The recent increase in childhood asthma has been a puzzling one. Recent views focus on the role of infection in the education of the immune system of young children. However, this so called hygiene hypothesis fails to answer some important questions about the current trends in asthma or to account for environmental influences that bear little relation to infection.The multi-factorial nature of asthma, reflecting the different ways we tend to interact with our environment, mandates that we look at the asthma epidemic from a broader perspective. Seemingly modern affluent lifestyles are placing us increasingly in static, artificial, microenvironments very different from the conditions prevailed for most part of our evolution and shaped our organisms. Changes that occurred during the second half of the 20th century in industrialized nations with the spread of central heating/conditioning, building insulation, hygiene, TV/PC/games, manufactured food, indoor entertainment, cars, medical care, and sedentary lifestyles all seem to be depriving our children from the essential inputs needed to develop normal airway function (resistance). Asthma according to this view is a manifestation of our respiratory maladaptation to modern lifestyles, or in other words to our increasingly artificial habitats. The basis of the artificial habitat notion may lie in reduced exposure of innate immunity to a variety of environmental stimuli, infectious and non-infectious, leading to reduced formulation of regulatory cells/cytokines as well as inscribed regulatory pathways. This could contribute to a faulty checking mechanism of non-functional Th2 (and likely Th1) responses, resulting in asthma and other immuno-dysregulation disorders.In this piece I discuss the artificial habitat concept, its correspondence with epidemiological data of asthma and allergy, and provide possible immunological underpinning for it from an evolutionary perspective of health and disease. Asthma is a major health problem that has reached alarming proportions in the past two decades in western societies . What liThe apparent association between asthma and western lifestyle has lead to numerous studies trying to link novel or increased exposures associated with westernization-modernization, especially those occurring during childhood, to asthma. For example, exposure to gas cooking, tobacco smoke, trans fatty acids, domestic animals, and allergens were found to influence respiratory health, but did not provide a conclusive answer to the current trends in asthma -10. WhilSince its introduction in the nineties, the hygiene hypothesis (HH) continues to generate enthusiasm among asthma researchers as the most comprehensive theoretical framework, by which the relation between suspected environmental factors and allergy can be tested -13. ThisAsthma trends however, did not fit well with the hygiene model, which failed to explain the urban predominance of asthma, the increase in non-allergic asthma, the disparity between atopy and allergy in some populations, and the asthma inducing properties of some infections -27. SpecThe hygiene model on the other hand, involved an evolutionary logic alerting us to the negative potential of sudden elimination of exposures that have shaped throughout the ages our organs and systems . Health General trends of asthma show that populations who conserved elements of ancient lifestyles have low levels of asthma. The north-south, urban rural, gradients in asthma occurrence have been extensively documented ,37,39-43th century in industrialized countries with the spread of central heating/conditioning, building insulation, hygiene, TV/PC/games, manufactured food, indoor entertainment, cars, medical care, and sedentary lifestyles all seem to be depriving our children from the essential inputs needed to develop normal airway function (resistance).Modern life is increasingly placing us in static, artificial, micro-niches optimized for our convenience, but which bear little resemblance to the dynamic inputs provided by the environments that nurtured our evolution. In other words, we are increasingly living within an array of artificial habitats designed to handle us very well, but we may well not be equipped to handle them. Asthma according to this view, becomes a manifestation of our respiratory maladaptation to modern lifestyles. Changes that occurred during the second half of the 20The suggested view -called here the artificial habitat (AH)- can provide alternative interpretations to existing data starting with the protective effect of sibship size/birth-order, which is one of the landmark observations of the HH that has been ascribed to increased exposure to infection . It can Another important observation of the hygiene paradigm concerns the protective effect of early daycare attendance on later development of asthma, which is ascribed to increased exposure to infection . AlternaOn a different juncture of asthma research, a multitude of recently published reports show lower rates of asthma and atopy in children raised on a farm -68. HeavThe AH perspective is consistent with the assumption that time spent outdoors and level of physical activity should be protective against the development of asthma. A recent study by McConnell and colleagues however, has shown just the opposite, where the risk of developing asthma was positively associated with number of sports played and time spent outdoors  However,Finally, the AH concept can offer an explanation for some puzzling observations, such as the protective effect of dog ownership on asthma ,78. WhilNow how can the AH view be related to what we know about the immunopathology of asthma and allergy? Asthma is an immunological disorder with a predominant Th2 inflammatory response in the airways. This Th2 response is thought to be a remnant of our ability to expel parasites abundant in the cradle of human evolution, the tropical savannah . Indeed,But let's take one step back to look at another recent puzzling trend; the increase of Th1 autoimmune disorders such as type-1 diabetes and multiple sclerosis in western societies . Recent Taken together, it can be suggested according to the AH concept that dynamic/traditional lifestyles with associated exposures can ensure constant challenge of DCs and other elements of innate immunity giving rise to immune responses, but at the same time maintaining adequate turnover of regulatory cells and cytokines and inscribed regulatory pathways. This ongoing activation of regulatory pathways can help maintain healthy control of non-functional Th2 responses at the respiratory surface. The DC-orchestrated dynamic balance between Th2 responses and regulatory mechanisms is likely to influence all phases  of inflammation in the airways, and throughout the lifespan of the individual.While it offers no specific explanation to different asthma trends and variations, the suggested AH notion provides a generalizing scheme for the study of asthma, and provides novel insights for existing epidemiological observations. According to this perspective there is no single answer to the asthma epidemic, but different factors have different relevance depending on the population and environment in focus. In addition to being free from the HH one-dimensional approach for the relation between exposure-outcome, this view is evolutionary-driven allowing to place the asthma epidemic within the wider perspective of increasing discordance between us and our dramatically changing environments. Sedentary lifestyles, static indoor microenvironments, and automation of the food chain are apparently not only predisposing us to obesity ad cardiovascular disease but also depriving our respiratory system from many stimuli necessary for the development of normal airway resistance. The immunological basis of the AH notion can lie in the centrality of innate immunity and its ability to respond to different types of environmental stimuli, insuring adequate turnover of regulatory cells and mediators. The evolutionary tenet "the more we change the world the more we stay the same" probably lacks accuracy. Newer environments, constantly confront us with new adaptive challenges that should be looked upon, as in the case of asthma, within the evolutionary context of health and disease.HH- hygiene hypothesisAH- artificial habitatDCs- dentritic cellsBHR- bronchial hyper-responsivenessIL10- interleukin 10hsps- heat shock proteinsTh1- T helper cell type 1Th2- T helper cell type 2Tregs- regulatory T cellsIgE- immunoglobuline ETLRs- Toll-like receptorsThe author(s) declare that they have no competing interests.Dr. Wasim Maziak is the sole author and contributor to this manuscript.The pre-publication history for this paper can be accessed here:


Loud noise is generally considered an environmental stressor causing negative effects on acoustic, cardiovascular, nervous, and endocrine systems. In this study, we investigated the effects of noise exposure on DNA integrity in rat adrenal gland evaluated by the comet assay. The exposure to loud noise (100 dBA) for 12 hr caused a significant increase of DNA damage in the adrenal gland. Genetic alterations did not decrease 24 hr after the cessation of the stimulus. We hypothesize that an imbalance of redox cell status is responsible for the induction and persistence of noise-induced cellular damage. During daily life, people are exposed to potentially hazardous noise levels related to work environment, urban traffic, household appliances, discos, and the like . The WorExtraauditory effects of noise have been related to psychophysiologic stress and the involvement of the pituitary–adrenocortical axis . Most stThe purpose of the present study was to investigate whether levels of loud noise comparable with those present in modern daily life  were ablad libitum, and kept under closely controlled environmental conditions . Animals were treated in accordance with the Guidelines for the Care and Use of Laboratory Animals  were used for the experiments. Animals were housed in the animal facility, fed  Animals . All posNoise level was set at 100 dBA by the use of two loud speakers (15 W)  and lastTo check for potential occurrence of cell death, we processed tissue samples using routine histologic procedures. Briefly, 8-μm-thick sections were cut with a microtome and stained with hematoxylin-eosin and toluidine blue. No cell death was observed.We evaluated DNA integrity in rat adrenal gland by the use of alkaline single-cell gel electrophoresis or comet assay, according to p < 0.001), compared with controls, in the adrenal gland soon after the cessation of acoustic stress, as shown in We evaluated the effect of loud noise on the presence of DNA damage in single cells dissociated from adrenal gland as the percentage of migrated DNA after electrophoresis in exposed and control rats. We observed a significant increase of DNA migration  were previously demonstrated to be effective in inducing ultrastructural alterations in rat adrenal cells, mainly involving the mitochondria and endoplasmic reticulum . The adrConcerning the persistence of genetic damage, it is noteworthy that DNA single-strand breaks are usually repaired within 15 min and that DNA double-strand breaks are repaired within 2 hr . Thus, sOur results on DNA damage might be interpreted as the output of two main events, namely, the clastogenic effect of oxyradicals and/or the DNA repair of oxidized bases, which implies the expression of alkali-labile sites, detected by the alkaline comet assay.The negative effects of noise on cell structure and function were supposed to be, at least in part, mediated by the increase of reactive oxygen species (ROS) . ROS lev


