Ospedale San Giuseppe

Udgivelsesdato: 2007-Jun

The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) follow the guidelines jointly issued by the two societies in 2003 and 2007 [1,2]. Publication of a new document 6 years after the previous one was felt to be timely because, over this period, important studies have been conducted and many new results
\nhave been published on both the diagnosis and treatment of individuals with an elevated blood pressure (BP), making refinements, modifications and expansion of the previous recommendations necessary.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by a Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential con?ict of interest is reported on the websites of the ESH and the ESC

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Committee; LVH: left ventricular hypertrophy; LVM: left ventricular mass; PDE-5: phosphodiesterase-5; PPAR-γ: peroxisome proliferators-activated receptor-γ; PWV: pulse wave velocity; SBP: systolic blood pressure; WHO: World Health Organization. Introduction In the 2 years since the publication of the 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) [1], research on hypertension has actively been pursued and the results of new important studies (including several large randomized trials of antihypertensive therapy) have been published. Some of these studies have reinforced the evidence on which the recommendations of the 2007 ESH/ESC guidelines were based. However, other studies have widened the information available in 2007, modifying some of the previous concepts, and suggesting that new evidence-based recommendations could be appropriate. The aim of this document of the ESH is to address a number of studies on hypertension published in the last 2 years in order to assess their contribution to our expanding knowledge of hypertension. Furthermore, some critical appraisal of the current recommendations of the ESH/ESC, as well as of other guidelines, might be a useful step toward the preparation of a third version of the European guidelines in the future. The most important conclusions are summarized in boxes. The points that will be discussed are reported in Box 1.Box. 1Assessment of subclinical organ damage for stratification of total cardiovascular risk The 2007 ESH/ESC guidelines recommend total cardiovascular risk be evaluated in each patient to decide about important aspects of treatment: the blood pressure (BP) threshold at which to commence drug administration, the target BP to be reached by treatment, the use of two-drug combinations as the initial treatment step, and the possible addition to the antihypertensive treatment regimen of lipid-lowering and antiplatelet agents [1]. Among the criteria to assess total cardiovascular risk, the European guidelines consider subclinical organ damage to be a very important component, because asymptomatic alterations of the cardiovascular system and the kidney are crucial intermediate stages in the disease continuum that links risk factors such as hypertension to cardiovascular events and death. On the basis of a number of criteria (prognostic importance, prevalence in the population, availability and cost of the assessment procedures, etc.), the 2007 European guidelines considered detection of organ damage as important for the diagnostic and prognostic evaluation of hypertensive patients. They further subdivided the different types of organ damage into (1) those that can be identified by relatively simple and cheap procedures [electrocardiogram, serum creatinine, estimated glomerular filtration rate (eGFR), and measurement of urinary protein excretion in order to detect microalbuminuria or proteinuria], which were thus regarded as suitable for routine search in the whole hypertensive population, and (2) those that require more complex procedures or instrumentations (echocardiogram, carotid ultrasonography, pulse wave velocity), which were for this reason only recommended for a more in-depth characterization of the hypertensive patient. Since then, other studies have added useful information on the importance of detecting subclinical organ damage in the hypertensive population, strengthening the recommendation to use the most easily available and the least costly procedures in the routine examination of individuals with hypertension. Heart A few recent papers have revived interest in the power of the electrocardiogram to predict the risk of cardiovascular events. In a prospective survey including 7495 American adults, a new indicator of left ventricular hypertrophy (LVH), the Novacode estimate of left ventricular mass index that is based on both voltage and strain pattern criteria, has been reported to be significantly related to 10-year cardiovascular mortality [2]. The relation remained significant after adjusting for age, SBP, smoking, cholesterol, and diabetes. Furthermore, in the LIFE trial, the investigators have reported that in hypertensive patients with electrocardiographic LVH, left bundle branch block identifies individuals at increased risk of cardiovascular mortality (hazard ratio 1.6), sudden cardiovascular death (hazard ratio 3.5), and hospitalization for heart failure (hazard ratio 1.7) [3]. Finally, a very recent prospective study [4] focused on the R-wave voltage in lead aVL as being rather closely associated with left ventricular mass (LVM), and additionally predictive of incident cardiovascular events even when hypertension is not accompanied by electrocardiographic LVH (9% higher risk for each 0.1 mV higher R-wave). Additional evidence is also available on the predictive power of cardiac abnormalities, as detected by echocardiography, an approach of continuing interest because of its ability to more directly and precisely quantify LVM and geometric LVH patterns. A retrospective study has recently updated information from more than 35 000 normotensive and hypertensive participants with normal left ventricular ejection fraction [5]. Despite normal left ventricular function, an abnormal left ventricular geometric pattern was found in 46% of the patients (35% left ventricular concentric remodeling and 11% LVH), and the associated risk of all-cause mortality was twice as large as that of patients with normal left ventricular geometry. Although in another study on an African–American population, the relationship between left ventricular geometric patterns and all-cause mortality was markedly attenuated after adjusting for baseline variables, and remained significant only in men [6], the increased risk associated with LVH has been confirmed by other observations. In a prospective study on a cohort of 1652 Greek hypertensive patients followed up for 6 years, echocardiographic LVH was significantly associated with either a composite of all-cause mortality and cardiovascular events (hazard ratio 1.53) and with stroke (hazard ratio 2.01), after adjustment for major cardiovascular risk factors [7]. Furthermore, a retrospective analysis of 1447 Japanese hypertensive patients who participated in the CASE-J trial showed that cardiovascular events occurred about 2.6 times more frequently in patients with a LVM index 125 g/m2 or more compared with those with a LVM index below this value [8]. Finally, in the PAMELA population, echocardiographic LVH was associated with a four-fold to five-fold significant increase in cardiovascular morbidity and mortality when data were adjusted for a large number of potential confounders, including office, home, and ambulatory BP values. A 10% increase in LVM increased the risk more markedly when baseline LVM was already abnormal, but an increasing risk was evident also when calculated from LVM values within the normal range [9]. Blood vessels The relationship of carotid intima–media thickness (IMT) and plaques with subsequent cardiovascular events, already discussed in the 2007 guidelines, has been further strengthened by data from ELSA [10], which have shown that baseline carotid IMT predicts cardiovascular events independent of BP (clinic and ambulatory) and this occurs both for the IMT value at the carotid bifurcations and for the IMT value at the level of the common carotid artery. This suggests that both atherosclerosis (reflected by the IMT value at the bifurcations) and vascular hypertrophy (reflected by the common carotid IMT) exert an adverse prognostic effect in addition to that of high BP. An adverse prognostic significance of carotid plaques (hazard ratio 2.3) has also been reported in a sample of residents of the Copenhagen County free of overt cardiovascular disease, which was prospectively followed for about 13 years [11]. Evidence has also accrued on the adverse prognostic value of arterial stiffening. In the Copenhagen County population, an increased pulse wave velocity (PWV >12 m/s) was associated with a 50% increase in the risk of a cardiovascular event [11]. Furthermore, an independent predictive value of PWV for cardiovascular events has been shown in Japanese men followed for 8.2 years [12]. Finally, indirect indices of aortic stiffness and wave reflection, such as central BP and augmentation index, have been confirmed as independent predictors of cardiovascular events in two recent studies [13,14]. In particular, in one of these studies of 1272 normotensive and