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Background The primary neuropathological characteristics of AD include intracellular, filamentous inclusions of hyperphosphorylated microtubule associated protein tau (MAPT) in neurons (neurofibrillary tangles, NFTs) and extracellular deposits of the beta-amyloid peptide (A-Beta) in senile plaques. While A-Beta plaques are unique to AD, NFTs are observed in a wide variety of neurodegenerative diseases, including AD, frontotemporal dementia, cortical basal degeneration and other disorders, collectively termed tauopathies. Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in AD and other tauopathies. Increasing evidence suggests that microglia contribute to the pathopysiology of AD including; correlational studies in human AD and mouse models, retrospective epidemiological studies demonstrating that use of nonsteroidal anti-inflammatory drugs (NSAIDs) substantially reduces AD risk, genome-wide association studies of human AD and studies utilizing genetically modified mouse models. Neuronal-microglial communication through the chemokine fractalkine (CX3CL1) and its cognate receptor, CX3CR1, plays a critical role in neuroinflammation and neuroprotection. First, CX3CL1 is highly expressed by neurons while CX3CR1 is only expressed by microglia within the CNS. Second, CX3CL1 is neuroprotective in models of neuroinflammation. Finally, studies of Cx3cr1 knockout mice revealed enhanced neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson’s Disease (PD).

Background Generations of biogerontologists have repeatedly observed striking variations in lifespans among individual members of genetically identical cohorts from a wide variety of species when aged under apparently identical environments. It is a reasonable assumption that these differences are accompanied by contrasting patterns of healthspan. Recent studies with C. elegans provide strong evidence that these lifespan variations are largely non-heritable (SL Rea et al., Nature Genet37:894, 2005). One can therefore, conclude that they are driven by stochastic events. Methods The frequencies of somatic mutation seem insufficient to explain these variations. They seem likely to be epigenetically based. I have suggested an explanation (GM Martin, Aging Cell 8:761, 2009) that can be viewed as an extension of the antagonistic pleiotropic model of aging proposed by the late George C. Williams (Evolution 11: 398, 1957). In brief, it is proposed that variegated gene expression within families of homologous cells was selected by evolution as an adaptive trait to ensure survival within unpredictable ecologies.

Results Results will be presented along three fronts. First, SNPs associated with both cholesterol and with AD (other than APOE SNPs) include SNPs within LIPC and HMGCR. In particular, the HMGCR SNP (rs3846662) is associated with the splicing efficiency of HMGCR exon 13; the allele that reduces exon 13 inclusion has been reported to reduce HMGCR activity and is associated with reduced AD risk. This SNP has also been associated with statin response. Overall, these results suggest that this SNP may modulate AD and the response of AD to statin treatment. Second, SNPs associated with rheumatoid arthritis are generally not associated with AD, reinforcing the hypothesis that rheumatoid arthritis is associated with reduced AD risk, perhaps because the associated long-term antiinflammatory use. Third, the primary AD-associated SNP within CLU, rs11136000, is associated with the expression of CLU1 but not CLU2 in the brain. Both CLU1 and CLU2 produce soluble clusterin protein in transfected cell studies. Since the protective allele of rs11136000 is associated with increased CLU1 expression, agents that upregulate CLU1 may reduce AD risk. Of particular interest, histone deacetylase inhibitors (HDACI) induce CLU1 robustly, suggesting that HDACI such as the widely used epilepsy drug valproic acid may have some utility in reducing AD risk. Lastly, we note that normalizing RNA measurements to correct for variation in cell-type within the brain fragments used for RNA preparation in these studies was critical to discerning SNP association with gene expression or splicing. Conclusion Although AD GWAS results have not yielded another AD risk factor with the impact of the APOE SNPs, they have succeeded in identifying “bottlenecks” in AD-related pathways that modulate AD risks. Hence, elucidating the actions associated with these SNPs by using a combination of bioinformatics, human tissue correlative studies and in vitro functional studie sm ay provide insights into AD therapeutic strategies.

Background Brain lipids such as cholesterol play critical roles in neuronal membrane homeostasis and synaptic functions. Apolipoprotein E (apoE) is a major lipid transporter in the brain. Of the three human apoE isoforms (E2, E3 and E4), apoE4 is a strong risk factor for late-onset Alzheimer’s disease (AD). Brain apoE/lipoprotein particles, produced primarily by astrocytes, deliver cholesterol and other lipids to neurons to support synapses via apoE receptors, which belong to the low-density lipoprotein receptor (LDLR) family. To ultimately understand why apoE4 is a risk factor for AD, it is essential to study the differential functions of apoE isoforms in brain lipid transport and synaptic functions, and what specific roles apoE receptors play in these processes.

Leishmania LeIF antigen, homologous to eukaryotic initiation factor eIF4A, was originally described as a Th1-type natural adjuvant and as an antigen that induces an IL-12-mediated Th1 response in the peripheral blood mononuclear cells (PBMC) of leishmaniasis patients. We aimed at addressing the role of this protein and defining the minimum fragment necessary for inducing cytokine secretion. The study necessitated expression cloning of LeIF and 9 domains. Comparative biochemical and genetic analyses of LeIF and yeast eIF4A showed that LieIF is both an RNA-dependent ATPase and ATP-dependent RNA helicase in vitro and highlighted differences with yeast protein. In vivo experiments in yeast showed that LeIF cannot complement the deletion of the essential TIF1 and TIF2 genes in the yeast Saccharomyces cerevisiae that encode eIF4A. However, expression of LeIF results in a dominant negative phenotype, which is abolished by deletion of the most divergent 25 N-terminal residues. LeIF is able to interact with yeast eIF4G; this suggested a role in the translation machinery. The assays measuring production of cytokines IL-12p70, IL-10 and TNF-α by PBMC-derived monocytes of healthy donors exposed to the different proteins showed that LieIF was able to induce the secretion of these cytokines. Unlike previous reports on LeIF from L. braziliensis and L. major, both amino and carboxyl parts of the protein were shown to induce the secretion of cytokines at significant levels. Our results suggest that this activity could be primarily located in amino acids 1-129 and 261-403. Furthermore, the induction of cytokines in monocytes of healthy subjects is not unique to the Leishmania protein. Indeed, 5 homologous proteins DEAD box in mammals and yeast were also able to induce the secretion of cytokines. This study confirms the importance of LeIF protein as a vaccine target and underscores its potential as drug target.