Toxoplasma-infection and novelty seeking was reported. The authors suggested that changes of personality trait were caused by manipulation activity of the parasite, aimed at increasing the probability of transmission of the parasite from an intermediate to a definitive host. They also suggested that low novelty seeking indicated an increased level of the neurotransmitter dopamine in the brain of infected subjects, a phenomenon already observed in experimentally infected rodents. However, the changes in personality can also be just a byproduct of any neurotropic infection. Moreover, the association between a personality trait and the toxoplasmosis can even be caused by an independent correlation of both the probability of Toxoplasma-infection and the personality trait with the third factor, namely with the size of living place of a subject. To test these two alternative hypotheses, we studied the influence of another neurotropic pathogen, the cytomegalovirus, on the personality of infected subjects, and reanalyzed the original data after the effect of the potential confounder, the size of living place, was controlled.Recently, a negative association between In the case-control study, 533 conscripts were tested for toxoplasmosis and presence of anti-cytomegalovirus antibodies and their novelty seeking was examined with Cloninger's TCI questionnaire. Possible association between the two infections and TCI dimensions was analyzed.The decrease of novelty seeking is associated also with cytomegalovirus infection. After the size of living place was controlled, the effect of toxoplasmosis on novelty seeking increased. Significant difference in novelty seeking was observed only in the largest city, Prague.Toxoplasma and cytomegalovirus probably induce a decrease of novelty seeking. As the cytomegalovirus spreads in population by direct contact (not by predation as with Toxoplasma), the observed changes are the byproduct of brain infections rather than the result of manipulation activity of a parasite. Four independent lines of indirect evidence, namely direct measurement of neurotransmitter concentration in mice, the nature of behavioral changes in rodents, the nature of personality changes in humans, and the observed association between schizophrenia and toxoplasmosis, suggest that the changes of dopamine concentration in brain could play a role in behavioral changes of infected hosts. Toxoplasma gondii specifically influences the behavior of intermediate hosts. Infected mice have impaired motor performance  .Previous studies suggested that several confounders such as the level of education, size of place of residence, intelligence and motivation of experimental subjects could bias the TCI dimensions. Therefore, we repeated the analyses with the independent factors CMV infection, Toxoplasma  and the concentration of anti- CMV antibodies .If the infection induces a shift in the personality dimension, the amount of personality shift should correlate with the concentration of specific antibodies. Such an effect (significant in one-tailed tests) was observed for both the CFT titre of anti-Toxoplasma-infected subjects as reported previously were not observed for either CMV infection or toxoplasmosis in the present study. In fact, slightly lower intelligence was recorded in CMV-free than CMV-infected subjects . The significant effect of Toxoplasma infection on intelligence also disappeared after adjustment for the confounder size of place of residence .Lower intelligence scores and education level in Toxoplasma-infection in Prague, while in villages and smaller cities the correlation was not significant. The effect of both infections, although highly significant, was rather low, explaining about 2 % of total variability of the novelty seeking in our experimental set. The study also revealed several other significant effects CMV or Toxoplasma infections and their interaction on personality traits. While the effect of the infections on novelty seeking was a priori expected, other effects were revealed by an ex post analysis. Therefore, the results concerning the other effects have to be corrected for multiple statistical tests. After the Bonferroni's correction for multiple tests, no ex post revealed effect remained significant.Our results showed that CMV infected subjects had lower scores in the personality dimension novelty seeking than the CMV-free subjects. Novelty seeking in infected subjects negatively correlated with levels of anti-CMV antibodies. Negative correlation was also found between novelty seeking and Toxoplasma-positive subjects suggest that infected men are on average more reflective, tend to require more detailed information when making an opinion and are not easily distracted. They are also more reserved, slow, controlled; they do not waste their energy and feelings. They tend to be organized, methodical, and prefer activities with strict rules and regulations. The association between latent toxoplasmosis and low novelty seeking scores has already been reported [Toxoplasma infection and size of place of residence and between size of place of residence and novelty seeking scores. Surprisingly, toxoplasmosis and CMV infections were associated with considerably lower novelty seeking scores only in large cities. There were no significant differences in novelty seeking between infected and pathogens-free subjects in settlements with fewer than 10 thousand population (CMV) or fewer than 100 thousand population (Toxoplasma). At present we have no explanation for this phenomenon.The lower values novelty seeking in the reported . The preToxoplasma-infected subjects scored lower in verbal intelligence as measured with the Otis test and showed lower probability of achieving secondary education than Toxoplasma-free subjects [Toxoplasma infection and b) probability of achieving secondary education and higher verbal intelligence. This model was strongly supported by the results of the present study. All associations between Toxoplasma infection and education level or intelligence disappeared after adjustment for the effect of place of residence. It is also noteworthy that CMV infection, which shows a similar prevalence rates in villages and small and large cities, has no association with education level or intelligence.A previous study performed on a larger set of experimental subjects revealed that subjects . It was subjects  that preNeither the psychopathological antecedents nor the pre-infection personality data of the subjects were available for our analysis. Based on a case-control study, it is not possible to tell whether there is a causal relation between two statistically associated factors (e.g. infection and lower novelty seeking scores) and/or to determine the direction of such a relation. Theoretically, the infection could induce personality changes, personality factors may have influenced the risk of infection and possibly a third factor, such as the socioeconomic status, may have played a role in both personality dimensions and the risk of infection. In our view, however, the most parsimonious explanation is that the infection, more precisely the presence of pathogens in the brain of infected subjects, induces changes in neurotransmitter levels, causing in turn changes in TCI personality dimensions. This hypothesis is based on several lines of indirect evidence:Toxoplasma and CMV infections. However, CMV infection was detected with equal frequency among Toxoplasma-free and Toxoplasma-infected subjects.a) Two different neurotropic pathogens with quite different life cycles and transmission routes are associated with the same psychological effect. This makes the existence of a third factor responsible for both lower novelty seeking scores and higher risk of infection rather unlikely. Moreover, the existence of such a factor would cause a statistical association between Toxoplasma and CMV. Such a correlation between the intensity of personality change and specific immunity could hardly be found if novelty seeking would influence the risk of infection or if an unknown factor would independently influence both novelty seeking and the risk of infection.b) The existence of correlation between novelty seeking scores and levels of specific antibodies (significant in one-tailed tests) was observed for both Toxoplasma [Toxoplasma/CMV infections has already been experimentally established in rodents.c) A decrease in neophilia in naturally neophilic mice and a decrease of neophobia of naturally neophobic rats, probably caused by lower ability of discriminating between familiar and novel surroundings, was also observed in animals experimentally infected with xoplasma ,4,8, andxoplasma . TherefoToxoplasma [d) Lower novelty seeking scores are claimed by several authors -33 to coxoplasma  and CMV xoplasma .+ depolarization in mesencephalic cell cultures [Toxoplasma and CMV persist in the brain of infected individuals for many years. The activation of acute disease in immunocompromised patients and immunohistochemical data obtained on mice [The specific neurological mechanism underlying the association between the infections and novelty seeking was not the subject of the present study. The available results of neuroimmunological studies, however, suggest that several cytokines engaged in inflammation processes, like interleukins 1, 2 and 6, directly influence the level and turnover of many neuromodulators, including dopamine -53. An ecultures  and stricultures . Injecticultures  and subccultures . Seriouscultures ,57,58. D on mice  suggest  on mice -64. ThisToxoplasma gondii, are associated with higher risk of schizophrenia [Toxoplasma or CMV infection.It has been reported repeatedly that both toxoplasmosis and contact with cat, the definitive host of ophrenia -28. Simiophrenia . The bacophrenia -68 and aophrenia . Clinicaophrenia ,71. It cToxoplasma and cytomegalovirus probably induce a decrease of novelty seeking of infected subjects. As the cytomegalovirus spreads in population by direct contact (not by predation as with Toxoplasma), the observed changes are the byproduct of brain infections rather than the result of manipulation activity of a parasite. Four independent lines of indirect evidence, namely direct measurement of neurotransmitter concentration in mice, the nature of behavioral changes in rodents, the nature of personality changes in humans, and the observed association between schizophrenia and toxoplasmosis, suggest that the changes of dopamine concentration in brain tissue could play a role in behavioral changes of infected hosts.The author(s) declare that they have no competing interests.MN and JF designated the study, wrote the manuscript and participated in analyses. JH, JK, JH and MP collected the data, participated in analyses and in manuscript writing. KR did serological analyses. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


