Squamous cell carcinoma of the external auditory canal, middle ear and temporal bone is a rare and unusual malignancy. The lack of a unifying classification system in the past, along with the rarity of the disease has made the development of clear treatment guidelines difficult. In this report, we describe a clinical case of a patient with this rare malignancy, discuss the challenges associated with the diagnosis and treatment of the disease, and review the literature for trends while outlining the most beneficial treatment strategy for this patient population. The ear canal, middle ear and temporal bone are rare sites of malignancies among which squamous cell carcinoma is the most commonly occurring cancer type . The incWhile there is a lack of data for optimal tumor treatment, a convincing body of evidence has shown that early stage cancer is associated with a higher treatment success and survival rate, compared to late stage disease ,6. ThereIn light of these diagnostic and therapeutic challenges, the present report described a case of advanced squamous cell carcinoma of the external auditory canal in a patient whose cancer was initially diagnosed and treated as osteomyelitis, in the setting of chronic ear infections, at a non-US institution.A 73-year-old Hispanic female with a past medical history of diabetes and chronic left-sided suppurative otitis media that resulted in mastoidectomy in her mid-thirties, was admitted to our institution with left-sided otalgia. The pain was associated with a serosanguineous ear discharge, dizziness, headache, fever, sore throat, generalized weakness and a twenty-pound unintentional weight loss. Previously, the patient had been diagnosed and treated for chronic mastoiditis and later for temporomandibular joint osteomyelitits that extended to the temporal bone. She received several courses of antibiotics, without relief. At the time, cultures of the ear grew staphylococcus epidermidis and diphteroid species. Left ear canal biopsy revealed a small number of keratinizing atypical squamous cells and chronic inflammation, suspicious for neoplasia.6/μl, but otherwise normal laboratory parameters. Cultures of the blood and ear discharge were both negative. The chest roentgenogram was within normal limits. Computed tomography (CT) of the head with and without contrast, revealed a soft tissue mass invading the left middle cranial fossa with destruction of the adjacent sphenoid and temporal bones  or Union for International Cancer Control (UICC) staging system for this type of neoplasm. Arriaga et al suggeste al(et al in 2000  al(et al.Although the lack of a unifying classification, along with the rarity of the disease have made the development of clear treatment guidelines difficult, there have been uniform observations in the literature, that may help us outline the most beneficial treatment strategies for this patient population.Surgical resection is crucial as a treatment modality, and early surgical intervention is associated with increased survival –11. Addiet al(et al(Tumors that are limited to the external auditory canal with or without limited bone erosion and soft tissue involvement are classified as Pittsburgh stages T1 and T2 . In theset al found th al(et al suggest  al(et al.et al(et al(In Pittsburgh stage T3 disease, i.e., with middle ear extension, Kollert et al again reet al. Prasad  al(et al noted th al(et al. While s al(et al, other a al(et al.Involvement of the petrous apex, cochlea, carotid, jugular foramen, dura, temporomandibular joint or the styloid process as well as the presence of facial paresis signal Pittsburgh stage T4 disease . In caseet al(Irrespective of stage of the disease, Moffat et al emphasizet al,14–17. Het al(et al(There is conflicting data in the literature regarding the benefits of chemotherapy with or without radiation. While Ogawa et al did not  al(et al has suggIn a small study  that evaPredictors of poor survival in this patient population include extensive tumor involvement, neck node metastasis, facial nerve paralysis, pain, middle ear involvement, cervical or periparotid lymphadenopathy and concomitant chronic otitis media ,7,15,19.In conclusion, in this report, we describe a case of a rare and aggressive tumor type for which the most beneficial therapeutic approach remains to be determined. It is clear however, that, if diagnosed late, this disease exhibits poor outcomes, while it is associated with higher response rates and increased survival at early stages.Thus, emphasis should be placed on the importance of early detection, diagnosis and treatment of squamous cell carcinoma of the temporal bone and middle ear as the simplest and most effective measure to increase patient survival. We also urge the medical community for prompt diagnostic work-up in patients with chronic and treatment-resistant ear infections.