untreated hypertensive patients, only central SBP consistently and independently predicted cardiovascular mortality after adjustment for various cardiovascular risk factors, including LVM and carotid IMT [14]. However, it should be emphasized that in most available studies, the additive predictive value of central BP beyond brachial pressure appears limited, which leaves the question whether central BP measurements should be regularly considered in the clinical profiling of hypertensive patients in need of further investigation. Kidney Several new data [15] reinforce the already solid evidence on the prognostic value of eGFR that was available at the time of the 2007 guidelines [1]. In the population of Gubbio (Italy), an eGFR in the lowest decile was associated with a significantly higher incidence of cardiovascular events (hazard ratio 2.14) [16], and in the above-mentioned Greek study [7], an eGFR between 15 and 59 ml/min per 1.73 m2 was associated with a 66% increase in the composite endpoint of all cause mortality and cardiovascular events after adjustment for baseline cardiovascular risk and independent of LVH [7]. Likewise, in a post hoc analysis of data from the VALUE trial [17], eGFR according to the MDRD formula was significantly predictive of all outcomes except stroke (with hazard ratios between 1.23 and 1.70 according to the different outcomes) and was more sensitive than calculation of the creatinine clearance value according to the Cockroft–Gault formula, which was only predictive of all-cause mortality. The baseline eGFR by the MDRD formula turned out to be importantly predictive of both renal and cardiovascular events also in the large number (n = 11 140) of type 2 diabetic patients included in the ADVANCE trial, even when data were adjusted for many potential confounders, including the concomitant urinary protein excretion value. For every 50% reduction of baseline eGFR the risk of cardiovascular events significantly increased 2.2-fold, the concomitant increase in the risk of cardiovascular death and renal events being 3.6-fold and 63.6-fold, respectively [18]. New evidence is also available to support the already large amount of data in favor of the prognostic value of the moderate increase in urinary protein excretion, defined as microalbuminuria [19,20]. In two population studies, the Gubbio study [16] and the Copenhagen County study [11], microalbuminuria was confirmed as an important predictor of cardiovascular outcome, the adjusted hazard ratio being, respectively, 2.15-fold and 3.10-fold greater in patients with microalbuminuria compared with those without. In the Gubbio study, the association of microalbuminuria with low eGFR had a multiplicative effect (hazard ratio 5.93). In the ADVANCE trial [18], a change from one clinical stage of albuminuria to the next was associated with a 1.6-fold, 2.0-fold, and 3.3-fold increase in the multivariate-adjusted risk of cardiovascular events, cardiovascular death, and renal events, respectively, this being the case also when the change from normoalbuminuria to microalbuminuria was involved. The effects of higher baseline urinary protein excretion and reduced eGFR were independent of each other and the association of microalbuminuria and an eGFR value less than 60 ml/min per 1.73 m2 brought about an additional increase in risk: 3.2-fold for cardiovascular events, 5.9-fold for cardiovascular mortality, and 22.2-fold for renal events. Additional measures of organ damage The 2007 European guidelines mention a number of additional measures of organ damage for which evidence of prognostic relevance was available, but no use in the clinical practice could be foreseen because of drawbacks of practical relevance, such as the high cost and low availability of the devices involved, the complexity and time consumption inherent in the procedures, and in several instances the lack of standardization of the values obtained between laboratories and across countries. Based on the evidence available in the last 2 years, no addition to the measures of organ damage included in the 2007 guidelines can be supported, although the growing availability of more sophisticated techniques and the reduced cost of their use brought about by technological progress, makes future additions likely. In this context, the use of nuclear magnetic resonance deserves special mention. Although not prospective in nature, a very recent study systematically employing nuclear magnetic resonance imaging in a group of 142 hypertensive patients without overt cardiovascular disease has provided the interesting information that silent cerebrovascular lesions are even more prevalent (44%) than cardiac (21%) and renal (26%) subclinical damage, and do frequently occur in the absence of other signs of organ damage [21]. Increasing evidence also relates these lesions to cognitive dysfunction [22,23], a problem of primary importance because of the senescence of the population [24]. With magnetic resonance imaging becoming more and more frequently employed in diagnostic procedures, silent cerebrovascular disease is likely to become more frequently investigated in prognostic and therapeutic studies in hypertension. The prognostic value of structural alterations in small subcutaneous arteries has recently been confirmed by two independent studies [25,26]. However, the invasive nature of this measurement prevents larger scale application of this method. A new noninvasive method for assessing the media–lumen ratio of small retinal arteries seems promising for large-scale evaluation [27], although its predictive value remains to be investigated. Evidence remains inconclusive on a marker of a vascular alteration that has been actively investigated in the past decade, namely endothelial dysfunction. In a population sample of individuals without overt cardiovascular disease (67% with hypertension and 22% with diabetes mellitus) from the Northern Manhattan study, measures of flow-mediated vasodilatation predicted the incidence of cardiovascular events, but this effect was not independent of traditional cardiovascular risk factors [28]. Likewise, in the large cohort of elderly patients of the Cardiovascular Health Study, flow-mediated vasodilatation added very little to the prognostic accuracy of traditional risk factors [29]. On the contrary, Muiesan et al.[30] have recently reported that in a small cohort (n = 172) of uncomplicated hypertensive persons followed for about 8 years, flow-mediated vasodilatation of the brachial artery below the median value was significantly associated with a 2.7-fold increase in incident cardiovascular events even after adjusting for all major cardiovascular risk factors. However, the same group of investigators also have reported that endothelial dysfunction in the subcutaneous vessels of hypertensive patients was not predictive of cardiovascular events [31], possibly because endothelial dysfunction in different vascular beds may have a different prognostic significance. Clearly, the prognostic value of endothelial dysfunction in hypertension remains to be further elucidated. It should be emphasized that the addition of new measures of organ damage to the assessment of total cardiovascular risk requires not only the demonstration of their prognostic importance, but it has to improve the power to predict the incidence of cardiovascular events. This is by no means easy to be documented, and indeed data are available that in some instances new risk factors of individual prognostic significance do not improve, when added to the others, the accuracy by which cardiovascular risk can be quantified, thus only making the diagnostic procedures more complex, time consuming, and costly. This is exemplified by the recent results of the Framingham study, which showed that inclusion of inflammatory markers did not lead to any substantial improvement in the accuracy (sensitivity and specificity) by which total cardiovascular risk was assessed [32]. Subclinical organ damage as a marker of high cardiovascular risk Although subclinical organ damage undoubtedly increases the level of cardiovascular risk, the question arises whether it always brings the patient into the high-risk category, that is, an absolute risk of at least 20 cardiovascular events in 10 years per 100 patients. The 2007 European guidelines classify hypertensive patients with subclinical organ damage among those with a high total cardiovascular risk. This is further supported by more recent evidence on the contribution of subclinical cardiac, vascular, and renal damage to the total cardiovascular risk. As regards to subclinical cardiac damage, analysis of the data provided by some of the major prospective studies indicates that in hypertensive patients, echocardiographic LVH, particularly if of the concentric variety, is associated with an incidence of cardiovascular events equal to or above 20% in 10 years [5,7,33]. An incidence greater than 20% in 10 years has also been reported for men, but not for women, with echocardiographic LVH in the Framingham population study [34]. Finally, in the hypertensive patients of the CASE-J trial, echocardiographic LVH was associated with a 10-year incidence of cardiovascular events of 24% compared with the 10% incidence seen in patients