As in other Biotechnological fields, the microbial production of recombinant proteins and other biomolecules can be approached from multiple angles through the help of diverse technologies of increasing complexity. To better reach all the specialized niches in bioproduction, Microbial Cell Factories is now inviting authors to prepare concise Reviews , covering relevant areas that deserve specific and highly focused attention. By the publication of such contributions, the journal will promote the revision of new insights around the Cell Factory concept in a highly comprehensive way, in molecular, cellular and environmental contexts. The spontaneous diversification of science is notably increasing the number of niches in which scientists specialize. Therefore, despite the multidisciplinary profile of current scientific approaches, the speedy enrichment of defined conceptual areas generates multiple "hot spots" with a particular interest. To this end, updating the scientific and technological record through the publication of Reviews, requires a detailed coverage of such fields, that while keeping a broad interest need to be of additional value for specialists.Bioproduction science is not distinct from this universal stream. The growing number of host cell systems being explored as factories, the rising types of bioproducts, the continuous improvement of vectors and the gene expression setting-up, the increasing awareness of the host cell physiology and stress responses occurring under controlled production, and the implementation of new technologies for strain selection-improvement and for process control-monitoring are demanding more refined, topic-oriented attention.. Such contributions, whilst of general interest in the bioproduction landscape, will particularly fulfill the changing needs within highly specialized technical and scientific areas.Therefore, apart from the publication of broad standard Reviews, Microbial Cell Factories is adjusting its policy to encourage the publication of highly focused Reviews , covering core aspects of the Cell Factory concept with self-contained interest. Authors are invited to submit proposals for such concise Reviews, that are to be prepared under the general journal Review style


Extrapulmonary tuberculosis is one of the great mimickers of medicine, and often masquerades as malignancy. As a result, patients may be referred to oncologists and surgeons for further evaluation and management, delaying the institution of appropriate anti-tuberculous drug therapy.Mycobacterium tuberculosis from tissue samples obtained under image guidance, enabled the correct diagnosis to be made.We present the case of a 21 year old man with tuberculous osteomyelitis, who was referred to the Bone and Soft Tissue Sarcoma Service at our institution with a provisional diagnosis of malignancy. Further investigation revealed extensive retroperitoneal abdominal and pelvic lymphadenopathy. The recognition of certain patterns on imaging, and finally the isolation of This case highlights the importance of remaining cognisant of the protean manifestations of extrapulmonary tuberculosis, and illustrates the advantage of a clinically directed multi-modality imaging approach to diagnosis. Mycobacterium tuberculosis and an increasing number of immune compromised individuals and immigrants from the developing world [Over the past decade, there has been a significant rise in the prevalence of extrapulmonary tuberculosis in the developed world, owing to the emergence of multi-drug resistant strains of ng world -3. DespiTo highlight these issues we present the case of a young male with pain and swelling of the right elbow, referred to the Bone and Soft Tissue Sarcoma Service at our institution with a presumptive diagnosis of malignancy. Further investigation revealed extensive retroperitoneal abdominal and pelvic lymphadenopathy. The case illustrates the importance of a clinically directed multi-modality imaging approach for the exclusion of malignancy and the accurate diagnosis of tuberculous infection, by identifying sites of pathology and obtaining adequate tissue samples for histological and microbiological confirmation.A previously well 21 year old East Timorese male presented to his local medical officer with a 2 month history of right elbow pain, associated with swelling and progressive limitation of movement. He also reported a 6 kg loss of weight during this time, but denied any other constitutional symptoms.He appeared well, was afebrile, and had no abnormality on chest or abdominal examination. Examination of the right elbow revealed a firm, tender swelling, approximately 2 cm in diameter, over the lateral humeral epicondyle, with associated limitation of elbow flexion to 60 degrees.Initial investigation with plain XR of the right elbow joint revealed a joint effusion Figure . As thesUltrasound examination of the elbow showed a large joint effusion Figure . ScintigCT scan confirmed the presence of cortical erosions involving the right lateral epicondyle of the humerus and the ulna. Further, there was increased attenuation within the proximal medullary shaft of the ulna, and diffuse soft tissue thickening around the proximal ulna and radial head, with an associated joint effusion Figure .Further functional imaging with Thallium 201 chloride revealed intense early uptake in the right lateral epicondyle of the humerus and proximal ulna Figure . The delMR demonstrated erosive changes involving the lateral epicondyle, a loculated joint effusion and thickening and enhancement of the joint capsule and the annular ligament of the superior radio-ulnar joint. These changes suggested either a neoplasm or possibly infection Figure .The patient was therefore referred to the Bone and Soft Tissue Sarcoma service for further investigation.Biopsy of the right elbow joint demonstrated chronic synovial inflammation and numerous polymorphonuclear cells in the synovial fluid, but no malignant cells Figure . MicrobiCT scanning of the chest, abdomen and pelvis, performed in light of the thallium findings, revealed extensive retroperitoneal lymphadenopathy. The lymphadenopathy was characterised by peripheral enhancement with prominent central areas of low attenuation Figures  and 10.Subsequent CT guided biopsy of the retroperitoneal lymphoid tissue revealed necrotising granulomatous lymphadenitis indicative of Mycobacterium tuberculosis infection Figure . While nA final diagnosis of disseminated extrapulmonary tuberculosis was therefore made. Anti tuberculous therapy was commenced with good clinical response.Extrapulmonary tuberculosis, a condition whose resurgence can be ascribed to the emergence of multi-drug resistance and an increasing number of immune compromised individuals and immigrants from the developing world, remains a difficult diagnosis to make -3. It isAlthough a positive tuberculin test and chest imaging findings are supportive of the diagnosis, absence of these does not exclude it ,5. ThereMusculoskeletal involvement occurs in 1 to 3 percent of patients with tuberculosis, usually due to haematogenous seeding ,6. In moWhile the most common site of osseous involvement is the spine, followed by the femur, tibia and the small bones of the hands and feet, any bone can potentially be affected ,4,6,9,10Plain XR findings in bony tuberculosis include osteopenia, osteolytic foci with poorly defined edges, and varying amounts of sclerosis and periostitis ,5,9. TheThere are a few radiographic features, however, that favour tuberculous infection over neoplasia. These include the presence of small juxtacortical abscesses or rings of inflammatory tissue, due to cortical destruction and spread of infection to the extraosseous tissues . RegardlNuclear Medicine techniques of value in the evaluation of tuberculous bony involvement include Tc99m methylene diphosphonate bone scanning, particularly in multifocal bone involvement. Sensitivity is reduced significantly however in pure septic arthritis and discitis without concomitant osteomyelitis. In these clinical situations, MRI is the modality of choice.Another useful radiotracer technique is functional metabolic imaging, which assesses the basal metabolic activity of inflammatory and neoplastic lesions. Thallium-201 chloride (TI-201) scanning is a good example of this modality. TI-201 is a potassium analogue that is actively concentrated in cells by the sodium-potassium ATPase pump and by a co-transport system mediated by a calcium-dependent ion channel . As enhaJoint involvement in skeletal tuberculosis occurs commonly due to direct invasion from an adjacent focus of osteomyelitis, as in the case presented in this report ,6. CharaAbdominal tuberculosis, like musculoskeletal involvement, is a difficult diagnosis to make, due to its varied clinical presentations, and is again often mistaken for malignancy. Lymphadenopathy is the most common manifestation, with up to two thirds of patients with abdominal tuberculosis demonstrating lymph node involvement ,16. The Certain features on CT imaging help distinguish tuberculous lymphadenopathy from these neoplastic causes. In tuberculous infection, the nodes are usually multiple and large, averaging 2 to 3 cm in diameter . PeripheBecause of this overlap in imaging appearances between extrapulmonary tuberculosis and malignancy, even in cases where the imaging and clinical features strongly suggest tuberculosis, the diagnosis requires histopathological and bacteriological confirmation. In the past, this often necessitated open surgical biopsy. Now core needle biopsy has been shown to be quick, safe and effective alternative for obtaining tissue specimens under image guidance .The clinical and radiologic features of extrapulmonary tuberculosis often mimic those of many other pathological processes, in particular malignancy. Oncologists and surgeons must therefore remain cognisant of the possibility of tuberculous infection, and of radiological features that help distinguish this condition from neoplastic processes. However, even with the use of multiple imaging modalities and laboratory diagnostic tools, a definitive diagnosis still requires a positive culture or histologic analysis of biopsy specimens in many cases. Image-guidance facilitates optimal tissue samples to be obtained for analysis.Tc99: Technicium 99TI-201: Thallium 201TB: tuberculosisThe author(s) declare that they have no competing interests.SAA drafted and revised the manuscript, and was involved in the editing of the images.PFC, PJS, GJP and JS critically evaluated and revised the manuscript. They also provided information from their respective areas of expertise, which was critical to the discussion section of the manuscript.SMS was responsible for the conception of this case report, and was also involved in the drafting and revision of the manuscript.All authors have read and given final approval of the submitted version of the manuscript.


