Colorectal cancer (CRC) is the third most commonly diagnosed type of malignancy in males and the second in females, with over 1.2 million new cancer cases and 608,700 deaths estimated to have occurred in 2008 . MoreoveAlthough there is now solid evidence regarding the clear protective role of lifestyle modification in terms of preventing colorectal neoplasias, there is lack of specific guidelines from the leading health organizations and professional bodies, with the currently available guidelines providing general rather specific frameworks for establishing national preventive policies. Herein, we attempt to pinpoint in a best evidence topic frame the key findings in the field of primary prevention of colorectal neoplasias, underlining the necessity of a qualitive turn towards setting specific lifestyle modification targets instead of general guidance.Increased physical activity is considered to be an important preventive factor concerning the risk of colorectal neoplasias, mainly through modifying the metabolic profile , reducing the body mass index, decreasing the gut transit time and enhancing the anti-cancerous properties of the immune system. However, the exact mechanisms that regulate the above mentioned interactions have not yet been completely elucidated.A recent meta-analysis revealed the presence of an inverse association between physical activity and colon polyps in both sexes (risk reduction by 15%) , 7, whicThe adoption of a western-type dietary pattern has for long been considered as one of the most significant risk factors for the development of colorectal neoplasias; hence, the reduction of CRC risk after the implementation of qualitive and quantitive modifications of the dietary intake has been extensively investigated.According to a recent meta-analysis evaluating the existence of a nonlinear association of fruit and vegetable intake with CRC risk, the daily consumption of 100 - 200 g of vegetables was found to reduce CRC risk about 10%, while consumption of 600 g of fruits daily resulted in a similar risk reduction of 15% . With reCurrent smokers have a modestly higher risk of developing CRC, as demonstrated in the meta-analysis of Tsoi et al  than nevSimilarly, a causal relation has been proven to exist between high intake of alcohol and increased risk for CRC, providing additional evidence of an association for moderate intake of alcohol and a shape for the dose-risk relationship . Comparea priori induction in colorectal neoplasias chemoprevention schemes in the daily practice. Finally, in the same study, the researchers suggest that calcium supplementation could reduce the recurrence of adenomas in patients with increased risk of developing CRC, but no similar conclusion was drawn with respect to the general population.Currently, chemoprevention is one of the most debated issues in the framework of primary prevention of colorectal neoplasias, with the most well-investigated agents being aspirin and other NSAIDs in terms of commonly used drugs and calcium, vitamin D, folic acid and antioxidants  in terms of micronutrients. Concerning the first group, Cooper et al, in their study evaluating the clinical effectiveness and cost-effectiveness of drug and micronutrient interventions for the prevention of CRC and/or adenomatous polyps , found t


This manuscript offers a comprehensive review about the bacterial amino acid decarboxylase activity and biogenic amines content of an artisanal cheese produced in Italy, named as Pecorino cheese. It is highlighted the importance of controlling primary production of raw milk, as well as cheese-making process to avoid the release of free amino-acids and viability of microorganisms possessing amino acid decarboxylating activity. Variation in other physico-chemical parameters, such as water activity or protein content, or during ripening may produce the selection of different microbial populations which could increase the formation of biogenic amines in the final product. Among the biogenic amines described in the manuscript, the formation of diamines (putrescine and cadaverine) and specially, tyramine content resulted to be present in high proportion in most of Pecorino cheeses. In some cases, mild thermal treatments applied in milk appear not to be sufficient to eliminate decarboxylase-positive bacteria in cheeses. Additionally, proteinases and peptidases released from rennet could be responsible of high content of biogenic amines. The authors concluded that the formation of biogenic amines depends on several factors and it would be necessary to study case-by-case each cheese type given the high variability in physico-chemical composition. The quality of raw milk, processing conditions, ripening, and subsequent storage before consumption may influence the biogenic amines formation. There are not so many studies made in this area and this could be particularly interesting in other cheese types, where artisanal production is commonly followed.


The accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) results in ER stress that triggers cytoprotective signaling pathways, termed the unfolded protein response (UPR), to restore and maintain homeostasis in the ER or to induce apoptosis if ER stress remains unmitigated. The UPR signaling network encompasses three core elements, i.e., PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein-1 (IRE1). Activation of these three branch pathways of the UPR leads to the translation arrest and degradation of misfolded proteins, the expression of ER molecular chaperones, and the expansion of the ER membrane to decrease the load of proteins and increase the protein-folding capacity in the ER. Recently, the essential roles of the UPR have been implicated in a number of mammalian diseases, particularly viral diseases. In virus-infected cells, the cellular translation machinery is hijacked by the infecting virus to produce large amounts of viral proteins, which inevitably perturbs ER homeostasis and causes ER stress. This review summarizes current knowledge about the UPR signaling pathways, highlights two identified UPR pathways in plants, and discuss progress in elucidating the UPR in virus-infected cells and its functional roles in viral infection. In ArabR Figure  (Iwata eR Figure . In respR Figure  (Iwata aR Figure . Upon trR Figure . AlthougR Figure , no infoC. elegans have revealed that the IRE1-XBP1 and the ATF6 arms of the UPR might activate a common set of genes involved in stress tolerance and worm development, indicating a functional redundancy between these two arms (Shen et al., It is conceivable that IRE1, PERK, and ATF6 pathways communicate with each other extensively in many aspects, including activation, function, and feedback regulation. A seminal work discovering the crosstalk between these three arms comes from Hela cells, where XBP1 mRNA could be induced by ATF6 and spliced by IRE1 in response to ER stress (Yoshida et al., These crosstalks further add to the complexity of the UPR induced by abiotic and biotic cues such viral infection. For example, some viruses, such as HBV, Rotavirus, and DEN, usually activate two or even three pathways to promote reproduction (Li et al., AtPDI genes was found to decrease in the AtbZIP60 mutant but not in the AtIRE1-2 mutant, indicating that the additional UPR signaling complements AtbZIP60 in the activation of AtPDI gene expression during ER stress (Lu and Christopher, So far, two UPR pathways have been identified in plants. Their crosstalk, however, does exist and appear diverse. The expression of In higher eukaryotes, many critical biological processes are dependent on intercellular/intracellular communication, which requires relevant proteins timely and adequately expressed with high fidelity in folding. Therefore, the folding function of the ER and the signaling of the ER stress-induced UPR pathways have emerged as an important aspect of cell biology with broad implications to diverse physiological and pathological processes. Despite the recent advances made in understanding the UPR mechanisms implicated in abiotic and biotic stress such as viral infection, many critical questions still remain unanswered. The molecular and structural basis for recognition of the upstream signal by the ER stress sensors has only begun to be understood. Although several recognition models have been proposed mainly based on data using pharmacological chemicals and experimental stress conditions as the inducers of the UPR Figure , we cannAs a complex signal transduction network, the UPR protects the organisms against normal and unusual levels of ER stress by enhancing ER capacity, by reducing ER load, and by inducing programmed cell death. Different cell types may have different levels of sensitivity to ER stress. In response to specific viral infection and other stimuli, little is known about the regulation of UPR signaling in distinct cells, and how the kinetics and amplitude of signaling of each UPR branch is controlled. Our current knowledge about the roles of the downstream effectors of UPR transducers is also limited. For instance, it is unknown how the transcriptional activity of XBP1 is blocked in virus-infected cells Figure . In planThe 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.


