Hippocration General Hospital

In recent years, great emphasis has been placed on the role of arterial stiffness in the development of cardiovascular diseases. Indeed, the assessment of arterial stiffness is increasingly used in the clinical assessment of patients. Although several papers have previously addressed the methodological issues concerning the various indices of arterial stiffness currently available, and their clinical applications, clinicians and researchers still report difficulties in selecting the most appropriate methodology for their specific use. This paper summarizes the proceedings of several meetings of the European Network for Non-invasive Investigation of Large Arteries and is aimed at providing an updated and practical overview of the most relevant methodological aspects and clinical applications in this area.

DOCUMENT REVIEWERS: Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

OBJECTIVE: To analyze the clinical and immunologic manifestations of antiphospholipid syndrome (APS) in a large cohort of patients and to define patterns of disease expression. METHODS: The clinical and serologic features of APS (Sapporo preliminary criteria) in 1,000 patients from 13 European countries were analyzed using a computerized database. RESULTS: The cohort consisted of 820 female patients (82.0%) and 180 male patients (18.0%) with a mean +/- SD age of 42 +/- 14 years at study entry. "Primary" APS was present in 53.1% of the patients; APS was associated with systemic lupus erythematosus (SLE) in 36.2%, with lupus-like syndrome in 5.0%, and with other diseases in 5.9%. A variety of thrombotic manifestations affecting the majority of organs were recorded. A catastrophic APS occurred in 0.8% of the patients. Patients with APS associated with SLE had more episodes of arthritis and livedo reticularis, and more frequently exhibited thrombocytopenia and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis, and migraine. Male patients had a higher frequency of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. In 28 patients (2.8%), disease onset occurred before age 15; these patients had more episodes of chorea and jugular vein thrombosis than the remaining patients. In 127 patients (12.7%), disease onset occurred after age 50; most of these patients were men. These patients had a higher frequency of stroke and angina pectoris, but a lower frequency of livedo reticularis, than the remaining patients. CONCLUSION: APS may affect any organ of the body and display a broad spectrum of manifestations. An association with SLE, the patient's sex, and the patient's age at disease onset can modify the disease expression and define specific subsets of APS.

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

An RNA virus, designated hepatitis G virus (HGV), was identified from the plasma of a patient with chronic hepatitis. Extension from an immunoreactive complementary DNA clone yielded the entire genome (9392 nucleotides) encoding a polyprotein of 2873 amino acids. The virus is closely related to GB virus C (GBV-C) and distantly related to hepatitis C virus, GBV-A, and GBV-B. HGV was associated with acute and chronic hepatitis. Persistent viremia was detected for up to 9 years in patients with hepatitis. The virus is transfusion-transmissible. It has a global distribution and is present within the volunteer blood donor population in the United States.

AIMS: To calculate robust quantitative estimates on the predictive value of central pressures and derived central haemodynamic indices for cardiovascular (CV) outcomes and all-cause mortality by meta-analysis of longitudinal studies. METHODS AND RESULTS: We meta-analysed 11 longitudinal studies that had employed measures of central haemodynamics and had followed 5648 subjects for a mean follow-up of 45 months. The age- and risk-factor-adjusted pooled relative risk (RR) of total CV events was 1.088 (95% CI 1.040-1.139) for a 10 mmHg increase of central systolic pressure, 1.137 (95% CI 1.063-1.215) for a 10 mmHg increase of central pulse pressure (PP), and 1.318 (95% CI 1.093-1.588) for a 10% absolute increase of central augmentation index (AIx). Furthermore, we found that a 10% increase of central AIx was associated with a RR of 1.384 (95% CI 1.192-1.606) for all-cause mortality. When compared with brachial PP, central PP was associated with marginally but not significantly higher RR of clinical events (P = 0.057). CONCLUSION: Central haemodynamic indexes are independent predictors of future CV events and all-cause mortality. Augmentation index predicts clinical events independently of peripheral pressures, while central PP has a marginally but not significantly (P = 0.057) better predictive ability when compared with peripheral PP.