Disorders of the nervous system affect one in three Americans and present an extraordinary challenge for health science research. As part of its broad mission to understand the interplay between environmental factors and genetic susceptibility in human health and disease, the NIEHS has an active extramural research program in neuroscience, particularly in the areas of neurodevelopment and neurodegeneration. The NIEHS recently joined the Neuroscience Blueprint, a formal collaboration among 15 NIH institutes that support research on the nervous system. Scientific programs implemented under the Blueprint are intended to accomplish goals that strengthen the neuroscience enterprise and make it more effective and that also affect many or all of the individual disciplines within neuroscience. These goals include pooling of resources and expertise, establishing economies of scale, addressing large and complex challenges within neuroscience, and developing tools and infrastructure to serve the entire neuroscience community.During its first full year of operation, the Neuroscience Blueprint has acted to expand a number of existing resources and has established an infrastructure for the efficient development and implementation of new initiatives. One of the initial Blueprint activities was the expansion of the Microarray Consortium. Four microarray centers are now available to serve the expression profiling and single nucleotide polymorphism (SNP) genotyping needs of neuroscience investigators funded by any of the Blueprint institutes. The consortium provides advice on experimental design, experimental services, data analysis, manuscript preparation support, and training. Extensive expertise, laser-capture microdissection, and multiple microarray platforms are available. NIEHS-funded investigators with an active grant in neuroscience are eligible to access the consortium to perform neuroscience experiments, and, because NIH pays most consortium costs, user fees are very reasonable.A number of Neuroscience Blueprint initiatives are being implemented in 2006. These include training initiatives in neuroimaging and computational science, the development and dissemination of knockout mouse lines, the establishment of core facilities for neuroscience research, and the development of a standard data collection instrument for neuroepidemiologic research. Planning for Fiscal Year 2007, new Blueprint initiatives will focus on tools and resources for neurodegeneration. Future initiatives for subsequent fiscal years will focus on development and plasticity.http://neuroscienceblueprint.nih.gov/Additional information about the Neuroscience Blueprint can be found at Cindy Lawler, PhD | (919) 316-4671,lawler@niehs.nih.gov


The aim of this paper is to describe a rare case report of a pediatric patient with secondary Sjögren's syndrome (SSS). A 12-year-old female child was referred to the Pediatric Dentistry Clinic with the chief complaint of tooth pain, dry mouth, and tooth sensibility. The patient was submitted to orthodontic treatment prior to syndrome diagnosis. The clinical treatment consisted of the interruption of orthodontic treatment and restoring the oral condition with dental treatment and the use of artificial saliva in an innovative apparatus. Dental therapy involved the control of dental caries, periodontal disease, and opportunistic fungal infections and the use of fluoride-rich solutions. The present clinical case describes clinical and laboratory aspects of SSS in pediatric patients. The management of the oral findings promoted an improvement in the oral health status and quality of life of the child. Sjögren's syndrome (SS) is a chronic autoimmune disease of the exocrine glands characterized by focal lymphocytic infiltration and destruction of these glands . SS may Primary disease is rare in childhood . ParotidTherefore, this report describes a rare case of SSS that affected a 12-year-old girl submitted to an orthodontic treatment prior to the diagnosis. The case describes severe tooth destruction with oral rehabilitation and hyposalivation management.A 12-year-old female patient was referred to the Pediatric Dentistry Clinic, complaining of dry mouth, tooth sensibility, and dental pain. The patient reported three episodes of parotid gland enlargement. Her medical history included rheumatoid arthritis diagnosed 6 months before consultation. Regarding family history, her mother reported that both she and her sister presented symptoms of autoimmune diseases. In the current case report, the diagnosis of Sjögren's syndrome was confirmed by anti-Ro/anti-La antibodies, magnetic resonance imaging of the parotid and sublingual salivary glands, and also parotid contrast sialography. The patient was monitored by a doctor in regular appointments for the control of Sjögren's syndrome and rheumatoid arthritis and the treatment consisted of corticoid therapy.An extraoral investigation showed dry lips and no glandular enlargement. During the intraoral exam , extensiThe patient was instructed to use alcohol-free mouthwash and to replace her toothpaste and toothbrush with others with the following characteristics: fluoride toothpaste with low abrasion and a toothbrush with a small head and straight, soft bristles. In order to moisturize the lips, the patient was advised to use cocoa butter lipstick.It was possible to observe caries lesions in both clinical  and radiTo alleviate the xerostomia and manage the hyposalivation, artificial saliva was manipulated. We prepared a tray identical to those used in tooth whitening to be filled with artificial saliva  overnighThe preexistence of rheumatoid arthritis led to the classification of the patient as a case of SSS. Furthermore, the diagnosis was confirmed based on the most recent guidelines , 17. In In the current case report, the patient reported autoimmune diseases in her family history. SSS presents in association with other autoimmune diseases . In primDecreased salivary secretion can lead to major changes in the oral mucosa, difficulty in swallowing and speaking, a sensation of burning in the mouth, and an increase in dental caries, but also to greater susceptibility to developing periodontal diseases . PeriodoThe treatment of xerostomia in these patients is basically supportive therapy, with the aim of stimulating saliva production. In treating the oral symptoms of patients with respect to xerostomia, the use of artificial saliva and chewing gum without sugar is often indicated . Also, tThe dental therapeutic approach involved the control of caries, periodontal disease, and opportunistic fungal infections, oral hygiene instruction, the use of fluoride-rich solutions, the use of artificial saliva in a tray, and regular follow-up at short intervals. This approach proved to be effective in recovering the oral health and self-confidence and consequently improved the quality of life of the patient.


Instigated at the beginning of the 20th century, modern transplantation has triggered an unprecedented era for medical therapeutics. Indeed, the feasibility to successfully transplant cells, tissues, or organs derived from an allogeneic donor has opened the way to novel approaches to rescue and prolong the life of patients with end-stage organ failure. However nowadays, due to an increasing gap between the demand for organs and the limited number of human donors, allogeneic transplantation is, unfortunately, a therapeutic option that is not always available to those in need.In the dramatic scenario of human donor shortage and increasing transplantation waiting lists, transplanting organs from other species such as the pig into man, a condition known as xenotransplantation, might represent an appealing therapeutic solution for a larger population of patients affected by organ failure. Despite the well-established similarities with regards to some aspects of anatomy and physiology between pigs and humans, transplanting pig tissues and organs into man is known to elicit an aggressive immune reaction that commonly results in premature failure of the graft.Breakthroughs in the understanding of the mechanisms underlying xenograft rejection, that include advancements in glycoimmunology, proteomics, and molecular signaling, have enabled the development of novel modalities to prevent or delay the development of antixenograft immune responses. In fact, innovative strategies have been devised to modulate the recipient's immune response to xenografts, to reduce the immunogenic power of transplanted cells, tissues, and organs, or to create a physical barrier between the human blood and the xenograft. However, the route to the clinical application of xenotransplantation still presents many hurdles that will need to be overcome before reaching its ambitious therapeutic goal.The Role of NK Cells in Pig-to-Human Xenotransplantation). In this context, the authors accurately describe specific molecular strategies to overcome the human NK response directed against porcine endothelial cells. As previously evidenced for NK immune responses, costimulatory molecules represent a key target of intervention to optimize immunomodulation in xenotransplantation. In the review by K. P. Samy et al. (in The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation), the central role of such approaches is illustrated in enabling xenotransplantation of solid organs, as kidney, heart, and liver, as well as of islets. Specifically, advancements in terms of survival achieved in preclinical models with the introduction of monoclonal antibodies against CD154, CD40, and CTLA-4 are discussed. E. Montanari et al. cover another strategy that might possibly improve xenograft durability. This approach is represented by the protection offered to hepatocytes by cotransplantation with multipotent mesenchymal stem cells (MSCs) . In fact, alginate-encapsulated hepatocytes demonstrated higher viability and albumin secretion upon coculture with MSCs thanks to the paracrine effect of their secreted cytokines CCL2, CXCL12, and macrophage migration inhibitory factor (MIF). Such original results are of great interest for the success of cell transplantation in the setting of acute liver failure and once again, confirm the powerful immunomodulatory and protective abilities of MSCs when applied as ancillary therapies or alone.In this special issue, we aim to offer an overview of the state of the art of xenotransplantation with reference to the continuous innovation and potential issues in this challenging medical field. In particular, G. P. Yung and colleagues review the role of human natural killer (NK) cells in the pathophysiological mechanisms leading to xenograft rejection . In addition, they highlight the importance of organ size match since discrepancies may ultimately be a cause of xenograft failure. Lastly, in their review, C. G. A. McGregor and G. W. Byrne examine the current barriers hindering access of heart xenotransplantation in the clinical arena . Following an accurate description of the technological progress that has enabled the current preclinical results in nonhuman models, the remaining key preclinical studies indispensable to ensure the efficacy and safety of clinical cardiac xenotransplantation are discussed.Besides immune response, other pitfalls in the clinical application of xenotransplantation could be represented by inappropriate organ function and growth adaptation, also developed in the long term. J. A. Shah and colleagues analyze the possible causes of post-transplant proteinuria in preclinical renal xenotransplantation and summarize the preventive strategies that are currently being tested/applied (in In this continuous cross talk between fundamental and applied research, progress is very encouraging and clinical translation of novel therapeutic solutions based on the use of animal-derived cells, tissue, or organs appears increasingly closer.Laura IopVered Padler-KaravaniEmanuele Cozzi


