Osteopetrosis is a rare, inherited, bone disorder, characterized by osteosclerosis, obliteration of the medullary cavity and calcified cartilage. The autosomal dominant form is compatible with a normal life span, although fractures often result from minimal trauma, due to the pathologic nature of bone. Osteomyelitis is common in patients with osteopetrosis because of a reduced resistance to infection, attributed to the lack of marrow vascularity and impairment of white cell function. Only one case of osteomyelitis of the proximal third of the femur has been previously reported, treated with several repeated debridements and finally with femoral head resection. Here we present for the first time a case of a staged implant of a cementless total hip prosthesis for the treatment of a septic hip in femoral neck nonunion in osteopetrosis.A 36-years-old woman, affected by autosomal dominant osteopetrosis was referred to our department because of a septic hip arthritis associated with femoral neck septic non-union, with draining fistulas. The infection occurred early after a plate osteosynthesis for a closed perthrocanteric fracture of the femur and persisted in spite of osteosynthesis removal, surgical debridement and external fixation. In our hospital the patient underwent accurate debridement, femoral head and greater trochanter resection, preparation of the diaphyseal intramedullary canal and implant of an antibiotic-loaded cement spacer. The spacer was exchanged after one month, due to infection recurrence and four months later, a cementless total hip arthroplasty was implanted, with no clinical and laboratory signs of infection recurrence at two years follow-up.In case of hip septic arthritis and proximal femur septic non-union, femoral head resection may not be the only option available and staged total hip arthroplasty can be considered. Osteopetrosis is a rare inherited bone disorder originally described in 1904 by Albers-Schonberg, a German radiologist . DespiteOsteopetrosis has been categorised clinically into three primary types: infantile, or "malignant" osteopetrosis, inherited in an autosomal recessive pattern; "intermediate" autosomal recessive osteopetrosis and "benign" autosomal dominant osteopetrosis . The sevFractures typically occur in the appendicular skeleton, most commonly in the proximal femur ,20,21, aTwo of these problems, osteoarthritis and certain periarticular nonunions, may be recalcitrant to other treatment options and may be considered for treatment with total joint arthroplasty. It is recognized that the hard brittle bone, often without a normal medullary canal, makes arthroplasty implantation difficult, may compromise the outcome and lead to more frequent complications .Osteomyelitis is common in patients with osteopetrosis because of a reduced resistance to infection The increased incidence of osteomyelitis has been attributed to the lack of marrow vascularity in osteopetrotic bone and impairment of white cell function ,4. The mTo date, only one case of osteomyelitis of the proximal third of the femur has been described and treated successfully with femoral head resection . This isA 36-years-old woman C.I. was referred to our department in November 2008 because of a septic left hip arthritis and femoral neck non-union, with a draining fistula. Her medical history included the disorder of osteopetrosis , which was diagnosed at the age of 9. In her lifetime she had suffered a right femoral neck and right tibia diaphyseal fractures.Gemella morbillorum, occurred early after a plate osteosynthesis for a femoral intertrochanteric neck fracture, 12 months before the admission to our department. Following the infection occurrence, she underwent removal of the osteosynthesis, surgical debridement and external fixation. In March 2008 the external fixator was removed, due to infection persistence and draining from the proximal pins. When she came to our observation (November 2008) she presented great functional limitation of the left hip, pain and persistence of the infection, with a draining fistula. X-ray films showed increased bone radiodensity, coxa vara and femoral neck non-union with misalignment of the stumps and the complete absence of an intramedullary canal  custom-made cement spacer Figure . SystemiFour months later, in the absence of clinical signs of infection and normal C-reactive protein serum levels, we removed the spacer and implanted a cementless modular hip revision prosthesis  Figure . All theAt 2-year follow-up, there are no clinical signs of infection recurrence while laboratory tests remain in the normal range value and the prosthetic components do not show any sign of osteolysis at the radiographic examination Figure . The patAt present, no effective medical treatment for osteopetrosis exists. Treatment is largely supportive and is aimed at providing multidisciplinary surveillance and symptomatic management of complications. Fractures and arthritis are common and require treatment by an experienced orthopaedic surgeon due to the brittleness of the bone, and the relatively frequent occurrence of secondary complications such as delayed union or non-union of fractures and osteomyelitis .Degenerative changes often occur after the age of 40 ,24,31-33Many intraoperative and postoperative difficulties have been encountered in patients with osteopetrosis. The poor quality of bone complicates surgery because of its resistance to drilling and tendency to fracture with minimal trauma, resulting in increased surgical time.In case of osteomyelitis, surgical débridement and "en bloc" resection are necessary ,30. AggrAnother challenge in the management of osteopetrotic patients is arthroplasty. The hardness of osteopetrotic bone and obliteration of the medullary cavity precludes the use of hand reamers . The surDespite difficulties in femoral canalization in these patients, total joint arthroplasty has proved to be effective in treating osteoarthritis and periarticular fractures. Three total knee and 15 total hip arthroplasties have been reported in the English-language literature to date ,26,32,34Rolauffs et al. reported the only case available in the English literature, that, similarly to ours, did presented a chronic osteomyelitis following internal fixation of a proximal femoral fracture in a patient affected by osteopetrosis; in that case, the authors report that four debridements were required to manage the recurrent infection. Weakening of the bone finally occurred, and the patient suffered a femoral neck fracture, that obliged to a resection arthroplasty. In the light of our result, we cannot agree with the statement of these authors that "treatment options such as arthroplasty of the osteomyelitic bone" should be ruled out in these patients, while we may suggest to consider a staged hip cementless implant.Total joint arthroplasty may be considered as a last option to treat osteopetrosis associated with osteoarthritis. However, many intraoperative and postoperative challenges need to be overcome when performing arthroplasty in patients with osteopetrosis. The greatest challenge in all these surgical procedures is the creation of an intramedullary canal in osteopetrotic bone without a semblance of an intramedullary canal. This is the first report, to our knowledge, that shows staged total hip replacement as a successful option for the treatment of chronic osteomyelitis of the proximal third of the femur and septic hip arthritis.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.GM wrote the draft of the manuscript and participated in the follow-up examination of the patient and clinical material. DR and NL participated in the surgical and medical treatment and followed up the patient. They also have been involved in drafting the manuscript or revising it critically. CLR performed the surgery, coordinated and helped to draft and finalize the manuscript. All authors read and approved the final manuscript.CLR is the Director of the Centro di Chirurgia delle Infezioni Osteo-articolari of the research orthopaedic institute Galeazzi in Milano, Italy. Past -president of the Italian Studygroup on Osteoarticular Infecitons, he actually serves as President of the European Bone and Joint Infection Society.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/50/prepub


Hypohidrotic ectodermal dysplasia (HED) is characterized by severe hypohidrosis, hypoplasia of sweat, sebaceous, submucous, meibomian and mammary glands, hypotrichosis, and oligodontia. In early childhood, HED is a life-threatening disorder based on the risks for hyperthermia and pneumonia. Awareness of the hazards related to this rare genetic disease is most helpful in preventing avoidable calamities. Prognosis therefore depends on the time point of diagnosis.EDA, EDAR, EDARADD and NEMO can then be arranged to make a definitive diagnosis. Infants with HED may also be identified by their inability to sweat. A survey conducted among parents of 100 children with ectodermal dysplasia registered with the German-Swiss-Austrian patient support group revealed that almost all parents had observed episodes of unexplained fever during the first year of life. If infants had to be placed in an incubator after birth, body temperature recording proved to be of utmost importance and often allowed early clinical diagnosis of HED. Furthermore, recent studies of our group confirmed a consistent, quantifiable defect of sweat gland function in male individuals with HED as a disease biomarker. Pilocarpine-induced sweat volume, palmar or plantar sweat duct density and skin conductance before and after stimulation were determined also in newborn infants. Genotype-phenotype correlation was seen across all measurements of sweat gland function, but, surprisingly, not with respect to the number of sweat glands (which can be determined very soon after birth) and the degree of oligodontia . This is important, since such easily recognizable signs obviously do not allow prediction of the risk of hyperthermia and the associated morbidity and mortality in HED patients.Typical facial features  may allow immediate postnatal recognition of HED, if the disease is known to the family or the doctor. Molecular analysis of one or more of the 4 candidate genes


Exposure to second hand smoke is a major cause of chronic obstructive pulmonary disease (COPD) in the non-smoker. In this review we explore the use of animal smoke exposure models and their insight into disease pathogenesis. The methods of smoke exposure, including exposure delivery systems, are described. Key findings from the acute and chronic smoke exposure models are outlined, including descriptions of the inflammation processes, proteases involved, oxidative stress, and apoptosis. Finally, alternatives to rodent models of lung disease are presented. Chronic obstructive pulmonary disease (COPD) is a major cause of disability and death worldwide, with a prevalence estimated at 10% of the general population and up to 50% in heavy smokers , leading to unopposed neutrophil elastase activity, had an increased incidence of emphysema  fluid and lung tissue , mediated through the NADPH oxidase (NOX) pathway, is another important component in the oxidative stress pathway critical in emphysema development. Lee and colleagues have shown that deficiency of TLR4 leads to upregulation of NOX2 in lungs and endothelial cells, causing increased oxidant generation and elastolytic activity within the parenchyma  and resistant (ICR) strains demonstrates that alveolar macrophages from susceptible mice release increased proinflammatory cytokines and MMPs when exposed to cigarette smoke, and have a higher baseline production of reactive oxygen species as compared to those obtained from resistant mice  (Stecenko et al., Non-human primate smoking models have been utilized to demonstrate the effects of environmental smoke exposure with studies focusing on infants, lung development, and pre vs. post-natal effects. This model is particularly useful for studying the effects of maternal smoke exposure during pregnancy (United States. Public Health Service. Office of the Surgeon General, The use of large animals including lambs and non-human primates offer the advantage of more closely mimicking human exposure, especially in prenatal and neonatal environments. However, the disadvantages of all of the large animal models include cost, size, and feasibility of smoke exposure studies, as well as a lack of available reagents.In conclusion, there is a substantial amount of information pertinent to second hand smoke exposure that can be gained from an understanding of animal models of disease. It is important to understand the limitations of each model of smoke exposure. Rodents, while widely used, have several limitations, including strain differences in disease susceptibility, and relatively mild forms of emphysema. However, there is significant information that can be gained from the use of mouse models, especially in an era of transgenic manipulation. The most attractive alternative smoke exposure animal models are guinea pigs and rabbits, both developing clear evidence of inflammation and emphysema. A better understanding of the benefits and drawbacks of these models will assist researchers in best choosing the appropriate species and exposure model prior to conducting smoke exposure experiments.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.