Investigations of the legacy of natural selection in the human genome have proved particularly informative, pinpointing functionally important regions that have participated in our genetic adaptation to the environment. Furthermore, genetic dissection of the intensity and type of selection acting on human genes can be used to predict involvement in different forms and severities of human diseases. We review here the progress made in population genetics studies toward understanding the effects of selection, in its different forms and intensities, on human genome diversity. We discuss some outstanding, robust examples of genes and biological functions subject to strong dietary, climatic and pathogen selection pressures. We also explore the possible relationship between cancer and natural selection, a topic that has been largely neglected because cancer is generally seen as a late-onset disease. Finally, we discuss how the present-day incidence of some diseases of modern societies may represent a by-product of past adaptation to other selective forces and changes in lifestyle. This perspective thus illustrates the value of adopting a population genetics approach in delineating the biological mechanisms that have played a major evolutionary role in the way humans have genetically adapted to different environments and lifestyles over time. Our understanding of the patterns of human genome diversity has improved considerably over the last 10 years. The complete sequence of the human genome, which was published in 2001 . These GWAS have made a major contribution to our understanding of the genetic basis of human phenotypic variation in both health and disease, by identifying genes/variants associated with the variation of traits of interest, disease susceptibility/severity and differences in response to treatment.These data sets for human genetic variation in health have also been very useful for the interpretation and design of genome-wide association studies (GWAS) on many human diseases. By the end of 2012, more than 1500 GWAS had been published on more than 250 traits or diseases as varied as height, hair color, obesity, smoking behavior, schizophrenia and colorectal or bladder cancer , and a transitory increase in the strength of linkage disequilibrium associated with the selected allele(s).In some cases, the occurrence of new genetic variants may be advantageous in a given environment, increasing the fitness of individuals, and the frequency of such variants may therefore rise due to balancing selection  can improve our understanding of the genetic mechanisms and traits underlying speciation. In turn, studies of the effects of selection on specific human populations are particularly useful for the identification of genes/variants responsible for the phenotypic diversity observed in human populations, in health  and disease .Each type of selection leaves a distinctive molecular signature  in the genomic concerned. Such molecular signatures can be detected with various statistical tests that can be broadly subdivided into those that search for selection at the inter-species level  and those that focus on particular aspects of within-species data .N/dS test (Yang N/dS test detects selection acting on protein-coding loci by comparing the ratio of non-synonymous (dN) to synonymous (dS) substitutions. Under neutrality, synonymous and non-synonymous substitutions should occur at a similar rate and we would therefore expect dN/dS = 1. However, the negative selection of non-synonymous variants would result in dN/dS < 1, whereas the positive selection of such variants would result in dN/dS > 1. In the MK test, which also considers polymorphic data, the two classes of mutations are assumed to be evolutionarily equivalent: patterns of polymorphism and divergence should therefore be the same for both classes of mutations. Non-independence between the counts of non-synonymous and synonymous polymorphisms and fixed differences  is assessed by Fisher's exact test. An excess of fixed differences for non-synonymous mutations (assumed to be subject to selection) with respect to synonymous variants is typically considered indicative of adaptive evolution. In contrast, an excess of polymorphic non-synonymous variants may result from weak negative selection or local, population-specific positive selection.Inter-species neutrality tests make use of data concerning the divergence between closely related species, such as humans and chimpanzees, to detect relatively ancient selective events, such as those occurring at the time at which the two species considered diverged. In some cases, these tests also take into account data concerning polymorphism within species, making it possible to detect both older and more recent selective events. Inter-species tests include the traditional dest Yang , the McDest Yang , and itsest Yang . The dN/D, Fu and Li's D* and F* and Fay and Wu's H tests , through the demonstration of an excess of high-frequency derived alleles of the targeted genes (or linked variation).Intra-species neutrality tests focus on the level of polymorphism within a single species, such as humans, and therefore detect selection events that have occurred more recently. They can be subdivided into distinct groups, each focusing on different aspects of the genetic data. Allele frequency spectrum-based tests determine whether the frequency spectrum of mutations conforms to the expectations of the standard neutral model, and are extensively reviewed elsewhere Kreitman . Deviatis Tajima . NegativFST statistics, are based on the level of genetic differentiation between populations historically exposed to different selection pressures , integrated haplotype score (iHS), and LD decay (LDD) tests , by examining the patterns of haplotype homozygosity (haplotype length) associated with particular alleles. These tests include the long-range haplotype  with background expectations for that statistic generated from genome-wide data, which should reflect neutrality. Thus, simulation-based or empirical procedures can be used to distinguish between the effects of demographic factors and those of natural selection events targeting specific genomic regions, providing evidence of past adaptation to new climates, foods or pathogens.However, it is possible to overcome these problems by applying a basic principle of population genetics: demographic events affect the whole genome, whereas natural selection acts more locally and is restricted to particular genomic regions. Thus, when considering the impact of demographic factors on patterns of diversity, demographic models based on multiple, non-coding regions of the genome, taking into account realistic scenarios for the demographic history of human populations  can be incorporated into neutral expectations  in the promoter of the lactase gene (LCT), increasing the expression of this gene , which also increases LCT expression, has been shown to be positively selected over the last 7000 years among East African pastoralists   that have allowed them to adapt to high-altitude conditions, where oxygen concentrations are about 40% lower than those of sea level. The genetic basis of such adaptations to extreme environmental conditions has started to be deciphered only recently. Recent studies have provided evidence of positive selection targeting various genes or gene regions involved in oxygen metabolism and sensing in Andeans and Tibetans, the strongest signals of selection being observed in the Another important selective pressure that has confronted humans over time is that imposed by pathogens and infectious diseases. Indeed, pathogens have been, and still are in regions in which antibiotic treatment, vaccine administration and hygiene improvements are limited, a major cause of human mortality, thus exerting strong selective pressure on the human genome  or Andeans , and for the only gene targeted by positive selection in both populations, EGLN1, the selected haplotypes markedly differ between the two populations  and East Asians (ADAM17 and ATRN) , subsequently becoming strongly constrained within the human lineage.Signatures of positive selection have also been reported for certain genes known to play a direct or indirect role in cancer risk. Some of these studies focused on signatures of selection between species, to highlight adaptive selection in humans, as a whole, with respect to other species. For example, at the inter-species level, PPP2R5E gene, which is involved in the negative regulation of cell growth and division  have been found in the upstream portion of the gene (Sun et al. At the intra-species level, some studies, which have made use of polymorphic data in humans, have found signatures of positive selection at some genes. For example, a genomic scan of 142 genes for signals of recent positive selection identified the There is increasing evidence to suggest that some diseases of modern societies, such as obesity, hypertension, inflammatory or autoimmune diseases, allergies or even cancers, may simply be a by-product of past adaptation to other selective forces and changes in lifestyle. Genetic modifications occur more slowly than changes in lifestyle. It has therefore long been suggested that ancient selection events may have favoured variants that are no longer advantageous and may even have become detrimental in modern societies.The ‘thrifty gene hypothesis’ was first introduced by James Neel Neel , who sugAnother example of maladaptation may reflect changes in the selective pressures imposed by infectious diseases over time (Barreiro and Quintana-Murci Another compromise that has been suggested for adaptation is antagonistic pleiotropy. Pleiotropy is defined as the situation in which one gene controls more than one phenotypic trait in an organism; ‘antagonistic pleiotropy’ is the term used when at least one trait is beneficial and another is detrimental. The antagonistic pleiotropy hypothesis was firstly proposed by George C. Williams in 1957 to explain senescence Williams , as genePopulation genetic studies have greatly improved our knowledge of the way in which humans have genetically adapted to variation in environmental pressures and changes in lifestyle over time. Likewise, the investigation of how natural selection has driven the evolution of particular genes and biological functions has proven a useful tool to inform the relationship between genetic diversity, adaptive phenotypes and disease. In this context, detailed studies combining population genetic approaches making use of the massive whole-genome sequence-based data sets for various human populations, such as the 1000 Genomes Project (1000 Genomes Project Consortium


The distal structural/functional domains of the neuron, to include the axon and presynaptic nerve terminal, contain a large, heterogeneous population of mRNAs and an active protein synthetic system. These local components of the genetic expression machinery play a critical role in the development, function, and long-term viability of the neuron. In addition to the local mRNA populations these presynaptic domains contain a significant number of non-coding RNAs that regulate gene expression post-transcriptionally. Here, we review a small, but rapidly evolving literature on the composition and function of microRNAs that regulate gene expression locally in the axon and nerve terminal. In this capacity, these small regulatory RNAs have a profound effect on axonal protein synthesis, local energy metabolism, and the modulation of axonal outgrowth and branching. The distal structural/functional domains of the neuron  are well known to contain a highly diverse population of mRNAs and an active protein synthetic system. In large, asymmetric neurons, these basic components of the genetic machinery play an especially important role in the development and maintenance of its cellular polarity, as well as in its synaptic plasticity, regeneration, and repair . These highly conserved, small, non-coding RNAs play a key role in the post-transcriptional regulation of gene expression. In general the bio-genesis and function of miRNAs in the nervous system has been well reviewed . In thisIn a recent study, Of course, estimation of the number of miRNAs present in the axon, as derived from microarray profiling, is totally dependent upon the numerical threshold used to determine a positive signal . To address this issue, the authors employed the convergence of the microarray data with the results obtained from quantitative RT-PCR analyses. High correlations between the microarray data and the results of quantitative RT-PCR were obtained for miRNAs with microarray signal intensities greater than one standard deviation above median background values. Hence, using this as a “cut-off” value it was determined that there was approximately 137 different miRNAs in the axons of rat superior cervical ganglion neurons . It bearBioinformatic search for putative mRNA targets of the axonally abundant miRNAs revealed an enrichment of transcripts that encode proteins that function in neuronal signaling, mRNA and protein transport, as well as, mRNA transcription and translation. Interestingly, this analysis also identified a subset of axonal miRNAs that potentially target multiple mRNAs involved in related cellular functions. These observations suggest that these small, non-coding RNAs in the axon could function to integrate/orchestrate multiple functions in the axon.Many miRNAs are expressed as clusters on a single polycistronic transcript. Interestingly, the relative abundance of some miRNAs derived from polycistronic transcripts differ markedly in the axon as compared to their parental cell soma . For exaOne of the most abundant miRNAs present in the axons of sympathetic neurons is miR-16. Results of a bioinformatics search for mRNAs whose 3′untranslated regions (UTRs) contained miR-16 binding sites revealed two mRNAs that encoded eukaryotic translation initiation factors, eIF2B2 and eIF4G2 . The cogOne surprising feature of all axons studied to date is the presence of a large number of nuclear-encoded mitochondrial mRNAs. It has been estimated that in large invertebrate axons and presynaptic nerve terminal nearly one-quarter of the newly synthesized protein is destined for mitochondria, and that the membrane potential and activity of this organelle is highly dependent on the local synthesis of these rapidly turning over proteins .Figure 1). Axonal transfection studies conducted with chimeric reporter gene constructs containing these putative binding sites established that they were bona fide targets of miR-338  and ATP synthase (ATP5G1) contain a binding site for miR-338 in their 3′UTRs. Both of these binding sites are situated in a hairpin-loop structure that could facilitate miRNA accessibility . Thus, through this mechanism, miR-16 could affect the local expression of large numbers of gene products. One might speculate that some of these locally synthesized proteins are likely to play an important role in the activity-dependent modulation of the function of the axon and nerve terminal, as well as in synaptic plasticity.On a more global level, non-coding RNAs, such as miR-16, have been shown to regulate the activity of the axonal protein synthetic system, itself. This effect was mediated through the modulation of the expression of two translation initiation factors . In this regard, it is well known that transcription factors can be locally synthesized in the axon and retrogradely transported to the neuronal cell nucleus, especially in response to neurotrophic signaling and/ or neuronal injury  underlying the transport of these RNAs to the distal regions of the neuron. Several models have been proposed for the selective shuttling of miRNAs to the synapse (for example, see l injury . HoweverFuture characterization of the axonal miRNA regulatory landscape will generate further insights into the molecular basis of axonal activity, maintenance, and neuronal function. Moreover, recent studies have delineated the functional significance of miRNAs in the regulation of local translation in developing axons, dysregulation of which might ultimately underlie the etiology of neurodevelopmental disorders and mental illness.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.


