patients appear to be more prone to ARD related to i.v. high dosages of FUR, perhaps because their hemodynamics is more seriously harmed by the drop, FUR-related, in venous return and cardiac preload, as compared to CHF patients with reduced (45-30%) LVEF.

[Renoprotective effect of small volumes of hypertonic saline solution in chronic heart failure patients with marked fluid retention: results of a case-control study]. / Renoprotektiver Effekt kleiner Volumina hypertoner Kochsalzlösung bei Patienten mit chronischer Herzinsuffizienz und Ödembildung: Ergebnisse einer Fall-Kontroll-Studie.

During intensive therapy of chronic heart failure (CHF) patients with marked fluid retention using high doses of i.v. furosemide the additional effect of agents which might exert osmotic attraction of interstitial fluids has been proposed. They are thought to impede the impairment of renal blood supply and glomerular filtration rate, which may be caused by a combined action of cardiac preload acute reduction, hypotension and neurohormonal activation.We therefore assessed in CHF patients with NYHA class III and BNP values from 900 to 1500 pg/ml, who were treated with i.v. furosemide, the predictors of iatrogenic short term creatinine impairment by means of a case-control observational study from two centers. Patients with CHF had been treated for 6-8 days with intravenous loop diuretics alone or with an additional i.v. administration of other agents (plasma expanders, albumin, mannitol, inotropic support etc.). A rise in serum creatinine ≥ 25% of the basal value was considered as renal impairment.A total of 15 cases and 38 controls were enrolled. At univariate analysis, serum creatinine basal value ≥ 2.2 mg/dl, absence of hypertonic saline solution (HSS) in the therapeutic protocol, hyposodic diet and refractory oligoanuria were associated with an increased risk of worsening renal function precipitated by i.v. diuretic therapy. At multivariate analysis as a predictor of loop diuretic-related renal function impairment, we found a serum creatinine ≥ 2.2 mg/dl at baseline (OR: 63.33, 95% CI: 3.68-1088.73, p=0.0043) and the absence of HSS in the therapeutic regimen (OR: 25.0461, 95% CI: 2.07-302.53, p=0.0113). Moreover, in multivariate analysis ascites had some predictive value of renal deterioration (OR: 13.28, 95% CI: 1.0055-175.41, p=0,0495).

The risk of worsening CHF is positively related to unitary increase in mitral regurgitation size: a case-cohort study derived from a II NYHA class CHF patient population.

AIM: The passage from II to III New York Heart Association (NYHA) class is indicative of cardiopulmonary impairment and unfavourable prognosis. Among chronic heart failure(CHF) II NYHA class patients, the topic has been debated what criteria have be assumed for identifying the patients prone to accelerated progression towards III NYHA class. METHODS: A case cohort study, including a number of CHF II NYHA class patients, was carried out, to evaluate the role as predictor of CHF worsening of some ultrasonographic parameters, listed as follows: left ventricular ejection fraction, as continuous and as a dichotomous variable, i.e. subdivided as follows: 1) LVEF larger than 40% and 2) LVEF ranged from 30% to 40%; mitral regurgitation (MR), as continuous and as a dichotomic variable (i.e. moderate-to-severe MR, defined by transmitralic jet planimetric area estimated as larger than 20% of left atrium area), restrictive LV filling pattern and pulmonary systolic arterial pressure >40 mmHg. The pts were subdivided in 3 categories, as follows:1) diastolic CHF, i.e. heart failure with normal or only mildly impaired left ventricular ejection fraction - 20 patients; 2) systolic CHF, i.e. heart failure with reduced left ventricular ejection fraction - 19 patients; and 3) CHF due to "organic" mitral insufficiency-19 patients. All patients were treated with pharmacologic therapy, according to their respective clinical features and typology of basal heart disease. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for the composite endpoint death and hospitalization due to worsening CHF were investigated, concerning each of the above-mentioned criteria. Moreover, the odds ratios (OR) were calculated, by not conditional logistic regression analysis, to achieve information about risk of death and/or worsening CHF, as well as the respective profiles of risk, assessed by relative risk (RR). RESULTS: From 173 followed-up patients, 58 patients,70+/-12 aged, whose 15 cases (transition to III NYHA class) and 43 controls, were included in retrospective analysis. Notewhorty, moderate-to-severe MR only seemed to play a role as reliable predictor of worsening CHF(sensitivity: 93.3%; specificity: 69.7%; PPV: 51.8%; NPV: 96.7%; RR:15.93; OR: 32.3), as its sensitivity and PPV, particularly, were shown to exceed far and away the values of sensitivity and PPV associated to each of other echographic and/or clinical variables. Nevertheless, at multivariate analysis,MR expressed as continuous variable only, but not as "categorical" variable-was demonstrated to independently predict the transition from II to III NYHA class, over two years clinical follow up. CONCLUSION: The present data seem to support the view that the larger regurgitant jet of mitral insufficiency, the higher the risk of worsening CHF during a two years follow up. Likewise, it is plausible the moderate-severe MR represents a predictor of increased risk of transition to III NYHA class among the CHF II NYHA class patients. In addition, this study seems to indicate that a surgical therapy (prosthetic replacement or mitral valvuloplasty)should always be planned in the case of II NYHA class CHF patient who has been recognized affected by moderate-to-severe MR, since the chances of successful pharmacological prevention of clinical impairment in this setting turned out to be very slight.

