Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation- the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study.

Aim: We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF). Methods and results: This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75-1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49-0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32-0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29-0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH. Conclusions: LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status. Clinical trial registration: http:www.clinicaltrials.gov. Unique identifier: NCT00262600.

[Secondary hypertension: diagnosis and treatment]. / Ipertensione arteriosa secondaria: diagnosi e trattamento.

Hypertension does not recognize obvious pathogenic causes in the majority of patients (essential hypertension). However, a secondary underlying cause of hypertension can be recognized in 5-10% of unselected hypertensive patients, and this prevalence may increase to more than 20% in patients with hypertension that is difficult to control or frankly resistant to treatment. In children, secondary hypertension is most often due to aortic coarctation, distal thoracic or abdominal aortic stenosis, or specific gene mutations. In adults or elderly individuals, secondary hypertension is most often due to atherosclerotic renal artery stenosis, primary hyperaldosteronism, and Cushing's disease or syndrome. Parenchymal nephropathy and hyperparathyroidism can cause hypertension at all ages, while pheochromocytoma and paraganglioma tend to occur more often in adolescents or young adults. In general, secondary hypertension should be suspected in subjects with: (a) onset of hypertension under 30 years of age especially if in the absence of hypertensive family history or other risk factors for hypertension; (b) treatment-resistant hypertension; c) severe hypertension (>180/110 mmHg), malignancy, or hypertensive emergencies; d) rapid rise in blood pressure values in previously well controlled patients. Any clinical signs suspicious or suggestive of hypertension from endocrine causes, a "reverse dipping" or "non-dipping'" profile at 24 h ambulatory blood pressure monitoring not justified by other factors, signs of obvious organ damage may be helpful clues for diagnosis. Finally, patients snoring or with clear sleep apnea should also be considered for possible secondary hypertension.

Cardiac Contractility Modulation Therapy in Patients with Amyloid Cardiomyopathy and Heart Failure, Case Report, Review of the Biophysics of CCM Function, and AMY-CCM Registry Presentation.

Cardiac amyloidosis may result in an aggressive form of heart failure (HF). Cardiac contractility modulation (CCM) has been shown to be a concrete therapeutic option in patients with symptomatic HF, but there is no evidence of its application in patients with cardiac amyloidosis. We present the case of TTR amyloidosis, where CCM therapy proved to be effective. The patient had a history of multiple HF hospitalizations due to an established diagnosis of wild type TTR-Amyloidosis with significant cardiac involvement. Since he was highly symptomatic, except during continuous dobutamine and diuretic infusion, it was opted to pursue CCM therapy device implantation. At follow up, a significant improvement in clinical status was reported with an increase of EF, functional status (6 min walk test improved from zero meters at baseline, to 270 m at 1 month and to 460 m at 12 months), and a reduction in pulmonary pressures. One year after device implantation, no other HF hospital admission was needed. CCM therapy may be effective in this difficult clinical setting. The AMY-CCM Registry, which has just begun, will evaluate the efficacy of CCM in patients with HF and diagnosed TTR amyloidosis to bring new evidence on its potential impact as a therapeutic option.

Osmophobia as an early marker of migraine: a follow-up study in juvenile patients.

BACKGROUND: Osmophobia is frequent in children with migraine (20-35%) but can also occur in up to 14% of cases with tension-type headache (TTH). So far, the prognostic role of this symptom in children with primary headaches has never been evaluated. METHODS: A longitudinal prospective study was conducted on 90 young patients with TTH (37 with osmophobia, 53 without osmophobia). We evaluated whether osmophobia could predict the diagnosis transformation from TTH to migraine after a 3-year follow-up. RESULTS AND DISCUSSION: In our cases the rate of diagnosis change was significantly greater in cases with osmophobia (62%) than in those without (23%). Osmophobia persisted at a 3-year follow-up in the majority of our cases (85%) and it was found to be one of the major predictors for the development of migraine; other predictors of evolution to migraine were phonophobia, a probable rather than certain diagnosis of TTH and olfactory triggers (p < 0.05). CONCLUSION: Our data confirm that osmophobia has an important diagnostic and prognostic role in children with primary headaches and should be systematically investigated at diagnosis and during follow-up.

