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Laxminarayan R.,Center for Disease Dynamics | Laxminarayan R.,Princeton University | Laxminarayan R.,Public Health Foundation of India | Duse A.,University of Witwatersrand | And 24 more authors.
The Lancet Infectious Diseases | Year: 2013

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed. © 2013 Elsevier Ltd.


Howard P.,Leeds Teaching Hospitals NHS Trust | Pulcini C.,Nancy University Hospital Center | Pulcini C.,University of Paris Descartes | Levy Hara G.,Hospital Carlos G Durand | And 4 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014

Objectives: To report the extent and components of global efforts in antimicrobial stewardship (AMS) in hospitals. Methods: An Internet-based survey comprising 43 questions was disseminated worldwide in 2012. Results: Responses were received from 660 hospitals in 67 countries: Africa, 44; Asia, 50; Europe, 361; North America, 72; Oceania, 30; and South and Central America, 103. National AMS standards existed in 52% of countries, 4% were planning them and 58% had an AMS programme. The main barriers to implementing AMS programmes were perceived to be a lack of funding or personnel, a lack of information technology and prescriber opposition. In hospitals with an existing AMS programme, AMS rounds existed in 64%; 81% restricted antimicrobials (carbapenems, 74.3%; quinolones, 64%; and cephalosporins, 58%); and 85% reported antimicrobial usage, with 55% linking data to resistance rates and 49% linking data to infection rates. Only 20% had electronic prescribing for all patients. A total of 89% of programmes educated their medical, nursing and pharmacy staff on AMS. Of the hospitals, 38% had formally reviewed their AMS programme: reductions were reported by 96% of hospitals for inappropriate prescribing, 86% for broad-spectrum antibiotic use, 80% for expenditure, 71% for healthcare-acquired infections, 65% for length of stay or mortality and 58% for bacterial resistance. Conclusions: The worldwide development and implementation of AMS programmes varies considerably. Our results should inform and encourage the further evaluation of this with a view to promoting a worldwide stewardship framework. The prospective measurement of well-defined outcomes of the impact of these programmes remains a significant challenge. © The Author 2014.


Fiszlejder L.,Hospital Carlos G Durand | Fiszlejder P.M.,Hospital Df Santojanni
Revista Argentina de Endocrinologia y Metabolismo | Year: 2012

Despite modern treatments for acromegaly, this disease is associated with a two to three-fold increase in cardiovascular risk in relation to the normal adult population. This results from a long term exposure of cardiomyocytes to GH excess, which causes histological changes in the geometric configuration of myofibrils, interstitial fibrosis and biventricular hypertrophy. The natural history of acromegalic heart disease includes several stages. In the early phase, there is a slow development of myocardial hipertrophy, subsequently associated with heart rhythm abnormalities. These arrhythmias, which represent a major risk factor for cardiovascular events, are secondary to the above mentioned structural changes in the myocardium, and make up the so-called "hyperkinetic syndrome of acromegaly". According to various epidemiological studies, a variable rate of patients with acromegaly (25% to 50%) has hypertension. This complication is secondary to sodium retention and the consequent plasma volume expansion, which implies cardiac overload and constitutes a worsening factor for cardiovascular disease. In the second stage, there are echocardiographic signs of reduced ventricular diastolic filling. The third stage is characterized by alteration of one or more heart valves and impaired systolic and diastolic function at rest, as well as signs of dilated cardiomyopathy, leading to congestive heart failure. This last stage is irreversible even with adequate therapy. Thus, early diagnosis of disease and a close monitoring of serum CH-IGF-I levels are mandatory. Copyright © 2012 por la Sociedad Argentina de Endocrinología y Metabolismo.


The activity of the somatotropic function in Functional Hypothalamic Amenorrhea (FHA) is increased at the central level, and paradoxically, the peripheral hormonal behaviour, intermediate metabolism and several clinical aspects may be similar to those observed in somatotropic axis deficiency. Baseline and daily GH secretion levels are high, but its pulsatile profile is irregular. This results in resistance to GH, i.e., downregulation of hormone receptors, which, together with the decrease in GH binding protein (GHBP), impair GH ability to stimulate the synthesis of IGF-I, IGFBP-3 and the acid-labile subunit in the liver. This causes a decrease in the availability of free IGF-I in tissues. In addition, IGFBP-1 and IGF-BP2 significantly increase. Even if these peptides are regulated by GH, their inverse correlation with insulin activity (which is decreased in these patients) and the low protein diet, respectively, appear to be more important factors. The increase in the serum levels of these peptides also contributes to the decrease in free IGF-I. Alterations in secretory patterns lead to a decrease in leptin concentration (an adipokine) and to an increase in Ghrelin, which, in turn, facilitates GH secretion and has a remarkable incidence in intermediate metabolism in these undernourished patients. These hormonal changes can be interpreted as a mechanism of homeostatic adaptation tending to preserve availability of energetic nutrients. Thus, there is an initial predominance of lypolisis followed by proteolysis at muscle level. If dietary restriction continues, a process of neoglucogenesis occurs in the liver and muscle tissue, with proteins and free fatty acids (NEFAs) being used as substrates. This is followed by glucogenolysis, which produces glucose. However, the increase in NEFAs and the potential presence of ketone bodies in highly restricted diets, suggest the presence of metabolic acidosis. This clinical condition implies an increased cardiovascular risk and the possibility of premature death, a potential outcome in undernourished patients with FHA. Copyright © 2011 por la Sociedad Argentina de Endocrinología y Metabolismo.