Throughout the developing world, the long-term consequences of insufficient amounts of essential micronutrients in the human diet can be more devastating than low energy intake. Micronutrients are involved in all aspects of development, growth, and physiology of the human body (including from early embryonic stage), and their deficiencies can cause birth defects, permanent physical and mental impairment, as well as an increased risk of death by infectious and chronic diseases. As plant scientists, we are now facing challenging and urgent goals: how to feed the world's increasing population and how to feed it better. In other words, we need to produce more plant food in sustainable ways and such food should be of the highest nutritional value.This e-Book aims to provide the most recent advances on plant biofortification for micronutrients as well as a comprehensive overview of the different approaches that can be pursued for producing micronutrient-rich staple plants. We list here some of the major points arising from these papers.1, B6, C, or D in edible parts of the plant are discussed, together with the possible effects of such increases on plant tolerance to stress.Vitamins are organic compounds that are required in limited amounts for normal human growth and activity and that cannot be synthesized by the human body. Various genetic engineering approaches for increasing the concentrations of vitamin B1 (thiamin) can result in fatal neurological and cardiovascular disorders. Pourcel et al. . Vanderschuren et al.  to such food crops.Vitamin Bn et al.  comment 3 biosynthesis requires UV-B rays for its photochemical conversion from pro-vitamin D3, a process occurring in the human body; therefore, depending on latitude or season, people may be at risk for vitamin D deficiency if sufficient vitamin D is not consumed through supplementation or through a vitamin D-rich diet. Fish are good sources of vitamin D, whereas only small amounts of vitamin D can be found in plants  for humans, for whom severe deficiency causes scurvy and can lead to death. Sub-optimal vitamin C intake, by leading to increased susceptibility to infections and diseases, can represent a health threat for both developing and developed world populations. In the review by Locato et al. , possiblIron (Fe) and zinc (Zn) are two essential metal micronutrients for human health; their deficiencies in the human diet contribute to high rates of mortality in developing countries. Manganese (Mn) deficiency, though less prevalent than Fe and Zn deficiency, can also lead to serious health problems, including birth defects (Bashir et al., Japonica rice variety were also achieved by stacking a set of Fe homeostasis genes (Masuda et al., Success in increasing Fe and Zn concentrations in polished seeds of a major rice variety in Myanmar, through a transgenic approach targeting metal transport and accumulation, is presented by Aung et al. . In anotPvZIP12, is proposed in Astudillo et al. (OsNAC5 gene in senescence and metal re-mobilization (Ricachenevsky et al., Three different gene families have been described in detail and proposed as possible targets for future Zn or Fe biofortification strategies: the NAC transcription factors (Ricachenevsky et al., o et al.  and a mo−3 to I− and that such reduction is dependent, at least in part, on external iodine conditions. Such results suggest the existence of an iodate reductase in plant roots (Kato et al., 3 during growth.Iodine is a non-metal micronutrient that is essential for human health and whose deficiency impairs thyroid functions. When severe deficiency occurs, fetal development can be affected with consequent irreversible brain damage and mental retardation. A possible approach to produce plants biofortified with iodine is to administer exogenous iodine salts to the soil during plant growth. Kato et al.  demonstrThe papers presented in this e-Book demonstrate how knowledge in plant metabolism, physiology, and molecular biology can provide approaches for increasing the nutritional value of plant derived foods. The contributions also draw attention to the need for multidisciplinary efforts to cope with the challenges of food security and micronutrient malnutrition. We believe that the information presented in this e-Book will provide several novel ideas and will stimulate new directions amongst researchers in the field of plant biofortification. We also hope that these contributions can serve as a good source of background knowledge to educate and bring new scientists into the field. We are indebted to the many authors who have contributed to this e-Book and for their continued work in this important field of science. We feel privileged to have had the opportunity to oversee and edit this fine group of papers.


Denollet et al. claim that high social inhibition and negative affectivity, termed type D personality, predict negative cardiovascular disease outcomes, and notably mortality . Our groWe provided data from our study to Grande et al. for inclusion in their meta-analyses . ConsistIn a further meta-analysis, Grande et al. combined multivariate analyses from Denollet et al. that consistently exceeded the number of allowable covariates, making spurious results likely. Problems in the credibility and generalizability of such overfit regression equations  are not Grande et al. found substantial heterogeneity and evidence of publication bias in their meta-analysis and should have further pursued that this was due to what they termed a striking rift between “very large effects in small studies and low or null effects from the largest studies,”  which weOnly after presenting their analyses, do Grande et al. concede “Our review cannot overcome some serious methodological shortcomings in Type D research,” Grande et al. then cataloged many of the criticisms of this research that we  had prevOur assessment is that this literature is indeed ailing, but we believe that pulling the plug is better than keeping it on life support. There simply is no encouragement from adequately powered studies conducted outside the Tilburg group to continue this line of research. This would be apparent in a meta-analysis that used an appropriate statistical approach in calculating type D and accurately pointed to the source of the publication bias in studies sharing some characteristics: positive results from small samples, inappropriate statistics, and having been conducted by a single investigator group.