Atrial fibrillation and mortality in patients with acute myocardial infarction: a systematic overview and meta-analysis.

Atrial fibrillation (AF) confers an increased risk of mortality in patients hospitalized for acute myocardial infarction (AMI). However, it is unclear whether new-onset and preexisting AF portend a different risk. We extracted data from studies that evaluated in-hospital mortality in patients with AMI and included information on cardiac rhythm. Overall, the risk of mortality was higher in patients with AF than in those in sinus rhythm (OR 2.00, 95 % CI: 1.93-2.08; P < 0.0001). Compared with patients who remained in sinus rhythm, the risk of death was increased in patients with new AF certain (sinus rhythm on admission, new AF during hospitalization, and history of no evidence of prior AF; OR 3.38, 95 % CI: 2.98-3.83; P < 0.0001), new AF uncertain (sinus rhythm on admission, AF during hospitalization, but no clear information about previous history of AF; OR 1.90, 95 % CI:1.83-1.98; P < 0.0001), and permanent AF (AF before and during hospitalization; OR 2.01, 95 % CI:1.70-2.38;P < 0.0001). In a meta-regression analysis, the risk of death was 87 % higher in patients with new AF certain than in those with permanent AF (P = 0.013) or AF uncertain (P = 0.003), and not dissimilar in patients with new AF uncertain and permanent AF (P = 0.706).

Craniometaphyseal dysplasia with severe craniofacial involvement shows homozygosity at 6q21-22.1 locus.

Craniotubular dysplasias (CTD) are a heterogeneous group of genetic disorders of skeletal development, whose clinical and etiological classification is still much debated. One of the most common form is the autosomal dominant craniometaphyseal dysplasia (CMD) which is associated with mutation in the ANKH gene. In the literature a few families are reported with CMD phenotype that suggest an autosomal recessive (AR) pattern of inheritance. A candidate locus at 6q21-22 has been mapped in a large inbred Brazilian family, but the gene of the recessive form is still unknown. Our data on a female patient with CMD phenotype, born from healthy first degree cousins and displaying homozygosity for polymorphic markers at the 6q21-22 locus, further support the existence of an AR CMD, expanding its clinical spectrum to a more severe phenotype.

The Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) Study.

The Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) Study is a prospective registry of morbidity and mortality in initially untreated patients with essential hypertension whose initial diagnostic evaluation included 24-hour ambulatory blood pressure (ABP) monitoring according to a standardized protocol. The present article summarizes the main results of the PIUMA Study. The PIUMA Study is conducted in three hospitals in Umbria, Italy. After their initial assessment at entry, patients are followed in the outpatient clinic of the referring hospital and in collaboration with their family doctors. Telephone interviews with patients and meetings with family doctors are periodically conducted to ascertain the incidence of major complications of hypertension. The PIUMA Study gave us a tremendous opportunity to investigate several aspects related to hypertension: 1) cross-sectional studies focused on the association between clinic and 24-hour ABP and organ damage; 2) longitudinal studies focused on the association between 24-hour ABP and hypertensive organ damage at cardiac level and other levels with the subsequent incidence of major cardiovascular events and mortality; 3) longitudinal studies exploring the prognostic impact of other risk factors in hypertensive patients (i.e. diabetes, dyslipidemia, atrial fibrillation, left ventricular dysfunction, etc.). The PIUMA Study provided the first ever evidence of the prognostic value of: 1) 24-hour ambulatory blood pressure monitoring; and 2) regression of echocardiographic left ventricular hypertrophy in hypertensive patients. The PIUMA Registry gave us an enormous opportunity for investigating several pathophysiologic, diagnostic and therapeutic aspects related to management of hypertensive patients. Some of our studies have been mentioned in several hypertension guidelines to support some specific statements.

ß-Blockers reduce mortality in patients undergoing high-risk non-cardiac surgery.