Coral disease has emerged over recent decades as a significant threat to coral reef ecosystems, with declines in coral cover and diversity of Caribbean reefs providing an example of the potential impacts of disease at regional scales. If similar trends are to be mitigated or avoided on reefs worldwide, a deeper understanding of the factors underlying the origin and spread of coral diseases and the steps that can be taken to prevent, control, or reduce their impacts is required. In recent years, an increased focus on coral microbiology and the application of classic culture techniques and emerging molecular technologies has revealed several coral pathogens that could serve as targets for novel coral disease diagnostic tools. The ability to detect and quantify microbial agents identified as indicators of coral disease will aid in the elucidation of disease causation and facilitate coral disease detection and diagnosis, pathogen monitoring in individuals and ecosystems, and identification of pathogen sources, vectors, and reservoirs. This information will advance the field of coral disease research and contribute knowledge necessary for effective coral reef management. This paper establishes the need for sensitive and specific molecular-based coral pathogen detection, outlines the emerging technologies that could serve as the basis of a new generation of coral disease diagnostic assays, and addresses the unique challenges inherent to the application of these techniques to environmentally derived coral samples. The world's coral reefs are in decline, with hard coral cover on Caribbean reefs decreasing by an average of 80% in the last 30 years in situ, describing macroscopic characteristics such as species affected, extent and pattern of tissue loss Despite the serious threat that coral diseases pose to the health of reef ecosystems globally, little is known about many of these diseases, including their etiologies, transmission dynamics, and the steps that can be taken to prevent, control, or reduce their impacts. This work has been frustrated by the inability to determine etiological agents for many diseases see , insuffiRattus norvegicus), the house mouse (Mus musculus), and the common fruit fly (Drosophila melanogaster), have been integral to unraveling the intricate interactions between host, pathogen, and environment that lead to disease. A few coral species, including A. millepora in the Indo-Pacific and A. palmata in the Caribbean, have emerged as “lab rats” for the study of coral genetics A. palamata, which was once the dominant coral species throughout much of the Caribbean, was added to the IUCN Red List of critically endangered species The development of effective coral disease diagnostics requires efficient methods for identifying microbial drivers of disease and an understanding of the pathogenesis of identified disease agents. In the field of human health, investigations using surrogate hosts, including the common rat  would allow researchers to tease out the targets of specific pathogens within the coral holobiont. By focusing research on a few, well-chosen model systems, researchers will be better able to identify potential pathogens and study their virulence mechanisms in an efficient, environmentally friendly, and easily comparable manner.Once potential pathogens are identified and their virulence mechanisms determined in surrogate hosts, researchers must confirm these findings within the complex coral holobiont. Captive-bred coral juveniles and laboratory-maintained In recent years, an increased interest in coral microbiology, in combination with the application of histology and biomedical approaches, has revealed several bacterial species linked to coral disease lesions Recent reviews have highlighted immunological indicators of coral stress and disease A. sydowii, the causative agent of aspergillosis, through the production of antifungal agents that inhibit germination of A. sydowii spores Exposure of corals to pathogens also induces production of antibiotic compounds, which may instill some resistance against invading microbes. Gorgonian corals have been shown to resist infection by the fungus Recent investigations have revealed the melanization cascade to be an integral component of coral immunity. The melanization cascade involves the production of prophenoloxidase (PPO), which is involved in wound healing, encapsulation, and disease resistance In this section, we highlight the role that specific and sensitive pathogen detection will play in advancing our understanding of the etiology, spread, and ultimately management of coral diseases.Montastraea faveolata colonies. These community-level bacterial profiling approaches facilitate diagnosis at the earliest stages of infection when mitigation measures would be most effective The coral holobiont comprises a complex association between the coral animal and its microbial partners, including symbiotic dinoflagellates (zooxanthellae) Vibrio shiloi, which was initially identified as the agent responsible for annual bleaching of the Mediterranean coral Oculina patagonica, no longer appears to cause bleaching in this coral species Aspergillus sydowii, which was shown to cause disease in gorgonians, has also been found on healthy coral colonies, leading Toledo-Hernandez et al. While some coral diseases are tightly linked with the presence of a specific pathogen, the causes of many other diseases and disease-like syndromes remain elusive Paramuricea clavata and seawater temperatures, chlorophyll concentrations, and the presence of culturable Vibrio spp. in the surrounding seawater. Tools for monitoring pathogen density would provide a deeper understanding of how pathogen load and virulence respond to natural  and anthropogenic  fluctuations, allowing researchers and managers to closely follow these dynamics and model pathogen response to environmental change.Emerging evidence suggests that the abundance of coral pathogens varies on reefs throughout the year and within coral hosts during the course of infection V. shiloi nicely demonstrates the utility and importance of molecular-based pathogen detection techniques in the study of coral epidemiology It is currently unclear if the emergence of coral diseases on reefs is associated with the introduction of pathogenic organisms, or whether potentially pathogenic microbes are a normal component of reef ecosystems that increase in virulence because of altered environmental conditions and/or reduced host resistance. To better understand the dynamics of coral disease outbreaks and ensure that they are effectively managed, information regarding pathogen sources, vectors, and reservoirs is needed. Pathogen sources are the avenues through which a pathogen enters the environment, reservoirs are biotic or abiotic entities that harbor a pathogen, and vectors are living entities that do not cause or suffer from a disease, but transmit a pathogen from one host to another To effectively manage coral disease outbreaks, a deeper understanding of the causes of observed diseases, how they are spread between colonies and populations, and how environmental parameters influence pathogen virulence and host susceptibility to infection is required Effective diagnostic tools must be sensitive, reproducible, and specific in their detection of targeted microbial organisms. In the field of human pathogen detection, culture and colony counting, immunology, and nucleic acid-based methods are most commonly used Vibrio bacteria from other bacterial species. While known coral pathogens, including V. coralliilyticus and V. shiloi, can be grown on TCBS agar, they cannot be effectively discriminated from other Vibrio species The culture and plating method is the oldest bacterial detection technique and remains a cornerstone of human pathogen detection. This method involves plating of samples onto selective growth media followed by an incubation period and then colony counting. Specialized growth media can contain inhibitors of nontarget species/strains, substrates that only the targeted microbe can degrade, and/or substances that confer a particular color to the growing colonies Serratia marcescens, the presumed etiological agent of white pox in the Caribbean, involving two subsequent colorimetric culture steps followed by inoculation onto nonselective media. Interestingly, this method revealed human sewage to be a likely source of the pathogen on reefs in the Florida Keys. Where appropriate selective media exist, most probable number (MPN) methods can be used to estimate the concentration of bacteria In a few cases, culture protocols have been developed to selectively grow specific coral-associated microbes. For example, Sutherland et al. V. shiloi antibodies have provided insight into the dynamics of pathogen invasion and spread within the O. patagonica coral host, suggesting a temperature-dependent host defense against the pathogen The use of antibody technology is well established in human medical diagnostics and has been applied with some success to the detection of coral pathogens. Immunology-based pathogen monitoring involves the production of either polyclonal or monoclonal antibodies and the detection of antibody/antigen complexes that indicate the presence of the targeted pathogen within a sample. Specific anti-Nucleic acid-based techniques using molecular probes and/or PCR offer an appealing alternative to culture and immunology-based methods because of their potential for high specificity and sensitivity. Here we discuss the utility of fluorescent in situ hydridization (FISH) and PCR-based techniques in coral pathogen detection.V. shiloi-specific FISH probes also revealed the marine fireworm Hermodice carunculata as the reservoir and transmission vector of this coral bleaching pathogen FISH allows identification, localization, and visualization of individual microbial cells within healthy and diseased tissue PCR-based methods allow high sensitivity and specificity by targeting and amplifying short nucleic acid (DNA or RNA) sequences within the genomes of coral-associated microbes V. penaeicida in the prawn Litopenaeus stylirostris and aquaculture facilities in New Caledonia V. coralliilyticus. This technique, which is capable of detecting the bacterium at concentrations as low as 1 CFU ml−1 in seawater and 103 CFU cm−2 on coral fragments, is currently being used to investigate the epidemiology of V. coralliilyticus, including information on its distribution and role in the initiation and spread of white syndrome lesions in the Indo-Pacific. This assay represents the first application of qPCR technology for the detection of an established coral pathogen.The combination of high sensitivity and specificity, low contamination risk, ease of performance, and speed make real-time, quantitative PCR (qPCR) technology an appealing option for specific coral pathogen detection qPCR technologies fall into two broad categories on the basis of their fluorescence chemistries: (1) intercalating dyes and (2) oligonucleotide-specific probes . IntercaFor the development of molecular diagnostic assays, the choice of a nucleic acid target is just as important as the platform used to detect it. To allow for high specificity, nucleic acid targets must be both well-conserved within the genome of the target species/strain and distinct from nontarget sequences. Therefore, a great deal of care must be taken in genetic target selection, primer/probe design, and assay optimization. Ribosomal and mitochondrial DNA are the most common targets for nucleic acid-based microbe detection because of their genetic stability and high copy numbers within cells V. coralliilyticus shares greater than 98% 16S sequence similarity with its closest phylogenetic neighbor, V. neptuniusSeveral ribosomal RNA genes, including 16S, 18S, 23S, and internal transcribed spacer region (ITS) genes, have served as targets for nucleic acid-based detection. With the public availability of over 2 million 16S rRNA sequences (GenBank), spanning both the variable and more highly conserved regions of this ubiquitous bacterial gene, the 16S rRNA gene provides an obvious nucleic acid target. Since its introduction in the late 1980s, most FISH applications have targeted rRNA genes because of the large number of publically available sequences and its high copy number in bacterial cells V. coralliilyticusThe accelerated use of genetic sequencing as a means of differentiating closely related bacterial species and strains has led to the proliferation of sequence information from a large number of nonribosomal phylogenetic marker genes in a diverse sampling of microbial species. In some of the better-studied groups, such as the vibrios that contain four of the seven described coral pathogens, sequence data from several phylogenetic marker genes are available for all described species tdh) has been used as a target for detection of the human pathogen V. parahaemolyticus and the gene is also inferred as a direct marker of its pathogenicity vvh) has been targeted for the specific detection of V. vulnificus in oysters rtxA) unique to virulent strains of V. cholerae, Gubala In the field of human medicine, an increasing number of molecular-based pathogen detection assays have targeted genes directly involved in virulence. For example, the thermostable direct hemolysin gene (vcpA) in V. coralliilyticus and the Toxin P gene in V. shiloi, both of which could serve as molecular targets Specific virulence factors have been described in two coral pathogens, the Zn-metalloprotease gene  from coral-derived samples. The complex nature of the coral holobiont, which contains genetic material from the coral host as well as its associated algae, bacteria, and viruses, in combination with the presence of high concentrations of PCR inhibitors  make successful DNA extraction and pathogen detection from coral tissue extremely difficult. Several extraction methods have been developed to overcome these limitations, but consistently obtaining high quality DNA from coral samples remains a persistent challenge to coral researchers. Furthermore, there is the potential for gene copy number variability even between closely related bacterial strains as well as horizontal gene transfer between distantly related species, which could confound accurate detection and quantification. Early pathogen detection assays will therefore require extensive testing to confirm their specificity and sensitivity.Further development and application of diagnostic tools for coral pathogen detection is limited by a lack of knowledge of the organisms and genes involved in the onset and progression of most coral diseases. In particular, current knowledge of the causes of a large number of coral diseases is rudimentary, with only a few actual pathogens identified (reviewed in As coral diseases continue to threaten reefs worldwide, there is increasing urgency for tools to understand and control their spread. Several approaches, including phage therapy and probiotic addition, have been suggested to mitigate coral disease outbreaks