Leishmania infantum causes visceral and cutaneous leishmaniasis in northern Morocco. It predominantly affects children under 5 years with an incidence of 100 cases per year. Genetic variability and population structure has been investigated for 55 strains isolated from infected dogs and humans in Morocco. A multilocus microsatellite typing (MLMT) approach was used in which a MLM type based on size variation in 14 independent microsatellite markers was compiled for each strain. MLMT profiles of 10 Tunisian, 10 Algerian and 21 European strains which belonged to zymodeme MON-1and non-MON1 according to multilocus enzyme electrophoresis (MLEE) were included for comparison. A Bayesian model-based approach and phylogenetic analysis inferred two L. infantum sub-populations; Sub-population A consists of 25 Moroccan strains grouped with all European strains of MON-1 type; and sub-population B consists of 25 Moroccan strains grouped with the Tunisian and Algerian MON-1 strains. Theses sub-populations were significantly different from each other and from the Tunisian, Algerian and European non MON 1 strains which constructed one separate population. The presence of these two sub-populations co-existing in Moroccan endemics shed the light on the possible scenarios of multiple introduction of L. infantum from/to Morocco; (1) Introduction from/to the neighboring North African countries, (2) Introduction from/to the Europe. These scenarios are supported by the presence of sup-population B and sub-population A respectively. Gene flow was noticed between sup-populations A and B. Five strains showed mixed A/B genotypes indicating possible recombination between the two populations. MLMT has proven to be a powerful tool for eco-epidemiological and population genetic investigations in Leishmania.

Leishmaniasis is a parasitic disease caused by a protozoan parasite of the genus Leishmania (L.), using the macrophage as the main host cell where it can survive and replicate. The infection outcome depends on the balance between the ability of the host to activate the macrophage microbocidal mechanisms to kill the parasite, and the pathogen’s ability to suppress the host immune response and survive in the harsh environment of phagolysosomes. This ability to circumvent the host immune response may be the result of pressure exerted by the parasite on macrophage gene expression in a way that promotes their survival and multiplication. In this study, we compared the expression kinetics of 82 Bone-Marrow-Derived Macropahge (BMDM) gene transcripts, from susceptible (BALB/c and PWK) and resistant (C57BL/6 and MBT) mice strains, following in vitro infection with L. major parasites, the causative agent of human zoonotic cutaneous leishmaniasis. These genes belong to several functional families e.g., IFN? pathway, TLRs, chemokines, nitric oxid production pathway or involved in various metabolic pathways. Our results showed a clear contrast between the different profiles according to the infection stage (early vs. middle or late) in the four mice strains: regardless to targeted transcripts, the BMDM gene expression profile reflects, at early stages (3h post-infection), the genetic mice background and their susceptibility to Leishmania infection; whereas there is no such correlation at later stages. Indeed, and independently of the gene function, macrophages of susceptible BALB/c and PWK mice showed a general inhibited expression profile while the resistant C57BL/6 and MBT mice expression profile levels are higher compared to non-infected BMDM. Strikingly, this observation was not seen at later times of infection (24h and 72h post-infection) and the expression level depends on each transcript; a direct relationship between the mouse background and the level of expression of a given gene being less obvious. Whether, this early strain-specific effect of parasites on BMDM is due to a general phenomenon that may be encountered with any phagocytosed particle or specific to L. major will be discussed. This study provides a strong argument that susceptibility versus resistance to Leishmania infection of mice with different genetic backgrounds, would be partly due to the innate immunity. These results indicate that these differences in activation of innate immunity illustrate, at least in part, the differences in clinical expression of experimental leishmaniasis in the four mice strains.

The definition of altruism will be presented, highlighting the enigma behind this phenomenon in today’s highly competitive world of market economy. The growing challenges of hunger and poverty plague the world even as we entered the new millennium. As the gap between the rich and the poor widens, there is also a trend showing the increase of charitable acts and a growing interest in altruistic activities. Hong Kong, where the East meets the West, has developed into a community that is highly competitive and market-oriented. Yet its citizens, while famous for being hard-driven and target-oriented, have also nurtured a charitable spirit that is widespread and deep-rooted. Most, if not all, of her citizen regularly engage in charitable donations and sacrificial services. Each year, the community here donates an amount that, on a per capita basis, ranks amount the top of the world. Data from donor profiling by one of the larger fundraising charities provide clues as to why people give and how they choose their favorite charities. While donating money was the starting point of charitable work, current trend showed that more and more people now choose to donate their time serving the needy, by volunteering and even working fulltime with charities of their choice. The author recounts his 14-year experience of fulltime service with an international charitable organization in Mainland China and East Asia, and discusses what motivated many of his colleagues to serve in impoverished regions of Asia. Foregoing the comfort and luxuries of modern world, young professional people with high education background chose to use their professional skills to serve the needy rather than making money for themselves. The motivation behind their decisions is discussed. Evidence point to the fact that instead of being selfless, most donors and workers choose to serve because of a conviction that serving others bring satisfaction and / or reward to themselves. This concept of rewards is of course not in monetary terms. Alternative worldviews are common among workers in charitable organizations. The basis of these worldviews will be discussed.

The nuclease is a surface enzyme unique to trypanosomatid parasites. These organisms lack the pathway for de novo purine biosynthesis and thus are entirely dependent upon their hosts to supply this nutrient for their survival, growth, and multiplication. There is a cluster on chromosome 30 which carries 2 copy of nuclease genes and 5 identical nuclease like proteins in L. major which are in cis form with 700-800 bp intergenic regions which have more than 80% homology. These data shows that this enzyme might play an important role in facilitating the survival, growth, and development of this important human pathogen. In previous studies, have been shown that L. major 3′NT/NU which is expressed specifically in promastigotes is not the key molecules involved in host purine salvaging pathway and thus in better understanding parasite strategies adopted to survive in sandflies. Therefore, only deletion of nuclease genes followed by sandfly infections experiments will allow determining its precise role in purine salvaging and sandfly infection and specificity. We have developed nuclease cluster heterozygote and homozygote knockout mutants, with homologous recombination technique, to evaluate deletion effects on survival of parasite and infection.