BACKGROUND: ß-Adrenergic receptor antagonists (beta-blockers) are frequently used with the aim of reducing perioperative myocardial ischemia and infarction. However, randomized clinical trials specifically designed to evaluate the effects of beta-blockers on mortality in patients undergoing non-cardiac surgery have yielded conflicting results. OBJECTIVE: This study aimed to examine the effect of perioperative ß-blockers on total and cardiovascular mortality in patients undergoing non-cardiac surgery. METHODS: We conducted a meta-analysis of randomized clinical trials that examined the effects of ß-blockers versus placebo on cardiovascular and all-cause mortality in patients undergoing non-cardiac surgery. We extracted data from articles published before 30 November 2009 in peer-reviewed journals indexed in MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and CINAHL. Data extraction was carried out independently by two reviewers on the basis of an intent-to-treat approach, and inconsistencies were discussed and resolved in conference. The present meta-analysis was undertaken according to the Quality of Reporting of Meta-analyses (QUORUM) statement. RESULTS: A total of 2148 records were screened, from which we identified 74 randomized controlled trials for non-cardiac surgery. After excluding 49 studies that did not report the clinical outcome of interest or were subanalyses or presented duplicate data, the final search left 25 clinical trials. Treatment with ß-blockers had no significant effect on all-cause mortality (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.92, 1.43; p = 0.2717) or cardiovascular mortality (OR 1.13; 95% CI 0.85, 1.51; p = 0.5855). However, surgical risk category markedly differed across the studies. According to Joint American College of Cardiology and American Heart Association guidelines for perioperative assessment of patients having non-cardiac surgery, five trials evaluated the effect of ß-blockers in patients treated with emergency and vascular surgery (high-risk category) whereas 15 and five trials evaluated the effect of ß-blockers in intermediate low and intermediate high surgical risk categories, respectively. Subgroup analyses showed that the surgical risk category and dose titration of ß-blockers to target heart rate affected the estimate of the effect of ß-blockers for all-cause and cardiovascular mortality. ß-Blockers reduced total mortality by 61% more in patients who underwent high-risk surgery than in those who underwent intermediate high- or intermediate low-risk surgery. When cardiovascular mortality was assessed, the benefit of ß-blockers was 74% greater in trials that titrated ßblockers to heart rate than in trials that did not, although formal statistical significance was not achieved. CONCLUSIONS: These data suggest that ß-blockers may be useful for reducing mortality in patients who undergo high-risk non-cardiac surgery.

The optimal blood pressure target for patients with coronary artery disease.

None of the available outcome-based studies was primarily designed to compare different blood pressure (BP) goals in patients with coronary artery disease (CAD). Consequently, there is uncertainty about the most appropriate BP treatment goal in these patients. Although US guidelines recommend a target less than 130/80 mm Hg, recent European guidelines state that such aggressive target is not consistently supported, therefore making the case for a less aggressive target (<140/90 mm Hg) in all hypertensive patients including those with CAD. A low systolic BP may be beneficial to limit myocardial workload, but an excessive lowering of diastolic BP might impair coronary perfusion, with potentially adverse effects (J-curve phenomenon). The optimal BP target for patients with CAD remains undefined. A reasonable target appears to be in the range of 130-140/80-90 mm Hg. Any further reduction may be safe, but not much productive from a prognostic standpoint.

[ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus]. / ACE-inibitori, sartani e sindrome respiratoria acuta da coronavirus 2.