In part, this is because viruses so intimately associate with their hosts that decoupling host and virus biology is difficult, and virus-host interactions occur at multiple scales, from within cells to populations, each of which is intrinsically complex. As a consequence, ecologists, population biologists, evolutionary biologists, and researchers from quantitative fields, including mathematics, statistics, physics and computer science, make significant contributions to the field of virology. Our understanding of virus dynamics and evolution has substantially benefited from these multidisciplinary efforts. It is now common to see advanced phylogenetic reconstruction methods used to determine the origins of emergent viruses, to estimate the effect of natural selection on virus populations, and to assess virus population dynamics. Mathematical and statistical models that elucidate complex virus and host interactions in time and space at the molecular and population level are appearing more regularly in virology and biomedical journals. Massive quantities of data now available due to technological innovation in imaging, increased disease surveillance efforts, and novel approaches to determine social contact structure are changing approaches to study the dynamics and evolution of viral infections in heterogeneous environments. The next decade presents exciting new opportunities and challenges for the expanding field of researchers investigating dynamics of viral infections that will lead to innovation and new insight on virus interactions in both individual hosts and in populations. The compilation of articles in this 1.1.et al. [in vitro infection experiments. These investigators assess the dynamics of host innate defenses to two strains of Respiratory Syncytial Virus (RSV) that have distinct epidemiological patterns but can coinfect an individual. The authors used spatial statistical methods to evaluate how the resistance of naïve cells to a challenge infection with one of the RSV strains changed as a function of proximity to a cell infected with a different RSV strain and the time between the primary and challenge infection. In this experimental setting, every infected cell is a data point. An important result of their study is that even in cell lines, asynchrony in growth and replication in a culture can change the susceptibility of cells to infection, which is presumably due to an intrinsic property of replicating or differentiating cells and not an innate immune response to virus infection. However, despite the background heterogeneity in cell susceptibility to infection, the authors demonstrate that one RSV strain, but not the other, can limit the ability of the heterologous strain to establish infection; an effect that would be obscured if the authors had used aggregate instead of point process analysis in their study. Further development of spatial statistical models will be imperative as data on responses of individual cells in population of cells become more widely available.Tissue culture is a mainstay for virologists studying cellular response to virus infection and efficacy of therapeutic interventions and treatment; response variables are typically aggregate counts of infected cells or production of a soluble factor. However, averaging values over cells, which are in different growth phases or stages of viral infection, can obscure or confound important responses to virus infection. Simenov et al.  report oSpecial Issue on “Virus Dynamics and Evolution” reveal important features of virus-host interactions by integrating detailed knowledge of viral life history strategy with viral sequence evolution over the course of infection of the natural host organisms. Virus evolutionary changes are determined by mutation rate and viral generation time and by selective pressures imposed by the host environment. These metrics inform variation in virus replication under changing host conditions. However, there are many features of virus life history strategy that can confound estimating these standard evolutionary parameters. For example, the efficacy of viral strategies to modulate host immunity is not constant over time. As the host environment changes, so does viral replication and this can complicate rate estimates that are based on viral sequence data. Harrison et al. [Three manuscripts in this n et al.  explain et al. [et al. [et al. [Carpenter et al.  address  [et al.  discuss  [et al.  for HBV.et al. [Viral infections, although complex on their own, rarely occur in isolation. Polymicrobial infections can exacerbate clinical consequences to the host but can also attenuate disease. Feline immunodeficiency virus (FIV) infection of its domestic cat host is an exemplary system to explore the mechanisms by which an avirulent FIV strain (PLV) attenuates CD4 cell loss induced by a virulent FIV in the absence of measurable antibody or cellular defenses [et al.  compared1.2.et al. [in vivo infection, virus cycling among host species does not unambiguously constrain virus fitness in either host or lead to a fitness trade off if specialization occurs. On the contrary, fitness can increase in sequential passage of virus between insects and vertebrates and, of significance, virus fitness in some vertebrate or mosquito species may be less constrained than in related host species. Thus, specialization or enhanced fitness in one environment does not necessitate trade-offs. These experimental studies highlight important areas for future research. Much of the work in this field relied on consensus sequencing and therefore failed to assess the full extent of virus diversity. Advances in sequencing technology will allow thorough exploration of sequence diversity from in vitro evolution experiments. However, our understanding of the significance of diversity in viral populations is also limited . DetailWhereas virus life history strategy is a key factor driving virus dynamics and evolution within a host, host life history, behavior, and social structure have profound effects on the patterns of virus transmission and consequently the dynamics of viruses in populations. For example, the number and type of contacts an individual has affects virus transmission in a specified population. Network science provides an intriguing approach to study virus spread in a population of known contact structure . The rel1.3.et al. [Virus infections affect the population structure of host organisms and can have a profound influence on the interaction among individuals and their environment. Hence, the consequences of virus and other pathogen infection are central to the interests of ecologists. Vandegrift et al.  discuss et al.  in this At cellular to population scales, our paradigms in virology are largely based on virus infections that have a detrimental affect on the host. However many—and probably most—viruses are not pathogens and some are beneficial to their host. Not surprisingly, the ecology and biology of apathogenic viruses have not been extensively investigated. The article by Roossinck  provides2.Special Issue reveal new information about virus host interaction at each of these scales and demonstrate the unique perspective that virus evolution provides into the complex environment of the host. New tools will continue to capture virus dynamics and evolutionary change at finer spatial and temporal scales, which will lead to new challenges and opportunities for researchers trained in a variety of disciplines to contribute to data analysis and interpretation. Collectively, these efforts will advance our knowledge of viral pathogenesis, elucidate innovation in evolving protein structures, provide specific targets for therapeutic intervention, and inform models of infection spread in heterogeneous populations.Virus infection is inherently a dynamic process from the protein to the population level. The articles in this