Functional Hypothalamic Amenorrhea (FHA) is a secondary process to an adaptive response in women with inadequate diets and modified body composition. This process triggers hormonal reactions in the hypothalamus for preservation of metabolic homeostasis. It involves a "central circuit" made up of a network of hypothalamic hormones interrelated with a "peripheral circuit" made up of leptin and adiponectin, among other adipocytokines, and ghrelin, synthesized in the upper gastrointestinal tract. Fat mass reduction in these undernourished women and the resulting decrease in leptin leads to neuropeptide Y (NPY) synthesis in the hypothalamus. This peptide, through direct or indirect action mediated by CRH stimulation, and the activation of the opioid and dopaminergic system block the receptors of the GnRH-synthesizing neurons in the arcuate nucleus to inhibit, and thus disturb, the gonadotropin pulsatile activity. The increase in ghrelin also blocks this activity through a complex mechanism: NPY synthesis is stimulated and NPY, in turn, inhibits GABA interneurons, thus altering the suppressant action normally exerted by this neurotransmitter on the CRH. The increase in serotonin levels activates the limbic-hypothalamic-pituitary-adrenal system, probably indirectly, mediated by desensitization of glucocorticoid receptors of CRH immunoreactive neurons, thus inducing secretion. CRH concentrations in cerebrospinal fluid, as well as 24-h mean plasma cortisol concentrations are high, and their half-life is prolonged. Additionally, there is a decrease in CBG associated with elevated free urinary cortisol levels. Basal serum cortisol levels are not suppressed by the administration of dexamethasone and the ACTH response to CRH stimulation is blunted. These findings suggest an alteration of cortisol negative feedback effects on CRH-ACTH secretion. The mechanisms of this resistance to cortisol are not fully elucidated. Animal studies suggest that prolonged stress modifies the density and ratio of gluco- and mineralocorticoid receptors and post-receptor activity. By extrapolation, it could be inferred that this resistance to cortisol in patients with amenorrhea is a mechanism that tends to perpetuate adrenal axis hyperactivity. In addition, the activation of the sympathetic system with the increase in norepinephrine and epinephrine and its association with other factors produces an increase in glucose release and in the availability of NEFA, free fatty acids and amino acids, enhanced cardiac activity, alertness and anxiety. These features can be observed in these patients with FHA, who frequently present a major psychosomatic component in their etiopathogenesis. Conclusions: activation of the NPY-CRH-opioid, serotoninergic, GABAergic, dopaminergic and noradrenergic systems not only affects gonadal function, but may also be involved in the development of osteoporosis and risk of fractures, immune system depression, increased cardiovascular risk and sudden death, a potential outcome in these undernourished patients with FHA. Copyright © 2011 por la Sociedad Argentina de Endocrinología y Metabolismo.


Di Pace J.L.,Hospital Carlos G Durand
Prensa Medica Argentina | Year: 2011

Acute flaccid paralysis or acute muscle weakness is mainly due to acute presentation of neuromuscular diseases. It develops within hours, days or up to four weeks. Acute muscle weakness may be a medical emergency due to compromised respiratory muscles. Causes can be early recognizing through a complete history and clinical examination and with proper use of ancillary tests allows early treatment without threatening the patient's life. This article reviews the general characteristics of the syndrome and some of the most representative etiologies.


The imbalance between energy intake and energy expenditure observed in malnourished or frankly undernourished women with functional hypothalamic amenorrhea triggers an increased activity of hypothalamic hormones and peripheral neuropeptides, at facilitating the availability of endogenous energy metabolites. Osteoporosis, immune depression, hypothalamic amenorrhea and increased cardiovascular risk can be interpreted as secondary effects of the homeosthatic adaptation reactions by central and peripheral hormones. The extent of somatotropic axis deficiency, hypoestrogenism and time of evolution condition the nature of coronary circulation alterations and myocardial structural and functional involvement. An unfavorable lipid profile (normal LDL/ low HDL and hypertriglyceridemia), the rise in peripheral markers of fibrinolytic and inflammatory processes, results in a proatherosclerotic and prothrombotic environment. A premature presence of atheroma plaques in carotid walls, intima media thickness and subsequent artery stiffness may be frequently observed. This makes blood flow difficult, leading to coronary ischemia and predisposition to stroke. Echocardiographic studies show a decrease in the muscle mass of the left ventricle walls and the interven tricular septum. These structural changes correlate with a volume reduction in the post-stress systolic ejection fraction, which subsequently occurs at rest at rest.The reduction in diastolic filling volume can be observed if the course of the disease is relatively long, showing, a serious compromise of cardiac performance. Even if the incidence of supraventricular extrasystoles, atrial fibrillation and bradycardia is not statistically significant, the presence of such arrhythmias increases CVR and the possibility of potential sudden death. Copyright © 2012 por la Sociedad Argentina de Endocrinología y Metabolismo.