The development of vaccines is one of the most important public health achievements. However, as the incidence of vaccine-preventable diseases has decreased, the general public has become increasingly concerned about vaccine safety. Vaccine safety is evaluated extensively through animal safety studies, clinical trials, and post-licensure surveillance. Safety monitoring in post-licensure surveillance has relied mainly on passive reporting systems such as the Vaccine Adverse Event Reporting System in the United States and epidemiological studies. Vaccine safety profiles cannot necessarily be generalized to developing countries, where the incidence, type and severity of serious adverse events may differ significantly because of local environmental and genetic influences[1]. With the recent introduction of newly developed vaccines in sub-Saharan Africa (e.g., pneumococcal and rotavirus vaccines), the extensive use of established vaccines in preventive mass vaccination campaigns (e.g., yellow fever vaccine), and the planned introduction of vaccines for use primarily in resource-poor settings (e.g., malaria vaccine), there is an increased need for effective surveillance of serious adverse events following immunization (AEFI). Compared to high-income countries, few low-income economies have functional national pharmacovigilance (PV) systems in place, due primarily to a lack of resources, infrastructure and local PV expertise. The importance of functional national PV systems has recently been underlined with the implementation of yellow fever (YF) mass campaigns as part of the Yellow Fever Initiative (YFI). The recent and novel use of YF vaccine for preventative mass vaccination campaigns in sub-Saharan Africa has increased the urgency of establishing functional PV systems. Between 2006 and 2013, the YFI will distribute vaccines to residents of high-risk areas in 12 West and Central African countries. A condition of funding from the GAVI Alliance is the implementation of AEFI surveillance. To address this requirement, AMP and WHO have provided technical support, including the development of surveillance tools (e.g., operational guide, notification and investigation forms, standard operating procedures for taking and transporting biological samples), the introduction of active case finding methods, and the creation and training of national expert committees to review and classify suspected serious AEFIs. Reference laboratories, including the Institut Pasteur in Cameroon, and the Robert Koch Institute in Germany provided diagnostic test results to facilitate the YF AEFI classification process. Best practices have been shared between different countries and African-based consultants have been trained to become local experts. Their expertise is now being requested for AEFI surveillance of additional vaccines such as the serogroup A meningococcal conjugate vaccine.

Signaling through the Akt/mammalian target of rapamycin (mTOR) pathway plays a pivotal role in the regulation of multiple cellular processes, including proliferation, apoptosis, protein synthesis and autophagy. It is therefore a major target of microbial infections and tumors. Protozoa of the Leishmania genus cause a wide spectrum of diseases in humans, termed leishmaniases, with clinical manifestations ranging from self-healing skin ulcers to life-threatening visceral disease. These parasites primarily infect macrophages and are renowned for their ability to sabotage host-cell signal transduction pathways. Here, we report that infection of Balb/c bone marrow-derived macrophages with the promastigote stage of Leishmania major results in rapid, time-dependent degradation of key components of the Akt/mTOR axis, including Akt, mTOR and the tuberous sclerosis complex-2 (TSC-2). Disruption of the Akt/mTOR pathway by L. major is dependent on the surface metalloprotease gp63, an important virulence factor of the parasite, and appears to be strain- and species-specific. The consequences of the degradation of key intermediates in the Akt/mTOR pathway on downstream responses are currently being investigated. These studies highlight a novel mechanism by which L. major interferes with macrophage functions and responses and will provide a better understanding of Leishmania pathogenesis.

Primary immune deficiencies are a heterogeneous group of inherited disorders in which dysfunctions of the immune system cause an enhanced susceptibility to infections. Their frequency is higher in Tunisia and the Maghreb as compared to European and North American countries. Indeed, our population is characterized by a high frequency of consanguineous marriages and this may account for the higher incidence of autosomal recessive primary immune deficiencies observed. During the last fifteen years, we have been able as a reference center in Tunisia to establish the diagnosis of primary immunodeficiency in 397 patients including 12 patients from Algeria and Libya. The immunological investigation including phenotypic analysis of peripheral blood cells, lymphocyte proliferation assays, phagocytic cells functions and measurement of immunoglobulins as well as complement allowed us to classify these cases in combined immune deficiencies (27%), predominantly antibody deficiencies (23%), phagocytic cells defects (23%), complement deficiencies (1%), other well-defined syndromes (24%) and other immunodeficiencies (2%). The study of the molecular basis of these diseases in our settings as compared to other European, North American and Asian studies shows a high incidence of autosomal recessive diseases including Ataxia-telangiectasia, Bare Lymphocyte syndrome, Mendelian susceptibility to mycobacteria and Leukocyte adhesion deficiency. Moreover, we have observed a higher frequency of autosomal recessive forms of classically X-linked immune deficiencies such as autosomal recessive agammaglobulinemia and chronic granulomatous disease. A founder effect in our population with a single gene mutation accounting for most cases has been observed for several of these primary immune deficiencies. The establishment of an accurate diagnosis allowed the appropriate treatment of these patients according to the cellular and molecular basis of the disease by bone marrow transplantation, substitutive immunoglobulin therapy, IFNg therapy...etc. The genetic study was aimed: first, to allow an appropriate genetic counselling and a prenatal diagnosis in these consanguineous affected families; second, to help unravelling the immune system functioning since these particularly rare autosomal forms of immune deficiencies offer a unique physiopathological model to study specific host defense pathways in humans.

Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans. It is the third most prevalent mycobacterial disease in the world. The disease has been reported in over 30 ountries, mainly in tropical and subtropical regions of Africa and has often been associated with swampy areas. This flesh-eating disease imposes a harsh reality on its victims who endure prolonged periods of suffering. Major challenges to the prevention and control of Buruli ulcer disease are the lack of knowledge surrounding the reservoir and route of transmission of M. ulcerans, lack of diagnostic tests that can easily be performed in rural areas, and limited treatment options. During this decade, the Institut Pasteur International Network developed interest on Buruli ulcer, bringing together scientists from around the network and other research institutes, and allocate funds. It is in this way that a multidisciplinary effort was undertaken in Centre Pasteur of Cameroon on epidemiological and environmental factors associated with M.ulcerans to understand the mode of transmission. Our first research work focused on risk factors and outlined protective factors such as the use of bed nets and the proper care of skin lesions with antiseptic solutions. These results were then used to reinforce education in a basic public health measures by awareness raising campaign. Our more recent studies assessing the role of water bugs as M. ulcerans host and/or vector in environmental context provided a first full picture in terms of biodiversity and seasonal and regional dynamics link with variation in the insect tissue colonization rate. Furthermore, the Centre Pasteur of Cameroon initiated an international course on Microbiology of M. ulcerans. This course brought together scientists from 11 African endemic countries and provided knowledge for PCR detection of M. ulcerans, the most sensitive and quickest tool available for diagnosis and in tracing environmental sources of M.ulcerans. The Centre Pasteur takes advantage of this competence to serve also at country level, as Reference Laboratory for the National BU control programme; it provides diagnostic support for cases confirmation and expertise in different Public health interventions. In conclusion, within Institut Pasteur International Network there is interest on Buruli ulcer, but more could be done; there are many opportunities to contribute from scientific point of view.