Cerebrospinal fluid thrombomodulin and sVCAM-1 in different clinical stages of multiple sclerosis patients.

In order to investigate whether brain endothelial cells activation and/or damage could be selectively monitorized, soluble vascular cell adhesion molecule 1 (sVCAM-1) and thrombomodulin (TM) levels were studied in serum and cerebrospinal fluid (CSF) of 39 multiple sclerosis (MS) patients in various phases of the disease, 19 patients with other non-inflammatory neurological diseases (OND) and 15 patients with inflammatory neurological diseases (IND). No differences in sVCAM-1 CSF levels were detected, except for lower levels in IND compared to OND. Serum TM levels were lower in IND compared to progressive MS patients. Moreover, a significant decrease both in VCAM index and in TM index was detected in IND compared to all other groups. TM index was higher in MS patients in progression as compared to OND. The combined analysis of sVCAM-1 and TM might be a useful tool in monitoring brain endothelium activation or damage in different phases of MS.

Genetic abnormalities of the protein C system: shared risk factors in young adults with migraine with aura and with ischemic stroke?

Migraine, particularly migraine with aura (MA), may be a risk factor for ischemic stroke (IS). The reasons for this association are unknown. We investigated the presence of genetic abnormalities of the protein C system in 83 MA patients, 31 IS patients, and 124 healthy controls, all aged under 45 years. We found an increased frequency of activated protein C resistance due to Arg506Gln factor V mutation, and of protein S deficiency in both disorders, with figures higher than those reported in the general population and significantly different from those found in controls. These prothrombotic genetic abnormalities may be shared risk factors in IS and MA, and may play a role in increasing the risk of cerebrovascular disease in migraineurs.

Physical effort-induced changes in immune parameters.

Physical stress induces changes in immune system parameters; these changes depend on effort schedule and are influenced by customary training. The mechanisms whereby they take place are not fully elucidated: sympathetic activation-mediated mobilization of cells of lymphoid organs, including the spleen, has been suggested. We studied exercise-induced changes (20' of cycloergometer test conducted up to 80% of maximal expected heart rate) in white blood cells (WBC), lymphocyte subsets, plasma catecholamine and cortisol levels in three groups of subjects: swimmers, untrained controls and splenectomized individuals. Physical exercise induced increase of WBC and significant changes in the percentage of most investigated lymphocyte subsets (NK, CD3+, CD4+, CD8+ and CD4/CD8 ratio), except for DR+ cells. No changes occurred in the percentage of CD14+ cells. Norepinephrine (NE) levels increased after effort, while epinephrine (E) and cortisol levels were unchanged. Splenectomized patients displayed similar effort-induced changes in investigated parameters as controls and swimmers. The results support the interactions between physical work and immune response and minimize the role of the spleen in this context.