1. INTRODUCTION 1.1 Principles The 2013 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines continue to adhere to some fundamental principles that inspired the 2003 and 2007 guidelines, namely to base recommendations on properly conducted studies identified from an extensive review of the literature; to consider, as the highest priority, data from randomized, controlled trials and their meta-analyses, but not to disregard the results of observational and other studies of appropriate scientific calibre; and to grade the level of scientific evidence and the strength of recommendations in order to more effectively alert physicians on recommendations that are based on the opinions of the experts rather than on evidence (Tables 1 and 2). When appropriately recognized, this can avoid guidelines being perceived as prescriptive and favour the performance of studies wherein opinion prevails and evidence is lacking.TABLE 1: Classes of recommendationsTABLE 2: Levels of evidenceThis shortened version of the ESH/ESC guidelines is for the practicing physician who often requires simplified information. However, whenever the physicians would like to know the source of the data upon which the recommendations are based, they are encouraged to consult the extensive version of the ESH/ESC guidelines wherein adequate references are given. These guidelines, however, do not override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient. 1.2 New aspects Because of new evidence on several diagnostic and therapeutic aspects of hypertension, the present guidelines differ from the 2007 ones in several points: Re-emphasis on integration of blood pressure (BP), cardiovascular risk factors, asymptomatic organ damage and clinical complications for total cardiovascular risk assessment. Update of the prognostic significance of out-of-office BP (both ambulatory and home BP), white-coat hypertension and masked hypertension. Initiation of antihypertensive drug treatment only in patients with SBP or DBP values at least 140 or 90 mmHg, independent of level of total cardiovascular risk. Unified target SBP (<140 mmHg) in both higher and lower cardiovascular risk patients. Revised recommendations on treatment of hypertension in young people and in the elderly. Liberal approach to initial monotherapy, without any all-ranking purpose scheme. Revised therapeutic algorithm for achieving target BP. Revised attention to resistant hypertension. 2. DEFINITIONS AND CLASSIFICATIONS The continuous relationship between BP and cardiovascular and renal events make the distinction between normotension and hypertension difficult. In practice, however, cut-off BP values are universally used to facilitate the decision about treatment (Table 3).TABLE 3: Definitions and classification of office blood pressure levels (mmHg)In order to help prognosis, total cardiovascular risk should be stratified in different categories (low, moderate, high and very high risk referred to the 10-year risk of cardiovascular mortality), based on BP category, cardiovascular risk factors, asymptomatic organ damage and presence of diabetes, and symptomatic cardiovascular disease or chronic kidney disease (CKD), as summarized in Fig. 1.FIGURE 1: Stratification of total cardiovascular risk in categories of low, moderate, high and very high risk according to SBP and DBP and presence of risk factors (RFs), asymptomatic organ damage (OD), diabetes, chronic kidney disease (CKD) stage or symptomatic cardiovascular disease (CVD). Individuals with a high normal office but a raised out-of-office BP (masked hypertension) have a cardiovascular risk in the hypertension range. Individuals with a high office BP but normal out-of-office BP (white-coat hypertension), particularly if there is no diabetes, OD, CVD or CKD, have lower risk than sustained hypertension for the same office BP. BP, blood pressure; CV, cardiovascular; DBP, diastolic blood pressure; HT, hypertension; SBP, systolic blood pressure.3. DIAGNOSTIC EVALUATION The initial evaluation of a patient with hypertension should confirm the diagnosis of hypertension; detect causes of secondary hypertension; and assess cardiovascular risk, organ damage and concomitant clinical conditions. This calls for BP measurement, medical history including family history, physical examination, laboratory investigation and further diagnostic tests. Some of the investigations are needed in all patients; others only in specific patient groups. 3.1 Blood pressure measurement 3.1.1 Office and out-of-office blood pressure Although conventional office BP measurement currently remains the ‘gold standard’ for screening, diagnosis and management of hypertension, it is generally accepted that out-of-office BP provides important adjunct information. At present, BP can no longer be estimated using a mercury manometer in many – although not all – European countries. Auscultatory or oscillometric semiautomatic sphygmomanometers are used instead, but these devices should be validated according to standardized protocols and their accuracy checked periodically. Table 4 gives instructions for correct office BP measurements, and Table 5 provides clinical indications for out-of-office BP measurement, namely measurements at home or over the 24 h.TABLE 4: Office blood pressure measurementTABLE 5: Clinical indications for out-of-office blood pressure measurement for diagnostic purposesOffice BP is usually higher than ambulatory and home BP and the difference increases as office BP increases. Cut-off values for the definition of hypertension by home and ambulatory BP are reported in Table 6.TABLE 6: Definitions of hypertension by office and out-of-office blood pressure levels3.1.2 White-coat and masked hypertension The term ‘white-coat’ or ‘isolated office’ hypertension refers to a condition in which BP is elevated in the office at repeated visits and normal out of the office either on ambulatory blood pressure monitoring or on home blood pressure monitoring. Conversely, BP may be normal in the office and abnormally high out of the medical environment, which is termed ‘masked’ or ‘isolated ambulatory’ hypertension. Cut-off values to be used are those in Table 6. 3.1.3 Central blood pressure Owing to the variable superposition of incoming and reflected pressure waves along the arterial tree, aortic BP (central BP) may be different from brachial BP. Central BP can be estimated indirectly by various methods. The current guidelines consider that, despite the growing interest in these methods, more investigation is needed before recommending the routine measurement of central BP for clinical use. 3.2 Medical history The information to be obtained at the time of the first diagnosis of hypertension is indicated in Table 7.TABLE 7: Personal and family medical history3.3 Physical examination Physical examination aims to establish or verify the diagnosis of hypertension, establish current BP, screen for secondary causes of hypertension and refine global cardiovascular risk. Procedures for BP measurement are indicated in Tables 4 and 5. Other information to be obtained by physical examination is in Table 8.TABLE 8: Physical examination for secondary hypertension, organ damage and obesity3.4 Laboratory investigations Laboratory investigations are directed at providing evidence for additional risk factors, searching for secondary hypertension and looking for organ damage. Investigations should proceed from the most simple to the more complicated ones, as summarized in Table 9.TABLE 9: Laboratory investigations3.5 Searching for asymptomatic organ damage Owing to the importance of asymptomatic organ damage as an intermediate stage in the continuum of cardiovascular disease, and as a determinant of overall cardiovascular disease, signs of organ involvement should be sought carefully by appropriate techniques as indicated below.Figure3.6 Searching for secondary forms of hypertension A specific, potentially reversible cause of BP elevation can be identified in a relatively small number of adult patients with hypertension. However if basal work-up leads to the suspicion of a secondary form of hypertension, the patient should be referred to a specialized centre where specific diagnostic procedures may be performed. 