High consumption of sugar sweetened beverages (SSBs) has been linked to unhealthy weight gain and nutrition related chronic disease. Intake of SSB among children remains high in spite of public health efforts to reduce consumption, including restrictions on marketing to children and limitations on the sale of these products in many schools. Much extant literature on Australian SSB consumption is out-dated and lacks information on several key issues. We sought to address this using a contemporary Australian dataset to examine purchase source, consumption pattern, dietary factors, and demographic profile of SSB consumption in children.Data were from the 2007 Australian National Children's Nutrition and Physical Activity Survey, a representative random sample of 4,834 Australian children aged 2-16 years. Mean SSB intake by type, location and source was calculated and logistic regression models were fitted to determine factors associated with different levels of consumption.SSB consumption was high and age-associated differences in patterns of consumption were evident. Over 77% of SSB consumed was purchased via supermarkets and 60% of all SSB was consumed in the home environment. Less than 17% of SSB was sourced from school canteens and fast food establishments. Children whose parents had lower levels of education consumed more SSB on average, while children whose parents had higher education levels were more likely to favour sweetened juices and flavoured milks.SSB intake by Australian children remains high and warrants continued public health attention. Evidence based and age-targeted interventions, which also recognise supermarkets as the primary source of SSB, are recommended to reduce SSB consumption among children. Additionally, education of parents and children regarding the health consequences of high consumption of both carbonated and non-carbonated SSBs is required. There has been a well-documented rise in the prevalence of overweight, obesity and lifestyle related diseases in the Australian population over recent decades . AlthougDespite much research, and significant public health and media attention, prevention and effective long term treatment of excess weight gain and lifestyle related conditions remains elusive. Although it is likely that these conditions are due to a combination of factors, the rapid increase in their prevalence suggests changing environmental factors may play a significant role. One potential factor, which is temporally associated with the rise in overweight and obesity, is an increased consumption of refined carbohydrate .Sugar sweetened beverages (SSBs) are a significant source of refined carbohydrate in the diet of developed nations such as the United States and Australia -7. CurreIn recognition of the link between SSB and excess weight gain, the Australian Dietary Guidelines  recommenDespite the increased public health attention, additional restrictions on marketing, and limitations on the sale of these products in many schools, intake of SSBs by children remains high. Moreover, the extant literature lacks comprehensive descriptions of the nature of SSB consumption in Australia with respect to the source, pattern, demographic and other dietary factors associated with intake. We aim to address this by describing the major sources of SSB, the patterns of consumption, and demographic and dietary factors associated with high and regular consumption in a representative random sample of Australian children. Additionally, we sought to identify potential target areas for future public health intervention.Data were from the 2007 Australian National Children's Nutrition and Physical Activity Survey (NCNPAS), funded jointly by the Australian Government Department of Health and Aging, Australian Government Department of Agriculture, Fisheries and Forestry and industry group the Australian Food and Grocery Council. The NCNPAS was designed to assess the nutrient intake and physical activity levels of a representative sample of Australian children. Demographic, dietary, physical activity and basic anthropometric data were collected from 4,487 children aged between 2 and 16 years. Interviews were conducted from February through August of 2007.Food, beverage and supplement intake was collected from participants and caregivers, for children 8 years and younger who required assistance, in two standardised multiple-pass 24 hour recalls. Additional information regarding usual dietary habits, including self- or caregiver reported usual daily intake of fruit and vegetables (number of serves), type of milk consumed, whether salt was added to cooking or meals, and type of salt used (iodised or non-iodised) was collected. This dietary intake information, in addition to socio-demographic data, was collected during a computer assisted personal interview (CAPI) and a second, follow up computer assisted telephone interview (CATI) was completed within 7 to 21 days. Height, weight, and waist circumference data were collected using recognised protocols . The finFor the purpose of this analysis, beverages were classified as follows: water, non-flavoured milk, sugar sweetened beverages (SSB), pure fruit juice (no added sugar), hot tea and coffee (regardless of added sugar), alcohol, artificially sweetened diet beverages, and other . SSBs were further categorised into carbonated products (including energy drinks), juices with added sugar, cordial (defined as flavoured drink concentrate), sports drinks, milkshakes/smoothies, and flavoured milk. Flavoured milks included both low- and high-fat products as both have substantial sugar content and sugar levels were generally comparable.Location of beverage consumption was provided on the NCNPAS dataset as: home or any other residence, place of purchase, institution (including school and childcare), during transport, leisure activity and other.The source of beverage referred to where the product was purchased and included the following categories: fast food outlets including school canteens, packaged beverages purchased from supermarkets, and fresh products such as homemade juices, milkshakes or smoothies. As the contribution from fresh products was small, for analytic purposes this category was combined with products from unknown sources.Children were classified as high, low-moderate or non-consumer of SSB based on their level of intake of SSB during the study period. Children whose SSB intake contributed more than one third of their total daily intake of beverages by volume were classified as high consumers. As the average volume of beverage consumed by children was approximately 1.4 litres per day, this cut-point was equivalent to slightly less than two glasses of SSB and approximately 50 grams of sugar per day. Those who reported no SSB consumption during the study were labelled non-consumers, and the remaining children were considered low-moderate consumers. Additionally, high consumption of each subgroup of SSB was classified separately. Children whose consumption was in the 90th percentile or above for each of the three main categories, carbonated drinks, sweetened juice or flavoured milk, were considered high consumers.In order to investigate factors associated with regular intake, consumption on both days of dietary data collection was used as a proxy measure of regular SSB consumption. This analysis only included children who provided 2 days of completed dietary recall data . Children who reported consuming SSB on both recall days were classified as regular consumers . This classification was used as an additional measure of intake and it was unrelated to overall level of consumption. The majority of regular consumers (74%) were not considered high SSB consumers.Household variables included the total annual household income (before tax) at the time of the survey and number of children living in the household. Family type was derived and categorised into original family, step or blended family, one parent family, and other . The highest level of education achieved by either parent or caregiver within the household was categorised into university degree, vocational education (TAFE certificate or diploma), year 11-12 schooling, and year 10 schooling or below.Maternal age at the birth of the study child and breast feeding duration, as recalled by the mother, were included in modelling.Study age groups were selected to align with the Nutrient Reference Values for Australia and New Zealand age bands . Birth wDietary variables were based on the 2-day dietary recall data. Added sugar intake, excluding sugars from beverages and fruit, and saturated fat consumption were calculated as a percentage of total daily energy intakes from dietary recall data.Average calcium intake was calculated from dietary recall data and compared to age and sex based recommended dietary intakes references. Average daily caffeine intake was similarly calculated and compared to age relevant cut-offs. As no Australian recommendations exist for intake of caffeine by children, values were compared to age-based Canadian recommendations . In addiAll statistical analyses were carried out using SAS Version 9.2  taking into account population weights and the complex survey design. Population level average intake was calculated using survey weights and associated standard errors were calculated using expansion in Taylor series and the ultimate cluster variance estimate technique . Mean inSix logistic regression models were fitted, adjusting for the complex sample design, to evaluate the associations between demographic and dietary factors and high, no and regular SSB consumption. Factors associated with high consumption of the most commonly consumed sub-groups of SSBs, carbonated beverages, sweetened juices and flavoured milk, were determined. Sports drinks, smoothies/milkshakes and cordials contributed little to overall consumption, and therefore these categories of SSB were not included in sub-group analyses. Variables were eliminated from the final models if statistically non-significant, as determined by Wald's test , and the most parsimonious model reported.Sensitivity analysis was undertaken to investigate the effect of altering the cut-point used to define high SSB consumption. Logistic regression models were run using alternative cut-points  in order to assess the impact on the strength and direction of results. The average difference between the results of these models was less than 10 per cent, and the use of different cut-points did not change the direction of any results, not did it affect the interpretation of the final models.With respect to the general characteristics of the sample, comparisons with the national census figures  revealedApproximately 14% of participants were considered high SSB consumers, 66% were low-moderate consumers and approximately 20% reported no SSB consumption on either study day (Table p < 0.001).The contribution of SSB to total daily energy intake is displayed in Table p < 0.001). There was no reduction in the volume of non-carbonated SSBs consumed among the older age groups to compensate for the higher carbonated SSB consumption . The proportion of SSB consumed at the place of purchase, in institutions and during leisure activities and transport was higher in older age groups. However, even amongst the oldest children who reported the greatest variation in the location of consumption, over 60 per cent of SSB was still consumed in the home (Table p < 0.001) . Although the average contribution of SSB from fast food sources was higher in successive age groups, it remained relatively small  whose SSB intake is approximately 10 per cent of their energy intake . However years whThe majority of SSB in the diet of children in all age groups was sourced from supermarkets and consumed at home. Only a small percentage of SSBs were purchased from fast food sources. Even among the 14-16 year age group, who typically would have a higher level of independence from parents and some discretionary spending compared with younger children, around 75 per cent of their SSB intake was purchased from supermarkets. These findings are similar to those of Wang and colleagues who reported, in a study of US children, 55 to 70 per cent of the calories from SSBs were consumed in the home environment . AlthougThe variation in the pattern of SSB consumption by age is noteworthy. Of particular interest was the high consumption of sweetened juice by the 2-3 year old children. Similarly, Wang and colleagues reported, in US children, the main type of SSB consumed by children aged 2-5 years was sweetened fruit punch and fruit juice . During The demographic and dietary factors associated with high consumption of carbonated SSBs and non-carbonated SSBs differed. While high consumption of carbonated drinks was related to a number of markers of unhealthy dietary patterns and lower levels of household education, non-carbonated SSBs were not. These findings are similar to those of Ranjit and colleagues who reported that high carbonated beverage consumption was associated with poor dietary and physical activity patterns in US children, while consumption of non-carbonated drinks was associated with positive health behaviours . The varUsing the various definitions of high and regular intake we consistently found SSB intake to be associated with markers of poor dietary patterns. For example, high intake of caffeine, and lower intake of calcium, fruit and vegetables. This finding is supported by previous literature linking SSB consumption with unhealthy dietary habits . HoweverGrowing evidence supports a mechanistic link between the high sugar, and specifically high fructose, content of SSBs and the risk of chronic disease and excess weight gain. The unique metabolic and hormonal effects of fructose are linked to a number of adverse short-term effects including enhanced de novo lipogenesis and triglyceride production resulting in dyslipidaemia, increased systolic blood pressure, reduced insulin and leptin sensitivity, impaired appetite control and visceral adiposity -36. ThesThe current analysis is limited by its reliance on 2-day dietary recall, a cross sectional study design and the potential for misclassification of beverage type or source. As individual consumption was based on 2 days of dietary recall it is possible that individual consumption on the survey days was not representative of their typical consumption patterns, in particular, for children who did not consume SSBs. However, as the survey days were randomly selected for each survey child, population estimates of average consumption of SSB should be unbiased. As data were self-reported, actual consumption may vary from recorded intakes. Further, the involvement of the parent or caregiver in dietary data collection in younger children (2-8 years) may have potentially influenced the accuracy of results. However, these biases are likely to underestimate the consumption of unhealthy foods such as SSBs and therefore reported intakes are likely to be biased towards the null, leading to an underestimation of the reported associations. The cross-sectional design means it is impossible to associate current consumption with the development of long term health outcomes such as obesity or chronic disease. Due to the use of random digit dealing for participant recruitment no demographic information was available for non-respondents. As a result, differences between study participants and non-respondents could not be determined and potential bias between these groups could not be assessed. However, households participating in NCNPAS typically had slightly higher levels of education and income in comparison to the general Australian population, and this could potentially bias results and limit the generalizability of the research.These findings reveal opportunities to close possible gaps in public understanding of the role of both carbonated and non-carbonated SSBs in a healthy diet. Additionally, they highlight the need for evidence based, and age relevant public health interventions which target the primary sources and location of SSB consumption in order to effectively reduce levels of intake by Australian children. Finally, the importance of periodic monitoring of child health and nutrition status, to allow public health strategies to remain effective and relevant to the changing needs of the population, is clear.The authors declare that they have no competing interests.KH, FM and DL conceived the original idea for the study. All authors contributed to the development of the study methodology. KH undertook the data analysis and wrote the first draft of manuscript. All authors contributed to writing the paper, and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/950/prepub