Levy Hara G.,Hospital Carlos G Durand
Journal of Global Antimicrobial Resistance | Year: 2014

Selection of resistant pathogens by antimicrobial use is probably the most important cause of antimicrobial resistance. Antimicrobial stewardship (AMS) refers to a multifaceted approach to optimise prescribing. The benefits of AMS programmes have been widely demonstrated in terms of reductions in antimicrobial use, mortality, Clostridium difficile and other healthcare-associated infections, hospital length of stay and bacterial resistance. Several kinds of interventions (i.e. restriction of drugs, pre-authorisation of certain antimicrobials, joint clinical rounds with prescribers, implementation of guidelines and education) have shown positive results. Regrettably, in most hospitals in Latin America, Asia and Africa as well as in a significant proportion of institutions in Europe and North America, essential human and material resources are scarce or absent, and teams are neither developed nor well functioning. Despite current or potential barriers, we should start or improve our already ongoing initiatives on AMS by considering the main specific problems and act accordingly with the available human and material resources. From supervising the use of specific classes of drugs to implementing more sophisticated decision support programmes, there is a wide range of possible useful interventions. © 2013 International Society for Chemotherapy of Infection and Cancer.


Androgens are synthesized and secreted into the blood stream for circulation mainly as a form of testosterone. These hormones affect a number of diverse responses in a variety of peripheral target tissues. Their biological actions are mediated in the peripheral target cell via the androgen receptor (AR). The AR complex is a ligand bound nuclear receptor, combining general transcriptional complex with a large number of receptorassociated co-regulators. The AR is a member of the steroid hormone receptor family, which is found in a variety of tissues, and changes throughout development, aging, and malignant transformation. Recently, cloning and characterization of several AR co-regulators have allowed for cellular and molecular analysis of many different aspects of androgen physiology and pathophysiology. After entering its target cells and before it can exert its specific function, To will either be metabolized by aromatase into estradiol in the hypothalamus, bone and many other tissues, or be metabolized by 5 α-reductase into dihydrotestosterone in most of the male reproductive organs. Androgen receptor plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, vascular smooth muscle cell, endothelial cells, central nervous system, adipose tissue, and bone, which makes it a desirable therapeutic target. Numerous types of androgen receptor mutations have been linked to a wide range of clinical manifestations, from the partial androgen insensitive syndrome (PAIS) to complete testicular feminization, prostate cancer, polycystic ovary syndrome, male infertility, Klinefelter syndrome, etc. Besides, polymorphism of the AR glutamine tract has been reported to reduce receptor function and increase the risk of male infertility and defective spermatogenesis. When expansion exceeds 40 repeats, it causes a rare neuromuscular disorder, spinal and bulbar muscular atrophy (Kennedy's disease), which is also associated with decreased virilization, testicular atrophy, reduced sperm production, and infertility. These results indicate a direct relationship between the length of this AR-specific variable polymorphic region and defective sperm maturation caused by decreased functional competence of the AR. However, a correlation can not be established between the variable CAG (polyglutamine)-repeat and the presence of illness in all the different ethnic groups. In this review, we provide a brief overview of genomic androgens/AR actions, as well as of the regulation of their co-regulators. We also explore several complex aspects of the molecular biology of AR and co-regulators that are related to clinical diseases. Copyright ® 2015 por la Sociedad Argentina de Endocrinología y Metabolismo.


Garcia Gallo M.S.,Hospital Carlos G Durand | Martinez M.P.,Hospital Carlos G Durand | Abalovich M.S.,Hospital Carlos G Durand | Gutierrez S.,Hospital Carlos G Durand | Guitelman M.A.,Hospital Carlos G Durand
Pituitary | Year: 2010

Langerhans cell histiocytosis (LCH) is a rare granulomatous disease of unknown etiology. We retrospectively reviewed data from four patients (3 males and 1 female), mean age 33.5 years old (range: 21-40), with histopathological diagnosis of LCH. All of them presented with symptoms suggestive of endocrine involvement. The main complaint was goiter in two patients and polyuria and polydipsia in three. Before the LCH diagnosis, two patients had unevaluated symptoms of diabetes insipidus (DI) and hypogonadism. The mean time from symptoms onset to diagnosis was 6.25 years (range: 2-13). Histopathological diagnosis was established by total thyroidectomy (TT) biopsy in two patients, skin lesion biopsy in one, and pituitary stalk biopsy in the other. In the two-first patients, surgery was indicated after the fine-needle aspiration biopsy (FNAB) showed a false positive result of differentiated thyroid carcinoma and immunohistochemistry was used for diagnosis confirmation. Three cases were treated with chemotherapy; one of them had already received radiation therapy on the hypothalamic-pituitary region, developing post-radiation hypopituitarism. © 2010 Springer Science+Business Media, LLC.

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