Transcriptomes as assessed by either microarrays or next-generation sequencing have produced a hitherto unprecedented data flood regarding transcript identity and levels in plant systems. Microarray data has been extensively used over the last 15 years or so and evaluation of the data thus produced has progressed well beyond early statistically quality evaluation and descriptive lists to a mature science whereby gene networks and cascades have been able to provide mechanistic insight. The development of sensitive quantitative PCR for lowly expressed genes such as transcription factors has additionally allowed another layer of complexity to be accessed and the modeling of transcription factor expression with that of target genes has met considerable success. Yet more recently, data emanating from RNAseq studies have greatly improved the coverage of transcript profiling. That said, this technology further compounded transcriptome analysis by making it possible to identify differentially spliced transcripts etc. In this research topic we would like to provide an “on the fly” portrait of the use of either microarray or RNAseq based datasets in contemporary Plant Systems Biology.Given the relative simplicity of doing so, much information has been gleaned from microarray datasets by assuming guilt-by-association. The success of this approach is summarized by articles of Provart  and TohgJunker et al.  follow ahttps://www.genevestigator.com/gv). But much information and potentially knowledge is untapped by adopting this approach. This leaves one wondering if aided by modern biostatistics and bioinformatics one shouldn't be able to do better. To improve this situation Klie et al. (However, when it comes to data analysis of whole genome expression datasets, particularly those obtained from complex temporally and/or spatially resolved experiments visualization helps in finding “the meaning within the noise.” Thus, currently the researcher typically zooms in on a particular subset of the data which excites their biological curiosity, often obtaining such data from public repositories such as genevestigator (e et al.  present e et al.  is appliAs is evident from the multitude of manuscripts dealing with microarray data, there is still much to be learned from these data sets. However, time moves on and whilst it seems difficult to teach old dogs new omics tricks, RNAseq is slowly becoming more and more popular. Already machine learning techniques are trickling in to help separating noise from the data. Thus, Thieme et al.  try to fSuch analyses are assuming, however, that one actually knows which transcripts to deal with. But one of the perceived beauties of RNAseq is that one could learn about the transcriptome on the fly whilst analysing the data by assembling the reads into transcripts. This seems, however, an ambituous goal and thus in their article Schliesky et al.  address Rose et al.  then rouFinally, in his article Kliebenstein , tries t


The major commercial NGS platforms available to researchers are the 454 Genome Sequencer (Roche), Illumina (formerly Solexa) Genome analyzer, the SOLiD system (Applied Biosystems/Life Technologies) and the Heliscope (Helicos Corporation). The techniques and different strategies utilized by these platforms are reviewed in a number of the papers in this special issue. These technologies are enabling new applications that take advantage of the massive data produced by this next generation of sequencing instruments.Next Generation Sequencing (NGS) refers to technologies that do not rely on traditional dideoxy-nucleotide (Sanger) sequencing where labeled DNA fragments are physically resolved by electrophoresis. These new technologies rely on different strategies, but essentially all of them make use of real-time data collection of a base level incorporation event across a massive number of reactions  reads produced by NGS Technologies. Another review article [In this special issue, nine papers review and demonstrate the utility and potential of next generation sequencing. One of the biggest consequences with NGS technologies is how to deal with all of the data produced by these platforms. Magi et al.  review tlleagues  introduc article  on bioinet al. [Another application that is particularly well-suited for the types of data produced using NGS is microRNA sequencing. MicroRNAs (miRNAs) and short interfering RNAs (siRNAs) are small RNA molecules of 17 to 24 bases that have been shown to play a critical role in gene regulation by mediating RNA interference. Motameny et al. ,6 in thiet al. [et al. [The subjects of metagenomics  and sequencing of ancient DNA samples are two additional areas where NGS platforms have provided unforeseen opportunities for generating previously unattainable levels of understanding from these samples. Rooks et al.  demonstr [et al.  utilized [et al.  review t [et al.  review dThe articles in this special issue represent a cross section of applications demonstrating the utility of NGS. New sequencing platforms are being introduced  by companies utilizing single molecule detection techniques to record individual DNA molecules during incorporation (Pacific Biosciences) or reading DNA directly by sieving it through nanopores. It is an exciting time in the field of genomics with rapidly changing and advancing technologies. The costs of sequence will surely continue to decrease and new applications of this technology will be introduced to address critical areas in academic and clinical research. I would like to thank all the authors and reviewers who contributed to this special issue and look forward to hearing about new sequencing technologies and application advances in the future.


Some of these actions probably occur through non-conductive mechanisms, such as intrinsic enzyme activity or conformational coupling with other membrane proteins , by an interaction mediated by PDZ domain.Following the lead of the seminal studies in lymphocytes  are homo- or heteropentamers of α and β subunits. These were originally identified in the nervous system, but are now increasingly recognized to be widely expressed outside the nervous system (Egleton et al., Another central aspect of the function of normal and neoplastic cells is the regulation of cell volume, as reviewed by Pedersen et al. . This ap+ to support cancer cell survival and invasiveness and is the only human CA isoform containing an extracellular proteoglycan domain (Monti et al., A key step of the neoplastic progression is the regulation of cell migration, whose derangement is implicated in the metastatic cascade (Becchetti and Arcangeli, Several of the above papers describe the potential therapeutic applications of targeting specific ion channels and transporters. Cancer treatment is however more specifically addressed by Huber et al. , who illBesides illustrating some of the hot topics in the field, the papers of the present Research Topic Issue constitute a most useful introduction to a literature that has already become too vast to be mastered by a single investigator.