The efficacy of targeted therapies in leukemias and solid tumors depends upon the accurate detection and sustained targeting of initial and evolving driver mutations and/or aberrations in cancer cells. Tumor clonal evolution of the diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumors. Moreover, drug-resistant subclones present at initiation of therapy or emerging as a result of targeted therapies represent major challenges for achieving success of personalized therapies in providing meaningful improvement in cancer survival rates. Here, I briefly portray tumor cell clonal evolution at the cellular and molecular levels, and present the multiple types of genetic heterogeneity in tumors, with a focus on their impact on the implementation of personalized or precision cancer medicine. The lifetime risk of a clinical cancer diagnosis in humans is around one in three, with more than 10 million cases diagnosed each year [It has been known that a large number of patients treated for cancer don’t respond to therapy given to them. This indicates that every drug does not work similarly in every patient, given that every patient has a unique biology and unique tumor architectures. These variations should be reflected in their choice of therapy to improve efficacy and minimize side effects. Several molecular mechanisms have been implicated in the development of neoplastic lesions and therapy resistance, and novel targeted agents to treat these neoplasms after diagnosis and/or relapse have been developed. However, variable efficacy has been observed in late-stage clinical trials, most likely because of the lack of complete understanding of the tumor development process and the biological heterogeneity of these tumors. The key response to the long-term disappointments in the fight against cancer must be revolutionary and lies in implementation of personalized or precision medicine where cancer therapy is tailored to each patient’s biology and tumor signatures to achieve the best medicinal outcome for that individual.Precision cancer medicine traditionally involves determining the biological status of an individual tumor before therapy by assessing genetic signatures, hormone metabolism, and signaling activity, and then directing tailored treatment accordingly. The recent surge in Next Generation Sequencing (NGS) of cancer genomes has supported the expansion of molecular cancer profiling to support precision cancer medicine. However, translation of these genetic and metabolic findings into clinically valuable genetic, epigenetic, proteomic, biochemical, metabolic and imaging biomarkers for diagnosis, prognosis, and response to therapy is an extended intricate process that remains critical for the wide implementation of precision medicine in cancer therapy. The remaining central challenges for this approach include selection of optimal drug targets, evaluation of genetic profiles and genetic interactions, determining proper combinations of therapies, implementing clinical platforms in phase I studies, and resolving the organizational, commercial, regulatory, and societal challenges facing these precision cancer medicine approaches. To name a few, organizational challenges include structure and administration of personalized clinical trials, commercial concepts of personalized therapy such as pay for performance of multiple tailored treatments replacing blockbuster drugs, regulatory evaluation of outcome of personalized medicine, ethical considerations of genetic testing, and level of acceptance of cancer patients to the new paradigm of personalized medicine studies. Ultimately, a better understanding of the tumor and metastatic developmental process, and an optimum design of targeted tailored therapies are instrumental in the success of precision cancer medicine. Two concepts have recently gained a great deal of attention, and remain at the center stage of our understanding of tumor development for designing better-tailored therapies; these are tumor cell clonal evolution and tumor heterogeneity.NGS for cancer samples is now widely accessible, increasingly affordable, and provides a transformative influence on cancer care with a particular insight into the complexity of the cancer genome . With itIt is believed that leukemia and neoplasms in general are abnormal outgrowth from a TIC(s) whose progeny sequentially accumulate nested genetic and epigenetic mutations in cancer genes, over an extended period of time during clonal evolution , that geIn addition to genetic drivers, non-genetic drivers of clonal tumor cell selection during clonal evolution are also recognized, and among them are activation of alternative signaling, cell quiescence and epigenetic drivers. The first of these non-genetic drivers of formation of dominant clones during clonal evolution include the activation of alternative or downstream signaling pathway through signaling plasticity to achieve growth advantage or resistance to targeted therapy, a phenomenon termed oncogenic bypass . AdditioTumor heterogeneity is recently recognized in leukemias and solid tumors , and is The recognition that driver mutations frequently encode protein kinases has led the recent use of EGFR inhibitors , ALK inh