Sociocultural forces promoting a thin ideal body for women have shaped our understanding of problematic eating attitudes and behaviours throughout the 20th century, giving rise to the modern, thinness-oriented definition of disordered eating. More recent cultural expectations of a lean and muscular body, particularly for males, have been named as likely contributors to the growing prevalence of muscularity-focused body image disturbance amongst boys and men. However, disordered eating in the pursuit of muscularity appears in stark contrast to that which is motivated by the drive for thinness, suggesting that a new disordered eating framework specific to muscularity is needed. We define muscularity-oriented disordered eating and propose a framework constituting five major components, including body image concerns, eating, nutritional supplements, appearance and performance enhancing drugs, and exercise. We critically analyse the nature, prevalence and effects of these facets of muscularity-oriented disordered eating, and suggest improvements and directions for future research. Intentions of this framework are to inform clinicians engaged in the treatment of muscularity-related body image and eating disturbance, and to guide future empirical research and interventions in this field.Body Image stream of the 2013 ANZAED Conference.This abstract was presented in the


Atherosclerosis results from dyslipidemia and systemic inflammation, associated with the strong metabolism and interaction between diet and disease. Strategies based on the global profiling of metabolism would be important to define the mechanisms involved in pathological alterations. Metabonomics is the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. Metabonomics has been used in combination with proteomics and transcriptomics as the part of a systems biology description to understand the genome interaction with the development of atherosclerosis. The present review describes the application of metabonomics to explore the potential role of metabolic disturbances and inflammation in the initiation and development of atherosclerosis. Metabonomics-based omics study offers a new potential for biomarker discovery by disentangling the impacts of diet, environment and lifestyle. Living systems are dynamic and complex, and their behavior may be hard to predict from the properties of individual parts. Systems biology is the strategy of integrating complex data about the interactions in systems of biological components from diverse experimental sources using interdisciplinary tools and personnel . AtherosMetabolomics requires the employment of efficient analytical tools simultaneously together with bioinformatics. Nevertheless, there is not a single analytical platform nowadays capable of analyzing the full set of metabolites in a biological sample. Metabonomics, and the related field of metabolomics, uses tools such as liquid chromatography-mass spectrometry (LC-MS) or gas chromatography-mass spectrometer (GC-MS)or capillary electrophoresis and nuclear magnetic resonance (NMR) spectroscopy to analyze chemical components . Jeremy Moreover, to compare with proteomics and transcriptomics, metabonomics is rather rapid and economic . MetabonMultiple analytical techniques and metabolome database are developed in recent years. Spectral processing and post-experimental data analysis are the major tasks in metabonomics studies. While in data analysis, the Principal Components Analysis (PCA), Hierarchical Cluster Analysis (HCA), Soft Independent Modeling of Class Analogy (SIMCA) and Artificial Neural Network (ANN) are the major techniques. The researchers could select them according to the research destination . The datMeanwhile, there are more and more database, e.g., Small Molecule Pathway Database (SMPDB), LIPID Metabolites And Pathways Strategy (LIPID MAPS), Human Metabolome Database (HMDB) to support metabolomics study ,22. HMDBThe global collection of metabolites in a cell or organism is often called the metabolome; this refers to all small molecules that exclude nucleic acids and proteins. There is a new term "Lipidomics" , a brancMetabolic disturbance of atherosclerosis exist not only in circulation, but also could be found in local vessel. Using 2-dimensional gel electrophoresis and mass spectrometry, researchers identified 79 protein species that were altered during various stages of atherogenesis . SimultaMetabonomics also offers a deep insight on the clinical study of atherosclerosis related disease. The plasma of patients with stable carotid atherosclerosis have been fingerprinted with both GC-MS and 1HNMR . 24 metaMore and more studies in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis. The development of atherosclerosis-induced metabolic perturbations of fatty acids, such as palmitate, stearate, and 1-monolinoleoylglycerol, showed that palmitate significantly contributes to atherosclerosis development via targeting apoptosis and inflammation pathways . MetabolGiven the strong interaction between metabolic disturbances and inflammation, we would expect metabonomics study should hold substantial promise in defining the mechanism involved in this collection of pathologies. Kleemann and co-workers  used a cMetabonomics study has also been used to assess anti-inflammatory drug efficiency in atherosclerotic cardiovascular disease such as myocardial infarction (MI). Using metabolomic profiling of the inflammatory lipid mediators, Li N and colleagues ,36 documAs the field of metabonomics advances, the ways in which metabolites affect atherosclerotic states will become clearer, and prevention and treatment of this process will become more focused. The integration of metabonomics with genetics, proteomics, and transcriptomics would provide a systems biology description of atherosclerotic cardiovascular diseases. A major challenge in the future will be the bioinformatics side of metabonomics. For systems biology, the integration of multi-level Omics profiles  is considered as central element ,38. TradThe authors declare that they have no competing interests.DJW and BJZ drafted the manuscript. XDW designed and helped to revise the manuscript. All authors read and approved the final manuscript.


A large number of scientists from a wide range of medical and surgical disciplines have reported on the existence and characteristics of the clinical syndrome of pelvic girdle pain during or after pregnancy. This syndrome refers to a musculoskeletal type of persistent pain localised at the anterior and/or posterior aspect of the pelvic ring. The pain may radiate across the hip joint and the thigh bones. The symptoms may begin either during the first trimester of pregnancy, at labour or even during the postpartum period. The physiological processes characterising this clinical entity remain obscure. In this review, the definition and epidemiology, as well as a proposed diagnostic algorithm and treatment options, are presented. Ongoing research is desirable to establish clear management strategies that are based on the pathophysiologic mechanisms responsible for the escalation of the syndrome's symptoms to a fraction of the population of pregnant women. Pain localised at the pelvic girdle during and after pregnancy has been identified and recorded as an entity since the 4th century BC by Hippocrates. Contemporary medical research since the early 20th century has attempted to clarify the spectrum of the different pathologies that this clinical syndrome represents -3.Despite extensive clinical interest and an increasing number of related publications during the past two decades Table , there iThe scientific and clinical implications of PPGP require the multidisciplinary interaction of a wide number of health-related specialties, including obstetrics and gynaecology, general medicine, orthopaedic surgery, physiotherapy, rheumatology and clinical psychiatry Table . This imLately, efforts to establish guidelines and accurate definitions of the manifestations of this clinical syndrome have been ongoing and offer the basis for further international research . FollowiThe aim of this minireview article is to present in a comprehensive manner the existing consensus regarding the diagnosis, management and prognosis of PPGP. The PubMed search engine was used to set a query on 20 January 2010 with the keywords "pelvic arthropathy" OR "osteitis pubis" OR "pelvic insufficiency" OR "pelvic pain" OR "pelvic instability" OR "pelvic girdle pain" OR "posterior pelvic pain" OR "low back pain" OR "lumbopelvic pain" OR "symphysis pubis dysfunction" in the title, as well as the term "pregnancy" in any of the search fields of the publications. Whenever additional studies were identified from the references of the retrieved publications, they were also included in this review. In total, 209 studies from 1923 to today are presented in this review according to the terminology that was used by the authors, the decade of publication and the origin of the research , presenting symptoms  or related topography  Table .All of these attempts to define the problem have been unsuccessful either because they narrowed the spectrum of this pain syndrome or because they confused its nature by blending it with the syndrome of chronic low-back lumbar pain. There is an existing consensus ,59 that While the responsible pathophysiological mechanisms remain obscure, this clinical syndrome is best defined descriptively by its presentation and topography. With regard to its onset, it has been associated with symptoms beginning between the first trimester, at labour or even during the postpartum period. Thus, terms limiting PPGP to a certain phase pregnancy appear insufficient to cover the whole spectrum of the clinical problem. With regard to this concept, the European Guidelines  are baseThe exact mechanisms that lead to the development of PPGP remain uncertain. A variety of approaches have been proposed that suggest hormonal -64, biomOn the basis of all of these hypotheses, the accumulated evidence advocates in favour of a multifactorial condition during pregnancy and postpartum. The effect of the levels of relaxin and progesterone to the pelvic girdle ligaments is established ; howeverAmong a large number of potential factors, those of strenuous work , a history of low-back pain, pelvic girdle pain or previous trauma to the bony pelvis were identified ,80,82,83Among all the relevant studies, the incidence of PPGP ranges from 4% to 76.4% depending on the definition used, the diagnostic means utilised  and the design of the studies (retrospective or prospective).et al. [As reported by Wu et al. , on averet al. ,84 and tet al. ,83, shouet al. ,85. HoweUsing the definition described above and including only prospectively designed studies of large series of patients with objectively verified symptoms, the prevalence of PPGP is between 16% and 25% ,83,86-88The PPGP diagnosis should be considered after the exclusion of painful visceral pathologies of the pelvis , lower-back pain syndromes , bone or soft tissue infections , urinary tract infections, femoral vein thrombosis, obstetric complications , rupture of symphysis pubis, and bone or soft tissue tumours ,37,90,91A thorough medical history, physical examination and appropriate laboratory tests should always be performed to successfully reach the diagnosis of PPGP. Obviously, a multidisciplinary approach and consultation may be needed, as this syndrome expands to a wide field of anatomically related medical specialties ,24,40,60PPGP, as defined previously, has been associated with pain  located at the general area of pelvic girdle, either posteriorly close to the sacroiliac joints and extending to the gluteal area or anteriorly to the vicinity of the symphysis pubis. It may radiate to the groin, perineum or posterior thigh, lacking a typical nerve root distribution. A precise localisation of the pain is often impossible and may also change during the course of the pregnancy ,92.Current classification systems of PPGP are based on pain localisation ,92. TheyThe onset of PPGP varies significantly and has