4. TREATMENT APPROACH 4.1 Recommendations of previous guidelines revised The 2007 ESH/ESC Guidelines, like many other scientific guidelines, recommended the use of antihypertensive drugs in patients with Grade 1 hypertension even in the absence of other risk factors or organ damage after nonpharmacological treatment had proved unsuccessful. This recommendation also specifically included the elderly hypertensive patient. The 2007 Guidelines also suggested drug treatment of patients with diabetes, previous cardiovascular disease (CVD) or CKD even when their BP was in the high normal range (130–139/85–89 mmHg). Furthermore, a lower BP target was recommended for these high or very high risk patients (<130/80 mmHg) than in patients at low–moderate risk (<140/90 mmHg). These recommendations were reappraised in a 2009 ESH Task Force document on the basis of an extensive critical review of the evidence. The following now summarizes the conclusions for the current guidelines: attention should be directed to the Class of recommendation and the Level of evidence, in order to distinguish what is considered compelling and what simply prudent. Figure 2 also summarizes recommendations and suggestions for treatment initiation and BP targets in the context of total risk stratification of hypertensive individuals.FIGURE 2: Initiation of lifestyle changes and antihypertensive drug treatment. Targets of treatment are also indicated. Colours are as in Fig. 1. See 4.3 and 6.5 for evidence that, in patients with diabetes, the optimal DBP target is between 80 and 85 mmHg. In the high normal blood pressure (BP) range, drug treatment should be considered in the presence of a raised out-of-office BP (masked hypertension). See 4.2 and 6.3 for lack of evidence in favour of drug treatment in young individuals with isolated systolic hypertension. CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; HT, hypertension; OD, organ damage; RF, risk factor; SBP, systolic blood pressure.4.2 When to initiate antihypertensive drug treatmentFigure4.3 Blood pressure treatment targetsFigure5. TREATMENT STRATEGIES 5.1 Lifestyle changes Appropriate lifestyle changes are the cornerstone for the prevention of hypertension. They are also important for its treatment, although they should never delay the initiation of drug therapy in patients at high level of risk. In addition to the BP-lowering effect, lifestyle changes contribute to the control of other cardiovascular risk factors and clinical conditions. The lifestyle measures that have been shown to be capable of reducing BP and therefore recommended are as follows: salt restriction to 5–6 g/day; moderation of alcohol consumption to no more than 20–30 g of ethanol per day in men and 10–20 g/day in women; high consumption of vegetables and fruits and low-fat dairy products; reduction of weight to a BMI of 25 kg/m2 and waist circumference to less than 102 cm in men and less than 88 cm in women; at least 30 min of moderate dynamic exercise on 5 to 7 days per week. 5.2 Pharmacological therapy 5.2.1 Choice of antihypertensive drugs The current guidelines reconfirm that all major classes of antihypertensive agents are suitable for the initiation and maintenance of antihypertensive treatment either in monotherapy or in some combinations, and that no all-purpose ranking of drugs for general antihypertensive usage is evidence based. All classes have their advantages but also contraindications, and may be preferentially used or avoided in specific conditions. Contraindications and preferred indications are listed in Tables 10 and 11.TABLE 10: Compelling and possible contraindications to the use of antihypertensive drugsTABLE 11: Drugs to be preferred in specific conditions5.2.2 Monotherapy and combination therapy The current guidelines share the 2007 Guidelines’ opinion that monotherapy can reduce BP to target only in a limited number of patients and that most patients require the combination of at least two drugs, and they reconfirm that initiation with a drug combination can be considered in patients at high cardiovascular risk or with markedly high BP. The algorithm of Fig. 3, however, is a modification of the 2007 one, to emphasize that adding drugs to drugs should be done with attention to results and any compound overtly ineffective or minimally effective should be replaced, rather than retained in an automatic step-up multiple-drug approach. Combinations to be preferred or avoided are illustrated in Fig. 4.FIGURE 3: Monotherapy vs. drug combination strategies to achieve target blood pressure (BP). CV, cardiovascular.FIGURE 4: Possible combinations of classes of antihypertensive drugs. Green continuous lines: preferred combinations; green dashed line: useful combination (with some limitations); black dashed lines: possible but less well tested combinations; red continuous line: not recommended combination. Although verapamil and diltiazem are sometimes used with a β-blocker to improve ventricular rate control in permanent atrial fibrillation, only dihydropyridine calcium antagonists should normally be combined with β-blockers. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. *Thiazide diuretics also include thiazide-like compounds (chlorthalidone) and indapamide.Strengths of recommendations about choice of drugs and combinations of antihypertensive agents are given in the summary table below.Figure6. TREATMENT STRATEGIES IN SPECIAL CONDITIONS Summary recommendations for antihypertensive treatment strategies in various conditions are listed below. 6.1 White-coat and masked hypertensionFigure6.2 ElderlyFigure6.3 Young adultsFigure6.4 WomenFigure6.5 Diabetes mellitusFigure6.6 Metabolic syndromeFigure6.7 Diabetic and nondiabetic nephropathyFigure6.8 Cerebrovascular diseaseFigure6.9 Heart diseaseFigure6.10 Atherosclerosis, arteriosclerosis and peripheral artery diseaseFigure6.11 Resistant hypertensionFigure7. TREATMENT OF ASSOCIATED RISK FACTORSFigure8. FOLLOW-UP 8.1 Follow-up visits After initiation of antihypertensive drug therapy, it is important to see the patient at 2-week to 4-week intervals to evaluate the effects on BP and to assess possible side-effects. Some medications will have an effect within days or weeks but a continued delayed response may occur during the first 2 months. Once the target is reached, a visit interval of a few months is reasonable. 8.2 Elevated blood pressure at control visits Patients and physicians have a tendency to interpret an uncontrolled BP at a given visit as due to occasional factors and thus to downplay its clinical significance. Due attention should be given to poor adherence or irregular consumption of drugs (sometimes because of adverse effects), to the white-coat effect and to substances or drugs opposing the antihypertensive effect of treatment. 8.3 Can antihypertensive medication be stopped? In some patients, in whom treatment is accompanied by an effective BP control for an extended period, it may be possible to reduce the number and dosage of drugs. This may be particularly the case if BP control is accompanied by healthy lifestyle changes. Reduction of medications should be made gradually and the patient should frequently be checked because of the risk of reappearance of hypertension. 9. IMPROVEMENT OF BLOOD PRESSURE CONTROL IN HYPERTENSION Despite overwhelming evidence that hypertension is a major cardiovascular risk factor and that BP-lowering substantially reduce the risk, there is evidence that all over the world a noticeable proportion of hypertensive individuals are unaware of this condition or, if aware, do not undergo treatment; target BP values are seldom achieved; failure to achieve BP control is associated with persistence of an elevated cardiovascular risk; and the rate of awareness of hypertension and BP control is improving slowly or not at all. As a consequence, high BP remains a leading cause of death and cardiovascular morbidity in Europe, as elsewhere in the world. Overall, three main causes of the low rate of BP control in real life have been identified: physician inertia; patient low adherence to treatment; and deficiencies of healthcare systems in their approach to chronic diseases. Methods to improve adherence to physicians’ recommendations are listed in Table 12.TABLE 12: Methods to improve adherence to physicians’ recommendations