The hand, foot and mouth disease (HFMD) has emerged as a major infectious disease affecting children in China since March, 2008. Over 2.7 millions cases have been reported according to the proceeding of the Ministry of Health of China so far. Majority of patients have mild symptoms such as fever and blisters in the mouth and a skin rash, but some patients develop more severe neurologic symptoms and even die from pulmonary edema due to brainstem infection. Of note, severe cases and fatalities arise dramatically this year. However, what factors cause the current outbreaks and affect the clinical outcome of patients remains unclear. We carried out a retrospective case-control study on Fuyang HFMD outbreaks. We found that the proportions of children who had timely received poliovirus vaccine are 70.9%, 62.4% and 41.7% in health control, HFMD patients without pulmonary edema and HFMD patients with pulmonary edema, respectively. There was a significant difference in the proportion of children who had received the recommended OPV immunization between the group with edema and the controls. In addition, there was also a significant difference between the patients with edema and the one without edema, suggesting that the untimely poliovirus vaccination correlates to the HFMD severity, namely pulmonary edema. Our recent preliminary study in animal model suggests that pre-existing memory CD4 T cells specific for poliovirus can recognize EV71 and may help to mitigate the disease of EV71 infection.

The occurrence of thyroid nodules increases with age [1]. In geographical areas with a normal iodine intake, approximately 10% of the population develops a palpable thyroid nodule. This proportion increases in areas with insufficient iodine intake. Non-palpable thyroid nodules are usually diagnosed by a neck echography carried out for various reasons and are 5-10 folds more common than palpable nodules. When evaluating a thyroid nodule, we must be aware that two conditions require particular attention: a) the possibility of a “hot” (hyperfunctioning) nodule, which can induce thyrotoxicosis; b) the possibility of a malignant nodule. Both these pathological conditions increase with age [2,3]. In particular, elderly patients often show a multinodular goiter, where both hyperfunctioning nodules and hypofunctioning nodules suspicious for malignancy may coexist. When FT3 is high and/or TSH is suppressed a hyperfunctioning nodule should be suspected. In order to confirm this diagnosis the patient should carry out a thyroid scintigram. In the case that both FT3 and TSH are in the normal range, the nodule should be regarded as non-functioning. In this case a thyroid scintigram is not useful whereas a fine needle aspiration (FNAB) is the diagnostic procedure of choice [4]. Both hyperfunctioning and malignant thyroid nodules are more common in elderly patients. Notably, hyperthyroidism is a more serious condition in the elderly than in the young because of an increased risk of cardiac dysfunction. Moreover, thyroid cancer behaves more aggressively in elderly patients. In these patients thyroid cancer is usually less differentiated and lacks the ability to concentrate iodine. Therefore, thyroid cancer metastases cannot be treated with radioiodine. In the case of a hyperfunctioning nodule the therapy of choice is a thyroid lobectomy. In contrast, in the case of a multinodular goiter or of a malignant nodule, a total thyrodectomy is required.

Older adults are predisposed to osteomyelitis either because of an increased incidence of associated disorders (e.g., peripheral vascular disease, diabetes mellitus, malnutrition and poor dentition) or because of surgical procedures that are frequently performed in the elderly population (e.g., dental extractions, open-heart surgery, and prosthetic joint replacement or osteosynthesis). Two types of haematogenous osteomyelitis that are seen in the elderly are vertebral and long bone osteomyelitis. The most common pathogen is Staphylococcus aureus. Osteomyelitis secondary to contiguous foci of infection can occur in older adults without vascular insufficiency (secondary to pressure ulcers) or with vascular insufficiency due to diabetes mellitus or peripheral vascular disease from atherosclerosis. Chronic osteomyelitis may be defined as osteomyelitis that has a duration of more than 6 weeks or that recurs or is not cured after the initial infection. Chronic osteomyelitis may be associated with certain surgical procedures (e.g., sternal osteomyelitis after open-heart surgery or implant-related infections after orthopaedic and traumatological procedures), poor dentition or dental extraction (mandibular osteomyelitis), and, more commonly, with systemic disorders (e.g., peripheral vascular disease and diabetes mellitus). Acute osteomyelitis can in some cases be cured with antimicrobial therapy alone but surgical management is often required and includes extensive debridement, obliteration of dead spaces, stabilisation, adequate soft tissue coverage, and restoration of an effective blood supply. Chronic osteomyelitis may be caused by S. aureus or coagulase negative staphylococci, but is often due to gram-negative organisms. Because of the presence of infected bone fragments without a blood supply (sequestra), cure with antibiotic therapy alone is rare, if ever, possible and adequate surgical debridement is the cornerstone of therapy. Bone repair and bone mineral density may be significantly retarded and may be corrected by eliminating risk factors, supplementing the diet with calcium, bisphosphonates, and/or vitamin D, and treating with testosterone and/or estrogen when deficient. Sodium fluoride treatment and anabolic steroids may be used as alternatives. Septic arthritis is a medical emergency, and prompt recognition and rapid and aggressive treatment are critical to ensuring a good prognosis. The treatment of septic arthritis includes appropriate antimicrobial therapy and joint drainage. Adverse effects of prescribed antibacterials occur more often in the elderly patient than in young adults. The physician can help to minimise the incidence of adverse effects and improve outcomes by being aware of the principles of clinical pharmacology, the characteristics of specific drugs, and the special physical, psychological and social needs of older patients, Figure ​Figure1,1, ​,2,2, ​,3,3, ​,44. Figure 1 Septic knee prosthesis. The arrow shows the bone loss, due to infection and loosening of the implant. Figure 2 X-ray after septic prosthesis removal and antibiotic-loaded spacer implant Figure 3 Total knee re-implantation after 3 months. Note the filling of the bone defect in medial aspect of the tibial plateau Figure 4 Control after 2 years