Some Authors recently suggested that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be discontinued, even temporarily, given the current pandemic of SARS-CoV-2 virus. The suggestion is based on the hypothesis that ACE-inhibitors and ARBs may favor the entry and diffusion of SARS-CoV-2 virus into the human cells. ACE-inhibitors and ARBs may increase the expression of ACE2 receptors, which are the sites of viral entry into the human organism. ACE2 receptors are ubiquitous, although they are extremely abundant on the cell surface of type 2 pneumocytes. Type 2 pneumocytes are small cylindrical alveolar cells located in close vicinity to pulmonary capillaries and responsible for the synthesis of alveolar surfactant, which is known to facilitate gas exchanges. The increased expression of ACE2 for effect of ACE-inhibitors and ARBs can be detected by increased production of angiotensin1-7 and mRNA related to ACE2. There is the fear that the increased expression of ACE2 induced by ACE-inhibitors and ARBs may ultimately facilitate the entry and diffusion of the SARS-CoV-2 virus. However, there is no clinical evidence to support this hypothesis. Furthermore, available data are conflicting and some counter-intuitive findings suggest that ARBs may be beneficial, not harmful. Indeed, studies conducted in different laboratories demonstrated that ACE2 receptors show a down-regulation (i.e. the opposite of what would happen with ACE-inhibitors and ARBs) for effect of their interaction with the virus. In animal studies, down-regulation of ACE2 has been found as prevalent in the pulmonary areas infected by virus, but not in the surrounding areas. In these studies, virus-induced ACE2 down-regulation would lead to a reduced formation of angiotensin1-7 (because ACE2 degrades angiotensin II into angiotensin1-7) with consequent accumulation of angiotensin II. The excess angiotensin II would favor pulmonary edema and inflammation, a phenomenon directly associated with angiotensin II levels, along with worsening in pulmonary function. Such detrimental effects have been blocked by ARBs in experimental models. In the light of the above considerations, it is reasonable to conclude that the suggestion to discontinue ACE-inhibitors or ARBs in all patients with the aim of preventing or limiting the diffusion of SARS-CoV-2 virus is not based on clinical evidence. Conversely, experimental studies suggest that ARBs might be useful in these patients to limit pulmonary damage through the inhibition of type 1 angiotensin II receptors. Controlled clinical studies in this area are eagerly awaited. This review discusses facts and theories on the potential impact of ACE-inhibitors and ARBs in the setting of the SARS-CoV-2 pandemic.

Electrocardiography for diagnosis of left ventricular hypertrophy in hypertensive patients with atrial fibrillation.

Left ventricular (LV) hypertrophy at electrocardiography (ECG) predicts incident atrial fibrillation (AF). However, the diagnostic performance of ECG for diagnosis of LV hypertrophy in patients with AF is still not well characterized. We analyzed 563 hypertensive patients enrolled in the Umbria-Atrial Fibrillation (Umbria-FA) registry, an ongoing prospective observational registry in patients with AF. All patients underwent ECG and standard echocardiography at their entry in the Register. Mean age was 74 years and 43% of patients were women. Prevalence of ECG-LV hypertrophy, defined by Perugia criterion corrected for body mass index, was 23%. Echocardiographic LV mass was the reference standard. Sensitivity, specificity and diagnostic accuracy of ECG-LV hypertrophy were 37.4% (95% confidence interval [CI]: 31.6-43.4), 90.0% (95% CI: 86.0-93.2) and 64.5% (95% CI: 60.4-68.3), respectively. Performance was comparable in patients with AF or sinus rhythm at ECG recording. The area under the receiver-operating characteristic (ROC) curve was 0.622 (95% CI: 0.580-0.664) in the group with AF and 0.662 (95% CI: 0.605-0.720) in that with sinus rhythm (p â€‹= â€‹0.266 for comparison). These data suggest that standard ECG is reliable for diagnosis of LV hypertrophy in patients with a history of AF, regardless of the presence of AF or sinus rhythm at the time of ECG recording.

Cardiac Biomarkers and Left Ventricular Hypertrophy in Relation to Outcomes in Patients With Atrial Fibrillation: Experiences From the RE - LY Trial.