Endogenous retroviruses are mobile genetic elements hardly distinguishable from infectious, or “exogenous,” retroviruses at the time of insertion in the host DNA. Human endogenous retroviruses (HERVs) are not rare. They gave rise to multiple families of closely related mobile elements that occupy ~8% of the human genome. Together, they shape genomic regulatory landscape by providing at least ~320,000 human transcription factor binding sites (TFBS) located on ~110,000 individual HERV elements. The HERVs host as many as 155,000 mapped DNaseI hypersensitivity sites, which denote loci active in the regulation of gene expression or chromatin structure. The contemporary view of the HERVs evolutionary dynamics suggests that at the early stages after insertion, the HERV is treated by the host cells as a foreign genetic element, and is likely to be suppressed by the targeted methylation and mutations. However, at the later stages, when significant number of mutations has been already accumulated and when the retroviral genes are broken, the regulatory potential of a HERV may be released and recruited to modify the genomic balance of transcription factor binding sites. This process goes together with further accumulation and selection of mutations, which reshape the regulatory landscape of the human DNA. However, developmental reprogramming, stress or pathological conditions like cancer, inflammation and infectious diseases, can remove the blocks limiting expression and HERV-mediated host gene regulation. This, in turn, can dramatically alter the gene expression equilibrium and shift it to a newer state, thus further amplifying instability and exacerbating the stressful situation. Human endogenous retroviruses (HERVs) and related genetic elements occupy ~8% of human genome. They are thought to be remnants of multiple ancient retroviral infections —about 1 kb long fragments of DNA flanking the “body” of an element  is the method of choice for the high-throughput identification of the regulatory genomic regions. Similarly, transcription factor binding sites (TFBS) denote fragments of DNA with nuclear protein binding capacities . The families differed in their copy number, ranging from several copies as for the HERV-F, to more than 22,000 members as for the THE1B family. The total number of TFBS was also strikingly different—from zero  to ~13,000 (MLT1K). The densities of TFBS also varied among the families. This is also important to quantitate absolute numbers of TFBS in each family. For example, the LTR12 family had the biggest proportion of TFBS-positive members and donated ~1,300 TFBS to the human DNA, whereas the family MLT1K contributed the greatest number of TFBS , but had a small occurrence of TFBS-positive members. Interestingly, the TFBS and DHS tended to commonly appear in the same HERV elements. The probability that a particular element had DHS, was proportionate to the number of TFBS mapped herein  can in vivo generate transcripts that are reverse- complementary to the exons of those genes. Overexpression of the antisense transcripts resulted in approximately three- to four-fold decrease in mRNA levels for these genes  containing many human-specific and even polymorphic members, shows very high promoter and enhancer activities in the human germ cells and the corresponding tumors (seminoma), being transcriptionally silent in the other tissues  LTR sequence  inhibits the retroviruses by entering viral particles and inducing hypermutation of viral genome during reverse transcription, leading to G to A substitutions  derived from both a HERV element HUERS-P1 and an Alu retrotransposon, was shown to promote pluripotency by functioning as a molecular sponge for the let-7 family of microRNAs , due to regulatory HERV-H-driven intergenic non-coding RNAs that help to recruit the transcriptional activator genes by serving as the scaffold  LTR  proviruses are expressed in peripheral blood mononuclear cells at higher levels compared to the non-infected individuals (Bhardwaj et al., The biased expression of HERVs is considered as one of the triggers of autoimmune disorders (Suntsova et al., Compared to the normal controls, in the patients with rheumatoid arthritis, increased antibody response was detected against the HERV-K10 Gag protein (Nelson et al., Expression of HERVs may serve as the biomarker for various neurological diseases Table . For exaPRODH may be another active mechanism of HERV involvement in schizophrenia (Suntsova et al., The abnormally high levels of the HERV-W Env gene product were detected in the plasma of the patients with schizophrenia and bipolar disorder (Diem et al., Taken together, these findings suggest that at the early stages after insertion, the HERV is treated by the host cells as a foreign genetic element, and is likely to be suppressed by the targeted methylation and mutations. However, at the later stages, when significant number of mutations has been already accumulated and when the retroviral genes are broken, the regulatory potential of a HERV may be released and recruited to modify the genomic balance of transcription factor binding sites. This process goes together with further accumulation and selection of mutations, which reshape the regulatory landscape of the human DNA. However, developmental reprogramming, stress or pathological conditions like cancer, inflammation and infectious diseases, can remove the blocks limiting expression and HERV-mediated host gene regulation. This, in turn, can dramatically alter the gene expression equilibrium and shift it to a newer state, thus further exacerbating the stressful or unstable situation.All authors listed have made substantial, direct and intellectual contributions to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Achilles tendinopathy is one of the most frequently ankle and foot overuse injuries, which is a clinical syndrome characterized by the combination of pain, swelling, and impaired performance. The two main categories of Achilles tendinopathy are classified according to anatomical location and broadly include insertional and noninsertional tendinopathy. The etiology of Achilles tendinopathy is multifactorial including both intrinsic and extrinsic factors. Failed healing response and degenerative changes were found in the tendon. The failed healing response includes three different and continuous stages . The histological studies have demonstrated an increased number of tenocytes and concentration of glycosaminoglycans in the ground substance, disorganization and fragmentation of the collagen, and neovascularization. There are variable conservative and surgical treatment options for Achilles tendinopathy. However, there has not been a gold standard of these treatments because of the controversial clinical results between various studies. In the future, new level I researches will be needed to prove the effect of these treatment options. The clinical symptoms of pain, swelling, and impaired physical function of Achilles tendon are common in sports and daily life. Traditionally, many terms have been used to describe the disorders, including tendinitis, tendinosis, and paratenonitis. However, recent histopathological studies have found these disorders as a result of a failed healing response, which may cause degenerative changes in the tendon. The failed healing response includes three different and continuous stages  –3. HowevThe two main categories of Achilles tendinopathy are classified according to anatomical location and broadly include insertional  and noninsertional  tendinopathy .Achilles tendinopathy is one of the most frequently ankle and foot overuse injuries . This diChronic Achilles tendinopathy is more common in older people than in young people. In Kvist's study, among 470 patients who had Achilles tendinopathy, only 25% of the patients were young athletes and 10% were younger than 14 years . MoreoveThe risk factors of Achilles tendinopathy can be divided into intrinsic and extrinsic factors, either alone or combination. Intrinsic factors include biomechanical abnormalities of the lower extremity such as leg length discrepancy hyperpronation, varus deformity of the forefoot, pes cavus and limited mobility of the subtalar joint , and sysThe Achilles tendon originates from the merging of the soleus muscle with the two bellies of the gastrocnemius and it is inserted distally onto the calcaneus. The normal tendon is seen as a fibrillar and generally rounded structure that is white and elastic, because most of them are avascular. Two kinds of cells, tenoblasts and tenocytes, account for 90–95% of the cellular element of the tendon. The cells in a normal Achilles tendon are well organized. The remaining 5–10% of cells are chondrocytes at the entheses and a few synovial cells in the synovial tendon sheath –20. The The normal blood supply to the tendon is variable between different age and area. The Achilles tendon receives blood supply from three sources: the muscle-tendon junction, the bone-tendon junction, and the length of the tendon. The blood supply to middle portion of the tendon is by way of the surrounding paratenon (the most important blood supply to the tendon) , 26. TheThe nerve supply to the tendon comes from the overlying superficial nerves or from nearby deep nerves, the tibial nerve and its branches . The nerIn the Achilles tendinopathy patients, the tendon turns out to be thickened, uneven, and brownish. Histological examination of the affected tissue shows no macrophages, neutrophils, or other inflammatory cells. Therefore, traditional terms tendinitis and tendonitis