Methanocaldococcus jannaschii in 1996 (Bult et al., The publication of the genome of This collection of 11 papers attempts to put this quiet maturation in archaeal molecular biology in context with a mix of overview articles (Atomi et al.,


Dear Editor,et al.[We thank Rath et al. for the et al. and theiet al. is the same.They are correct in their supposition that the patient reported by us and Patil et al.[et al.[To quote from our article, “We are reporting this case because orbital involvement of actinomycetoma is very unusual. In our review of the literature, we did not come across any such case.” We do not claim to be the first to report a case of orbital actinomycetoma. Our literature search did not bring up the articles by Pagliani et al. and Sulll.[et al. and we tet al.[At the time of submission of our article (September 2008), we were not aware that this article was to be submitted by the dermatology department . Our ar


To the Editor,In our review article entitled “MicroRNA dysregulation in multiple sclerosis” published online on January 22nd, 2013, we have made an error that we would like to correct.We request to change the following sentences in the review article:“Examination of Treg cells in MS (De Santis et al., To“Examination of Treg cells in MS (De Santis et al., We would also like to apply this change in a revised figure Figure  that refFrontiers in Genetics and to the authors of the De Santis et al., manuscript, for this error that was not corrected during the review process of our manuscript.We apologize to the readers of


The burden of post-malaria cognitive impairment is often overlooked. Given the large number of infections occurring worldwide, the magnitude of the problem is likely to be substantial. The objectives of this paper are; (i) to assess the evidence on post malarial cognitive impairment or impact on school education; (ii) to assess the possible positive impact of malaria drug prophylaxis on cognition; and (iii) to suggest recommendations on minimizing the burden of post-malarial cognitive impairmentPUBMED and SCOPUS were searched for all articles with the key word 'Malaria' in the title field and 'cognitive impairment' in any field. Google Scholar was searched for the same keywords anywhere in the article. The search was restricted to articles published in English within the last 15 years (1995-2010). After filtering of abstracts from the initial search, 44 papers had research evidence on this topic.Cognitive abilities and school performance were shown to be impaired in sub-groups of patients  when compared with healthy controls. Studies comparing cognitive functions before and after treatment for acute malarial illness continued to show significantly impaired school performance and cognitive abilities even after recovery. Malaria prophylaxis was shown to improve cognitive function and school performance in clinical trials when compared to placebo groups. The implications of these findings are discussed. Mortality and morbidity due to malaria is still substantial in many tropical countries. In 2006, 247 million cases of malaria were estimated, resulting in 881,000 deaths [There exists an important hidden burden of malaria, namely, that of cognitive impairment and effects on school performance resulting from malaria infection in children. This effect could be postulated to have a long-lasting impact on patients' lives preventing them from achieving their full potential. This impact is difficult to summarize in terms of DALYs or traditional cost evaluation methods of estimating direct losses due to illness. However, given the large number of infections occurring worldwide annually, and the potential impact on lives of patients and family, this hidden burden is likely to be considerable.et al in 2001 on the same topic concluded that malaria infections  have a lasting effect on cognition, behaviour and performance in children [et al (2006) on post malarial cognitive impairment conclude that a significant proportion of children with cerebral malaria and severe falciparum malaria are at risk of subsequent cognitive impairment. This impairment in cognitive abilities was seen in all cognitive spheres; language, attention, memory, visuospatial skills and executive functions [A review published by Holding children . Howeverunctions ,4.This paper reviews the current evidence on cognitive impairment due to malaria and aims: (i) to assess the evidence on post malarial cognitive impairment or impact on school education; (ii) to assess the possible positive impact of malaria drug prophylaxis on cognition; and (iii) to suggest recommendations on minimizing the burden of post-malarial cognitive impairment.PUBMED and SCOPUS were searched for all articles with the key word 'Malaria' in the title field and 'cognitive impairment' in any field. Google Scholar was searched for the same keywords anywhere in the article (both terms together). The keywords were kept less specific to collect all relevant articles in the first screening. The search was restricted to articles published in English within the last 15 years (1995-2010). There were 971 abstracts in the original search with these restrictions. The software Endnote X3  was used to filter articles. Bibliographies of cited literature were also searched. All abstracts were read independently by the three authors, and key articles were identified based on a consensus among all authors. Related or cited papers were also included. Sources were screened for relevance to the topic. These sources included review articles published in core clinical journals, cohort studies, interventional studies, case control studies, case series and cross sectional analyses related to malaria and post infection cognitive impairment. The epidemiological data were downloaded from the websites of international agencies, such as the World Health Organization (WHO). After filtering of abstracts from the initial search, only 44 papers had research evidence on this topic.et al [In the past, recovery from cerebral malaria has generally been thought to be complete. Early studies suggested that neurological sequelae were relatively uncommon ; howeveret al  who asseet al [Idro et al  reportedIt is interesting to note the high percentage of behavioural problems observed in this series which included behaviours closely resembling a formal diagnosis of attention deficit hyperactivity disorder (ADHD), conduct disorder and pervasive developmental disorder. While it may be questioned whether the behavioural disorders were causally linked to cerebral malaria, it should be noted that the behavioural problems had started after recovery from cerebral malaria. The changed behaviours were well noticeable and disruptive to daily functioning of the child and family. These changes could be attributed to an alternative explanation (side effects of phenobarbitone) in only one child.Another study of behavioural problems following a diagnosis of cerebral malaria (n = 64), has also reported effects such as withdrawn/depressed behaviour(15.6%), thought problems (12.5%), aggressive behaviour (9.4%) and oppositional defiant behaviour (9.4%).et al [Though cerebral malaria may have a causal role in cognitive impairment, some authors hold that seizures per se during a malarial episode may not be strongly associated with cognitive impairment. Kihara et al  assessedet al retrospectively assessed a cohort of children aged 6-9 years who had an episode of cerebral