Background Cardiac biomarkers and left ventricular hypertrophy ( LVH ) are related to the risk of stroke and death in patients with atrial fibrillation. We investigated the interrelationship between LVH and cardiac biomarkers and their independent associations with outcomes. Methods and Results Plasma samples were obtained at baseline in 5275 patients with atrial fibrillation in the RE - LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. NT -proBNP (N-terminal pro-B-type natriuretic peptide), cardiac troponin I and T, and growth differentiation factor-15 were determined using high-sensitivity (hs) assays. LVH was defined by ECG . Cox models were adjusted for baseline characteristics, LVH , and biomarkers. LVH was present in 1257 patients. During a median follow-up of 2.0 years, 165 patients developed a stroke and 370 died. LVH was significantly ( P<0.0001) associated with higher levels of all biomarkers in linear regression analyses adjusting for baseline characteristics. Geometric mean ratios (95% CIs) were as follows: NT -pro BNP , 1.32 (1.25-1.38); hs cardiac troponin I, 1.67 (1.57-1.78); hs troponin T, 1.38 (1.32-1.44); and growth differentiation factor-15, 1.09 (1.05-1.12). For stroke, the hazard ratios (95% CIs) per 50% increase were as follows: NT -pro BNP, 1.09 (1.00-1.19); hs cardiac troponin I, 1.09 (1.03-1.15); hs troponin T, 1.14 (1.06-1.24); and growth differentiation factor-15, 1.22 (1.08-1.38) (all P<0.05). For death, hazard ratios (95% CIs) were as follows: NT -pro BNP , 1.24 (1.17-1.31); hs cardiac troponin I, 1.13 (1.10-1.17); hs troponin T, 1.28 (1.23-1.34); and growth differentiation factor-15, 1.31 (1.22-1.42) (all P<0.0001). LVH was not significantly associated with stroke or death after adjustment for biomarkers. Conclusions Cardiac biomarkers are significantly associated with LVH . The prognostic value of biomarkers for stroke and death is not affected by LVH . The prognostic information of LVH is attenuated in the presence of cardiac biomarkers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00262600.

The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction.

An association has been shown between plasma renin activity (PRA) and the risk of cardiovascular disease. There is also evidence that angiotensin II exerts detrimental effects on progression and instabilization of atherosclerotic plaque. The renin-angiotensin system (RAS) can be inhibited through inhibition of angiotensin I (Ang I) generation from angiotensinogen by direct renin inhibitors, inhibition of angiotensin II (Ang II) generation from angiotensin I by angiotensin-converting enzyme inhibitors and finally by direct inhibition of the action of Ang II receptor level. Aliskiren, the first direct renin inhibitor to reach the market, is a low-molecular-weight, orally active, hydrophilic nonpeptide. Aliskiren blocks Ang I generation, while plasma renin concentration increases because the drugs blocks the negative feed-back exerted by Ang II on renin synthesis. Because of its long pharmacological half-life, aliskiren is suitable for once-daily administration. Its through-to-peak ratio approximates 98% for the 300 mg/day dose. Because of its mechanism of action, aliskiren might offer the additional opportunity to inhibit progression of atherosclerosis at tissue level. Hypertension is an approved indication for this drug, which is also promising for the treatment of heart failure. The efficacy of this drug in reducing major clinical events is being tested in large ongoing clinical trials.

Impact of Chamber Dilatation on the Prognostic Value of Left Ventricular Geometry in Hypertension.

BACKGROUND: The different geometric patterns of the left ventricle may or may not coexist with chamber dilatation. The prognostic impact of such a combination is unclear. METHODS AND RESULTS: We studied a cohort of 2635 initially untreated patients with hypertension, mean age 50 years. At entry, 24-hour ambulatory blood pressure progressively increased across the patterns of normal geometry, concentric left ventricular (LV) remodeling, eccentric nondilated LV hypertrophy (LVH), eccentric dilated LVH, concentric nondilated LVH, and concentric dilated LVH. During a mean follow-up of 9.7 years, 360 patients developed a first major cardiovascular event at a rate (×100 patient-years) of 1.41. The event rate was 0.93 in the group with normal LV geometry, 1.10 in the group with LV concentric remodeling, 1.40 in the group with nondilated eccentric LVH, 2.10 in the group with eccentric dilated LVH, 2.34 in the group with nondilated concentric LVH, and 4.67 in the group with dilated concentric LVH (log-rank test: P<0.001). In a Cox model, after adjustment for several independent covariables (age, sex, diabetes mellitus, current smoking, total cholesterol, estimated glomerular filtration rate, and average 24-hour systolic blood pressure), concentric dilated LVH was associated with a 98% excess risk of cardiovascular events (P=0.0037). However, LV geometric pattern lost statistical significance when LV mass was entered into the model. CONCLUSIONS: In initially untreated patients with hypertension, LV dilatation adds an adverse prognostic burden to the patterns of eccentric and concentric LVH. This phenomenon is explained by the greater LV mass associated with LV chamber dilatation.