Uterine malformations consist of a group of miscellaneous congenital anomalies of the female genital system. Their mean prevalence in the general population and in the population of fertile women is approximately 4.3%, in infertile patients approximately 3.5% and in patients with recurrent pregnancy losses approximately 13%. Septate uterus is the commonest uterine anomaly with a mean incidence of approximately 35% followed by bicornuate uterus (approximately 25%) and arcuate uterus (approximately 20%). It seems that malformed uterus and especially septate uterus is not an infertility factor in itself. However, it may have a part in the delayed natural conception of women with mainly secondary infertility. On the other hand, patients with uterine malformations seem to have an impaired pregnancy outcome even as early as their first pregnancy. Overall term delivery rates in patients with untreated uterine malformations are only approximately 50% and obstetric complications are more frequent. Unicornuate and didelphys uterus have term delivery rates of approximately 45%, and the pregnancy outcome of patients with untreated bicornuate and septate uterus is also poor with term delivery rates of only approximately 40%. Arcuate uterus is associated with a slightly better but still impaired pregnancy outcome with term delivery rates of approximately 65%. Women who have undergone hysteroscopic septum resection and have been reported in the different series comprise a highly selected group of symptomatic patients with term delivery and live birth rates of only approximately 5%. Hysteroscopic treatment seems to restore an almost normal prognosis for the outcome of their pregnancies with term delivery rates of approximately 75% and live birth rates of approximately 85%. It seems, therefore, that hysteroscopic septum resection can be applied as a therapeutic procedure in cases of symptomatic patients but also as a prophylactic procedure in asymptomatic patients in order to improve their chances for a successful delivery.