are inappropriate for designating this tendon disorder . As the Healthy tendons are relatively avascular. Neovascularization, a descriptive term for the appearance of abnormal vessels, is one feature of Achilles tendinopathy , 38. NeoTendon repair involves a sequence of three phases. The first inflammatory phase lasts a few days. Erythrocytes and inflammatory cell migrate to the injury site within the first 24 h. Vasoactive and chemotactic factors are released with increased vascular permeability, initiation of angiogenesis, proliferation of tenocyte, and production of collagen fiber . After aMatrix metalloproteinases (MMPs) are a family of proteolytic enzymes, which are classified according to their substrate and primary structure. Previous studies indicated that the MMPs are important in regulating the extracellular matrix network remodeling, and their amounts are changing during Achilles tendon healing process .The quality of the tissue is weakened because of the abnormal healing process, with disordered proliferation of tenocytes, degeneration change of tendon cells, disruption of collagen fibers, and eventually increasing of noncollagenous matrix. If the source of the tendon injury persists, the area of degeneration or the tear may persist or worsen over time .2+, adenosine triphosphate (ATP)), neuropeptides (substance P (SP), neuropeptide Y), and neurotransmitters such as glutamate, have been found to be elevated in tendinopathy and proposed as causing pain [The sources of pain in Achilles tendinopathy are very complicated. The pain may originate from multiple factors. Increased production of prostaglandins (PGs) in matrix, neovascularization in tendon body, tenocyte changes in structure and function, and metabolites changes in tendinopathy are thought to be the sources of pain . Chemicaing pain , 48. Recing pain .In the acute phase, initial rest is the most important. The use of braces and immobilization with a cast or pneumatic walking boot are combined with modified activity . ImmobilUltrasound is a common prescribed program of physical therapy. In animal studies, ultrasound could stimulate collagen synthesis in tendon fibroblasts and cell division during the period of rapid cell proliferation . Therapeα in gene level [Low level laser therapy (LLLT) could reduce the expression of proinflammatory markers such as IL-6 and TNF-ne level . In the ne level , stimulane level , downregne level , 61. In ne level . Anotherne level . A meta-ne level . In the The scientific basis of NSAIDs used in chronic tendinopathy is questionable, because the histological examination in the tendinopathic tissue shows no inflammatory cells . The benCorticosteroid injections are reported to reduce pain and swelling and improve the ultrasound appearance of the tendon. The mechanism behind any positive effect of local steroids on chronic Achilles tendinopathy remains unclear. Some authors have hypothesized that any beneficial effects of corticosteroids in this condition are owed to other local steroid effects rather than suppression of inflammation, including lyses of tendon and peritendon adhesions or alteration of the function of pain generating nociceptor in the region . CorticoMany studies and systematic reviews have found that eccentric exercises are beneficial in the early treatment of noninsertional Achilles tendinopathy , 68, 73,Conflicting results have been reported for extracorporeal shockwave therapy (ESWT) . How ESWThe introduction of platelet-rich plasma (PRP) at the site of tendon injury is thought to facilitate healing because it contains several different growth factors and other cytokines that can stimulate healing of soft tissue . Animal Intratendinous hyperosmolar dextrose (prolotherapy) is thought to produce a local inflammatory response and increase in tendon strength. Clinical results indicated that intratendinous injections of hyperosmolar dextrose could reduce the pain at rest and during tendon-loading activities in patients with chronic of the Achilles tendinopathy , 86. MorNitric oxide is a small-free radical generated by a family of enzymes, the nitric oxide synthases. It can induce apoptosis in inflammatory cells and cause angiogenesis and vasodilation. Moreover, oxygen free radicals can stimulate fibroblast proliferation . Nitric Cryotherapy might play a role in reducing the increased capillary blood flow in Achilles tendinopathy, reducing the metabolic rate of the tendon and applying for relief of pain , 92. HowThe sclerosing agent that selectively targets the vascular may cause thrombosis of the vessel. As the concomitant sensory nerves have been implicated as possible pain generators, to destroy local nerves adjacent to neovessels may decrease pain . As vessDeep friction massage (DFM) and tendon mobilization may also be helpful in the treatment of Achilles tendinopathy. DFM has been advocated for tendinopathy and paratendinopathy. Friction has been shown to increase protein output of tendon cells . In combAprotinin is a broad spectrum serine protease inhibitor capable of blocking trypsin, plasmin, kallikrein, and a range of MMPs . Most prThe goal of surgery is to resect degenerative tissue, stimulate tendon healing by means of controlled, low-grade trauma and/or augment the Achilles tendon with grafts. It has been suggested that noninvasive treatment should be tried for at least 4 months prior to operative interventions . ConventSeveral operative treatments include percutaneous longitudinal tenotomies, minimally invasive tendon stripping, open tenosynovectomies, open debridement and tubularization, and tendon augmentation with flexor hallucis longus (FHL). Long-term results of operative interventions are promising but need more fair evidence to support the clinical use.Complications are common in surgical procedure. In a large series of 432 consecutive patients, Paavola et al. reported wound necrosis in 3%, superficial infection in 2.5%, and sural nerve injury in 1%, with further complications including haematoma, seroma, and thrombosis. Therefore, the overall complication rate was 11% and reoperation rate was 3% .Patients who do not respond to conservative treatment may need operative manage. No consensus exists regarding the duration before surgery, though most clinicians consider 3 to 6 months the minimum time necessary to evaluate the effect of conservative treatment .The operative strategy for insertional Achilles tendinopathy is removal of the degenerative tendon and associated calcification, excision of the inflamed retrocalcaneal bursa, resection of the prominent posterior calcaneal prominence, reattachment of the insertion as required, and/or augmentation of the tendo-Achilles with a tendon transfer/graft , 102. CaBiomechanical and clinical data suggest that 50% of the tendon attachment can be safely debrided without compromise of the insertion strength or risk of rerupture. When greater than 50% of the Achilles tendon is detached from the calcaneus, suture anchors are recommended to reattach the residual tendon. With extensive insertional, Achilles tendon disease and/or when greater than 75% of the tendon is excised, augmentation with local tissue, such as the flexor hallucis longus tendon and semitendinosus tendon, is advisable .Achilles tendinopathy is a clinical syndrome characterized by the combination of pain, swelling, and impaired performance. The etiology of Achilles tendinopathy is multifactorial including intrinsic and extrinsic factors. The histological studies demonstrate an increased number of tenocytes and concentration of glycosaminoglycans in the ground substance, disorganization and fragmentation of the collagen, and neovascularization. The sources of pain in Achilles tendinopathy are very complicated. The pain may originate from multiple factors. There are variable conservative and surgical treatment options for Achilles tendinopathy. However, there is no gold standard of the treatments because of the controversial clinical results between various studies. In the future, more new level I researches are needed to prove the effect of these treatment options.


Traumatic spinal cord injury (SCI) is a devastating neurological condition characterized by a constellation of symptoms including paralysis, paraesthesia, pain, cardiovascular, bladder, bowel and sexual dysfunction. Current treatment for SCI involves acute resuscitation, aggressive rehabilitation and symptomatic treatment for complications. Despite the progress in scientific understanding, regenerative therapies are lacking. In this review, we outline the current state and future potential of invasive and non-invasive neuromodulation strategies including deep brain stimulation (DBS), spinal cord stimulation (SCS), motor cortex stimulation (MCS), transcutaneous direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in the context of SCI. We consider the ability of these therapies to address pain, sensorimotor symptoms and autonomic dysregulation associated with SCI. In addition to the potential to make important contributions to SCI treatment, neuromodulation has the added ability to contribute to our understanding of spinal cord neurobiology and the pathophysiology of SCI. Traumatic spinal cord injury (SCI) is a devastating neurological disorder with a reported incidence in various countries and regions ranging from 10 to 80 million per population per year ,3. It isSCI is characterized by a constellation of symptoms including paralysis, paraesthesia, pain, cardiovascular, bladder, bowel and sexual dysfunction. The level of physical disability depends on the severity of the injury and the level of injury. The severity of the injury is commonly assessed by the International Standards for Neurological Classification of Spinal Cord Injury (ISCNSCI) developed by the American Spinal Injury Association (ASIA). This can be classified into different grades on the ASIA impairment scale . EpidemiArguably at least as important as the physical and physiological disability caused by SCI are its psychological and economic impacts. SCI predominantly affects a young adult population and the psychological impact of rendering an independent, healthy individual paraplegic or tetraplegic without bladder, bowel or sexual function can be devastating. In addition to the costs associated with medical care in SCI patients, there is an immense secondary economic burden associated with individuals incapacitated for most of their prospective career and the subsequent impact upon their families. One study estimated the lifetime economic burden of 1.5 million 2011 Canadian dollars per tetraplegic individual .In this review, we briefly outline the current management of acute and chronic SCI and focus on the potential of neuromodulation strategies in its treatment. In