malaria [et al, Carter et al showed that persistent epilepsy after malaria has an impact on cognition. Abubakar et al [et al, the role of seizure prophylaxis during an acute phase is still open to discussion. The failure to see a benefit in the treatment arm may be due to the use of phenobarbitone in the initial study which itself can cause cognitive impairment.In addition to short-term ill effects, cerebral malaria may have a long-term impact on cognition as well. Carter  malaria -12. Agaiar et al  assessedet al [In another prospective study over two years, John et al ,15 asseset al -18.et al [Many authors have acknowledged the difficulty in applying formal neuropsychological testing adopted in western populations to rural African communities given the cultural, language and educational differences. Therefore Kihara et al  have recet al [et al [et al [et al [et al [et al [Reliable predictors for cognitive impairment following cerebral malaria are clearly of importance. Kihara et al  identifil [et al  in theirl [et al . Holdingl [et al  suggest l [et al  in a sepl [et al describe l [et al  in theirl [et al ,12.et al, have assessed the impact of malaria on cognitive performance in Sri Lanka where a majority of the malaria infections acquired by children are acute uncomplicated febrile episodes from which they make an apparent complete recovery when treated. Several studies were carried out taking into consideration that school performance is a reflection of the cognitive ability of a child and is dependent on a number of factors including facilities available at school, the quality of teaching and other social factors such as parental supervision. In the first study, Fernando et al [There are few studies assessing the impact of post-malarial cognitive impairment outside Africa. Fernando do et al  assessedIn order to confirm these findings, two other studies were carried out in Sri Lanka ,24. The A further investigation was carried out to determine the impact of an acute attack of malaria on short-term educational achievements and on school absenteeism . Six hunet al [th centile for class/grade) school performance (p=0.04). Interestingly, in a small scale study (n=97) Boivin et al [Al Serouri et al  in a caset al . The numin et al  have demMany of the studies carried out outside Africa have demonstrated that uncomplicated malaria per se was a significant predictor of cognitive function after controlling for potential confounding factors. This further strengthens the fact that malaria contributes significantly to loss of school time, ill health and poor performance.et al [et al [Many of the studies cited above had arms with children diagnosed as having cerebral malaria. How certainly a diagnosis of cerebral malaria can be made would also affect the interpretation of results. In an autopsy study of 31 children thought to have died from cerebral malaria, Taylor et al  demonstrl [et al  and overl [et al -32. The l [et al . It is net al [et al [Taking this factor into account, Birbeck et al  followedl [et al  in anothHowever, it needs to be appreciated that the studies cited above are not comparable to each other in their designs and results for many reasons. Some have followed up patients with severe malaria, some with cerebral malaria and some have compared these two entities with healthy community controls. Others are more different in that they have enrolled participants from communities who would have had a spectrum of malaria infections from asymptomatic parasitaemia to severe malaria. Similarly, the age range of children tested also varied significantly and this brings forth two issues; the inapplicability of formal cognitive testing to very young children and the differences of cognitive impairments that would be observed depending on the age. The developing brain is more vulnerable to insults but some authors suggest that it may recover from it also due to plasticity. Damage to neuronal circuitry during early childhood may cause obvious defects in memory, language and learning but more subtle changes involving social sensitivity, social integration and executive functions may appear later as the child ages and when such skills become important. On the same note, there are many other confounding factors that can affect the observations of cognitive impairment such as, home and family environment, nutrition, quality of teaching, cultural and language barriers in applicability of neurocognitive testing. In fact, malaria transmission itself is determined by prevalent socioecomonic conditions of the community which may render some children more vulnerable than others and some communities more at risk compared to others. Therefore when referring to cognitive and behavioural effects of the studies cited above, all these coviariates and confounding factors have to be acknowledged. The 'cognitive' impact itself is not a single entity but varies according to the severity of illness, age of the child and methods of measurement.et al [While there are many studies assessing the cognitive impairment of children after malaria, the impact on adults is not addressed by systematic research. In an earlier study, Dugbartey et al  have shoIt is of fundamental interest to establish whether malaria is causally related to cognitive impairment, poor school performance and other behavioural disturbances as reported in previous studies. Cognitive impairment can be hypothesized to be an end result of many confounding factors  and it is important to understand whether malaria itself can be demonstrated as an independent causative factor for cognitive impairment.et al [In the study by Idro et al  the neuret al [et al [et al [et al [In the study by Kihara et al  which shl [et al ,11 the rl [et al  also shol [et al  which deIn the other community based studies outside Africa, similar adjustments were made for confounding factors and still the results showed a significant association even between uncomplicated malaria and cognitive impairment or school performance -26.Overall, in summation, it is fair to assume from reported methodology that all the key studies had made adjustments for potential confounding factors and still found a significant association for post malarial cognitive impairment after complicated/cerebral malaria as well as after uncomplicated attacks. This strongly favours an argument for malaria as an independent causative factor for cognitive impairment. The studies on the impact of malarial prophylaxis on cognition quoted later under the subtopic 'malaria and cognitive impairment; strategies on prevention and rehabilitation' of this article (see below) provides further evidence regarding the causal role of malaria in cognitive impairment. Still, what is obscure is the exact pathology for this impairment. The following section summarizes the current knowledge base in this regard.et al assessed the levels of different cytokines in cerebrospinal fluid (CSF) in 76 children with cerebral malaria and compared it with eight controls [The pathology of cerebral malaria and its neurocognitive sequelae is still open to debate. It is assumed that parasitic sequestration within cerebral circulation with resultant hypoxia, host immune response and cytokine induced damage via nitric oxide production may contribute to neuronal cell death . Animal controls . Many cyet al [As certain cognitive domains  and higher functions (speech and language) are shown to be selectively affected in cerebral malaria, it