Many important decisions on hypertension management must currently be taken without the support of evidence&#13;\nfrom large randomized controlled trials. The following issues appear in urgent need to be approached by simply&#13;\ndesigned trials.&#13;\n(1) Should antihypertensive drugs be prescribed to all patients with grade 1 hypertension, even when total&#13;\ncardiovascular risk is relatively low or moderate? Because of the very low rate of cardiovascular events&#13;\nexpected in these patients, a placebo-controlled trial using intermediate endpoints such as signs of organ&#13;\ndamage of recognized prognostic importance would be feasible, ethical, and clinically relevant.&#13;\n(2) Should antihypertensive drugs be prescribed to the elderly with grade 1 hypertension, and should antihypertensive&#13;\ntreatment achieve a goal of below 140/90mmHg also in the elderly? These trials could make use&#13;\nof hard cardiovascular outcomes and could be placebo-controlled.&#13;\n(3) Should antihypertensive drug treatment be started in diabetic patients or in patients with previous cerebrovascular&#13;\nor cardiovascular disease when BP is still in the high normal level, and should BP goal be below 130/&#13;\n80mmHg in these patients? These issues can be approached by placebo-controlled trials because no trial&#13;\nevidence is still available on the benefit of lowering high normal BP or of achieving BP goals below 130/&#13;\n80mmHg.&#13;\n(4) What are the lowest safe BP values to achieve by treatment in different clinical conditions? This issue should&#13;\nbe approached by trials comparing more or less intense BP-lowering treatment strategies in patients with&#13;\ndifferent cardiovascular risk levels.&#13;\n(5) Are lifestyle measures known to reduce BP also capable of reducing morbidity and mortality in hypertension?&#13;\nA controlled randomized trial using intermediate endpoints (organ damage) would be feasible and desirable&#13;\nin patients with high normal BP or grade 1 hypertension.