been recorded at stages between the end of the first trimester to the first month postdelivery, including the labour stage ,78,93,94Several authors ,50,83 haet al. [PPGP pain intensity is repeatedly reported ,89,96,97et al.  describeAlteration of gait patterns has also been associated with the syndrome regarding the inability of these patients to cover long distances or a temporary "catching" sensation or clicking on hip flexion, located mostly anteriorly or unilaterally posteriorly. The gait coordination of these patients is distinctly characterised by slower walking velocity, an increase in the amplitude of the horizontal rotation of the pelvis to the thorax and a reduced relative phase between these rotations, which differentiate PPGP patients from those with lower-back pain and healthy pregnant women ,53,98.Tenderness to deep palpation of the suprapubic and sacroiliac area along the course of the long posterior sacroiliac and sacrotuberous ligaments, as well as a palpable step of the pubic symphysis joint, may be evident. Signs of local inflammation  may exist in a small percentage of the cases ,100.A wide variety of clinical examinations have been evaluated regarding their usefulness in the assessment and differential diagnosis of PPGP. Earlier studies were more focused on deep palpation and radiologic findings, while lately the weight of diagnosis has shifted toward the cumulative results of specific pain provocation tests ,101-104.et al. [Because most of these tests have a proven high specificity but lower sensitivity, there appears to be a consensus for the combined use of all of these tests to minimise false-negative results. Leadbetter et al.  describeLaboratory blood tests are usually normal, with a nonspecific mild elevation of the acute phase reactants  in a number of cases. However, for reasons related to differential diagnosis, most authors report acquiring a complete blood count, biochemistry and urine analysis ,106,107.Radiological investigations have a more essential role in the evaluation of the PPGP syndrome. Standard anteroposterior, inlet and outlet pelvic films are used to measure the degree of symphyseal separation and to identify cortical sclerosis, spurring or rarefaction. The use of single-limb stance anteroposterior or flamingo views delineates more subtle cases of pubic symphysis separation and appears useful in quantifying the degree of pelvic girdle instability . The detThese imaging techniques are usually limited to postpartum females because of the hazard of exposing the foetus to ionising radiation. A magnetic resonance imaging (MRI) scan is suggested during pregnancy, offering additional advantages of increased resolution and its superiority in allowing visualisation of soft tissue and marrow reactions ,118-120.Transvaginal/transperineal ultrasonography has also been advocated for the diagnosis and monitoring of the progress of pubic symphysis PPGP, with the limitation of being a user-dependent examination ,121,122.Last, guided local anaesthetic injections to the sacroiliac or pubic symphysis joint and the resulting pain relief during previous positive provocation tests offer significant diagnostic specificity, reaching 100%, but reflect only intra-articular pathologies. PPGP related to extra-articular pathologies may be unaffected  ,123.Because of the large heterogeneity of the published studies and the inconsistent quality of the reviewed articles , no strong comparative evidence regarding the utilised methods of treatment is possible. Management of the PPGP syndrome as reported during the past few decades involves a variety of clinicians and specialities, as well as a combined interdisciplinary approach.Before labour, the available options for its management are limited by the presence and the potential hazards to the foetus. Also, the majority of symptomatic patients appear to recover gradually after the first few months postdelivery. For these reasons, a proposed algorithm of management should differentiate between pre- and postpartum cases Figure . Bed resRegarding the cases that remain symptomatic postdelivery, it has been shown that treatment based on specific stabilising exercises offers significant advantages over pain management, functional recovery and generalised health-related quality of life and physical status ,134. IndPain relief drug therapies have been evaluated extensively in the literature. The reported consensus is that paracetamol, although safe for use in the pregnant population, is considered inadequate on its own for the PPGP levels of pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) have a better pain relief effect but are linked to foetal malformations or pregnancy complications . LuckilyThe use of guided injections of local anaesthetics with corticosteroids was tested therapeutically in cases of evident arthritis of the pelvic joints ,139. In A limited number of studies have evaluated the efficacy of antenatal back care education and supplemental therapies such as massage , local aThe labour of a pregnant woman with established PPGP syndrome appears to be the phase less investigated with regard to its relationship to the persistence of the symptoms postdelivery. However, there appears to be a consensus regarding minimal stress on the pelvic girdle, avoidance of abduction of the hips over the prespinal/epidural anaesthesia comfort arc of the particular patient and minimisation of the duration of the lithotomy position  -152. CaePelvic fusion surgery has been evaluated in a number of case series studies ,140-142 et al. [The reported outcomes for patients with PPGP appear to be universally good in the vast majority of prepartum cases. The syndrome is described mostly as a self-limiting condition in which symptoms settle in 93% of the patients within the first 3 months postdelivery. By the first year postdelivery, only 1% to 2% of patients report the persistence of pain. These cases are mostly those patients who had very intense symptoms during the pregnancy period. As reported by Albert et al. , 79% of Among several related studies ,156,157,Recurrence of PPGP is commonly reported 41% to 77%), either with a subsequent pregnancy or related to the menstrual cycle ,77,80. T%, eitherContemporary clinical awareness of the PPGP syndrome appears to be increasing because of increased public awareness and the interaction of scientists from different medical specialties. Recently introduced definitions and proposed guidelines on PPGP diagnosis and management represent significant improvements, setting the basis for future comprehensive research on this multifactorial pain syndrome. Different treatment modalities and disease-specific outcome measures need to be investigated in multicentre, randomised clinical trials following the previous initiative of the Research Directorate of the European Commission .The authors declare no competing interests, the absence of any funding related to this article, no ethical approval was applicable, and there are no guarantors or acknowledgements.NKK participated at the design of the article, the acquisition of the data from the reviewed articles, their analysis and interpretation and the initial drafting of the manuscript. CSR assisted with the preparation of the final manuscript. PVG conceived the article and participated in its design and the final revision of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/15/prepub


Given the known mechanistic dissociations between spontaneous and evoked pain, and the primacy of the former as a clinical problem, we believe that widespread adoption of spontaneous pain measures such as the Rat Grimace Scale might lead to more successful translation of basic science findings into clinical application.We recently demonstrated the utility of quantifying spontaneous pain in mice via the blinded coding of facial expressions. As the majority of preclinical pain research is in fact performed in the laboratory rat, we attempted to modify the scale for use in this species. We present herein the Rat Grimace Scale, and show its reliability, accuracy, and ability to quantify the time course of spontaneous pain in the intraplantar complete Freund's adjuvant, intraarticular kaolin-carrageenan, and laparotomy (post-operative pain) assays. The scale's ability to demonstrate the dose-dependent analgesic efficacy of morphine is also shown. In addition, we have developed software, Rodent Face Finder This limitation is imposed by the nature of facial grimacing itself, which is also not observed in human chronic pain patients. Thus, the study of real-time spontaneous pain in chronic neuropathic assays awaits the development of a useful dependent measure.The authors declare that they have no competing interests.SGS, RES, AZ, AHT, LJM, JSW, JCSM, SZ, and SZ collected the data. JJM and ODK edited the manuscript. PW and ODK designed the software. JSM conceived of and designed the study (with assistance from JJM), and wrote the draft of the manuscript. All authors read and approved the final manuscript.Rat Grimace Scale (RGS): The Manual. This training manual describes detailed procedures for the implementation of the RGS.Click here for file


Complementary treatment approaches are increasingly requested by cancer patients and survivors to reduce side effects of conventional cancer treatment, enhance health-related quality of life, and improve clinical outcomes . As manyWhile the evidence for both conventional and complementary cancer treatments is increasing, few studies have explicitly tested an integrative oncology approach. The publication of the Society for integrative oncology practice guidelines in 2007 (updated in 2009) has been an important milestone , 5; howeThis special issue is dedicated to research in the field of integrative oncology. The peer-reviewed issue solicited original manuscripts in the field of integrative oncology with a focus on studies that combine conventional and complementary approaches to optimize patients' health outcomes. The accepted manuscripts represent a broad range of research including basic, clinical research, qualitative, and survey studies. Six of the included papers present the results of in vitro studies of herbs or natural products from Traditional Chinese Medicine, Traditional Korean Medicine, and Traditional African Medicine in animal or human cancer cell lines. One of these in vitro studies explicitly adopted an integrative point of view in that it investigated the synergistic inhibition of angiogenesis by the Chinese herb Artesunate and the western ACE inhibitor Captopril.Two further papers investigate the use of complementary and alternative medicine in pediatric oncology. A survey among Canadian pediatric cancer patients found that almost two-thirds had used complementary medicine. Another paper evaluated pediatric oncology best-cases based on NCI criteria. Complementary therapies use was also investigated in another survey in adult US breast cancer patients, focusing specifically on self-care approaches. More than two-thirds of the sample used complementary approaches. In a qualitative study, the needs and concerns of women during breast cancer chemotherapy and the perceived benefits of acupuncture were investigated. In this study, a highly valued outcome was enabling coping through the alleviation of symptoms and increased well-being.The remaining two papers explicitly addressed implementation of integrative oncology models in clinical practice. In a qualitative study, integration models in integrative oncology centers in Germany and the USA were investigated. Although differing in their type of integration model, this study found similarities regarding the philosophies and priorities between clinics. Both clinics placed an emphasis on research and evidence with the goal to offer evidence-based treatments. Finally, a review of integrative oncology discusses important theoretical, practical, and research issues.We are certain that this special issue, that covers a spectrum of Integrative Oncology, will advance the evidence-base of this emerging field and inform practitioners and researchers alike.