Survey on treatments for primary headaches in 13 specialized juvenile Headache Centers: The first multicenter Italian study.

AIM: The purpose of this retrospective multicenter study was to evaluate the use and the self-perceived efficacy and tolerability of pharmacological and non-pharmacological treatments in children and adolescents with primary headaches. METHODS: Study of a cohort of children and adolescents diagnosed with primary headache, consecutively referred to 13 juvenile Italian Headache Centers. An ad hoc questionnaire was used for clinical data collection. RESULTS: Among 706 patients with primary headaches included in the study, 637 cases with a single type of headache (migraine 76% - with and without aura in 10% and 67% respectively; tension-type headache 24%) were selected (mean age at clinical interview: 12 years). Acetaminophen and non-steroidal anti-inflammatory drugs (in particular ibuprofen) were commonly used to treat attacks, by 76% and 46% of cases respectively. Triptans were used overall by 6% of migraineurs and by 13% of adolescents with migraine, with better efficacy than acetaminophen and non-steroidal anti-inflammatory drugs. Preventive drugs were used by 19% of migraineurs and by 3% of subjects with tension-type headache. In migraineurs, flunarizine was the most frequently used drug (18%), followed by antiepileptic drugs (7%) and pizotifen (6%), while cyproheptadine, propanolol and amitriptyline were rarely used. Pizotifen showed the best perceived efficacy and tolerability. Melatonin and nutraceuticals were used by 10% and 32% of subjects, respectively, both for migraine and tension-type headache, with good results in terms of perceived efficacy and tolerability. Non-pharmacological preventive treatments (i.e. relaxation techniques, biofeedback, cognitive-behavioral therapy, acupuncture) were used only by 10% of cases (migraine 9%, tension-type headache 15%). DISCUSSION: Non-steroidal anti-inflammatory drugs, especially ibuprofen, should be preferred to acetaminophen for acute attacks of migraine or tension-type headache, because they were usually more effective and well tolerated. Triptans could be used more frequently as first or almost second choice for treating migraine attack in adolescents. Non-pharmacological preventive treatments are recommended by some pediatric guidelines as first-line interventions for primary headaches and their use should be implemented in clinical practice. Prospective multicenter studies based on larger series are warranted to better understand the best treatment strategies for young people with primary headaches.

Five children with deletions of 1p34.3 encompassing AGO1 and AGO3.

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.

Brief report: functional MRI of a patient with 7q11.23 duplication syndrome and autism spectrum disorder.

The duplication of the Williams-Beuren syndrome (WBS) region (7q11.23) is a copy number variant associated with autism spectrum disorder (ASD). One of the most intriguing aspects is that the reciprocal microdeletion causes WBS, characterized by hypersociability, marked empathy, and a relative capacity in verbal short-term memory and language. Herein, we studied, by using functional morphological and volumetric magnetic resonance, a 17-year-old male patient who displays a de novo 7q11.23 duplication and ASD. The limbic system of the patient appeared hypo-functional, while the total brain volume was increased, thus contrasting, in an opposite and intriguing manner, with the global brain volume reduction reported in WBS. Even if these findings come from the analysis of a single patient and, therefore, have to be considered preliminary results, they encourage carrying on further functional and volumetric studies in patients with 7q11.23 duplication, to fully elucidate the role of this gene-dosage alteration on brain development and limbic system function.