without LVH [8]. Similar evidence exists for vascular damage. In the elderly patients of the Cardiovascular Health Study [35], the 10-year incidence of major cardiovascular events was higher than 20% when the common carotid IMT was 1.06 mm or more (fourth and fifth quintiles) and below 10% in those with an IMT in the first quintile (<0.87 mm). In the hypertensive patients of the ELSA study [10], the incidence of all (major and minor) cardiovascular events was greater than 20% in 10 years when IMT (common carotid plus bifurcation) was in the third and fourth quartiles (≥1.16 mm) or when at least one plaque had been detected. In contrast, patients with IMT in the first or the smallest IMT quartile (<0.98 mm) had incident cardiovascular events below 10% in 10 years. In hypertensive patients, the 10-year incidence of major cardiovascular events was higher than 20% when carotid-femoral PWV (aortic stiffness) was 16.3 m/s or more (fifth quintile) and below 10% in those with an aortic stiffness in the first and second quintiles [36]. Furthermore, even asymptomatic peripheral vascular disease as detected by a positive ankle-brachial index has prospectively been found to be associated in men with an incidence of cardiovascular events approaching 20% in 10 years [37,38]. Finally, old and recent evidence leaves little doubt that in hypertensive individuals, renal subclinical organ damage is associated with a 10-year risk of cardiovascular events of 20% or more. It has already been reported some years ago that reduced renal function, defined by a serum creatinine more than 1.5 mg/dl is associated with a 10-year incidence of cardiovascular events 20% or more [39,40]. In the recent prospective cohort of Greek hypertensive patients [7], a low eGFR was associated with incident cardiovascular events of about 20% in 10 years, an even higher incidence being observed when low eGFR occurred together with LVH. Furthermore, in the hypertensive patients prospectively studied by Jensen et al.[41], the incidence of ischemic heart disease was 20% in 10 years in the presence of microalbuminuria and of only 5% in its absence. Also, in the Gubbio population study, the incidence of cardiovascular events was greater than 20% in 10 years, but only in those individuals in whom microalbuminuria in the highest decile was associated with eGFR in the lowest decile [16]. Over 78% of these patients had hypertension. The 2007 European guidelines classify patients with subclinical organ damage as being at high risk also when BP is in the high normal range, but admittedly evidence that this is invariably the case is less clear. In the general population of the Framingham study, no information was made available on the prognostic value of echographic LVH, separately in the normotensive and hypertensive population [34]. Furthermore, in the same population, the association of renal dysfunction with cardiovascular events was lost after adjustment for cardiovascular risk factors, including BP [42]. In the PREVEND population study [43], microalbuminuria (20–200 mg/l) was associated with only a 4.7% cardiovascular mortality in 10 years, that is, a moderate absolute risk according to the SCORE classification [44], and in the nonhypertensive, nondiabetic individuals of the Framingham study, a microalbuminuria above the median value was associated with a rate of incident cardiovascular events of only 8.8% in 10 years compared with a 2.9% rate in individuals with microalbuminuria below the median value [45]. Prognostic value of treatment-induced modifications of subclinical organ damage The 2007 European guidelines have emphasized that treatment-induced changes of organ damage affect the incidence of cardiovascular events, thereby recommending that organ damage be measured also during treatment. Reference was made to the data obtained in the LIFE study [46], in which hypertensive patients in whom treatment was accompanied by regression of echocardiographic LVH or a delayed increase in LVM had less incident cardiovascular events, including sudden death, than those in whom no regression from or earlier progression to LVH occurred. It was also mentioned that both in LIFE [47] and in other studies [48], a similar relationship was found between treatment-induced changes in and renal or cardiovascular events. This means compared with patients in whom treatment had little or no reduction in was associated with a reduced incidence of cardiovascular events and less progression to renal Since 2007, data on the relationship between treatment-induced changes in cardiac damage and cardiovascular have been by further of the LIFE study, which have shown that also treatment-induced changes in left left ventricular and in electrocardiographic signs of LVH with incident cardiovascular event rate Furthermore, have been that in changes in LVM during treatment affect cardiovascular Finally, the predictive power of treatment-induced IMT changes in the carotid arteries has for the first time been investigated in a recent analysis of ELSA trial This analysis to a predictive of IMT but the of these changes compared with the large individual in baseline IMT makes it to conclusions The of treatment-induced changes in with cardiovascular event incidence has been by some of the In this trial on a large number of high or very high cardiovascular risk patients, the group with a of an angiotensin-converting and an the study less increase in than the group on with one or the other but this effect was not accompanied by a reduction in cardiovascular events and was even associated with an increase in renal events However, these results do not the important that treatment-induced changes in can be a marker of the more or less effects of treatment because for the results are For in most patients had a normal renal and few overt which in a very number of the endpoint that for renal that is, renal Furthermore, in the very high cardiovascular risk population the of the system provided by the and might have an adverse effect of its that and the associated with a reduction in In favor of this are some recent of the ADVANCE study in patients with type 2 diabetes. In these patients, values of showed a independent association with both renal and cardiovascular events, the contribution of being to the concomitant values of eGFR [18]. Evidence on the important prognostic of subclinical organ damage to In both hypertensive patients and the general population, the presence of electrocardiographic and echocardiographic LVH, a carotid plaque or an increased arterial a reduced eGFR by the MDRD or microalbuminuria or increases the total cardiovascular risk, hypertensive patients into the high absolute risk The changes in or detected LVH by treatment the effects on cardiovascular events, thereby information on whether patients are more or less by the treatment Despite some recent results solid evidence suggests that this is the case also for treatment-induced changes in urinary protein excretion, although the problem remains for treatment-induced vascular assessing the presence of subclinical organ damage is of crucial importance in the hypertensive This assessment can use of simple and cheap procedures that can routine information and at various times during treatment. It can also on more sophisticated that can further cardiac and vascular In all organ damage assessment is useful because of the evidence that in the presence of two signs of organ damage when inherent to the same cardiovascular risk may be more markedly with an to the high cardiovascular risk It is not from published data whether subclinical organ damage can total cardiovascular risk to the high range also in patients with high normal BP. However, organ damage when it is particularly or or is accompanied by risk factors, is associated with a or increase in risk also in normotensive individuals and the 2007 guidelines recommend risk as a for the need of treatment in and patients. In this context, it is also important to that the of organ damage in patients that decide to the of several studies that the incidence of cardiovascular events is higher in than in untreated hypertensive patients even after adjustment for cardiovascular risk factors and past clinical This is with the that antihypertensive treatment even if a high total risk to a the that in treatment is organ damage when is not use of organ damage assessment may thus to a more about the of treatment and thus favor its greater Some of the discussed in of subclinical organ damage for stratification of total cardiovascular risk are summarized in Box approach guidelines on the management of hypertension recommend the of antihypertensive in all patients with a SBP or more a or and to the treatment in order for the patients to be below these values. They further recommend drug treatment to be within a BP range, that is, a SBP between and and a between and in patients with diabetes or a of cardiovascular or renal disease, at values The 2007 ESH/ESC guidelines have accompanied these recommendations with information on the evidence are based and a critical of this has recently been by of the in the of further information provided by recent The of the ESH document is to the and the type of evidence on which these recommendations are and thus the and