Actinomyces that colonize the oral cavity rarely cause infection. Fifty-percent of the cases of actinomycosis are in the cervicofacial area, more common in male patients and in infants. In most of cases, the onset of the disease occurs on the teeth or tonsils. Early diagnosis of cervicofacial actinomycosis has been reported in less than 10% of cases. The aim of this report is to emphasize less common etiologies in the diagnosis of adult patients with recurrent tonsillitis.Bacteria of the genus Actinomyces confirmed by PAS and Giemsa stains, with reactive hyperplasia of the subjacent lymphoid tissue. Specific rovamycin treatment for actinomycosis was administered for 14 days with general improvement of the clinical status.We report the case of a female patient, age 55, known with recurrent acute tonsillitis, hospitalized after two weeks of throat pain, dysphagia, odynophagia, cervical adenopathy, fever and intense asthenia, who remained symptomatic despite of oral cephalexin therapy. The clinical examination revealed hypertrophic palatine tonsils covered by exudates. After tonsillectomy, the diagnosis was carried out through biopsy of the tonsils. Histopathology revealed the infection with Early diagnosis of actinomycosis enables appropriate and prompt treatment, thus preventing the involvement of other important areas.


Following the recent advances in cardiac stem cell biology, cardiac tissue has become one of the targets of regenerative medicine. With the array of approaches that are currently being tested and the questions that they raise, it becomes increasingly clear that the regeneration of adult myocardium will require the integration of numerous factors that govern cardiac tissue biology in normal and pathological conditions. The current challenge in myocardial tissue engineering and regeneration is to establish a perfect combination of three components: cells, scaffolds, and signaling molecules .Since the recognition that the mammalian heart is characterized by cardiomyocyte turnover throughout the lifespan of an individual, a number of different cardiac stem cell populations have been identified in the postnatal and adult hearts. A desirable candidate cell for cardiac tissue engineering and regeneration would be autologous, capable of differentiation into all the cardiac cell types and of functional integration, and resistant to malignant transformation. The preclinical studies and clinical trials have employed different cell types, including embryonic stem cell-derived and fetal cardiomyocytes, skeletal myoblasts, bone marrow or peripheral blood-derived endothelial progenitors, haematopoietic and mesenchymal stem cells, and recently, reprogrammed adult somatic cells (induced pluripotent stem cells). These multiple cell choices, apart from being accompanied by important ethical and safety concerns, led to a rather uniform outcome, which consisted of a low degree of improvement in cardiac contractile function. Moreover, a regenerated tissue band, which would integrate functionally with the surviving myocardium, was observed only in few cases .The choice of cell population for myocardial regeneration should be based on the knowledge of stem cell biology and the mechanisms that regulate and control cardiac progenitor proliferation, apoptosis, and differentiation in the normal and pathological conditions . RecentlThe group of M. E. Roehrich et al. identified by flow cytometry yet another stem cell population, with high expression and activity of aldehyde dehydrogenase (ALDH), in the adult heart, and the results of the characterization of these cells are published for the first time in the present special issue. This population is enriched for cells expressing Sca-1, CD34, CD90, CD44, and CD106, which indicates that it is a heterogeneous cell population, and presents mesenchymal stem cell-like differentiation potential. Interestingly, ALDH bright cells had been already sorted from human cord blood, bone marrow and peripheral blood and identified in nonhaematopoietic tissues as neural, muscle, colonic, and mammary stem cells. The activity of this enzyme allows cells to survive oxidative stress and can influence numerous functions that are crucial for stem cell survival in hypoxic environment. Indeed, cells with high activity of ALDH homed to ischemic sites (in the infarcted heart and hind limb ischemia model) and mediated local vasculogenesis . Recent Many factors determine the outcome of regenerative cardiovascular therapy and are the possible reasons behind the variable results. In fact, the methods for cell isolation and purification, the procedures for their storage or propagation, the phenotype and number of injected cells, and the methods of cell administration are hugely inconsistent between studies. The current stem cell delivery methods for myocardial repair are reviewed in the present special issue by C. C. Sheng et al. The possibilities are continuously expanding and the report of the International Society for Cardiovascular Translational Research, with the recommendations for the delivery of stem cells that would be comparable between groups , should in vitro would be even more reliable and easier to translate in clinical application if performed in 3D culture platforms. 3D environment and high cell density play an important role in supporting the phenotypes of cells of cardiac lineages. Many of these aspects of scaffold composition and cellular biology are discussed in this special issue.An ideal scaffold for tissue engineering must be biocompatible, allow cell growth and differentiation, and integrate (or degrade in time-controlled manner) into the host tissue. While patch-based scaffolds for cardiac regeneration must reach the dimensions relative to infarct size in humans, comply with the tension developed in the ventricular wall during systole and diastole cycles, and still be applicable through minimally invasive procedures, injectable scaffolds must be able to pass through a small gauge catheter and reconstitute their fibrous structure through gelation. Preclinical studies indicate that the combined cell-biomaterial scaffold therapy is superior to cell therapy alone , but thein vitro. As such, it can represent a useful model for preclinical testing of cellular populations and stem cell-derived cardiomyocytes for tissue engineering. In addition, the research of D. Avitabile et al. offers the basis for a further optimization of stem cell and scaffold processing for myocardium repair, showing that embedding human cord blood-derived CD34+ cells into a collagen I-based hydrogel containing cytokines is a suitable strategy to promote proliferation and protect these cells from hypoxia-induced apoptosis. The properties of these injectable composites make them promising candidates for myocardial tissue regeneration and warrant further studies on their potential therapeutic application. First, the original contribution of K. Vukusic et al. describes the behaviour of cardiomyocytes, endothelial cells, fibroblasts, and c-kit-positive cardiac primitive cells in high density sphere cultures. The simple method of sphere formation and culture, starting from the pellet of cardiac cells that rounded up and formed spherical structure that floated in the culture media, adds to the previously characterized methods of cardiosphere generation (hanging drop or standard plate suspension culture). Growth of cardiac cells as cardiospheres enhanced expression of stem cell-relevant markers. Next, L. Ikonen et al. examined collagen-like synthetic self-assembling nanofiber hydrogels for their suitability for neonatal rat cardiomyocyte and human embryonic stem cell-derived cardiomyocyte culture in 2D. Although the differentiation of stem cells into cells of cardiac lineages in these hydrogels would be more indicative of their application in myocardial regeneration, it is of note that hydrogel was able to maintain the beating ability of differentiated cardiomyocytes With these and other scientific advances in basic science research, which provide clinicians with the tools for replacing damaged myocardium, the concept of cardiac regeneration should hopefully progress to a level that will allow the translation and application of tissue engineering triad, that is, cells, scaffolds, and signalling molecules, in the clinical setting. The success of this integrated approach will depend on the carefully designed and analyzed experiments and clinical trials.Daria NurzynskaMaria-Elena Padin IruegasClotilde CastaldoPatrick Müller-BestFranca Di Meglio


Cereals are the basis of human nutrition; they are the food source most intensively produced in the world, surpassing 2000 million tons annually. The production of wheat, corn and rice makes up over the 70% of the total cereal production and thus dominates world agriculture. All 3 cereal crops can determine adverse reactions with different mechanisms of immune-mediated hypersensitivity and through various routes of exposure . A paradigmatic example is that of wheat , which that can cause a range of reactions such as IgE-mediated food allergy, anaphylaxis and asthma, exercise-induced systemic reactions and cell-mediated reactions, such as celiac disease. The major allergens of cereals are represented by alpha-amylase inhibitors, some prolamins, such as gliadins in wheat and zeins in maize, and Lipid Transfer Proteins. These allergens are also differently implicated in the various clinical forms. So that their positivity in many cases actually can be considered diagnostic. The clinical diagnosis of allergy to cereals, because of their nutritional importance, should always be verified by double-blind placebo-controlled food challenged. Long term prognosis is quite favourable and the therapy is based essentially on their elimination, and on the treatment of symptoms in the case of ingestion.