The etiology of age related hearing loss (ARHI), or presbycusis, is multifactorial and includes both genetic and environmental influences. Much research effort has been put into elucidation of the environmental factors and nowadays a huge amount of data are available regarding the effects of noise exposure, ototoxic medication, exposure to chemicals, chronic medical conditions, malnutrition, tobacco smoking and alcohol abuse, although some of these factors remain still controversial [1] On the other hand, little is known about the role of genetic factors, despite the fact that the number of genetic studies on presbycusis is increasing at a surprising rate in the last few years. The hypothesis that genetic factors could play a significant role in AHRI was proposed as early as the ‘70s, based on the observation of several families whose members were affected by a presbycusis which manifested very early, occasionally before the age of 45, and the consideration that either the time of onset or the rate of progression of presbycusis vary greatly between individuals. In the ‘90s, heritability estimates have shown that approximately half of the variance in ARHI is due to heritable factors. An important contribution to the study of genetic factors in ARHI derives from laboratory research on inbred mice. Some of these strains present an early presbycusis and have in common the defective Cdh23 ahl allele of the gene encoding cadherin23, a protein localized in the stereocilia of the hair cells, which hold the cilia together. Lack or absence of otocadherins increases the vulnerability of hair cells either to aging, or to noise exposure. Experimental data obtained in mice has been found and confirmed in humans. Two genomewide linkage studies and a few association studies based upon candidate genes approaches for AHRI have been published in the last years. AHRI has been correlated with several single nucleotide polymorphisms (SNPs) in a region of KCNQ4; with a SNP in N-acetyltransferase 2 (confirming the role of oxidative stress in presbycusis); with a highly significant SNP in the GRHL2 gene; with a significant SNP at the GRM7 locus (indicating the possible effect of glutamate excitotoxicity in AHRI). These findings are important for both the management and possible future therapeutic intervention into presbyacusis.

The development of surgical techniques depends on the concomitant development of imaging techniques. Imaging with ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) is evolving at rapid pace. The basic need for treatment is mainly important for the endovascular aortic repair (EVAR) that requires information about many different anatomical aspects regarding aneurysmal neck, renal arteries, and diameter of aneurysmal free lumen, aortic bifurcation, diameter and length of iliac vessels. At present, the development of color-Doppler instruments is surely comparable with that of CT and MR imaging, and an important development has been made also for different types of ultrasonographic contrast medium. The intravascular US (IVUS) mode appears particularly important, that allows real-time detection of a lot of information useful in EVAR. At present, in elective treatment US examination plays a role in different steps: • diagnosis • AAA classification (below, iuxta or suprarenal AAA) • per operative management with IVUS mode [1] • postoperative follow-up. In emergency, the US examination has a place first of all as a bedside exam for patients with a suspected ruptured abdominal aortic aneurysm (rAAA). In haemodinamically stable patients the firtsline US examination appears mandatory during an examination of patients to detect the AAA and to avoid misdiagnosis or, in the opposite case, to abstain from undue X-rays exposition. Actually the physical examination allows the detection of an AAA in about 43% [2] of the patients, and its sensibility results lower for an iliac aneurysm, whereas that of US is up to 99% [3]. In haemodinamically instable patients emergency US exam appears at present the only possible evaluation in the immediately preoperative stage, as the CT exam provides an obligatory and dangerous delay. Moreover in haemodinamically instable patients an emergency IVUS exam could integrate the angiography during endovascular treatment of rAAA to better detect needed information,1 but physicians, nurses, and technicians need to work through a learning curve in order to properly interpret the images generated and maximize the usefulness of the technology. Hypothetically abdominal US through a friendlier learning curve could integrate the angiographic valuation to better define the outer diameter and the parietal features of the aortic neck, as the angiography does not reveal localization and extent of the thrombus and/or calcification.

Each year, the American Cancer Society (ACS) publishes a report summarizing its recommendations for early cancer detection, data and trends in cancer screening rates, and selected issues related to cancer screening. For endometrial cancer The ACS recommends that women at very high risk for endometrial cancer due to 1) known HNPCC genetic mutation carrier status; 2) a substantial likelihood of being a mutation carrier (ie, a mutation is known to be present in the family); or 3) the absence of genetic testing results in families with a suspected autosomal dominant predisposition to colon cancer should consider beginning annual testing for the detection of early endometrial cancer at age 35 years. For cervical cancer Screening for cervical cancer should begin approximately 3 years after first vaginal intercourse, but no later than age 21 years. Until age 30 years, women at average risk should receive either annual screening with conventional cervical cytology smears or biennial screening using liquid-based cytology. After age 30 years, a woman who has had 3 consecutive technically satisfactory Papanicolaou (Pap) tests with normal/negative results may choose to either undergo screening every 2 to 3 years. For ovarian cancer The guidelines recommend that women at average and increased risk should be informed about the high genetic risk. High-risk family histories with an elevated risk of developing ovarian cancer include >2 breast cancers and 1 or more cases of ovarian cancer at any age, >3 cases of breast cancer before age 50 years, sister pairs with cancers less than age 50 years, cases of breast cancer occurring at or before age 40 years. Preventive Surgery ( bilateral salpingo-oophorectomy ) can reduce risk of ovarian and fallopian tube cancers for BRCA1, BRCA2 carriers and might improve survival rates in women carrying the BRCA1 or BRCA2 genes by about half a year to over two years. For vulvar cancer The guidelines recommend that women at average and increased risk should be informed about the risk factors: the majority of women diagnosed with vulvar cancer are older than 50. However, a significant percentage (15%) of women under 40 develop vulvar cancer. Generally, vulvar cancer in younger women is associated with HPV infection and smoking; women with lowered immune systems have a higher risk of developing vulvar cancer; about 4% of women with lichen sclerosus develop vulvar cancer.

Hearing loss is one of the most prevalent chronic conditions affecting older adults. In U.S. studies, prevalent estimates of hearing loss in adults aged 65 and older range from 30% to 83% depending upon the definition used. European studies suggest a steady decline in hearing from the sixth to ninth decades. Although age-related hearing loss is not life-threatening, it affects quality of life and can have a negative effect on a person’s health. It diminishes an individual’s ability to communicate effectively, jeopardizes one’s autonomy, and has been correlated with an increased incidence of clinical depression and social isolation. These findings highlight the need for improved methods of identifying individuals with age-related hearing loss and improving services for providing hearing aids, and auditory rehabilitation. Identifying individuals with hearing loss and supplying appropriate hearing aids and teaching coping strategies may have a positive impact on quality of life for older people.