particular, we review the available clinical evidence for strategies such as deep brain stimulation (DBS), spinal cord stimulation (SCS), motor cortex stimulation (MCS), transcutaneous direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in affecting pain, sensorimotor symptoms and autonomic dysregulation, all of which are important sequelae in SCI.The mainstay of current management of acute spinal cord injury involves acute resuscitation and the prevention of secondary injury to the spinal cord. Acute resuscitation follows Advanced Trauma Life Support principles with particular importance to the airway and breathing in high cervical injuries that can impair diaphragmatic function, along with early spinal immobilisation. Circulatory resuscitation is also of paramount importance due to the phenomenon of neurogenic shock, which can cause profound bradycardia, hypotension and vasodilatation due to the loss of sympathetic tone. Standard first procedures include acute stabilisation, clinical assessment (ASIA score) and computerised tomography and magnetic resonance imaging (CT and MRI). Secondary injury to the spinal cord may be prevented by maintaining adequate perfusion to the cord ,8 and eaThere are currently no generally approved medical therapies to improve outcomes in acute SCI , althougSubsequent management involves a combination of intense rehabilitation to optimise functional outcomes and medical therapies, designed either to prevent complications, such as venous thromboembolic events, infections associated with indwelling catheters and pressure ulcers and osteoporosis or to treat specific symptoms such as neuropathic pain.Despite the advances of modern molecular and cellular science, there has been little clinical progress in regenerative and restorative therapies for chronic SCI. In vitro and in vivo models have often looked promising, but no disease modifying therapies have been successfully translated to humans . FollowiThe various proposals for using CNS stimulation in SCI and other neurotrauma are in part prompted by the apparent obstacles to other approaches. Electrical stimulation of a discrete anatomical pathway elicits a natural response that can be helpful, whereas the ultimate benefits of administering a mixture of slow-acting, powerful drugs with an array of adverse effects and issues of receptor specificity, timing of actions, dosing regimen, tolerance and spatial targeting remain unclear. Neurotrophic substances of potential interest additionally run the risk of uncontrolled deleterious axonal sprouting . The tesThe indications for functional neurosurgery, including deep brain stimulation (DBS), cerebral cortical stimulation and spinal cord stimulation (SCS), have expanded drastically over the last decade and now encompass a whole host of neurological disorders including movement disorders, psychological and psychiatric disorders, pain (including neuropathic pain and primary headache disorders), epilepsy, disorders of consciousness and cognitive disorders ,36.In the context of SCI, functional procedures have the potential to impact upon a number of different domains, including pain, functional motor/sensory recovery, bladder/bowel function and cardiovascular autonomic dysregulation. Many of these have been highlighted as important symptoms to address in large surveys of SCI patients ,38.There are three broad strategies for chronic SCI: (i) using technology to restore function without restoring neural architecture; (ii) taking advantage of plasticity to harness residual circuitry; and (iii) encouraging active regeneration of injured neurons. These are depicted in The first strategy involves suppressing or inducing immediate effects. Pain suppression is an obvious example, and the most clinically developed (see next section). Less obviously, one can try to evoke or improve some specific movements that have been lost. For example, to facilitate locomotor movements in incompletely injured individuals, the mesencephalic locomotor region can be stimulated, thus overcoming weakness in the spinal central pattern generator . This poThe second strategy focuses on stimulation of pathways assumed to possess considerable neuroplasticity in their normal functioning, pre-eminently the cortico-spinal tract . This prA final strategy that has met with some preclinical success assumes that certain brain regions are specifically adapted as centres for repairing recent mild neurotrauma ,45,46,47Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” . In the The use of neurostimulation to treat pain was reported as early as 1960 , predatiEvidence for the efficacy of DBS in the context of SCI-related pain is limited to a few patients that form part of small series which have had varying results ,71,72,73Another option for SCI-related pain is epidural motor cortex stimulation (MCS), although the limited reports in the literature suggest that SCI-related pain responds poorly to MCS compared with other pain syndromes ,82. HoweSCS has been used to treat a variety of pain syndromes for over 40 years and the first reports of its use for spinal cord injury date back to 1972 . It is bNon-invasive neuromodulatory strategies include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), both of which are purported to work on the basis of altering maladaptive plasticity within pain circuits, affecting nuclei in the thalamus and subthalamic regions ,87,88. AThe future of neurostimulation for pain in SCI lies in improving the level of evidence for each intervention and identifying subsets of patients and types of pain that benefit from specific interventions. Presently, DBS for various types of pain can yield a range of effects in different patients from dramatic and highly pleasing success to disheartening failure, and the factors leading to these variable outcomes are entirely unclear, although there are some weak statistical predictors . This taThere is little in the way of clinical evidence for the efficacy of neuromodulation for locomotor and sensory recovery following spinal cord injury. Perhaps the best evidence for efficacy of DBS in animal models comes from two landmark studies, showing the efficacy of DBS in improving gait in cord injured rats. The two studies used different targets, the mesencephalic locomotor region (MLR) and the nucleus raphe magnus and the PAG ,47, and Similar rodent and mammalian evidence also exists for SCS, which has been improved by the use of closed-loop feedback systems to refine stimulation parameters and improve gait ,103,104.Animal evidence also exists for the utility of combined MCS and spinal tDCS in promoting motor recovery after pyramidotomy, suggesting that stimulation proximal and distal to the injury could facilitate the improvement in function following SCI . TMS mayAutonomic functions, including bladder, bowel and sexual function, have consistently been highlighted as priorities for recovery in patients with SCI ,38. In tCardiovascular autonomic dysfunction is a major problem in SCI, and contributes to the excess cardiovascular mortality in SCI . In the Although there is little in the way of evidence for autonomic manipulation in the context of SCI, evidence from other conditions indicate that neuromodulation strategies may have a role . There iDBS has also been shown to affect blood pressure with dorsal central gray stimulation resulting in an increase in blood pressure and ventral central gray stimulation resulting in a decrease in blood pressure ,140,141.A number of other neuromodulatory strategies have also been reported for autonomic recovery, specifically for bladder, bowel and sexual function . AlthougThe plethora of applications for neuromodulation in SCI provides promise in a field currently devoid of disease-modifying therapies. The physiological, psychological and economic benefits associated with addressing issues such as pain, mobility and autonomic symptoms in SCI patients is large. Given the current dearth of treatment options, neuromodulation is an attractive emerging option. However, there are a number of outstanding questions that first need to be answered.Apart from the need to identify evidence-based indications for deep brain, motor cortex and spinal cord stimulation and the non-invasive strategies in the context of SCI, we also need a more nuanced understanding of the patient, injury and treatment factors that influence success. Specifically, the timing of interventions seems a crucial variable. The interventions for pain have thus far been performed many months to years after the injury once aberrant circuitry has become established and it remains to be explored whether more acute interventions could be more beneficial at preventing the development of maladapted circuits or promote regeneration . AnotherThe potential, in particular, of PAG DBS for addressing multiple symptoms is intriguing. The animal and human evidence presented earlier in this review have illustrated the potential to address pain, autonomic features and facilitate motor recovery in SCI. The fact that PAG is already a target in human DBS for pain makes it an ideal candidate for further investigation to target the disabling triad of pain, autonomic dysreflexia (both cardiovascular and sphincteric) and paralysis.Mechanistic insight studies, both in humans and animals, will also aid progress in the field. In particular, human electrophysiological and imaging studies in spinal cord injury both before and after neurostimulator implantation will allow us to develop a better understanding the biological processes underlying symptomatic improvement. For example, despite the use of DBS in the central gray for pain, the mechanism of action remains unclear . TheorieTechnological advances will also be of direct relevance to this field. Smaller nanodevices for stimulation may improve the specificity and reduce the side-effect profile. Such devices have also been reported to promote axonal regeneration in the cord  and may Despite the potential of neuromodulation strategies, the limitations must also be taken into consideration. All implants and surgical procedures are associated complications such as the foreign body response that reduces efficacy over time . SpecifiDespite the current paucity of clinical evidence for efficacy, functional neurosurgery has the potential to make contributions to the treatment of SCI. It can immediately relieve some of the many visceral and sensory-motor deficits and has the potential to effectuate some useful degree of reversal of the underlying neurodegeneration, albeit partially, by exploiting the capacity of electrical activity to increase sprouting or induce other plastic changes in neural pathways, such as maturation and integration of endogenous neural progenitor cells.