Background: There is broad consensus regarding the health impact of tobacco use and secondhand smoke exposure, yet considerable ambiguity exists about the nature and consequences of thirdhand smoke (THS).Objectives: We introduce definitions of THS and THS exposure and review recent findings about constituents, indoor sorption–desorption dynamics, and transformations of THS; distribution and persistence of THS in residential settings; implications for pathways of exposure; potential clinical significance and health effects; and behavioral and policy issues that affect and are affected by THS.Discussion: Physical and chemical transformations of tobacco smoke pollutants take place over time scales ranging from seconds to months and include the creation of secondary pollutants that in some cases are more toxic . THS persists in real-world residential settings in the air, dust, and surfaces and is associated with elevated levels of nicotine on hands and cotinine in urine of nonsmokers residing in homes previously occupied by smokers. Much still needs to be learned about the chemistry, exposure, toxicology, health risks, and policy implications of THS.Conclusion: The existing evidence on THS provides strong support for pursuing a programmatic research agenda to close gaps in our current understanding of the chemistry, exposure, toxicology, and health effects of THS, as well as its behavioral, economic, and sociocultural considerations and consequences. Such a research agenda is necessary to illuminate the role of THS in existing and future tobacco control efforts to decrease smoking initiation and smoking levels, to increase cessation attempts and sustained cessation, and to reduce the cumulative effects of tobacco use on morbidity and mortality. In this article, we aim to clarify ambiguities and misunderstandings in the scientific community regarding thirdhand smoke (THS), also known as residual or aged tobacco smoke. The significance of THS in the broader context of tobacco control efforts and its specific role in causing, contributing, moderating, or mediating tobacco-related illnesses have been questioned. To paraphrase an anonymous reviewer of an earlier manuscript on THS: THS is probably no more than a trivial nuisance, no worse than spilled coffee. This skepticism is in contrast to the positions taken by the public health community on issues of tobacco control in general and involuntary exposure to tobacco smoke in particular. The 2006 U.S. Surgeon General’s Report on the health consequences of involuntary exposure to tobacco smoke concluded: “The scientific evidence indicates that there is no risk-free level of exposure to secondhand smoke” . If decades of scientific research support the conclusion that there is no risk-free level of exposure to the potent mixture of carcinogens, irritants, and other toxicants in secondhand smoke (SHS), the composition, prevalence, and distribution of THS and the acute and cumulative exposure to those compounds among nonsmokers should be examined before we declare THS pollution and exposure a mere nuisance. We must better understand the role of THS exposure of people, particularly children, to the components of tobacco smoke. The implications of this exposure for disease mechanisms and their moderators and the THS-related acute and long-term risks of disease and premature mortality must be examined. Finally, we should consider the degree to which such understanding can inform and perhaps transform tobacco control policies, which would allow nonsmokers, their families, and the public to make more informed decisions about living in THS-polluted environments and to help smokers to better understand the risks their smoking brings to others. Perhaps a better understanding of THS and the associated risks to nonsmokers, stricter norms and attitudes, and economic and social contingencies will motivate nonsmokers not to start and prompt addicted smokers to quit. We propose that the “bench to bedside to population” approach of translational research will be useful in guiding research on THS and in fostering translation of findings to protect public health .We review the emerging evidence on THS and outline the case for an interdisciplinary research effort. The existing evidence provides strong support for pursuing a programmatic research agenda on THS to fill important gaps in our current understanding of the short- and long-term effects of involuntary exposure to tobacco smoke. We begin with brief definitions of THS and THS exposure. We then present a review of recent findings on the chemistry of THS, its persistence in indoor environments, implications for pathways of exposure and health effects, and behavioral and policy issues that affect and are affected by THS. We conclude with recommendations for interdisciplinary research efforts to address the gap in knowledge of the biological mechanisms of toxicity on cellular and molecular levels, as well as relevant behavioral, economic, and sociocultural considerations and consequences.SHS is a mixture of the sidestream smoke  and the mainstream smoke exhaled from the lungs of smokers. SHS contains more than 4,000 chemicals, many of which are known or suspected contributors to adverse health effects. These chemicals include ammonia, acrolein, carbon monoxide, formaldehyde, hydrogen cyanide, nicotine, nitrogen oxides, polycyclic aromatic hydrocarbons (PAHs), and sulfur dioxide, as well as other chemicals that are eye and respiratory irritants, mutagens, carcinogens, and cardiovascular and reproductive toxicants .THS consists of residual tobacco smoke pollutants that remain on surfaces and in dust after tobacco has been smoked, are re-emitted into the gas phase, or react with oxidants and other compounds in the environment to yield secondary pollutants. The constituents of THS identified to date include nicotine, 3-ethenylpyridine (3-EP), phenol, cresols, naphthalene, formaldehyde, and tobacco-specific nitrosamines (including some not found in freshly emitted tobacco smoke) .SHS exposure results from the involuntary inhalation of sidestream and exhaled mainstream smoke. In contrast, THS exposure results from the involuntary inhalation, ingestion, or dermal uptake of THS pollutants in the air, in dust, and on surfaces. Such exposure includes inhalation exposure to compounds re-emitted into the air from indoor surfaces and particles resuspended from deposits, and dermal and ingestion exposure to compounds partially derived from cigarette smoke and resulting particles that have settled, deposited, and accumulated on surfaces.Although the term THS is relatively new , the cheBased on our definitions of SHS and THS, total tobacco smoke exposure is the cumulative involuntary exposure to tobacco smoke pollutants during and after the time in which cigarettes are smoked. The exposure risk does not end when a cigarette has been extinguished and may persist in the absence of further smoking, because THS pollutants, trapped and deposited on surfaces and in dust, persist in environments in which smoking took place at some earlier points in time.Some of the pollutants present in SHS remain principally in the gas phase and can be removed by ventilation, but a significant fraction adheres to indoor surfaces and persists for a longer time. Complex physicochemical transformations of those compounds take place after smoking  that affect both short- and long-term exposure patterns of nonsmokers. Aging processes include chemical reactions of residual components of tobacco smoke deposited on indoor surfaces and may be influenced by pollutant transport between different indoor media . Physical and chemical transformations of tobacco smoke pollutants take place simultaneously over time scales that range from a few seconds to several weeks or months after their initial release during smoking. During an initial period of up to a few hours immediately after smoking, SHS and THS exposure coexist, with the latter becoming predominant once SHS is removed by ventilation.Indoor sorption–desorption dynamics. Indoor surface:volume ratios are often in the range of 1–10 m2/m3, which are much larger than typical outdoor ratios  that they exposed to tobacco smoke generated by machine-smoking. Exposure-relevant emission factors that account for sorptive uptake and re-emission have been determined for short-term (1 day) and long-term (1 month) periods for 26 gas-phase organic compounds present in tobacco smoke. Analytes included volatile aldehydes , aromatic hydrocarbons , nicotine, and tobacco-related amines . The emission factor of each individual compound was influenced by sorption and re-emission from indoor surfaces and materials. For each analyte, sorptive losses  were found to be highest at the highest level of furnishing  and for lower room ventilation rates . Losses were more marked for the less-volatile chemicals, and they were particularly remarkable for nicotine. In a month-long cyclic smoking study, after an initial accumulation period of ~10 days, re-emission of accumulated nicotine from indoor surfaces became a source of gas-phase nicotine equal in strength to smoking  and ammonia (NH3), respectively, that are often present at high concentrations indoors. In bench-scale studies, the sorptive capacity of common materials such as carpet and wallboard toward trimethylamine, a model amine, increased in the presence of CO2 and decreased in the presence of NH3 as a consequence of the enhancing protonation capacity of CO2 (acid) and the competition with NH3 (base) (Spectroscopic evidence suggests that amines adsorb predominantly in a protonated state in the presence of moisture . Sorptiv3 (base) .Indoor chemical transformations. Reactions driven by oxygenated and nitrogenated atmospheric species are the source of indoor secondary pollutants of potential toxicological relevance (N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA), 4-(methylnitrosamino)-1-(3-pyridinyl)-1-butanone (NNK), and N-nitroso nornicotine (NNN). The structures of these compounds as well as their mechanisms of formation are shown in N-nitrosopyrrolidine (a carcinogenic volatile nitrosamine) and various other multifunctional by-products.elevance . A recenelevance . HONO is2O2)] may generate oxidized products by reaction with some of the tobacco smoke components that remain sorbed to indoor surfaces. Thus, some of the respiratory symptoms associated with tobacco smoke may originate not from directly emitted air pollutants, but from volatile by-products that have low thresholds for eye, skin, and upper respiratory tract irritation . 