Osteoporosis is the most prevalent disease of bone metabolism, characterized by fragility and risk of fracture. The frequency of fractures increases with age and the cost of this disease increases more and more. Every thirty seconds someone in European Union suffers a hip fracture as a result of osteoporosis. The fractures of wrist, hip and vertebra are the most prevalent. Now the bone quality is more important than the BMD. The evaluation of patient begins with the analysis of risk fracture: age, familiarity of fragility fracture, calcium and vitamin D intake, BMI less than nineteen, early menopause, smoking, alcohol abuse, risk of falls. The people with at least one of these risk factors have to do the analysis of BMD, by DEXA at the femur or ultrasound at the fingers or the heel. The relationship between the BMD and the clinical situation of patient is important in order to understand who has to do the blood tests and the xray of dorsal and lumbar spine in LL. The blood exams need to differentiate the types of osteoporosis, to value the bone markers and vitamin D. I remember that the vitamin D level is important for the calcium, the bone and the muscle metabolism and for the good action of the drugs of osteoporosis. The X-ray of dorsal and lumbar spine needs to show the presence of vertebral fractures. We have to calculate the level of fracture and the SDI (Spine deformity index) by Genant’s SQ scale. At the end I show the therapy of osteoporosis and its criterion.

Background Neoplastic skin alterations are frequently seen in elderly Caucasian people, above all if they have worked for long periods under high UV exposure. Our region, Calabria, a peninsula in the south of Italy with a long coastline , is quite homogeneous for population and lifestyle. Its inhabitants are Caucasian, most dark skinned but some fair skinned. Elderly people generally refer to a history of working as fishermen or farmers and consequently they have been exposed to the sun rays for long periods. These facts explain the high incidence of basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and actinic keratosis (AK) in our region, namely in elderly people.

Even the thyroid, like all the other organs and tissues, has undergone anatomic-functional modifications during the senescence. One of the characteristics of ageing is the significant increase of thyroid disease and their different clinical expression. Moreover, thyroid disease in older patients requires special attention because of the increased gravity caused by the frequent co-existence of other pathologies or the greater risk of pharmacological interferences and a lower metabolism of the drugs. In particular, hyperthyroidism in old men is a pathology that should not be undervalued because of the peculiarity of the clinical and prognostic aspects which characterize this age. The prevalence of hyperthyroidism increases 7 times in people over sixty-five years old and, including the subclinical hyperthyroidism; the percentage of people over sixty-five years old oscillates from 0,7% to 4% according to the casuistry. The most frequent causes of hyperthyroidism in old men are the toxic multinodular goiter and the autonomously functioning solitary nodules, which in the iodineless areas represent over the 70% of the causes; moreover hyperthyroidism exogenous (iodine and iodathe composts, like amiodarone, means of radiological contrast, ingestion of intentional or unintentional suppressive doses of thyroid hormone). The clinical manifestations of hyperthyroidism are peculiar and they are often different in old men with respect to young men. In old men the apatetica production is frequent with not many aspecific symptoms and cardiovascular complications (atrial fibrillation or other arrhythmias). Also the therapy is different in old men with respect to young men. In fact it must be individualized not only because of the causes, but also the age, by the risk factors of cardiovascular illnesses and by the presence of others illnesses, too.

During the last decade surgical therapy of Parkinson's disease has been considerably revalued and electrical stimulation techniques have taken the place of neurolesive techniques. Surgical therapy objective is not a direct solution of the illness cause but to control the symptoms responsible for serious daily life limitations. Electrical stimulation techniques actually used in PD are Deep Brain Stimulation [1] and Motor Cortex Stimulation [2] Advantages of such techniques in comparison with neurolesive techniques are reversibility and adaptability. Deep Brain Stimulation is indicated for patients with PD in which symptoms are not controlled by the pharmacological therapy or that suffer from L-Dopa serious collateral effects. Stimulation system determines high frequency stimulation of anatomic-target structure of motor circuit with consequent functional block. Implanted system is formed by lead and pulse generator. Lead can be stereotactly implanted, monolateral or bilateral, at level of: a) Subthalamic Nucleus for all predominant illness symptom control (tremor, rigidity and akinesia) and L-dopa induced dyskinesias; b) Internal Globus Pallidum for the control of the rigidity and of the dyskinesias, c) VIM Thalamus Nucleus for the exclusive control of tremor. Motor Cortex Stimulation is a technique alternative to DBS indicated in advanced-complicated PD in cases of exclusion from DBS or of its ineffectiveness. Paddle lead is installed with neuronavigation system in epidural or subdural space beyond the motor area, controlaterally to the side where parkinsonian symptoms are prevailing. Stimulation effects are bilateral and stimulation is made with low frequency. Deep Brain Stimulation allows importing benefits suppressing PD symptoms, extending periods in which patient recovers normal and adequate functionality, reducing collateral effects induced by L-Dopa, improving quality of life and decreasing drugs intake. Despite the still limited experience, Motor cortex stimulation is effective in a special way on axial symptoms and also on cognitive performances and autonomic signs. Deep Brain Stimulation and Motor Cortex Stimulation are valid choices for advanced PD therapy. Advantages of such techniques in comparison with neurolesive techniques are safety, reversibility and adaptability.

Background The use of halogenated anaesthetics in cardiac surgery is still controversial. Preconditioning and postconditioning are the well described mechanisms that explain the protective myocardial effect of specific drugs in order to prevent the occurrence and/or to reduce the size of a necrotic post-ischemic myocardial area [1]: they play a well recognized role in the “protective effect” of the halogenated anaesthetics. Preconditioning and postconditioning protect the myocardial cell from oxidative stress and take place through the activation of specific receptors and second messengers systems [2]. Desflurane has shown a higher preconditioning and postconditioning power that could be optimal at 6% of Minimum Alveolar Concentration (MAC) [3]. The solubility of the halogenated anaesthetics can be altered during cardiac surgery: Desflurane has shown a rapid wash-in and wash-out profile in cardiac “on pump” surgery [5,6].