In female mammals, sexual maturation is initiated by a change in the release pattern of pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a consequential increase in the secretion of ovarian sex-steroids, estradiol and progesterone. Orchestrating these endocrine changes is a diffuse population of hypothalamic neurons that produce the neuropeptide, gonadotropin-releasing hormone (GnRH). Although the development and functional integration of GnRH neurons with the rest of the central nervous system is still poorly understood, recent progress has been made on several fronts. For example, there is now evidence that some mammalian species express more than one molecular form of GnRH (GnRH-I and GnRH-II), and that the two corresponding GnRH neuronal sub-populations may play different roles in the regulation of reproductive function and behavior. Moreover, through the use of transgenic animal models, neuronal fiber tracing, gene expression profiling, and electrophysiologcal recordings, new insights have been gained into the mechanisms that regulate GnRH release. This volume brings together 10 articles that reflect current thinking about the role of GnRH in mediating estrogenic feedback to the neuroendocrine reproductive axis. The main focus is on the negative and positive actions that estrogens exert within the hypothalamus of mammals, especially around the time of the preovulatory LH surge. However, the articles also present findings from other vertebrate classes, and so provide an intersting comparative perspective. Taken together, the knowledge presented in this volume represents a foundation upon which to develop more effective therapies for pubertal disorders, infertility, and menopause.The first article (Sower and Baron, A cluster of three articles then focus on hypothalamic neuropeptides that exert a major influences on the secretion of GnRH, and which are thought to mediate the feedback effects of sex-steroids on the reproductive axis. For example, studies in rodents have clearly shown the importance of kisspeptin to both pulsatile and surge modes of GnRH release Navarro, , while hAlthough the exact mechanism by which estrogens interact with the reproductive neuroendocrine axis is unclear, our general understanding of this issue is neatly summarized by a series of three reviews (Micevych and Sinchak, Various physiological functions show adaptations for life in an environment that undergoes marked changes across the 24-h day. For example, in many mammals the timing of the preovulatory LH surge occurs at a very specific time of day. Two articles discuss the interactions between the circadian timing system and estrogen-sensitive neural circuits that regulate GnRH secretion and the preovulatory surge (Sun et al., Finally, a novel hypothesis is proposed to explain the conundrum of how estrogens appear to exert both negative and positive feedback actions on the reproductive axis (Urbanski,


Moreover, clinical trials have further supported its use in the treatment of several diseases, in particular in the management of prostate cancer. Herein, we critically review the scientific knowledge about the current role and future prospects for the use of pomegranate extracts in the therapy of erectile dysfunction, benign prostatic hyperplasia, and prostate cancer.Multiple strands of research provide growing evidence that diet, nutrition, and life style play a role in the development and the course of urological diseases. Numerous micronutrients and polyphenols found in soy, green tea, and many fruits and vegetables have been described to impact diseases including erectile dysfunction, benign prostatic hyperplasia, and prostate cancer. However, oftentimes these reports lack both a scientific rationale and supportive evidence base. The efficacy of pomegranate, on the other hand, in the modulation of central biological processes like inflammation, hypoxia, and oxidative stress that are important in the pathogenesis of urological maladies has been robustly demonstrated in preclinical  As men age, there are inevitable changes that occur in the genitourinary tract that increase their risk of developing urological diseases such as ED (erectile dysfunction), prostatitis, BPH (benign prostatic hyperplasia), and PCA (prostate cancer). An autopsy study reported an incidence of BPH of only 8 percent in men during the fourth decade of life, while 50 percent of men have pathological BPH between ages 51 and 60 .In the past years, there is a growing body of literature that supports the role of environmental and other life style factors in impacting pathological alterations of the genitourinary tract. For example, Asian men usually have a significantly lower incidence of and mortality from prostate cancer when compared with men in Western Europe and North America. These differences frequently are mitigated after immigration to Western countries after only one generation . AuthorsModifiable lifestyle and nutrition habits and the long latency of many problems of men's health make them ideal candidates for prevention as well as complementary treatment strategies. Moreover, urological patients have a high desire to get alternative and complementary treatments. A meta-analysis has demonstrated that 30% of prostate cancer patients are using complementary alternative medicine (CAM) in addition to their standard treatments . In searPunica granatum) have been intently studied over the past decade. Preclinical and clinical studies provide evidence of their antiproliferative properties and modulatory effects on inflammatory pathways pyran-6-one), a metabolite of ellagic acid, punicalagin, and the ellagitannin extract that are all ingredients of pomegranate, was more often detected (P = 0.031) with higher levels in the POMx arm compared to placebo-treated patients (P = 0.007). In both benign and malignant prostate tissues, there was an inverse correlation between Urolithin A and the levels of oxidative DNA damage as measured by 8-OHdG levels. POMx reduced benign prostate tissue 8-OHdG by 33% (P = 0.003) in men with organ-confined disease. This was (a) a modest size study and (b) the time of treatment was within 4 weeks very short. As discussed in the previous sections, it has been suggested that the effects of pomegranate extracts become evident in long-term use by its ability to reduce chronic oxidative stress. Thus, the most important finding of this study was the proof of metabolite accumulation in the prostate and the strong trend for its association with reduced 8-OHdG in both benign and malignant tissues.Major criticisms of these two phase II studies have been the lack of placebo control, the lack of a dose-response effect, and the lack of prostate tissue to correlate PSA change with prestudy  makes inprestudy . The priAnother point of criticism to the studies above is the use of PSADT as a surrogate parameter for standard clinical outcomes such as survival. A retrospective study presented at the ASCO Meeting 2012 has shown that PSADT may increase even in the absence of therapy, possibly in part due to the duration of PSA followup . The finIn summary, the current clinical trials provide ample evidence for the biological activity of pomegranate extracts in prostate cancer. This conclusion has to be emphasized in the light of other alternative treatments with agents like celecoxib or rosiglitazone that did not improve the mean PSADT when compared to a placebo control group in randomized clinical trials , 60.P = 0.058). The secondary efficacy endpoint, an upgrading of the erectile function domain of the IIEF questionnaire, was not reached. The study was limited in being a small sample size trial with relatively short-term use of pomegranate extracts for treatment of ED; nevertheless, there was a signal for an efficacy of pomegranate extracts to improve mild-to-moderate ED. Further randomized controlled trials that are better powered to assess the efficacy of pomegranate extracts in ED therapy are, therefore, needed. In addition to this clinical trial, studies have examined the efficacy of pomegranate extracts to improve maladies that are typical risk factors for the development and progress of ED, including hypertension and the ability to inhibit serum angiotensin converting enzyme [One study investigated the improvement of ED in 60 sexually active, healthy males aged 21–70 years . Inclusig enzyme . The manP = 0.0085) with two-thirds of patients assayed having an increase compared to baseline. As described above, the increase in NO levels appears to be a key factor in lowering the tension of smooth muscle of the lower urinary tract via the NO/cGMP pathway and subsequently improving LUTS symptoms. Furthermore, the neoadjuvant POMx pill study [There is currently no completed clinical study evaluating the effect of pomegranate extracts in the treatment of BPH. However, a previous clinical trial provided justification for clinical testing in subjects with BPH . In thisll study  demonstrSee In vitro and in vivo preclinical experiments provide evidence supporting that pomegranate extracts are able to (i) inhibit proliferation, invasion, metastatic spread, development of castration-resistant PCA growth, and angiogenesis, (ii) modulate inflammatory pathways, and (iii) reduce oxidative stress. Clinical biologic activities of pomegranate have been tested in subjects with PCA and ED. Further randomized, double-blind, controlled trials are under way and will be completed soon.The biological processes of inflammation, hypoxia, and oxidative stress have a crucial function in the natural biology of men's urological diseases including ED, BPH, and PCA.