The Stroop Color and Word Test (SCWT) is a neuropsychological test extensively used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus attribute, well-known as the Stroop Effect. The aim of the present work is to verify the theoretical adequacy of the various scoring methods used to measure the Stroop effect. We present a systematic review of studies that have provided normative data for the SCWT. We referred to both electronic databases (i.e., PubMed, Scopus, Google Scholar) and citations. Our findings show that while several scoring methods have been reported in literature, none of the reviewed methods enables us to fully assess the Stroop effect. Furthermore, we discuss several normative scoring methods from the Italian panorama as reported in literature. We claim for an alternative scoring method which takes into consideration both speed and accuracy of the response. Finally, we underline the importance of assessing the performance in all Stroop Test conditions (word reading, color naming, named color-word).

BACKGROUND: Although the relationship between mortality and time delay to treatment has been demonstrated in patients with acute ST-segment elevation myocardial infarction (STEMI) treated by thrombolysis, the impact of time delay on prognosis in patients undergoing primary angioplasty has yet to be clarified. The aim of this report was to address the relationship between time to treatment and mortality as a continuous function and to estimate the risk of mortality for each 30-minute delay. METHODS AND RESULTS: The study population consisted of 1791 patients with STEMI treated by primary angioplasty. The relationship between ischemic time and 1-year mortality was assessed as a continuous function and plotted with a quadratic regression model. The Cox proportional hazards regression model was used to calculate relative risks (for each 30 minutes of delay), adjusted for baseline characteristics related to ischemic time. Variables related to time to treatment were age >70 years (P<0.0001), female gender (P=0.004), presence of diabetes mellitus (P=0.002), and previous revascularization (P=0.035). Patients with successful reperfusion had a significantly shorter ischemic time (P=0.006). A total of 103 patients (5.8%) had died at 1-year follow-up. After adjustment for age, gender, diabetes, and previous revascularization, each 30 minutes of delay was associated with a relative risk for 1-year mortality of 1.075 (95% CI 1.008 to 1.15; P=0.041). CONCLUSIONS: These results suggest that every minute of delay in primary angioplasty for STEMI affects 1-year mortality, even after adjustment for baseline characteristics. Therefore, all efforts should be made to shorten the total ischemic time, not only for thrombolytic therapy but also for primary angioplasty.