Presbyacusis is defined as the cumulative effects of aging on hearing ability. Each of them commonly feature different impairments, e.g on: sound hearing (mostly for high frequencies), speech understanding (mostly in noise), delayed speech processing by NCS and sound source localization. Its fuzzy and unclear simptomatology frequently leads to a delayed detection. In addition, the affected subjects rarely contact a specialist in order to sharply deal with such occurrences. Furthermore, whenever the presbyacusis is detected, only a small amount of patients will use hearing aids. To date, in US only the 20% of people supposed to need a hearing support, wear hearing aids and the 25-40% of those patients either leave or use them unevenly. Aims of this report are: - to examine the reasons leading people affected by presbyacusis to rarely wear hearing aids - to verify the possible technical hitches on fitting hearing-aids to aged patients (prosthetic grading), in order to provide them with correct rehabilitation pathways to an adequate sound and speech perception. The last part of this work concerns the rehabilitation issues for subjects affected by a multi-sensorineural impairment (e.g deaf-blindness).

The risk of falling represents one of the essential elements of the relationship elapsing between osteoporosis and rehabilitation activity. The damage received from the falls represents the sixth cause of death in persons over 65 years old. The risk factors for falling have been classified in two great groups: intrinsic factors and not intrinsic factors. Between the main intrinsic factors there are the muscular weakness, the deficit of equilibrium and coordination, the deficits of propriocettivity. Between the not intrinsic factors there are use of some drugs and the lack of security measures in the domestic atmosphere. The bathroom in particular represents the room of a house where there is a greater risk of fall. The most recent present studies in literature, such as the appraisal of this risk, must be conducted in multi-parametric way. A series of specific semeiological tests exist for the appraisal of some of these risk factors (chair test for the appraisal of the muscular weakness, for example). This semeiological appraisal can be completed from the data that can be obtained from the administration of FIM scale and ICF classification through the check list in the short form version.

Epidemiological and family-based studies in different populations underlined the existence of a genetic component in human longevity. Studies on families of centenarians demonstrated that parents, siblings and offspring of long-lived subjects have a significant survival advantage. In particular, the survival curve of siblings of centenarians is significantly higher than that people belonging to the same birth cohort. Moreover, siblings of centenarians have a lower risk of suffering from major age-related diseases, such as cardiovascular diseases, diabetes and cancer, when compared to appropriate selected controls from the same population. Indeed, studies on the concordance of the age of death in twins demonstrated a higher correlation in monozygotic than dyzigotic twins and suggested that approximately 25% of the variation in adult lifespan is caused by genetic differences between individuals. It was also demonstrated that the genetic component affecting longevity increases at advanced ages and it is generally stronger in males than in females. Furthermore, a positive correlation between population homozygosity and longevity was suggested, confirming the relevance of genetic differences between individuals for the susceptibility to a long lifespan. Identifying genes that affect human longevity can provide information about the molecular mechanisms involved in the aging process and shed light on the heterogeneity of the aging phenotype. Studies on experimental models suggest that caloric restriction improves age-related health and slow the aging process by limiting energy intake. Furthermore, in animal models specific alterations in single genes (age-1, daf2, sir2, methusela, p66) can dramatically extend or decrease lifespan. In humans, evidence is accumulating for an additive multilocus model, i.e. multiple genes with modest effect, working independently and as a network [1]. Because of the suggested additive effects of different genetic variants predisposing to longevity, the combined approach of linkage analysis in affected sib pairs (ASP) in candidate regions for high frequent variants and Genome Wide Association for less frequent polymorphisms [1] is considered promising for the identification of the genetic component of human longevity. Among the genes for which association has been demonstrated with human longevity, there are Apolipoprotein genes (APOE, APOB, ACE, APOC3), sirtuin genes (SIRT1 and SIRT3), genes belonging to the anti-oxidant (SOD1, SOD2, PON1, FOXO3A) and inflammatory pathways (Klotho, CETP, IL6). A relevant role seems to be represented also by the inherited and somatic variability of the mitochondrial genome.

There isn’t a consensus to the treatment of varicose veins because we don’t have randomized controlled trials [1]. Indication to the treatment is based on different criteria: etiological, clinical and diagnostic. The treatments include: conservative therapy, sclerotherapy, phlebectomy, endovenous laser therapy, radiofrequency ablation, and surgery involving saphenous ligation and stripping [2]. Short-term advantages appeared to be associated with sclerotherapy and endovenous treatments, and long-term effectiveness was more apparent following surgical intervention. Evidence suggests conservative therapy is less effective than sclerotherapy and surgery for the treatment of varicose veins. Ligation with stripping plus phlebectomy is generally regarded as the "gold standard" for treating primary long saphenous veins. Sclerotherapy and surgery both appear to have a place in the management of varicose veins. Sclerotherapy and phlebectomy may also be more appropriate in patients with minor superficial varicose veins not related to reflux of the saphenous system or as a post- or adjunctive treatment to other procedures, such as surgery. Current evidence suggests endovenous laser therapy and radiofrequency ablation are as safe and effective as surgery, particularly in the treatment of saphenous veins. Most importantly, the type of varicose vein should govern the intervention of choice, with no single treatment universally employed [2].

During the third age, rehabilitative intervention has some particular characteristics, connected to, without any doubt, functional and biological characteristics, which are typical of this period of human life, and on the other side, connected to the common way to consider elderly people, by the elderly people themselves, by the caregivers and by the social community. Too often pain, functional limitation, reduction of autonomy and of capacity to participate in life are considered normal, almost necessary, and accepted with resignation and without any opposition. This common idea of the elderly person is in contrast with scientific literature data, which show only the request of a longer time in more young people to reach the goals and for their reintegration, without having serious cognitive deficits or important pathologies. For this reason, fighting to change this negative common point of view about elderly age is a challenge belonging to “rehabilitation”. Consequently it’s important to improve the capacity of the elderly person (for example in a global vision like the bio-physical-social one proposed by ICF. In a femur fracture, a hip replacement or a osseous synthesis surgery are less meaningful if they can’t bring the patient to walk, to stand up, to sit down, to climb the stairs and take care of himself, like he did before his trauma. If the interdisciplinary work of the rehabilitation team is well done and appropriate (from the beginning soon after the trauma and the surgery), if it is constant and sufficiently protracted, it must and can warrant this result. Besides it must involve not only the elderly patient who does rehabilitation but also his family and the institutional environment that surrounds him. “Rehabilitation” has another challenge: to improve physical and functional conditions of elderly people to limit the use of drugs and surgery interventions. We are talking about interventions on osteoarthritis patients, but especially regarding intervention for the reduction of changeable risk factors of falls, which are the most frequent cause of fracture and its negative complications, including death. We have a double strategy: one is to intervene on the elderly population in general with AFA; the other one is to intervene on high risk elderly people through a specific work. These kinds of interventions are normally collocated in the strict cooperation between hospital or university structures and local health service structures.