Research over the past three decades has revealed that cellular behavior is governed by dynamic, complex networks of interactions among proteins, RNA, DNA, lipids and metabolites . As suchSaccharomyces cerevisiae began to address this data challenge by completing the first systematic effort to convert the interaction data embedded in the biomedical literature into a computable format [Schizosaccharomyces pombe and the thale cress Arabidopsis thaliana. In parallel, curation projects on human interactions in themed areas of biomedical interest have been undertaken. These datasets are disseminated by many different partner databases and meta-resources, including the Saccharomyces Genome Database [Our 2006 publication describing the comprehensive curation of protein and genetic interactions for the budding yeast e format . This cue format . The Bioe format . ComprehDatabase  and otheDatabase , and theDatabase . The ProDatabase , and anaDatabase .Since our original publication, the rate of generation of molecular interaction data has exploded. Over the past several years, a variety of different HTP approaches have been used to chart protein and genetic interaction networks, which have greatly extended the scope of biological interaction space and motivated many hypothesis-driven studies. In yeast, the protein interaction landscape has grown from about 23,000 non-redundant interactions in 2006 to over 75,000 at present, while the number of genetic interactions measured by synthetic growth effects has increased from about 14,000 non-redundant interactions in 2006 to over 140,000 at present . A host The availability of robust datasets derived from the primary literature and HTP studies has enabled graphical representation and interrogation of global interaction networks, and the prediction of gene and network function . Such toDespite the striking experimental progress that has ushered in the era of the hairball , the annA further formidable challenge will be the reconciliation of literature-based interaction data and HTP data, which are often still in discord. The level of detail and reliability of different studies varies greatly, and has led to a call for semi-quantitative metrics to score interaction reliability. The low affinity protein interactions that often underpin biological network regulation are particularly problematic in this regard, and undoubtedly account for a large fraction of currently uncharted interactions. In addition to focused studies in the literature that often draw on subtle inferences and clever experiments to detect such interactions, the application of new methods, such as protein cross-linking followed by mass spectrometric deconvolution, should help increase the rate of detection of transient regulatory interactions.The biomedical research community is now beginning to leverage the wealth of network data across multiple species to gain a better understanding of human health and disease . As the The utility of the comprehensive yeast interaction dataset that we described in 2006 has grown well beyond our original simple intended application as a benchmark for HTP datasets. BioGRID now houses a vast amount of data from multiple species, and is a general resource for experimental computational biologists alike. The BioGRID, its partner interaction databases, model organism databases, and public meta-resources will all play a crucial role in biomedical research in the post-genomics era. We close this brief overview by noting that there is an urgent need to develop the equivalent of a unified human model organism database that incorporates protein and genetic interaction data, regulatory data at the DNA, RNA and protein levels, polymorphism and disease-associated sequence variation data, quantitative phenotypic data, and drug-target interaction data. These integrated datasets will eventually set the stage for sophisticated computational models able to predict cellular behavior, disease outcomes and new modes of therapeutic intervention.BMC Biology tenth anniversary series. Other articles in this series can be found at http://www.biomedcentral.com/bmcbiol/series/tenthanniversary.This article is part of the


Traumatic brain injury (TBI) is a common problem and leading causes of morbidity and mortality in the general population. Sleep disorders are a common finding after the acute and chronic phase of TBI. They result in daytime somnolence which in turn may lead to poor daytime performance, altered sleep-wake schedule, heightened anxiety, and poor individual sense of well-being, insomnia and depression. Studies underscore the importance of examining the architecture of sleep in TBI patients that can use as objective diagnostic or prognostic markers of injury. Posttraumatic hypersomnia, sleep apnea, narcolepsy, periodic limb movement disorder (PLMD), Insomnia and Parasomnia because of REM behavior disorder (RBD) are the most common sleep disorders in TBI patients.The neuropathology associated with TBI will depend on the nature and location of the underlying injury. Sleep polysomnography (PSG) analyses may provide a somewhat crude biomarker of injury as an initial step in the diagnostic work-up. If abnormalities in the PSG are observed, more detailed electroencephalographic methods, using electrodes at multiple locations  could be further used to localize the site of the most severe lesions.Additional research will be required to determine whether the location and severity of sleep PSG abnormalities can be used as a predictor for longer-term disability. The present study suggest that sleep measures may be a sensitive measure of brain injury after TBI and, in theory, could be used for determining the anatomy of brain injury.Traumatic brain injuries, Polysomnography, Sleep disorders


Oligodendrocyte precursor cells (OPCs) originate in specific areas of the developing central nervous system (CNS). Once generated, they migrate towards their destinations where they differentiate into mature oligodendrocytes. In the adult, 5–8% of all cells in the CNS are OPCs, cells that retain the capacity to proliferate, migrate, and differentiate into oligodendrocytes. Indeed, these endogenous OPCs react to damage in demyelinating diseases, like multiple sclerosis (MS), representing a key element in spontaneous remyelination. In the present work, we review the specific interactions between OPCs and other glial cells  during CNS development and in the pathological scenario of MS. We focus on: (i) the role of astrocytes in maintaining the homeostasis and spatial distribution of different secreted cues that determine OPC proliferation, migration, and differentiation during CNS development; (ii) the role of microglia and astrocytes in the redistribution of iron, which is crucial for myelin synthesis during CNS development and for myelin repair in MS; (iii) how microglia secrete different molecules, e.g., growth factors, that favor the recruitment of OPCs in acute phases of MS lesions; and (iv) how astrocytes modify the extracellular matrix in MS lesions, affecting the ability of OPCs to attempt spontaneous remyelination. Together, these issues demonstrate how both astroglia and microglia influence OPCs in physiological and pathological situations, reinforcing the concept that both development and neural repair are complex and global phenomena. Understanding the molecular and cellular mechanisms that control OPC survival, proliferation, migration, and differentiation during development, as well as in the mature CNS, may open new opportunities in the search for reparative therapies in demyelinating diseases like MS. Since the founding of neurosciences in the nineteenth century, neurons, the fast excitable cells of the nervous system, have captivated the attention of almost all the successive generations of researchers. The huge number of neurons, their fascinatingly precise interactions in the mature central nervous system (CNS), and the diversity of physiological responses and behaviors that they elicit, undoubtedly deserve such consideration. Nevertheless, the number of glial cells in the CNS is close to one order of magnitude higher than that of neurons. A recent estimate of the number of neurons in the mature human cerebral cortex was lowered to a few billion, being approximately sixfold more glial cells . In the In recent years, the amount of data indicating that both astrocytes and microglia influences oligodendrocyte biology has grown steadily. Far from their classic roles as physical scaffolds and their participation in nutrient diffusion throughout the CNS, astrocytes have now been shown to modulate neuronal activity and to respond to neurotransmitters in a clear and excitable manner . In addiplp/dm-20 and these do not depend on PDGF-AA; (ii) the second and largest population of OPCs does depend on this growth factor and these cells express PDGFRα . Indeed, all three types of lesion plaques can be observed in the CNS of MS patients, independently of their clinical evolution and phenotype , traumatic and vascular accidents , neurodegenerative diseases, and schizophrenia . The larhenotype . This imDuring development, OPCs are generated in oligodendrogliogenic niches that form a patchwork pattern along the neural tube, from where they migrate to colonize the whole CNS . Along tIn vitro experiments have shown that BMP4 inhibits the expression of several myelin proteins during oligodendrocyte differentiation, such as PLP and MBP  and chemokines. BMPs are secreted by astrocytes  and they and MBP . Althougelopment , the regelopment  and theselopment . During elopment . The CXCin vitro  and astrin vitro . Indeed,in vitro .in vitro experiments showed that blocking megalin hinders optic nerve OPC proliferation and migration, and megalin+-astrocytes can internalize Shh for its subsequent release at a suitable concentration  direct transport of exogenous ferritin/transferrin across the BBB ; and ii. During feration . After frophages . Togethein vitro and in vivo approaches .It is becoming more established that the regeneration observed in MS lesions, i.e., remyelination, may be a consequence of changes in the local environmental equilibrium between pro-inflammatory/pro-myelin-damage and anti-inflammatory/pro-regenerative molecules/cells . Fundamein vitro . In thisin vitro . TherefoIGF-1 is one of the growth factors that has been studied most extensively in the CNS, being produced putatively by M2 microglia/macrophages to promote myelin repair. It enhances the survival of oligodendrocytes, promotes oligodendrocyte development, and stimulates the synthesis of myelin . It is lin vitro in normal or pseudo-pathological conditions  and therefore, the presence of branched O-mannosyl glycans on astrocytes, impeded OPC differentiation and therefore, reduced the remyelination rate . Different astrocyte-secreted cues during development  influence the behavior of OPCs, either directly or indirectly, driving the response to important signals and/or helping to generate their gradients in vivo. Moreover, controlling iron homeostasis by microglia and astrocytes is not only essential for OPCs during normal myelination  the consequences of functionally silencing the signaling pathways in astrocytes that represent an obstacle for neuroprotection and remyelination in chronic MS lesions. In this sense, current MS therapies hinge on the supposition that controlling the inflammatory response will not only limit cell damage by inactivating different components of the innate or adaptive immune system, but that it will also have positive consequences on neuro-repair. However, the latter hypothesis has yet to be studied in MS tissue. Thus, it would be important to assess the specific effects of immunoregulatory molecules on the behavior of adult human OPCs and moreover, the effect of these current MS treatments on microglia and astrocytes, now clearly established as crucial partners in all the biological processes involved in OPC development: proliferation, migration, differentiation, and survival.One of the most fundamental questions in neuroscience is whether it is possible to resolve pathological questions by recapitulating data obtained during the analysis of the CNS development. In this review we describe how microglia and astrocytes establish different interactions with OPCs, both in the normal CNS and in pathological conditions (a summary is described in lination  but alsolination . The ovelination  seems toly occur  could beThe 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.Diego Clemente wrote the manuscript, designed its content and prepared the figures; María Cristina Ortega wrote the manuscript and prepared the figures; Carolina Melero-Jerez wrote the manuscript; Fernando de Castro wrote the manuscript, designed its content and prepared the figures.