Prognostic usefulness of left ventricular hypertrophy by electrocardiography in patients with atrial fibrillation (from the Randomized Evaluation of Long-Term Anticoagulant Therapy Study).

It is unknown whether left ventricular hypertrophy (LVH) diagnosis by electrocardiography improves risk stratification in patients with atrial fibrillation (AF). We investigated the prognostic impact of LVH diagnosis by electrocardiography in a large sample of anticoagulated patients with AF included in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Study. We defined electrographic LVH (ECG-LVH) by strain pattern or Cornell voltage (R wave in aVL plus S wave in V3) >2.0 mV (women) or >2.4 mV (men). LVH prevalence was 22.7%. During a median follow-up of 2.0 years, 303 patients developed a stroke, 778 died (497 from cardiovascular causes), and 140 developed a myocardial infarction. LVH was associated with a greater risk of stroke (1.99% vs 1.32% per year, hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.18 to 1.93, p <0.001), cardiovascular death (4.52% vs 1.80% per year, HR 2.56, 95% CI 2.14 to 3.06, p <0.0001), all-cause death (6.03% vs 3.11% per year, HR 1.95, 95% CI 1.68 to 2.26, p <0.0001), and myocardial infarction (1.11% vs 0.55% per year, HR 2.07, 95% CI 1.47 to 2.92, p <0.0001). In multivariate analysis, the prognostic value of LVH was additive to CHA2DS2-VASc score and other covariates. The category-free net reclassification index and integrated discrimination improvement increased significantly after adding LVH to multivariate models. In conclusion, our study demonstrates for the first time that ECG-LVH, a simple and easily accessible prognostic indicator, improves risk stratification in anticoagulated patients with AF.

Anxiety and depression levels in prepubertal obese children: a case-control study.

INTRODUCTION: Childhood obesity has become a worldwide epidemic in Western and in developing countries and has been accompanied by many serious and severe comorbidities, such as diabetes, hypertension, sleep apnea syndrome, depression, dyslipidemia, impaired glucose homeostasis, steatohepatitis, and intracranial hypertension, as well as medical concerns unique to youth, such as accelerated pubertal and skeletal development and orthopedic disorders. To date, no specific studies about the psychological assessment in pediatric obesity are present. Therefore, the aim of this study was to evaluate the putative relationship between psychological troubles and obesity in a sample of school-aged children. MATERIALS AND METHODS: The study population consists of 148 obese subjects (body mass index [BMI] >95th percentile) (69 males, mean age 8.9±1.23 years) consecutively referred from clinical pediatricians to the Child and Adolescent Neuropsychiatry department at the Second University of Naples. In all subjects, weight, height, and BMI z-score were evaluated. In order to assess the anxiety levels and the presence of depressive symptoms, the Children Depression Inventory (CDI) and the Italian Self-Administered Psychiatric Scales for Children and Adolescents (SAFA) were administered. The control group consisted of 273 healthy children (129 males and 144 females) (mean age 9.1±1.8 years), enrolled in schools within the Campania region of Italy. RESULTS: No significant differences between the two study groups were found for age (8.9±1.23 years in the obese sample and 9.1±1.8 years in the control group) (P=0.228) or sex (ratio male/female: 69/79 in the obese group versus 129/144 in the control group) (P=0.983). Obviously, significant difference was found for the BMI z-score (2.46±0.31 in the obese group vs 0.73±0.51 in the control group) (P<0.001). The obese subjects showed significant higher level of depressive symptoms (CDI total score) (16.82±7.73 vs 8.2±2.9) (P<0.001) and anxiety (SAFA - Anxiety [SAFA-A]) scale score (58.71±11.84 vs 27.75±11.5) (P<0.001) compared with the control group. Moreover, the Pearson's correlation analysis showed a significantly positive relationship between the BMI z-score and both the CDI (r=0.677; P<0.001) and SAFA-A scores (r=0.591; P<0.001). CONCLUSION: Our findings highlighted the importance of assessing the presence of internalizing problems, such as anxiety and depression, in the common management of childhood obesity.