The ESH/ESC Guidelines represent the views of the ESH and ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the 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 conflict of interest is reported on the websites of the ESH and the ESC.

Information about reprints can be found online at: Reprints: document. Permissions and Rights Question and Answer this process is available in the click Request Permissions in the middle column of the Web page under Services. Further information about Office. Once the online version of the published article for which permission is being requested is located, can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions: by guest on March 4,

CONTEXT: The metabolic syndrome (MetS) is a cluster of metabolic abnormalities that increase the risk for type 2 diabetes mellitus and vascular disease. The common characteristics of MetS and hypercortisolemic conditions such as Cushing's syndrome (CS) suggest that the pathogenesis of MetS and central obesity might involve prolonged and excessive exposure to glucocorticoids. The present review summarizes the evidence on the potential role of cortisol in the pathogenesis of MetS and discusses new therapeutic approaches for these patients. EVIDENCE ACQUISITION: Using PubMed, we searched for publications during the last 20 yr regarding the possible pathogenetic role of cortisol in the development of MetS. EVIDENCE SYNTHESIS: Emerging data suggest that patients with MetS show hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to a state of "functional hypercortisolism." The cause for this activation of the HPA axis remains uncertain but may be partly associated with chronic stress and/or low birth weight, which are both associated with increased circulating cortisol levels and greater responsiveness of the HPA axis. Increased exposure to cortisol contributes to increased fat accumulation in visceral depots. However, cortisol metabolism is not only centrally regulated. The action of 11beta-hydroxysteroid dehydrogenase-1 at the tissue level also modulates cortisol metabolism. Increased 11beta-hydroxysteroid dehydrogenase-1 activity in adipose tissue and liver might contribute to the development of several features of the MetS. CONCLUSIONS: MetS shares many characteristics of CS, and cortisol might play a role in the development of MetS at both a central and a peripheral level.

he investigation of various me-chanical forces and the tissue de-formations they induce have beenextensively studied for over three centu-ries. The basic principles concerning therelationship between mechanical stressand strain of various materials were demon-strated by Robert Hooke (1635-1703) andproved to be essential for the improvementof bio-materials and the understanding ofpathophysiological mechanisms in the vas-cular bed. Subsequently, the ground-break-ing studies of Jean Poiseuille (1799-1869)led to the development of mercury mano-meters for blood pressure measurementand resulted in theories describing the flowinside a cylindrical conduit, widely knownas Poiseuille’s law. The present work aims to describeand provide an interpretation of basic me-chanical and haemodynamic phenomenarelated to forces applied to arterial wallsand especially shear stresses.