Substrains of the Spontaneously Hypertensive rat (SHR), a putative animal model of Attention-Deficit/Hyperactivity Disorder (ADHD), have demonstrated increased sensitivity to many drugs of abuse, including psychostimulants. Therefore, it was suggested that studies in SHR may help elucidate ADHD and comorbidity with substance use disorder (SUD). However, the drug intake profile of the SHR in the most relevant animal model of drug addiction, the self-administration (SA) test, and its response on the conditioned place preference (CPP) paradigm are not yet determined. In the present study, we employed SA and CPP tests to investigate the reinforcing effects of the psychostimulant methamphetamine in an SHR substrain obtained from Charles River, Japan (SHR/NCrlCrlj). Concurrent tests were also performed in Wistar rats, the strain representing "normal" heterogeneous population. To address if the presence of ADHD behaviors further increases sensitivity to the rewarding effect of methamphetamine during adolescence, a critical period for the onset of drug abuse, CPP tests were especially conducted in adolescent Wistar and SHR/NCrlCrlj. We found that the SHR/NCrlCrlj also acquired methamphetamine SA and CPP, indicating reinforcing effects of methamphetamine in this ADHD animal model. However, we did not observe increased responsiveness of the SHR/NCrlCrlj to methamphetamine in both SA and CPP assays. This indicates that the reinforcing effects of methamphetamine may be similar in strains and that the SHR/NCrlCrlj may not adequately model ADHD and increased sensitivity to methamphetamine. Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder characterized by the core symptoms such as hyperactivity, inattention and impulsivity ,2. It iset al , as druThe authors declare that they have no competing interests.ID and JHC conceived and designed the study. ID, HSA and JYC performed the SA and CPP experiments. ID performed the statistical analysis while SCY, JHR JHC provided insights on interpreting the results. All authors participated in drafting and in writing the final version of the manuscript.


Surgical correction of an anophthalmic enophthalmos secondary to inappropriate repair of the eye socket involves several difficult aesthetic issues associated with long-term use of a poorly fitting prosthetic eye. In this paper, we present two cases of anophthalmic enophthalmos. During the treatment of the first patient, unsatisfactory cosmetic problems including lower eyelid retraction, hypoglobus, and severe upper eyelid ptosis were revealed. Accordingly, a three-staged procedure was performed on the second patient, including autologous augmentation of the eye socket, correction of lower eyelid retraction with a cartilage graft, and a frontalis sling procedure to correct upper eyelid ptosis. Enophthalmos due to inappropriate primary repair of the eye socket is a serious cosmetic complaint of patients with anophthalmia. The goal of surgical correction of anophthalmic enophthalmos is to provide orbital symmetry relative to the unaffected side; however, there are several cosmetic concerns, including lower eyelid retraction, hypoglobus, and sever upper eyelid ptosis. Here we report a case in which a patient experienced an unfavorable cosmetic outcome during restoration of orbital asymmetry. Furthermore, we present the result of a three-staged procedure performed systematically on a patient requiring correction of enophthalmos.The first patient was a 54-year-old woman who underwent enucleation of the left eyeball after a motor vehicle accident three years before her visit to our hospital. She presented with a sunken eye and ptotic upper eyelid . We firsThe second patient was a 60-year-old woman with a recurrent schwannoma arising from the middle cranial base, who had undergone orbital exenteration at the age of 46. She complained of a sunken eye and drooping of the affected upper eyelid . Given tThere were a number of issues worth noting in the treatment of two patients with anophthalmic enophthalmos. First, eye prosthesis was prone to be customized as thick as possible to camouflage sunken eye. Second, the heavier prosthesis could have induced lower eyelid retraction, worsening the downward displacement of the prosthesis. Third, a prosthetic cornea was redesigned to camouflage the scleral show between the cornea and lower eyelid margin, which could increase the noticeability of hypoglobus, or downgazing appearance. Fourth, mechanical stress arising from attaching and detaching the bulky prosthesis could have led to dehiscence of levator aponeurosis, given that the effect of aponeurotic surgery observed in the first patient was mostly diminished during the first few postoperative months. These clinical findings indicate that at least three factors should be taken into consideration in the correction of anophthalmic enophthalmos. 1) Augmentation of the eye socket is the top priority, because restoring adequate orbital volume and convexity of the socket is essential to limit the use of a bulky prosthesis, which can cause various complications. We prefer autologous costal cartilage grafts to alloplastic implants for augmentation because of their low risk for extrusion and less resorption , 4. Howe Augmenta In conclusion, our findings suggest that the following three factors should be considered in the correction of anophthalmic enophthalmos: the remaining orbital volume and socket contracture, the presence of lower eyelid retraction, and severity of upper eyelid ptosis.


Inflammation is a coordinated response of the immune system which is aimed at maintaining or restoring tissue integrity. Sterile inflammation can be triggered by physical, chemical, or metabolic noxious stimuli. The individual stimuli  promote a carefully choreographed set of cell responses to stress. Many types of stress responses exist , and these can influence each other. Stress responses induce recruitment of inflammatory cells and result in inflammation. When the noxious stimuli persist over and cannot be eliminated or cleared inflammation fails to resolve, resulting in the development of a vicious circle which is part of the pathophysiology of many human diseases, including cancer, autoimmunity, chronic viral infections, chronic graft versus host disease, metabolic syndromes, and several acquired and inborn genetic disorders. Several proximal factors have been identified and proposed to play a role in the individual types of sterile inflammation, including redox responses, the occurrence of damage-associated molecular patterns molecules (DAMPs) and immune stimulatory heat shock proteins, and vascular remodeling. However, the detailed mechanism(s) linking stressful events and the development of inflammation have thus far remained elusive. The identification of the major molecular species in induction, development, and outcome of sterile inflammation, and the illumination of their mechanisms of action are therefore of paramount relevance for the design of effective therapeutic strategies for the treatment of the most common diseases of the Western world. Thus, this Special Topic focuses on articles that can shed new light on the molecular mechanisms of sterile inflammation. This collection of papers, written by experts in this field, addresses the most important current challenges in the topic of sterile inflammation.A significant focus is placed on the factors that mediate sterile inflammation: DAMPs, released during tissue injury, and cytokines of the IL-1 family. In this family, some members such as IL-1β and IL-18 are true cytokines, in that they undergo active secretion by inflammatory cells, highly regulated at the post-translational level by inflammasomes . Others,


There is a basic rule to mammalian neocortical expansion: as it expands, so does it fold. The degree to which it folds, however, cannot strictly be attributed to its expansion. Across species, cortical volume does not keep pace with cortical surface area, but rather folds appear more rapidly than expected. As a result, larger brains quickly become disproportionately more convoluted than smaller brains. Both the absence  and presence  of cortical folds is observed in all mammalian orders and, while there is likely some phylogenetic signature to the evolutionary appearance of gyri and sulci, there are undoubtedly universal trends to the acquisition of folds in an expanding neocortex. Whether these trends are governed by conical expansion of neocortical germinal zones, the distribution of cortical connectivity, or a combination of growth- and connectivity-driven forces remains an open question. But the importance of cortical folding for evolution of the uniquely mammalian neocortex, as well as for the incidence of neuropathologies in humans, is undisputed. In this hypothesis and theory article, we will summarize the development of cortical folds in the neocortex, consider the relative influence of growth- vs. connectivity-driven forces for the acquisition of cortical folds between and within species, assess the genetic, cell-biological, and mechanistic implications for neocortical expansion, and discuss the significance of these implications for human evolution, development, and disease. We will argue that evolutionary increases in the density of neuron production, achieved via maintenance of a basal proliferative niche in the neocortical germinal zones, drive the conical migration of neurons toward the cortical surface and ultimately lead to the establishment of cortical folds in large-brained mammal species. Cortical folding and brain development are tightly linked. The prenatal characterization of gyri and sulci may be used to identify functionally distinct cortical areas in many species and predict normal or pathological cerebral function at term. Close correlations between cortical morphology and behavioral function (or dysfunction) suggest that the early development of cortical folds constitutes an important step, either for normal development or as an indicator of normal development, in the construction of the human brain. Comparisons between normal and pathological human brains and between humans and other mammal species highlight important differences in progenitor cell-type abundances, cell-cycle dynamics, radial fiber organization, and gene expression profiles that account for gross phenotypic differences in neocortical morphology and function and even organismal behavior  the demarcation of primary gyri at human gestation weeks (GW) 23–31; and (2) the emergence of secondary gyri and the growth of sulcal length and depth between late stages of fetal development and early stages of postnatal life . Notwithstanding, there are quite divergent developmental pathways able to generate nearly identical phenotypes . But in either case, we may assume that selection at the gross morphological level is complemented by adaptations in developmental processes. Therefore, any understanding of the appearance and distribution of cortical folds must be gleaned from a comparison of neural progenitors during development across taxa Figure .At the onset of neurogenesis, neuroepithelial cells forming a pseudo-stratified epithelium divide rapidly and symmetrically, thus expanding the progenitor pool that will directly or indirectly generate all of the excitatory neurons in the neocortex. As neurogenesis proceeds and the epithelium thickens, neuroepithelial cells, while retaining their apical and basal contacts  and inner (ISVZ) region   = 3.834, P = 0.06] may explain the large ventricles and smooth cortices of the beaver and manatee. Furthermore, our analyses find significant scaling relationships between GM thickness and both brain weight and neuron density . However, the divergence of radial fibers exiting the OSVZ only organize the migration of neurons to the cortex, allowing them to fan out across an expanding surface rather than continue to populate an overcrowding cortical column . The ubiquity of gyrencephaly across mammalian orders, absent any genetic correlation between brain volume and GI (see above), suggests that the mechanistic ability for radial fibers in the OSVZ to diverge in response to rapid increases in neuron generation is either extremely adaptable or deeply homologous . But in either case, cortical folding is simply a conserved, mechanistic response to selection for an increased generation of neurons per neurogenic period. In the next section, we will discuss how maintenance of a proliferative niche in the OSVZ may underpin such increases in neuron generation.Conical expansion of the SVZ into outer and inner regions is a hallmark of increased neurogenic proliferative capacity (Smart et al., Extracellular matrix has been implicated in expansion of the SVZ (Barros et al., Brain size is subject to significant heritability. As such, selection pressures directing brain evolution in humans have ranged from tool-making abilities to diet to long-distance running [reviewed in Healy and Rowe ]. While Adult mammalian brains are not identical at the cellular level. Phylogenetic differences in the density of cortical columns and in the morphology and biochemistry of neurons have been identified in most orders (e.g., Beaulieu, 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.