BACKGROUND: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. METHODS: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. RESULTS: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). CONCLUSIONS: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

Pulmonary hypertension (PH) frequently complicates the course of patients with various forms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelae between the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualised within the extent of the underlying lung disease, which is best gauged through a combination of physiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in this article, as will the current state of knowledge with regard to the role of treatment with pulmonary vasoactive agents. Although such therapy cannot be endorsed given the current state of findings, future studies in this area are strongly encouraged.

Throughout this article, the reader will notice combinations of superscripted letters and numbers (eg, "Cricoid Pressure ALS-CPR&A-007B "). These callouts are hyperlinked to evidence-based worksheets, which were used in the development of this article. An appendix of worksheets, applicable to this article, is located at the end of the text. The worksheets are available in PDF format and are open access. The topics reviewed by the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force are grouped as follows: (1) airway and ventilation, (2) supporting the circulation during cardiac arrest, (3) periarrest arrhythmias, (4) cardiac arrest in special circumstances, (5) identifying reversible causes, (6) postresuscitation care, (7) prognostication, and (8) organ donation. Defibrillation topics are discussed in Part 6.

Human obesity is characterized by profound alterations in the hemodynamic and metabolic states. Whether these alterations involve sympathetic drive is controversial. In 10 young obese subjects (body mass index, 40.5 +/- 1.2 kg/m2, mean +/- SEM) with normal blood pressure and 8 age-matched lean normotensive control subjects, we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (electrocardiogram), postganglionic muscle sympathetic nerve activity (microneurography at the peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography). The measurements were performed in baseline conditions and, with the exception of plasma norepinephrine, during baroreceptor stimulation and deactivation caused by increases and reductions of blood pressure via intravenous infusions of phenylephrine and nitroprusside. Baseline blood pressure and heart rate were similar in obese and control subjects. Plasma norepinephrine was also similar in the two groups. Muscle sympathetic nerve activity, however, was 38.6 +/- 5.1 bursts per minute in obese subjects and less than half that level in control subjects (18.7 +/- 1.3 bursts per minute), the difference being highly statistically significant (P < .02). Muscle sympathetic nerve activity and heart rate were reduced during phenylephrine infusion and increased during nitroprusside infusion, but the changes were about half as great in obese subjects as in control subjects. Thus, even in the absence of any blood pressure alteration, human obesity is characterized by a marked sympathetic activation, possibly because of an impairment of reflex sympathetic restraint. This may be involved in the high rate of hypertension and cardiovascular complications seen in obesity.

BACKGROUND: In cross-sectional studies, ambulatory blood pressure (ABP) correlates more closely than clinic BP with the organ damage of hypertension. Whether ABP predicts development or regression of organ damage over time better than clinic BP, however, is unknown. METHODS AND RESULTS: In 206 essential hypertensive subjects with left ventricular hypertrophy (LVH), we measured clinic supine BP, 24-hour ABP, and left ventricular mass index (LVMI, echocardiography) before and after 12 months of treatment with lisinopril (20 mg UID) without or with hydrochlorothiazide (12.5 or 25 mg UID). Measurements included random-zero, clinic orthostatic, and home BP. In all, 184 subjects completed the 12-month treatment period. Before treatment, clinic supine BP was 165 +/- 15/105 +/- 5 mm Hg (systolic/diastolic), 24-hour average BP was 149 +/- 16/95 +/- 11 mm Hg, and LVMI was 158 +/- 32 g/m2. At the end of treatment, they were 139 +/- 12/87 +/- 7 mm Hg, 131 +/- 12/83 +/- 10 mm Hg, and 133 +/- 26 g/m2, respectively (P < .01 for all). Before treatment, LVMI did not correlate with clinic BP, but it showed a correlation with systolic and diastolic 24-hour average BP (r = .34/.27, P < .01). The LVMI reduction was not related to the reduction in clinic BP, but it was related to the reduction in 24-hour average BP (r = .42/.38, P < .01). Treatment-induced changes in average daytime and nighttime BPs correlated with LVMI changes as strongly as 24-hour BP changes. No substantial advantage over clinic supine BP was shown by clinic orthostatic, random-zero, and home BP. CONCLUSIONS: In hypertensive subjects with LVH, regression of LVH was predicted much more closely by treatment-induced changes in ABP than in the clinic BP. This provides the first longitudinally controlled evidence that ABP may be clinically superior to traditional BP measurements.