2, 19.5 μg/g, and 740 ng/m3, respectively. These values were measured several hours or days after smoking took place and were significantly higher than were those from cars where smoking bans were implemented and from cars belonging to nonsmokers , and they insert nonfood items in their mouths more frequently than do adults . It is estimated that infants and young children are 100 times more sensitive than adults to pollutants in house dust because of such factors as increased respiration relative to body size and immature metabolic capacity  , the proAlthough much THS appears to be stored in dust and on surfaces in a polluted environment, THS is not constrained to the physical space in which tobacco was smoked. Recognizable as stale tobacco smoke, THS is trapped on the clothes of smokers and nonsmokers who were exposed to SHS. Most important, THS is detectable on the hands of smokers beyond the environment in which they smoked , 2011, aWhen nonsmokers touch polluted surfaces in smoking environments, they sample pollutants via their hands. For example, THS is a special concern in multiunit housing where smoking is permitted . TobaccoIn summary, the available evidence on THS pollution of indoor environments shows that THS is ubiquitous and pervasive wherever tobacco has been smoked. Its presence in air and dust and on surfaces allows for multiple exposure routes, and THS creates special risks for nonsmokers who spend time indoors in proximity to polluted surfaces. Infants and children are especially vulnerable, because of their increased exposure and increased sensitivity to pollutants, as are persons with limited mobility and populations that spend time in multiunit housing and spaces with frequent changes in occupancy.Currently, assessing the independent health risks of THS is premature because of the lack of evidence on clinical outcomes. The characterization of health risks attributable to THS will require applying new knowledge from cell and molecular biology, conducting clinical trials , and gathering objective evidence of THS contamination and biomarkers to confirm individual exposure and relating these data to outcomes . Clinical significance, however, must take into account the impact of THS in the broader context of tobacco control efforts to prevent and reduce smoking behavior.Potential health risks. THS exposes people to mixtures of chemical compounds in gas phase and particulate phase similar to those contained in mainstream smoke and SHS, as well as to additional products of surface reactions involving tobacco smoke constituents. Because THS and SHS differ in the composition and distribution of pollutants and in exposure profiles, a simple quantitative comparison of pollutant concentrations is not possible. For instance, air nicotine levels of indoor environments in which active smoking takes place are excellent markers of SHS pollution and correlate well with SHS exposure as measured by urine cotinine levels , different pollutant concentrations in different media , novel pollutants not found in SHS, and different relative contributions of exposure routes  . ConsequHuman exposure to constituents of THS has not been well characterized, and it is therefore premature to assess the health risk of THS. Given this caveat, one can consider how some of the known THS components could affect human health. The chemicals that mediate adverse health consequences can be considered in categories such as irritants, carcinogens, and mutagens .Nicotine plays multiple roles in carcinogenesis through inhibition of apoptosis and cell proliferation . It is ka]pyrene, are also carcinogenic (IARC 2004). Particles and oxidant gases produce free radical species and oxidant injury that can promote inflammation, affect immune function, and activate thrombotic mechanisms  that are found in mainstream and sidestream smoke are continuously or intermittently present in THS (IARC 2004). TSNAs, such as NNK, are potent lung carcinogens, and some TSNAs form from nicotine on indoor surfaces through chemical reactions with ambient nitrous acid . See Burchanisms . Oxidantchanisms .in vitro and in animal models, measurement of human exposure based on validated biomarkers, and, eventually, epidemiologic studies of the association of THS exposure with morbidity and mortality.Comprehensive assessment of risks of THS will require characterization of levels of THS constituents in the environment, analysis of their cytotoxicity and genotoxicity iso-NNAL [1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanol) and iso-NNAC (4-(N-methyl-N-nitrosamino)-4-(3-pyridinyl)-butanoic acid], which might be measurable in urine. NNA or other substances derived from it might be suitable as markers of THS in dust or surfaces.Risk assessment will require the development of biomarkers of THS exposure. A logical initial focus for a selective biomarker might be metabolites of NNA, because NNA is the major TSNA formed from the reaction of nicotine and nitrous acid and has not been found in tobacco smoke. Likely metabolites are Risk assessments will benefit from careful consideration of sensitive populations  and at-risk environments . Because of the immature stage of their biological and behavioral development, the level of exposure and health risks are likely to be greatest for young children who are in direct contact with polluted surfaces and house dust.Broader clinical and public health consequences of THS on tobacco control efforts. Even though THS is a dynamic mixture of chemical compounds, it is important to remember that it is a consequence of smoking behavior, which is a modifiable human activity with well-understood harmful health outcomes. It is in this context that public awareness of THS, aversion to stale tobacco odor, and beliefs about THS take on clinical significance beyond any specific health effects of THS still to be demonstrated. For instance, knowledge about THS could be used clinically to encourage home and car smoking bans among individuals and to promote cessation. In one of the first studies on attitudes about THS, controlling for known confounders including SHS beliefs, respondents were asked whether they agreed that “smoking in a room today could cause harm to infants and children tomorrow”  and car rental companies  have adopted complete or partial smoking bans to protect nonsmokers from the effects of lingering tobacco smoke. These policies grew out of complaints and concerns about unpleasant odor, respiratory symptoms, and eye irritation among hotel guests and customers of rental cars. Similar consumer preferences for smoke-free environments are also noticeable in the used car and real estate markets. Research conducted in southern California has shown that used cars of smokers were valued 8–9% lower than were the equivalent priced cars owned by nonsmokers , and ren3/cigarette). Eye and nasal irritations were observed at levels one order of magnitude lower than previously thought, corresponding to a fresh air dilution volume of > 3,000 m3/cigarette. For comparison, a 1,000-square-foot apartment in the United States has a volume of < 300 m3. The practical significance of odor thresholds is captured by a popular saying in the real estate and used car markets: “If you can smell it, you can’t sell it.”In the absence of definitive scientific evidence on health risks of THS, how did these policies and consumer preferences develop? We believe that the distinct unpleasant odor of stale tobacco smoke and acute respiratory and eye symptoms played a critical role, alerting consumers to a tobacco-polluted environment. This explanation is consistent with Odor thresholds and health symptoms by themselves, however, do not explain the recent emergence of THS policies and market place responses. We believe that consumer knowledge of the health effects of tobacco use, changing norms, expectations, and attitudes toward tobacco smoke exposure empowered consumers to express their dislike, request a nonsmoking hotel room, ask for repairs and cleaning, and negotiate a lower price. Such a marketplace response to consumer demands shows that when the norm and expectation are a smoke-free apartment, hotel room, or car, it is not only desirable but profitable for private businesses to establish smoke-free policies.Although the emergence of smoke-free policies in the private sector appears to be a response to consumer demand, norms, and expectations, success of these policies in protecting nonsmokers is not at all certain. Whereas voluntary policies do not follow common standards for detecting THS pollutants, training employees, monitoring implementation, and enforcing compliance, public policies can introduce shared standards and direct attention to the neediest instead of the noisiest. Although consumer complaints about THS and demand for smoke-free environments provide an excellent starting point, we currently lack full understanding of how to promote or temper cultural demands for protection from THS exposure. We lack coordinated efforts to educate, reinforce, and strengthen norms toward establishing and maintaining 100% smoke-free environments should the toxicology and epidemiology justify such action. Public health policies regarding THS can emerge as an extension of current efforts to protect vulnerable nonsmokers from SHS as part of a coordinating tobacco control strategy toward completely smoke-free environments.The following summarizes directions and recommendations for an interdisciplinary research agenda on THS. Consistent with the risk assessment framework introduced by the Chemistry of THS. There is a considerable body of research on the chemistry of main and sidestream tobacco smoke and the agents that cause tobacco-induced diseases. However, much remains to be learned about the formation of new compounds by THS components through aging and interaction with environmental oxidants such as ozone, oxides of nitrogen and related compounds from both outdoor and indoor sources, and their relative proportion over the aging period. These processes need to be studied over days, weeks, and months in the presence and the absence of further smoking. The following research needs arise from the work to date and seem particularly relevant to us:Characterize as completely as possible the chemistry of THS; identify toxic and potentially toxic substances; examine how THS differs from SHS.Identify mechanisms of THS formation, reactive species, and reaction pathways.Examine how THS deposits and accumulates in dust, surfaces, and air, and how chemical mechanisms compare in these different media.Explore the interaction of THS with environmental oxidants such as air pollution and continued smoking through controlled lab studies and observational field studies of THS in actual indoor environments with typical smoking, cleaning, ventilation, and use patterns.Develop, test, and validate tracers of THS pollutants at different stages of aging  and for different media .Exposure assessment. The assessment of exposure to THS has to consider smoking behavior that generates tobacco smoke; the environment that becomes contaminated with tobacco smoke pollutants; the behavior of smokers and nonsmokers in a polluted environment that brings them in contact with the pollutants; multiple pathways and time profiles over which exposure takes place; and efforts to protect an environment from pollutants and behaviors to prevent exposure from occurring. Because of the importance of dust and surfaces in the accumulation of THS, infants and children are most at risk of higher THS exposures as a result of their increased contact with dusts and surfaces and their close association with adults. Although there is a considerable body of literature on the exposure to tobacco smoke pollutants among active and passive smokers, little is currently known, for instance, about how different smoking patterns contribute to the accumulation of THS pollutants; how pollutants accumulate in different media; the relative effectiveness of different strategies to protect an environment from the accumulation of THS; and the relative importance of different pathways and profiles of exposure in different populations. We believe that the following topics require special attention in experimental and epidemiological research:Develop, test, validate biomarkers of exposure to different THS pollutants and different stages of THS aging, especially biomarkers suitable for use in children.Investigate association between smoking behavior, tracers for THS pollutants in air, dust, surface, and biomarkers of THS exposure.Compare