is also plausible that imaging studies such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may reveal the involvement of specific brain areas related to these functions to be affected by cerebral malaria. However there are no case series or systematic studies with MRI/PET evidence other than isolated case reports ,40. Potcet al  report aet al ,14,39.Plasmodium berghei strain ANKA do manifest many characteristics of infection similar to cerebral malaria in humans. Desruisseaux et al [Attempts are being made to model the impact of cerebral malaria in animal models in view of extrapolating the findings to humans. However, such comparisons may not be valid due to species differences of both the host and the parasite. Still, it is observed that mice strain C57BL/6 infected with ux et al  studied ux et al .Failure to understand the pathogenesis of cerebral malaria has significantly slowed the development of neuroprotective pharmacological measures during the acute stage of illness. Different agents are being assessed on animal models with promising results but human trials are not still under way. The B5 complex provitamin pantetheine and the immunomodulatory agent glatiramer acetate have both shown promise in animal studies by down regulating the immune response . High doet al[Cognitive impairment of children living in endemic areas and the impact of prophylaxis has been assessed by a limited number of studies ,47,46,47et al [et al [A study with a different experimental design  assessedet al . In the l [et al  when thel [et al .et al [A more recent trial by Clarke et al  assessedConsidering the outcome of this study, a follow up controlled randomized trial is now underway in Kenya that plans to assess the impact of improved health  on improved literacy skills. The randomized design has divided schools in the region to 4 groups (25 schools in each group) to receive malaria intervention alone, literacy intervention alone (skill development of teachers in teaching English and Swahili), both interventions and none (control). The study is expected to be completed by 2012 .Still, rather than concentrating on pharmacological prophylaxis alone, there are many other cost effective simple measures of preventing malaria such as residual insecticide spraying and insecticide impregnated bed nets . Simply Another avenue to explore is the prevention of identified adverse prognostic indicators for subsequent cognitive impairment by the studies cited above. These include; preventing hyperpyrexia, hypoglycaemia, malnutrition and seizures during acute illness. The place for such measures needs to be properly assessed by trials.et al [The 'rehabilitation' strategies for post malarial cognitive impairment are another area assessed by several recent trials. The effect of cognitive training on children affected by severe malaria has shown a positive impact in a study by Bangirana et al . Sixty fet al [Cognitive rehabilitation in cerebral malaria has still not been evaluated extensively by systematic studies. Much of the speculated benefit of cognitive training is extrapolated from the studies on cognitive training in traumatic brain injury. Though 'traditional' therapist centered or computer based cognitive retraining may indeed be beneficial, the feasibility of such interventions in resource limited settings  is questionable. In a recent review on cognitive rehabilitation of children with cerebral malaria, Bangirana et al  describeet al [The number of studies assessing the impact of malaria on cognitive functions were few and those assessing the impact of prophylaxis were even fewer. The number of patients enrolled in observational studies and case series were in the range of 20-200 except in the trial by Clarke et al . In addiHowever despite these limitations some common themes emerge in the analysis of observations in the previously mentioned studies:1. The cognitive abilities and school performance were impaired in the groups with malaria  in almost all the studies at a statistically significant level compared to healthy controls.2. Hypoglycaemia, seizures and coma during cerebral malaria have been shown to predict later cognitive impairment ,17,20.3. While observations are made regarding cognitive impairment based on neuropsychological test batteries that concentrate on clinical performance, these are not supported by biochemical or imaging studies which could help to elicit the underlying pathology.4. Studies comparing cognitive functions before and after treatment of acute illness continue to show significantly impaired school performance and cognitive abilities even after recovery compared to healthy controls ,25,26.5. However, the three studies on malarial prophylaxis all show improved cognitive function/school performance compared to placebo groups at the end of follow up which in two studies were more than one year ,47,49.Given the large number of infections in endemic areas, these findings carry much weight and needs to be highlighted. This 'hidden' burden of malaria is often unnoticed and overlooked but may place vulnerable populations  at a disadvantage by causing cognitive impairment resulting in poor school performance and non achievement of full potential in life. This burden of illness is difficult to quantify and is probably much larger than the already publicized tangible costs of malaria. It must also be highlighted that treating an established attack of malaria in a child and preventing malaria in the same child have different consequences. As suggested by the available evidence, the latter option is the better choice.Therefore it is recommended that:1. Countries where malaria is endemic should pay special attention to prevent malaria by appropriate prophylaxis for populations at risk.2. Such programmes must pay special attention to infants, toddlers and children as this is a crucial age in cognitive development and for schooling. However, cognitive impairment in adults may also be significant but unfortunately this has not yet been assessed properly.3. The impact of malaria on cognitive development must be highlighted and the public should be educated to ensure compliance in prophylaxis campaigns.4. Early identification and treatment of malarial fever should be given priority with providing necessary infrastructure and staff education on clinical and parasitological diagnosis.5. Attacks of cerebral malaria, coma, seizures and hypoglycaemia during an acute attack must be actively looked for and avoided to prevent later cognitive impairment and local guidelines should stress these facts.Areas for further research on this timely topic include;1. Establishing the effect of acute malarial infections and prophylaxis on cognitive functions of adults in endemic areas.2. Observational studies to identify the pathophysiology of post malarial cognitive impairment by correlating biochemical markers, serum and CSF cytokine levels and imaging studies with clinical findings.3. Assessment of long term cognitive impact of recurrent malarial attacks with a longer prospective follow up (more than one year) with intermittent cross sectional assessments.4. Development of methods to quantify the impact of post malarial cognitive impairment in terms of financial costs.The authors declare that they have no competing interests.All authors have participated in designing, article search, information coding and writing of the manuscript. All authors have read and approved the final manuscript