This is a continuity of a series of taxonomic papers where materials are examined, described and novel combinations are proposed where necessary to improve our traditional species concepts and provide updates on their classification. In addition to extensive morphological descriptions and appropriate asexual and sexual connections, DNA sequence data are also analysed from concatenated datasets (rDNA, TEF-α, RBP2 and β-Tubulin) to infer phylogenetic relationships and substantiate systematic position of taxa within appropriate ranks. Wherever new species or combinations are being proposed, we apply an integrative approach (morphological and molecular data as well as ecological features wherever applicable). Notes on 125 fungal taxa are compiled in this paper, including eight new genera, 101 new species, two new combinations, one neotype, four reference specimens, new host or distribution records for eight species and one alternative morphs. The new genera introduced in this paper are Alloarthopyrenia, Arundellina, Camarosporioides, Neomassaria, Neomassarina, Neotruncatella, Paracapsulospora and Pseudophaeosphaeria. The new species are Alfaria spartii, Alloarthopyrenia italica, Anthostomella ravenna, An. thailandica, Arthrinium paraphaeospermum, Arundellina typhae, Aspergillus koreanus, Asterina cynometrae, Bertiella ellipsoidea, Blastophorum aquaticum, Cainia globosa, Camarosporioides phragmitis, Ceramothyrium menglunense, Chaetosphaeronema achilleae, Chlamydotubeufia helicospora, Ciliochorella phanericola, Clavulinopsis aurantiaca, Colletotrichum insertae, Comoclathris italica, Coronophora myricoides, Cortinarius fulvescentoideus, Co. nymphatus, Co. pseudobulliardioides, Co. tenuifulvescens, Cunninghamella gigacellularis, Cyathus pyristriatus, Cytospora cotini, Dematiopleospora alliariae, De. cirsii, Diaporthe aseana, Di. garethjonesii, Distoseptispora multiseptata, Dis. tectonae, Dis. tectonigena, Dothiora buxi, Emericellopsis persica, Gloniopsis calami, Helicoma guttulatum, Helvella floriforma, H. oblongispora, Hermatomyces subiculosa, Juncaceicola italica, Lactarius dirkii, Lentithecium unicellulare, Le. voraginesporum, Leptosphaeria cirsii, Leptosphaeria irregularis, Leptospora galii, Le. thailandica, Lindgomyces pseudomadisonensis, Lophiotrema bambusae, Lo. fallopiae, Meliola citri-maximae, Minimelanolocus submersus, Montagnula cirsii, Mortierella fluviae, Muriphaeosphaeria ambrosiae, Neodidymelliopsis ranunculi, Neomassaria fabacearum, Neomassarina thailandica, Neomicrosphaeropsis cytisi, Neo. cytisinus, Neo. minima, Neopestalotiopsis cocoës, Neopestalotiopsis musae, Neoroussoella lenispora, Neotorula submersa, Neotruncatella endophytica, Nodulosphaeria italica, Occultibambusa aquatica, Oc. chiangraiensis, Ophiocordyceps hemisphaerica, Op. lacrimoidis, Paracapsulospora metroxyli, Pestalotiopsis sequoiae, Peziza fruticosa, Pleurotrema thailandica, Poaceicola arundinis, Polyporus mangshanensis, Pseudocoleophoma typhicola, Pseudodictyosporium thailandica, Pseudophaeosphaeria rubi, Purpureocillium sodanum, Ramariopsis atlantica, Rhodocybe griseoaurantia, Rh. indica, Rh. luteobrunnea, Russula indoalba, Ru. pseudoamoenicolor, Sporidesmium aquaticivaginatum, Sp. olivaceoconidium, Sp. pyriformatum, Stagonospora forlicesenensis, Stagonosporopsis centaureae, Terriera thailandica, Tremateia arundicola, Tr. guiyangensis, Trichomerium bambusae, Tubeufia hyalospora, Tu. roseohelicospora and Wojnowicia italica. New combinations are given for Hermatomyces mirum and Pallidocercospora thailandica. A neotype is proposed for Cortinarius fulvescens. Reference specimens are given for Aquaphila albicans, Leptospora rubella, Platychora ulmi and Meliola pseudosasae, while new host or distribution records are provided for Diaporthe eres, Di. siamensis, Di. foeniculina, Dothiorella iranica, Do. sarmentorum, Do. vidmadera, Helvella tinta and Vaginatispora fuckelii, with full taxonomic details. An asexual state is also reported for the first time in Neoacanthostigma septoconstrictum. This paper contributes to a more comprehensive update and improved identification of many ascomycetes and basiodiomycetes.