Research into the pathogenesis of microbial infections has a long and fruitful history, rich with elucidation of mechanisms that have resulted in better treatments and new strategies for vaccine development. Stanley Falkow's investigations into the intimate relationships between bacteria and host cells followed his comment that, "The microbe is just trying to make a living." Structural Biology of Bacterial Pathogenesis, by Gabriel Waksman, Michael Caparon, and Scott Hultgren, is a state-of-the-art treatise describing the known molecular mechanisms by which bacterial pathogens actively probe, sense, and respond to their environment through 2-component systems and through sigma and anti-sigma factors. In addition, the authors describe in great detail the recognition of host receptors by pili and the pilus biogenesis by chaperon-user pathways. The chapter on the role of sortases on surface expression of surface proteins among gram-positive bacteria is comprehensive and well written. Four excellent chapters describe 6 secretion systems among bacterial pathogens and elucidate the specific mechanisms by which bacterial pathogens usurp intracellular mechanisms of the host cell.This book is enjoyable to read, is extensively referenced, and has 52 superb structural models in full color, based in part on x-ray crystallography. Unfortunately, these plates are all in 1 section and require the reader to page back and forth from specific chapters to the "core color plates." This book is not a compendium of bacterial toxins and virulence factors but rather a selection of molecular mechanisms of host-parasite interaction. This is a unique book that will be a valuable asset for researchers in the field of pathogenesis, graduate students, faculty who teach microbial pathogenesis, biotech companies, and pharmaceutical companies involved in antimicrobial drug or vaccine development.The sophisticated molecular mechanisms that pathogenic bacteria have developed through their evolution with the human host, as described in this book, are credible evidence that our adversaries, the microbes, are doing better than "just making a living."


Skeletal muscle is, in terms of volume, the most abundant tissue in the vertebrate body. It exerts a key role in controlling several physiological functions such as driving locomotion, maintaining body temperature, and hosting a significant portion of the metabolic activity. Myofibers are the primary unit of all skeletal muscles, and they are specialized multinucleated syncytial structures that express a specific array of proteins necessary for muscle contraction.Myofibers are formed during development as consequence of the proliferative growth and fusion of myogenic progenitors, or myoblasts. Similarly to the hematopoietic system, skeletal muscle is formed in subsequent phases of myogenesis involving different stages of myogenic progenitors . NeverthWork over the last 50 years attributed to satellite cells, which are muscle stem cells closely associated with the myofibers, a central role in mediating the regenerative response in skeletal muscle . Even th+ stem cells, adipose-derived stem cells (ASCs), amnion fluid stem cells (AFSCs), muscle-derived stem cells (MDSCs), side population (SP) cells and mesoangioblasts (MABs) , hematopoietic stem cells (HSCs), circulating AC133s (MABs) . The autex vivo expansion. Current applied stem cell therapies generally require many rounds of proliferation prior to use to obtain an adequate number of cells for transplantation purposes. In this issue, Gerben Schaaf et al. give a detailed description of the approaches used to culture different types of stem cells, in a way that preserves their regenerative potential. Particular attention is given to the parameters influencing the myogenic properties of satellite cells and of mesoangioblasts/pericytes, which are currently under evaluation in a clinical trial for the treatment of DMD.One of the major obstacles for the application of stem cells in regenerative medicine is the loss of regenerative and self-renewing potential occurring during Skeletal muscle is not only altered in muscular dystrophies, but is primarily or secondarily affected in various diseases, such as diabetes, AIDS, cancer, and aging. These pathological conditions not only affect muscle fibers, but also alter the properties of the stem cells resident in the muscles . Andrew + interstitial cells (PICs) and satellite cells /fibro-adipogenic progenitors (FAPs)/Pw1te cells . They diThe increasing interest in the application of muscle stem cells in regenerative medicine provides a strong stimulus to understand how the complicated process of muscle regeneration is orchestrated, which cells niches and signals are governing the fate of stem cells, and how the fine equilibrium between the different components of the muscle is affected in pathological conditions. A better comprehension of these events will be crucial in order to develop successful stem cell-therapy approaches for the treatment of muscle diseases.


Prison inmates are reported to exhibit higher rates of disease morbidity, mortality, and health care utilization than the general population , 2. The We determined the frequency of HIV, HBV, and HCV in 6371 male prisoners aged 16 and above examined between January and December 2006 in five prison blocks in the western part of Libya . The stuThese results showed a significantly higher seroprevalence of HIV and HCV among the prison inmates in Libya as compared with the seroprevalence of these infections previously reported in the general healthy group in Libya , 11 or iMany studies from different parts of the world indicated that the prisoners represent a high-risk group for blood-borne diseases. Homosexuality and high-risk behaviors among prisoners may contribute to the transmission of these diseases. However our study neither allows us to determine whether the inmates acquired the diseases while in prison nor does it provide direct evidence of transmission of infectious diseases in prison. Furthermore, as a rule, there are inadequate medical facilities and staff in the prisons in Libya, and access to appropriate care outside the Libyan prison system is very difficult for the inmates. This epidemiological study represents a disturbing reality and is a public health issue. It is clear that inmates have a substantial risk of contracting these infections while they are in prisons. The current study underscores a critical need for local prevention activities. The urgency is augmented by the marked rise in HIV sero-incidence documented among IDUs in Libya and is surely a harbinger of worsening conditions for a variety of opportunistic infections and other sexually transmitted diseases.Hisham ZiglamDepartment of Infectious Diseases, Central HospitalTripoli, LibyaEmail: hisham.ziglam@gmail.comAbdel-Aziz ZorganiDepartment of Microbiology and Immunology, Faculty of Medicine, Tripoli University, Tripoli, LibyaAhmed BalouzDepartment of Chest Medicine, Aboseta HospitalTripoli, LibyaAbdel Hafidh Abudher and Omar ElahmerNational Centre of Disease Control, Tripoli, Libya


Macrophages are highly plastic leukocytes that differentiate from monocytes following their entry into extravascular tissues. Macrophages can enter various tissues under inflammatory or non-inflammatory conditions and assume different functions and phenotypes according to the cues they receive from the environment. The notion that inflammation in general and macrophage responses in particular affect physiological phenomena that were previously considered to be not immune-related has enhanced and broadened our understanding of macrophage function during inflammation and its resolution.This volume brings together 14 manuscripts that cover various aspects of macrophage function during inflammation and its resolution, as well as in several pathologic states for which a significant, long-lasting, macrophage-mediated immune response plays a significant role. Two of the manuscripts present original research on macrophage phagocytosis and its implications. Five provide an overview of macrophage function during inflammation and its resolution, with an emphasis on the modulatory role of particular elements in this response, such as apoptotic leukocytes, specific pathogens, hypoxia, and hormone receptors. The remaining seven manuscripts outline the role of macrophages during inflammation and its resolution in different tissues, including the lung, cardiovascular and adipose tissues, injured skeletal muscle and neuronal tissues, and synovial and oral cavities.The two original research articles are devoted to the consequences of particle engulfment by macrophages. Labrousse et al.  describeOf the review articles that discuss the regulation of macrophage differentiation and function by discrete events, two cover the interaction between macrophages and apoptotic leukocytes during the resolution of inflammation. Korns et al.  outline Several review articles discuss the function of macrophages during inflammation and/or its resolution within distinct anatomical sites, taking into account the unique features of these tissue-specific macrophages, in particular the distinct environments in which they reside and their interactions with neighboring cells. Clària et al.  review cAltogether, the articles in this volume portray the complexity of the multiple roles played by macrophages and members of their lineage during inflammation and its resolution, and their manipulation by the injured milieu. These topics are currently heavily studied, and advances in the field, facilitated by state-of-the-art genetics and optical technologies, will undoubtedly continue to contribute to our understanding of the immune system's response to foreign insults, trauma, and inflammatory disorders.