indoor spaces with ongoing active smoking (SHS and THS) and indoor spaces that transitioned from smoker to smoke-free (aging THS).Examine occupational exposure risks .Conduct controlled human exposure experiments as a way of testing and validating biomarkers of exposure to THS.Evaluate the relative contribution of different exposure pathways in different settings and populations, such as in young children and in low-income households with other concomitant exposures such as traffic-related pollutants.Survey indoor environments  for THS tracers when exposed to environmental oxidants and investigate whether surrogate measure of oxidant levels  can predict formation of more toxic THS components.Investigate THS pollution levels as a function of smoking behavior, cleaning, ventilation, activity patterns, household appliance, environments by season , income, socioeconomic status.Investigate effectiveness of different efforts to prevent THS pollution and exposure .Investigate exposure disparities and environmental justice issues in THS exposures, especially in relation to low-income housing.Toxicology and health effects. Although there is a growing body of research on the toxicology and health effects of tobacco smoke and SHS , currently very little is known about the potential and actual health effects attributable to THS. To achieve a better understanding of health effects attributable to THS, future experimental and epidemiological research shouldDevelop biomarkers for disease or tissue damage caused by THS components.in vitro metabolism, toxicology, and genotoxic potential of THS components, especially compounds formed through aging and oxidant reactions.Study in vivo metabolism and toxicology studies of the most toxic compounds.Carry out Evaluate the toxicology of different exposure pathways  and exposure profiles  and exposure during sensitive periods, such as infancy.Evaluate risk in medically compromised populations: respiratory and pulmonary; immune system; prenatal and neonates; at-risk groups, such as infants, children, and pregnant women, by environment ; effects of exposure reduction in high-risk populations.Discriminate effects attributable to THS from those of SHS exposure and active smoking.Identify smoking behaviors and environments particularly hazardous to specific populations.Tobacco-related norms, preferences, and behaviors. Our review suggests that concerns associated with THS shape behaviors and attitudes of individuals, local policies, and marketing strategies targeting consumers. We know little currently about how concerns related to THS emerge and evolve, how they shape behaviors of smokers and nonsmokers, and how they can be leveraged to reduce smoking and SHS and THS exposure. The following topics seem particularly worthwhile:Research on the nature, origins, and pervasiveness of THS awareness, concerns, attitudes, and norms.Quasi-experimental and observational research on how the evolution of tobacco-related norms and their gradual change affect smoking, SHS, and THS practices and policies.Research on the relationship between THS awareness, attitudes, norms, and their expression in consumer preferences and behavior.Intervention trials on how best to conduct health education and promotion campaigns to influence norms and expectations, adopt stricter bans, and reduce smoking behavior.Focused THS education campaigns and interventions to affect the valuation of smoke-free environments .Development of counseling and coaching interventions for medically vulnerable populations to address disparities and to provide a more sensitive and immediate test of possible health benefits from intervention.Tobacco control policies: protecting nonsmokers from tobacco smoke pollutants. Our review indicates that public awareness and consumer preference have given rise to a range of policies at local levels and in private enterprises. Although they are evidence of interest in and demand for further control of smoking behavior, the impact and limitations of these emerging policies are not well understood. The following research areas can help contribute important evidence for developing and implementing effective public and private policies to protect nonsmokers from THS and to reduce tobacco use overall.Studying the effectiveness of emerging local ordinances, corporate policies, and private bans and rules.Examining policy loopholes, vulnerable population, and critical environments informed by basic and clinical research.Investigating the need for better occupational exposure protection .Connecting policy efforts at the local, regional, and state levels and in personal, public, work, school, and business domains.Working with consumer organizations to incorporate preferences about smoke-free environments in informal and formal norms, property valuation, and standards for monitoring and compliance.The emerging evidence on THS suggests important new directions for understanding the long-term consequences of tobacco use and for preventing and reducing tobacco use. Although it is premature to trivialize or dramatize the significance of THS, the existing evidence provides strong support for pursuing a programmatic research agenda to fill important gaps in our current understanding of the chemistry, toxicology, pollution, exposure, clinical significance, and policy implications of THS. Such a research program is necessary to illuminate the role of THS in existing and future tobacco control efforts to decrease smoking initiation and smoking levels, to increase cessation attempts and sustained cessation, and to reduce the cumulative effects of tobacco use on morbidity and mortality.


Buzzing of nanotechnology in each and every aspect of science and technology has been booming at a tremendous rate now a day. Started its journey from inorganic chemistry, this field has now even reached to aeronautical research, and a special attention has been drawn in the medical and allied braches for exploitation of the nanotech for attending the limitations of the current scenario. Carrying foreword the success of nanotechnology in field of physical, chemical, and medical sciences, it has now started revolutionizing the drug delivery sciences. The specific advantages include superior pharmacodynamics, pharmacokinetics, reduced toxicity, and targeting capability. Vehicle in the delivery sciences being critical quality attribute needs special attention for tailor made design to rationalize the formulation development; which can be successfully achieved via nanotechnology. Additionally, unique size-dependent properties of nanosystems/nanodevices offers excellent opportunities for the development of novel “point-of-care” devices and therapeutic tools. Drugs incorporated in the nanocarriers, either physically entrapped or chemically tethered, have the potential to target physiological disorder zone sparing normal cells from collateral consequences.Targeting several molecular mechanisms, for either treatment or prevention of difficult-to-treat diseases, for the design of the various nanotechnology-based drug delivery systems is one of prime focuses of the formulation scientist at the present juncture. Gene therapies and gene-based drug delivery using nanocarriers are booming especially in case of neoplastic extravasations. Various tumor suppressor genes are identified, isolated and successfully formulated for treatment of cancer. A remarkable number of such systems have already made their pave and are under clinical trials, being expected very soon at the end user level. Besides treating these diseases, nanotechnology also offers its contributions in development of preventive measures such as vaccines. Various nanotechnological adjuvants have been evaluated for their capabilities to deliver vaccine subunits without compromising the immunogenicity for successful design and development of vaccine delivery systems. Furthermore, regeneration ability of the visceral organs such as liver has also been evaluated using nanocarriers, and the postulations are on their way stating the enhanced cytoactivity of the transplanted cells when cultured in nanocarriers. The pharmacokinetic profile, especially transportation capabilities, of the drug substances have been greatly modified by incorporation in nanodrug delivery system. These include enhanced accommodation for targeting moieties such as chaperones and alteration in release rates comprising of controlled release and site-specific delivery by use of molecular engineering techniques. Additionally, encapsulation of the drug substances in various polymeric and inorganic composites has also been evaluated for their rationalizing the drug delivery systems. Such encapsulations are generally made for protecting the biologically active protein and peptide-based drug compounds from the detrimental effects of biological fluids. Newer nanoprodrug approaches have also been applied, which has posed enhanced therapeutic efficacy along with superior circulation time. Emerging methodologies for formulation of nanodrug delivery systems include newer versions of the top-down and bottom-up approaches. Additionally allied technologies such as atomization and pressurization have come in to play to facilitate the preparation of nanotechnological carriers. One such comprises a novel method of atomization, namely, electrohydrodynamic atomization used in electrospraying method. Pressurization techniques such as high hydrostatic pressure technology for encapsulation of genes into polymeric nanomaterials have recently been studied for their efficacy in delivering the biologically active compounds. These novel technologies offer advantages by eliminating the usage of toxic cationic polymers and chemical tethers further replacing them simple yet effective hydrogen bonding. Such advantages and simplifications of the process have already given their imminent revolutions in the field of drug delivery. With these advancements in the novel nanocarriers and their applicability, the analytical tools are also not lagging behind. In order to cope up with this and stand aside, newer evaluation methodologies are already in move of their development. These include scanning probe microscopy, more specifically atomic force microscopy and scanning tunneling microscopy, which have great capabilities for molecular and submolecular characterizations. in silico technologies), and so on to name a few. The extension and appliance will be the state-of-art for future research. Furthermore, various platform technologies at the nanoscale, often referred as nanoplatforms, have been coming in to play and booming for widespread applications of these cutting edge technologies for its applicability at end users. Basically, the common ones in the race include the nanocrystals , nanomaterials , nanomedicines, molecular self-assemblies , nanoelectronics (Finally, the common undeniable opinion highlighted in this issue is that, although it is too early to say whether these nanocarriers will wean the world from its current limitations, or monumentally backfire to cause harm, a deep understanding of the various mechanisms underneath the reported findings will favor great discoveries, even at the nanoscale. In nutshell, efforts are extensively made for utilizing the nanotechnology concepts for advancements in the current drug delivery sciences and, further to this, the fruitfulness of the efforts has been achieved which is well reflected in this present issue. Sanyog JainSanyog JainIjeoma F. Uchegbu Ijeoma F. Uchegbu Guru Betageri Guru Betageri Giorgia PastorinGiorgia Pastorin