Oral cancer is one of the most common malignant lesions of the head and neck. This cancer is an aggressive and lethal disease with no significant improvements in the overall survival in the last decades. Moreover, the incidence of oral HPV-positive tumors is rising, especially in young people. This oral neoplasm develops through numerous molecular imbalances that affect key genes and signaling pathways; however, the molecular mechanisms involved in the pathogenesis and progression of oral tumors are still to be fully determined. In order to improve the quality of life and long-term survival rate of these patients, it is vital to establish accurate biomarkers that help in the early diagnosis, prognosis and development of target treatments. Such biomarkers may possibly allow for selection of patients that will benefit from each therapy modality, helping in the optimization of intensity and sequence of the treatments in order to decrease side effects and improve survival.In this review we discuss the current knowledge of oral cancer and the potential role of omics approaches to identify molecular biomarkers in the improvement of early diagnosis, treatment and prognosis. The pursuit to improve the quality of life and decrease mortality rates of the oral patients needs to be centralized on the identification of critical genes in oral carcinogenesis. Understanding the molecular biology of oral cancer is vital for search new therapies, being the molecular-targeted therapies the most promising treatment for these patients. Oral cancer is part of a group of cancers named head and neck cancer (HNC), which enclose a wide set of diverse tumor types arising from various anatomic structures, such as oral cavity, oropharynx, larynx, hypopharynx and nasopharynx. Histopathologically, squamous cell carcinomas (SCCs) represent nearly 90% of all these tumors and over 50% arise in the oral cavity . The mosWorldwide, oral and pharyngeal tumors, when combined, represent the sixth most common cancer, with more than 300,000 estimated new cases and approximately 145,000 deaths from oral cavity cancer (including lip cancer) in 2012 . It is iDespite technological advances and improvements in OSCC diagnosis and treatment modalities, its 5-years survival rate stays low, around 50–60% . This diThe understanding about the biology and pathology of oral carcinogenesis process is still slow. Therefore, a better insight concerning oral cancer proliferation, invasion and cellular migration is clearly needed. This understanding is crucial to search and establish molecular targets to help in the early diagnosis, to predict the prognosis and also to direct the development of new therapeutic strategies. The purpose of this review is to provide a critical analysis of the current knowledge of oral cancer and to discuss the potential translation to clinical practice of molecular signatures using the emergent omic approaches.Diagnosing tumors in the oral cavity might be challenging. The inspection and examination of the oral cavity has an easy access and is simple to perform; however, benign lesions can sometimes mimic the alterations observed in cancer development . AdditioThe first-line treatment for OSCC has been surgery, which may be followed by chemo/radiotherapy. Surgery is a debilitating and considerably morbid procedure that impairs the patients’ quality of life as it implies drastic alterations in chewing, swallowing, speech or facial esthetics . A great®) in the clinical practice was a great advance in the field of targeted drugs. However, not all patients treated with Cetuximab respond well to therapy due to primary or acquired resistance, limiting significantly the clinical benefit of this drug [The use of Cetuximab, a monoclonal antibody targeting the extracellular ligand binding domain of the epidermal growth factor receptor (EGFR), combined with radiotherapy is approved for the treatment of locoregionally advanced HNC , and forhis drug . BesidesThe introduction of immune checkpoint inhibitors into HNC treatment has been explored, being the cosignaling of the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) one of the major pathways of interest. PD-1 is a co-inhibitory receptor, since the ligation of PD-L1 or PD-L2 to PD-1 inhibits T-cell proliferation and down regulates expression of the anti-apoptotic molecule Bcl-xL, cytokine expression and the mTOR pathway in immune cells –24. CurrAn apparently problem in this field of targeted therapies seems to be the identification of biomarkers that help in the selection of eligible patients to benefit these expensive treatments , which rEmerging OSCC omics data hold great promise for understanding of the oral carcinogenesis process, predicting prognosis and helping in the development of targeted therapies. Advances in the powerful omics technologies: genomics, epigenomics, transcriptomics, proteomics, metabolomics and lipidomics are opening new routes towards biomarker discovery in order to allow early diagnose and to differently discriminate the behavior of each tumor, providing personalized therapies for the patients. Considering the multifactorial nature of OSCC it is mandatory to combine different biomarkers that could lead to the implementation of prophylactic screening programs, decreasing the incidence and mortality and increase the quality of life of these patients. It is important to note that in omics technology, bioinformatics tools are required to extract relevant information from the complex huge amount of data and identify players in cancer pathways. Indeed, in this post-genomic era several questions remain to be addressed. The central question for oral oncology research seems to be the following: which alterations are likely to occur early in oral cancer, and how do these molecular imbalances thus affect the clinical outcome of the patients? It is very difficult to explain the different outcomes for patients with the same clinical disease submitted to the same treatment. In this way, integrative molecular research in larger cohorts is imperative to better understand this devastating disease. Additional questions are also important to be considered, namely: are clinicians up to date on pharmacogenomics to apply these data in their clinical choices? Can society afford personalized medicine at all, considering the actual costs related to high throughput technologies and targeted treatments?Oral cancer development lies in stepwise accumulation of genomic and epigenomic changes, compromising cell division, differentiation, immune recognition, tissue invasion and metastasis . DNA althTERC and SOX2 genes, is common in all squamous cell carcinomas and their detection could be important for early detection and for accurate prognosis of these patients [MYC and WISP1 genes seem to suggest higher propensity of tumors localized in the floor of the mouth [Genomic changes play a significant role in tumourigenesis as well as in inter- and intratumour heterogeneity . In OSCCpatients . We verihe mouth . Howeverhe mouth  and Agrahe mouth  identifihe mouth . Nowadayhe mouth . The prehe mouth . It mighbona fide mechanism for gene inactivation. New high-throughput methodologies provide information to characterize methylated sequences at single-base resolution on a genome-wide scale. Recent studies focused on identifying biomarkers of early disease detection, since DNA methylation is considered an early event in cancer process [WT1 gene promoter methylation is a predictor of a better prognosis and that MSH6 and GATA5 gene promoter methylation serve as predictors of a worse prognosis and a shorter survival rate in OSCC [PAX5 gene promoter methylation as associated with tongue tumors [CDKN2A and MLH1 promoter methylation in invasion of lymph nodes with cancer cells [Identification of epigenomic biomarkers has so far focused mainly on DNA methylation, since this is a well-known epigenetic phenomenon with an established role in cancer. Growing evidence supports promoter CpG island hypermethylation as a  process . We foun in OSCC . Moreovee tumors . Epigenoe tumors . Moreoveer cells . DNA meter cells . Consideer cells , 46.Different genomic expression in HNC samples compared with normal tissue suggests that gene expression signatures can be used as a predictor of outcome in these patients. Thus, large-scale transcriptome analysis in HNC allowed the categorization of these tumors in four distinct subtypes with differences in recurrence-free survival , 48. FurmicroRNAs (miRNAs) are a group of small RNAs that specifically modulate gene expression with a significant role in tumorigenesis. Several miRNAs have been found to be up or downregulated in OSCC . A molecBiochemical and biological techniques have been used to identify proteins, metabolites and lipids in OSCC.Nowadays, functional proteomics comprise a high-throughput analysis of both basal and phosphorylated proteins active in carcinogenesis process, allowing the assessment of cellular whole protein complements in tissues or the secreted proteins in the biofluids (secretome), such as serum, plasma, urine or saliva . StudiesMetabolite profiling of tissue and biofluid samples from HNC using mass spectrometry-based metabolomic analysis has been demonstrated to be capable of discovering potential biomarkers for disease detection and treatment monitoring . In seruThe alterations in lipid profile have also long been associated with cancer, since lipids play a key role in maintenance of cell integrity; however, few reports are available on plasma lipid profile in HNC. An inverse relationship was found between the lipid levels and occurrence of oral cancer, thus, lower plasma lipid status may be a useful indicator of neoplastic lesions , 69.Technological advances in high throughput microarrays, DNA sequencing, RNASeq methods and mass spectrometry approaches, together with computational and algorithmic progress, have generated progressively large amount of omics data accessible in public databases. The main problem in comparing results of data-sets generated by different research groups is the use of different platforms and also differences in sample preparation, being the correlations sometimes disappointing. The integration of omics data can yield more than the sum of the individual omics experiments, displaying the interactions that can occur among all classes of molecules in a cell, determining the cellular physiology and behavior , which sWhen patients are treated within one month of onset of the symptoms, they have a 5-year survival rate of 86%, but this decreases to 47% at seven months after the beginning of the symptoms, and there is very scarce possibility of survival if the treatment occurs only after twelve months . The nonIn the present review, we focused on the contribution of genomic, epigenomic, transcriptomic, proteomic, metabolomic and lipidomic studies to the understanding and identifying of biomarkers capable of predict the clinical behavior of oral tumors. These omics approaches will also play an important role in understanding relapses at the primary site after resection, distant metastasis and the development of second primary tumors. However, many questions in this field remain to be answered. The pursuit to improve the quality of life and decrease mortality rates of the oral patients needs to be centralized on the identification of critical genes in oral carcinogenesis. This will enable to choose the treatment strategy to individualized therapy based on the molecular patient’s profile. Besides the diagnosis of oral cancer, the molecular analysis will also make possible the monitoring of suspicious lesions in the higher risk populations. In this line, saliva could become in a near future a vital element in the early detection and screening of oral cancer. It will allow performing easy and non-invasive routine health screening of the high risk populations, such as individuals with HPV infection and heavy tobacco and alcohol consumption. It is also important to improve oral health care education and raise the awareness of the general population to this severe disease, which nonetheless has a favorable prognosis when early detected. Understanding the molecular biology of oral cancer is vital for search new therapies. The molecular-targeted therapies represent the most promising treatment for OSCC. EGFR-targeting agents have shown efficacy for treatment of these patients. Several studies including immunotherapeutic strategies and inhibitors of VEGFR, IGF-1R, PI3K/AKT/mTOR and MET have been conducted, being expected in a near future a shift in the management of oral cancer patients towards more personalized treatment.