The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign. Microscopy (direct and on histopathology) and culture are the cornerstones of diagnosis. Molecular assays can be used either for detection or identification of mucormycetes, and they can be recommended as valuable add-on tools that complement conventional diagnostic procedures. Successful management of mucormycosis is based on a multimodal approach, including reversal or discontinuation of underlying predisposing factors, early administration of active antifungal agents at optimal doses, complete removal of all infected tissues, and use of various adjunctive therapies. Our armamentarium of antifungals is slightly enriched by the addition of two newer azoles (posaconazole and isavuconazole) to liposomal amphotericin B, which remains the drug of choice for the initial antifungal treatment, according to the recently published guidelines by ECIL-6, as well as those published by ECMM/ESCMID. Despite the efforts for better understanding of the pathogenesis, early diagnosis and aggressive treatment of mucormycosis, the mortality rate of the disease remains high.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic, non communicable, multisystem disease that has reached epidemic proportions. Chronic exposure to hyperglycaemia affects the microvasculature, eventually leading to diabetic nephropathy, retinopathy and neuropathy with high impact on the quality of life and overall life expectancy. Sexual dysfunction is an often-overlooked microvascular complication of T2DM, with a complex pathogenesis originating from endothelial dysfunction. OBJECTIVE: The purpose of this review is to present current definitions, epidemiological data and risk factors for diabetic retinopathy, nephropathy, neuropathy and sexual dysfunction. We also describe the clinical and laboratory evaluation that is mandatory for the diagnosis of these conditions. METHODS: A comprehensive review of the literature was performed to identify data from clinical studies for the prevalence, risk factors and diagnostic methods of microvascular complications of T2DM. RESULTS: Diabetic nephropathy and retinopathy affect approximately 25% of patients with T2DM; diabetic neuropathy is encountered in almost 50% of the diabetic population, while the prevalence of erectile dysfunction ranges from 35-90% in diabetic men. The duration of T2DM along with glycemic, blood pressure and lipid control are common risk factors for the development of these complications. Criteria for the diagnosis of these conditions are well established, but exclusion of other causes is mandatory. CONCLUSION: Early detection of microvascular complications associated with T2DM is important, as early intervention leads to better outcomes. However, this requires awareness of their definition, prevalence and diagnostic modalities.

Maintenance of endothelial cell integrity is an important component of human health and disease since the endothelium can perform various functions including regulation of vascular tone, control of hemostasis and thrombosis, cellular adhesion, smooth muscle cell proliferation, and vascular inflammation. Endothelial dysfunction is encompassed by complex pathophysiology that is based on endothelial nitric oxide synthase uncoupling and endothelial activation following stimulation from various inflammatory mediators (molecular patterns, oxidized lipoproteins, cytokines). The downstream signaling via nuclear factor-κB leads to overexpression of adhesion molecules, selectins, and chemokines that facilitate leukocyte adhesion, rolling, and transmigration to the subendothelial space. Moreover, oscillatory shear stress leads to pro-inflammatory endothelial activation with increased monocyte adhesion and endothelial cell apoptosis, an effect that is dependent on multiple pathways and flow-sensitive microRNA regulation. Moreover, the role of neutrophil extracellular traps and NLRP3 inflammasome as inflammatory mechanisms contributing to endothelial dysfunction has recently been unveiled and is under further investigation. Consequently, and following their activation, injured endothelial cells release inflammatory mediators and enter a pro-thrombotic state through activation of coagulation pathways, downregulation of thrombomodulin, and an increase in platelet adhesion and aggregation owing to the action of von-Willebrand factor, ultimately promoting atherosclerosis progression.