Clinical and social background“The HR offers to dependent subjects, elderly and not,with an outcome of physical illnesses, mental or sensorymixed, not treatable at home, an average level of medi-cal, nursing and rehabilitation, accompanied by a highlevel of protect and hotel assistance, modulated accord-ing to the model of care adopted by the Regions andAutonomous Provinces (DPR 14.01.97). The HR areintended to subject self-sufficient, could not be treatedat home, affected by geriatric neurological and neurop-sychiatric stabilized diseases. Be expected: hospitalitypermanent relief to the family not exceeding 30 days, ofcompleting education and rehabilitation possible initia-tives in other principals of the NHS.” Essentially the HRare the practical response to the needs of actual society,more and more elderly, with various care needs that cannot be left solely to individual initiative resolvers house-hold. Depending on the provision of care to be paid,social workers and health board must ensure the ade-quacy of operation by the state of health of the subjectadmitted, in relation to “obligations of means” businessactivity, whereas the RSA however, is not a hospital or anursing home.ConclusionsSince the HR private structures, under the agreementwith the Regional Health Service, operating according tospecific rules, and receiving public money in respect ofservices rendered to citizens, thereby absolving - onbehalf of the State - constitutional requirements underArticle 32, can only portend a hypothesis of contractualliability in the event of default in the bonds due. Qualityfirst documented in Nursing, where the minimum per-formance level or base has now increased and qualifiedfor the presence in the so-called“modules” no longermere performers but by professionals who graduated inNursing. By providing the best qualified health RSA(medicalized HR) presence h24 nurses and the doctorworking in the daytime, with possible assistance at nightand weekend “on call” continuity of care or service orthe Emergency and Urgency 118 Service, it is clear howthe nursing care becomes - in these operational realities- an expression of the true guarantee of continuity ofcare and therapeutic. Remains decisive in achieving theoverall objectives, the operational integration of all theskills, both in health and social vocation, so that thequality of care may be considered appropriate to theneeds of users.

Endovascular treatment thirty-three after the first published report on angioplasty, continues to be a rapidly evolving field for the treatment of patients with peripheral arterial disease. A multitude of studies detailing technical improvements and innovative developments have been published. The morphology of a lesion may have an influence on the technical outcome, results at follow up and also risk of treatment. The TASC (TransAtlantic Inter-Society Consensus) document introduced a classification system that categorised lesions with regard to their accessibility to either percutaneus treatment or surgery. It categorised lesions into four types with: type A lesions ideal for endovascular approach; type B lesions where endovascular approach is still the preferred technique; type C lesions where surgical approach is preferred and type D lesions where surgery is the option of choice. Today, endovascular practice, percutaneous transluminal angioplasty (PTA) with or without stenting, is used far more frequently for all types of lower extremity occlusive lesions, reflecting the continuing advances in imaging techniques, angioplasty equipment, and endovascular expertise. The role of endovascular intervention, PTA/ stenting, in the treatment of peripheral arterial disease is also expanding, and its promise of limb salvage and symptom relief with reduced morbidity and mortality makes an attractive alternative to surgery and, as most endovascular interventions are performed on brief hospitalizations, hospital costs are cut considerably. Compared with open surgical procedures, endovascular interventions offer comparable or superior long-term rates of success.

Osteoporosis is currently considered a skeletal disease characterized by a diminished resistance of bone tissue, which predisposes to a greater risk of fractures. This disease, which affects mainly postmenopausal women, is constantly increasing, especially owing to a longer life-span; reliable epidemiological studies have reported that all over the world there are more than 200 million osteoporotic subjects. Osteoporosis is evaluated by calculating bone mineral density (BMD), analyzing bone quality, and estimating risk factors. BMD is calculated using DEXA (Dual-Energy Xray Absorptiometry), QCT (Quantitative Computed Tomography), and QUS (Quantitative Ultrasonography). The analysis of bone quality includes various factors such as microarchitecture, geometry, bone turnover, mineralization, and the properties of collagen and the extracellular matrix. The most common risk factors for osteoporosis are hereditary predisposition, sex, age, early menopause, smoking, use of corticosteroid drugs for long periods of time, malabsorption, and endocrine disorders. The orthopedic surgeon is increasingly more involved in treating so-called fragility fractures caused by osteoporosis. The sites most frequently affected by these fractures are the femoral neck, the proximal part of the humerus, the vertebrae, and the distal part of the radius. Currently, fragility fractures are often treated surgically by using devices, which allow obtaining stable internal fixation in a less resistant bone and early joint mobilization. In fact, the study of the most recent surgical devices has been oriented toward finding materials with osteoconductive and osteoinductive properties, which can be used while respecting and supporting the bone’s regenerative capacity. As far as medical treatment of osteoporosis is concerned, the most widely used drugs are bisphosphonates, peptides of the parathyroid hormone, selective modulators of estrogen receptors, and strontium ranelate. At present, the researchers involved in this problem are studying new drugs which not only treat the disease but can also be used to support the healing process of fractures in osteoporotic patients including those treated surgically, thereby enhancing the bone tissue’s regenerative potential and improving its mechanical properties.

The Massachusetts Male Aging Study [1] shows that male hormones decrease with aging. This is due to some testicular and hypothalamic-pituitary defects. Impaired hypothalamic secretory reserve, resulting in a reduced and chaotic secretion of GnRH, reduced pituitary response to GnRH, resulting in an increased but irregular LH pulse frequency [2] With aging, there is a 1.3% increase of sex hormone binding globulin (SHBG) levels per year [3]. SHBG binds strongly to testosterone, resulting in a reduction of bioavailable testosterone. The age-related reduction of testosterone seems genetically determined3.The Testosterone reduction plays many effects on body composition [4]. Testosterone also operates its effects on the penis leading to a reduction of smooth muscle cells/connettive tissue rate, neuronal nitric oxide synthases, arterial influx/venoocclusion rate. Recently, three scientific societies published some recommendations for the investigation, treatment and monitoring of this kind of hypogonadism, that has been renamed Late Onset Hypogonadism [5]. These recommendationshave been updated lately [6] and shared by two more scientific societies.