The relationship between inflammation and general health conditions in dairy cows and the link between inflammation, liver function, and fertility are poorly understood. To clarify these relationships, 120 multiparous dairy cows were followed throughout an entire lactation. Blood samples were collected during the first month of lactation for a metabolic profile, and milk yield, disease occurrence, and fertility parameters were monitored during the entire lactation. Twenty-four cows were culled, and another 19 were excluded because they had serious problems after 30 d in milk (DIM) and before the first insemination. The remaining 77 cows were pregnant at the end of lactation and were retrospectively grouped into quartiles based on liver activity index (LAI), which is based on plasma negative acute phase proteins. Cows in the lower (LO) and intermediate lower (INLO) quartiles of LAI had more severe inflammations with high concentrations of haptoglobin (0.77 and 0.61 g/L) and globulin (42.5 and 39.0 g/L), respectively, during the first week of lactation compared with cows in the upper (UP) and intermediate upper (INUP) quartiles of LAI (haptoglobin: 0.28 and 0.45 g/L, and globulin: 34.2 and 36.9 g/L, respectively). At 7 DIM, the cows in LO and INLO had greater bilirubinemia (8.7 and 10.5 vs. 6.3 microM/L in UP) and lower blood urea (3.5 and 3.7 vs. 4.1 mM in UP). The INLO group exhibited more days open (139 vs. 93) and services per pregnancy (2.68 vs. 1.65), but lower milk yield (38.3 vs. 40.8 kg/d at 28 DIM) compared with UP. The LO group did not have a significantly lower fertility status, but presented the lowest milk yield (34.1 kg/d at 28 DIM). Our data suggest that cows with lower LAI scores had a more pronounced inflammatory status during the first month of lactation, an impairment of usual hepatic functions (e.g., bilirubin clearance), and a larger negative energy balance. The same cows had poorer performance (lower milk yield and fertility) than cows with higher LAI scores. Overall data suggest that any effort to avoid the acute phase response in the transition period would be useful for optimizing the productive and reproductive performance of high-yielding dairy cows.

[Abridged] Star and planet formation are the complex outcomes of gravitational collapse and angular momentum transport mediated by protostellar and protoplanetary disks. In this review we focus on the role of gravitational instability in this process. We begin with a brief overview of the observational evidence for massive disks that might be subject to gravitational instability, and then highlight the diverse ways in which the instability manifests itself in protostellar and protoplanetary disks: the generation of spiral arms, small scale turbulence-like density fluctuations, and fragmentation of the disk itself. We present the analytic theory that describes the linear growth phase of the instability, supplemented with a survey of numerical simulations that aim to capture the non-linear evolution. We emphasize the role of thermodynamics and large scale infall in controlling the outcome of the instability. Despite apparent controversies in the literature, we show a remarkable level of agreement between analytic predictions and numerical results. We highlight open questions related to (1) the development of a turbulent cascade in thin disks, and (2) the role of mode-mode coupling in setting the maximum angular momentum transport rate in thick disks.

HERBAL MEDICINE IS THE USE OF MEDICINAL PLANTS FOR PREVENTION AND TREATMENT OF DISEASES: it ranges from traditional and popular medicines of every country to the use of standardized and tritated herbal extracts. Generally cultural rootedness enduring and widespread use in a Traditional Medical System may indicate safety, but not efficacy of treatments, especially in herbal medicine where tradition is almost completely based on remedies containing active principles at very low and ultra low concentrations, or relying on magical-energetic principles.In the age of globalization and of the so-called 'plate world', assessing the 'transferability' of treatments between different cultures is not a relevant goal for clinical research, while are the assessment of efficacy and safety that should be based on the regular patterns of mainstream clinical medicine.The other black box of herbal-based treatments is the lack of definite and complete information about the composition of extracts. Herbal derived remedies need a powerful and deep assessment of their pharmacological qualities and safety that actually can be realized by new biologic technologies like pharmacogenomic, metabolomic and microarray methology. Because of the large and growing use of natural derived substances in all over the world, it is not wise to rely also on the tradition or supposed millenarian beliefs; explanatory and pragmatic studies are useful and should be considered complementary in the acquisition of reliable data both for health caregiver and patients.

BACKGROUND: Small myocardial infarctions after percutaneous coronary intervention have been associated with higher risk of cardiac events during follow-up. Observational studies have suggested that statins may lower the risk of procedural myocardial injury. The aim of our study was to confirm this hypothesis in a randomized study. METHODS AND RESULTS: One hundred fifty-three patients with chronic stable angina without previous statin treatment were enrolled in the study. Patients scheduled for elective coronary intervention were randomized to atorvastatin (40 mg/d, n=76) or placebo (n=77) 7 days before the procedure. Creatine kinase-MB, troponin I, and myoglobin levels were measured at baseline and at 8 and 24 hours after the procedure. Detection of markers of myocardial injury above the upper normal limit was significantly lower in the statin group versus the placebo group: 12% versus 35% for creatine kinase-MB (P=0.001), 20% versus 48% for troponin I (P=0.0004), and 22% versus 51% for myoglobin (P=0.0005). Myocardial infarction by creatine kinase-MB determination was detected after coronary intervention in 5% of patients in the statin group and in 18% of those in the placebo group (P=0.025). Postprocedural peak levels of creatine kinase-MB (2.9+/-3 versus 7.5+/-18 ng/mL, P=0.007), troponin I (0.09+/-0.2 versus 0.47+/-1.3 ng/mL, P=0.0008), and myoglobin (58+/-36 versus 81+/-49 ng/mL, P=0.0002) were also significantly lower in the statin than in the placebo group. CONCLUSIONS: Pretreatment with atorvastatin 40 mg/d for 7 days significantly reduces procedural myocardial injury in elective coronary intervention. These results may influence practice patterns with regard to adjuvant pharmacological therapy before percutaneous revascularization.