BACKGROUND: Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol (LDL-C) levels. However, there is no long-term survival study that evaluated this statin. PATIENTS-METHODS: To assess the effect of atorvastatin on morbidity and mortality (total and coronary) of patients with established coronary heart disease (CHD), 1600 consecutive patients were randomised either to atorvastatin or to 'usual' medical care. The dose of atorvastatin was titrated from 10 to 80 mg/day, in order to reach the National Cholesterol Education Program (NCEP) goal of LDL-C <100 mg/dl (2.6 mmol/l). All patients were followed up for a mean period of 3 years. MAIN OUTCOME MEASURES: Primary endpoints of the study were defined as death, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation (coronary morbidity) and stroke. Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin. RESULTS: The mean dosage of atorvastatin was 24 mg/day. This statin reduced total chlesterol by 36%, LDL-C by 46%, triglycerides by 31%, and non-high-density lipoprotein cholesterol (non-HDL-C) by 44%, while it increased HDL-C by 7%; all these changes were significant. The NCEP LDL-C and non-HDL-C treatment goals were reached by 95% (n = 759) and 97% (n = 776), respectively, of patients on atorvastatin. Only 14% of the 'usual' care patients received any hypolipidaemic drugs throughout the study and 3% of them reached the NCEP LDL-C treatment goal. The cost per quaility-adjusted life-year gained with atorvastatin was estimated at $US 8350. During this study 196 (24.5%) CHD patients on 'usual' care had a CHD recurrent event or died vs. 96 (12%) CHD patients on atorvastatin; risk ratio (RR) 0.49, confidence interval (CI) 0.27-0.73, p < 0.0001. In detail, atorvastatin reduced, in comparison to 'usual' care, total mortality (RR 0.57, CI 0.39-0.78, p = 0.0021), coronary mortality (RR 0.53, CI 0.29-0.74, p = 0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71, p < 0.0001), and stroke (RR 0.53, CI 0.30-0.82, p = 0.034). All subgroups of patients (women, those with diabetes mellitus, arterial hypertension, age 60 to 75 years, congestive heart failure, recent unstable angina or prior revascularisation) benefited from treatment with atorvastatin. Withdrawal of patients because of side-effects from the atorvastatin group was low (0.75%) and similar to that of the 'usual' care group (0.4%). CONCLUSIONS: Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality, coronary morbidity and stroke, in comparison to patients receiving 'usual' medical care. Treatment with atorvastatin is well tolerated and cost-effective.

Echocardiography plays an important role in the diagnosis and follow-up of aortic diseases. Evaluation of the aorta is a routine part of the standard echocardiographic examination. Transthoracic echocardiography (TTE) permits adequate assessment of several aortic segments, particularly the aortic root and proximal ascending aorta. Transoesophageal echocardiography (TOE) overcomes the limitations of TTE in thoracic aorta assessment. TTE and TOE should be used in a complementary manner. Echocardiography is useful for assessing aortic size, biophysical properties, and atherosclerotic involvement of the thoracic aorta. Although TOE is the technique of choice in the diagnosis of aortic dissection, TTE may be used as the initial modality in the emergency setting. Intimal flap in proximal ascending aorta, pericardial effusion/tamponade, and left ventricular function can be easily visualized by TTE. However, a negative TTE does not rule out aortic dissection and other imaging techniques must be considered. TOE should define entry tear location, mechanisms and severity of aortic regurgitation, and true lumen compression. In addition, echocardiography is essential in selecting and monitoring surgical and endovascular treatment and in detecting possible complications. Although other imaging techniques such as computed tomography and magnetic resonance have a greater field of view and may yield complementary information, echocardiography is portable, rapid, accurate, and cost-effective in the diagnosis and follow-up of most aortic diseases.