Cardiovascular diseases are one of the major causes of deaths in adults in the western world. Elevated levels of certain blood lipids have been reported to be the principal cause of cardiovascular disease and other disabilities in developed countries. Several animal and clinical trials have shown a positive association between cholesterol levels and the risks of coronary heart disease. Current dietary strategies for the prevention of cardiovascular disease advocate adherence to low-fat/low-saturated-fat diets. Although there is no doubt that, in experimental conditions, low-fat diets offer an effective means of reducing blood cholesterol concentrations on a population basis, these appear to be less effective, largely due to poor compliance, attributed to low palatability and acceptability of these diets to the consumers. Due to the low consumer compliance, attempts have been made to identify other dietary components that can reduce blood cholesterol levels. Supplementation of diet with fermented dairy products or lactic acid bacteria containing dairy products has shown the potential to reduce serum cholesterol levels. Various approaches have been used to alleviate this issue, including the use of probiotics, especially Bifidobacterium spp. and Lactobacillus spp.. Probiotics, the living microorganisms that confer health benefits on the host when administered in adequate amounts, have received much attention on their proclaimed health benefits which include improvement in lactose intolerance, increase in natural resistance to infectious disease in gastrointestinal tract, suppression of cancer, antidiabetic, reduction in serum cholesterol level, and improved digestion. In addition, there are numerous reports on cholesterol removal ability of probiotics and their hypocholesterolemic effects. Several possible mechanisms for cholesterol removal by probiotics are assimilation of cholesterol by growing cells, binding of cholesterol to cellular surface, incorporation of cholesterol into the cellular membrane, deconjugation of bile via bile salt hydrolase, coprecipitation of cholesterol with deconjugated bile, binding action of bile by fibre, and production of short-chain fatty acids by oligosaccharides. The present paper reviews the mechanisms of action of anti-cholesterolemic potential of probiotic microorganisms and probiotic food products, with the aim of lowering the risks of cardiovascular and coronary heart diseases.

oronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing a dramatic pandemic. 1ombardy, in northern Italy, is one of the most affected regions worldwide. 2ardiovascular complications occur frequently in patients with COVID-19, 3 with challenges in acute management.We aimed to evaluate incidence, clinical presentation, angiographic findings, and clinical outcomes of ST-elevation myocardial infarction (STEMI) in patients with COVID-19.All hospitals with catherization laboratories in Lombardy were contacted to collect cases of patients with confirmed COVID-19 who underwent an urgent coronary angiogram because of STEMI between February 20, 2020 (date of first COVID-19 case in Lombardy) and March 30, 2020. 2 Data were collected retrospectively, in anonymized fashion without any sensitive data, therefore not requiring institutional review board approval.COVID-19 was confirmed with reverse transcription-polymerase chain reaction assays.STEMI was defined based on the presence of typical symptoms associated with ST-segment elevation or new left bundle-branch block. 4A stenosis was considered as the culprit lesion in case of angiographic evidence of thrombotic occlusion/subocclusion.Obstructive coronary artery disease was defined based on the angiographic evidence of a stenosis >50% on visual estimation.A total of 28 patients with COVID-19 with STEMI were included.All patients met the guideline definition of STEMI 4 with localized ST-elevation (25 patients, 89.3%) or new left bundle-branch block (3 patients, 10.7%), and all were treated in the setting of emergent activation.The Table displays a detailed overview of each included patient.The mean age was 68±11 years, 8 patients (28.6%) were women, 20 (71.4%) had arterial hypertension, 9 (32.1%) had diabetes mellitus, 8 (28.6%) had chronic kidney disease, and 3 (10.7%)had a previous myocardial infarction.For 24 patients (85.7%), the STEMI represented the first clinical manifestation of COVID-19, and they did not have a COVID-19 test result at the time of coronary angiography.The remaining 4 patients had STEMI during hospitalization for COVID-19.Twenty-two patients (78.6%) presented with typical chest pain associated with or not associated with dyspnea, and 6 patients (21.4%) had dyspnea without chest pain.On echocardiography, 23 patients (82.1%) had localized wall motion abnormalities, 3 (10.7%)had diffuse hypokinesia, and 2 (7.1%) did not have abnormalities.The left ventricular ejection fraction was <50% in 17 patients (60.7%).All patients underwent urgent coronary angiography, and none was treated with fibrinolysis.Out of 28 patients, 17 patients (60.7%) had evidence of a culprit lesion requiring revascularization, and 11 patients (39.3%) did not have obstructive coronary artery disease.

UNLABELLED: Although annular fibrosis is the hallmark of cirrhosis, other microscopic changes that affect liver function such as sinusoid capillarization or loss of metabolic zonation are common. A sustained virological response (SVR) may halt fibrosis deposition in hepatitis C virus (HCV)-infected patients, but its impact on the other cirrhosis-associated lesions is unknown. The aim of this study was to assess the impact of an SVR on cirrhosis-related histopathological features. Paired pre- and posttreatment liver biopsies from 38 HCV patients with cirrhosis with an SVR were analyzed. Fibrosis was staged using the METAVIR scoring system, and the area of fibrosis was measured using morphometry. Ductular proliferation, metabolic zonation, sinusoid capillarization, and hepatic stellate cell activation were assessed by anti-cytokeratin-7, anti-glutamine synthetase (GS), anti-cytochrome P4502E1 (CYP2E1), anti-CD34, and anti α-smooth muscle actin (αSMA). After 61 months from an SVR, cirrhosis regression was observed in 61%, and the collagen content decreased in 89%. Although periportal and lobular necroinflammation vanished, portal inflammation persisted in 66%. Ductular proliferation decreased in 92%. Before treatment, metabolic zonation was lost, as shown by GS and CYP2E1, in 71% and 88%, respectively, with normalization in 79% and 73%, after an SVR. Conversely, no changes in sinusoidal capillarization were observed after treatment, as assessed by CD34 (P = 0.41) and αSMA (P = 0.95). Finally, no differences in all the immunohistochemical scores emerged whether or not cirrhosis persisted. CONCLUSION: Cirrhosis regression and decreased fibrosis are frequently observed among HCV patients with cirrhosis with an SVR. Despite ductular proliferation vanishing and lobular zonation restoration, portal inflammation and sinusoidal capillarization may not regress after viral eradication.

BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).