Dear Editor,In recent article which is published in your journal Crisan D et al.  has beenNow in calculation of the severity of liver fibrosis, liver biopsy stayed the gold standard; however the acceptability of this method by patients is low. In addition this method has some major limitation and its limitations made it a non-favorable method . But it


Attention is one of the oldest and most pivotal themes in cognitive science. A current and widely accepted theory holds that anatomically-distinct, hierarchically-organized networks, each responsible for specific components of the attention process , constitute the attention system (Posner and Petersen, Geva et al.  recentlyA first interesting aspect of Geva et al.'s paper relates to the investigation of the putative interaction among the different attention networks, and in particular between the alerting and orienting components, a somewhat controversial topic that has recently received great interest. In fact, while Callejas et al.  showed tper se as in earlier theories of LC–NE activity (Aston-Jones et al., A second aspect of Geva et al.'s work that deserves particular attention is related to their attempt to extend the Aston-Jones and Cohen's  adaptiveIn summary, Geva et al.  provide


The purpose was to develop a questionnaire, gathering the professionals’ opinion, to measure the degree of collaboration between clinicians from different levels of care  in a given healthcare organisation. This questionnaire was originally developed to assess processes of care integration in the Basque Health System (Spain), but can also be used in other contexts.The questionnaire was based on the four-dimension model and 10 indicators of interprofessional collaboration in healthcare organisations proposed by D’Amour et al. [The resulting questionnaire was pre-tested and its construct validity and homogeneity evaluated in three healthcare organisations of the Basque Health Service.A 10 items questionnaire has been developed. Each of its items corresponds to one of the indicators proposed by D’Amour et al. [


Acute appendicitis is the most common surgical abdominal emergency. Immidiate diagnosis of this disease is crucial, because this condition can lead to appendiceal perforation, potential peritonitis, and even death. We read with great interest the article ‘The role of red cell distribution width (RDW) in the diagnosis of acute appendicitis: a retrospective case-controlled study’ by Narci et al. and wanted to discuss whether RDW alone provide certain information about the inflammatory status of the patient with acute appendicitis. We read with great interest the article ‘The role of red cell distribution width in the diagnosis of acute appendicitis: a retrospective case-controlled study’ by Narci et al. . They aiRDW which is used in the differential diagnosis of anemia, is an automated measure of the variability of red blood cell size . PreviouIn a previous study, two novel biomarkers, calprotectin (CP) and serum amyloid A (SAA) were found to be related to acute appendicitis . Recent We are of the opinion that the findings of Narci et al.  will leaWe have no competing interests to declare.


Additional remote-sensing information and output from land surface models were used to identify that groundwater losses are the major source of this trend. The approach used in this study provides an example of “best current capabilities” in regions like the Middle East, where data access can be severely limited. Results indicate that the region lost 17.3±2.1 mm yr−1 equivalent water height of groundwater during the study period, or 91.3±10.9 km3 in volume. Furthermore, results raise important issues regarding water use in transboundary river basins and aquifers, including the necessity of international water use treaties and resolving discrepancies in international water law, while amplifying the need for increased monitoring for core components of the water budget.In this study, we use observations from the Gravity Recovery and Climate Experiment (GRACE) satellite mission to evaluate freshwater storage trends in the north-central Middle East, including portions of the Tigris and Euphrates River Basins and western Iran, from January 2003 to December 2009. GRACE data show an alarming rate of decrease in total water storage of approximately −27.2±0.6 mm yr Amery and Wolf, Wolf and Newton, Wolf, Integrated Regional Information Networks, U.S. Department of Agriculture (USDA), Michel et al., Sullivan, Water scarcity in the Middle East, and the high frequency of conflict that emerges over what few resources do exist, is well established [e.g., Solomon, Food and Agriculture Organization (FAO), Wolf and Newton, Bayazit and Avci, FAO, Water management in the Tigris-Euphrates River Basin has been historically challenging Solomon, . The TigUnited Nations, Weiss, Two major issues complicate water management in the region. First, there are no formal water allocation rights for both surface and groundwater. At the core of this dilemma are underlying differences in the interpretation of international water law [Chenoweth et al., Jones et al., Kavvas et al. [A second challenge is the paucity of hydrologic data for the region. Inconsistent monitoring combined with a lack of data transparency and accessibility is a problem that plagues water managers around the globe, and the Tigris-Euphrates region is no exception. Such data scarcity and inaccessibility result in an incomplete understanding of water availability and use in this area of the Middle East. Although there have been other studies in the region [s et al.  showed tTapley et al., Lettenmaier and Famiglietti, Rodell et al., Tiwari et al., Famiglietti et al., Rodell and Famiglietti, Wahr et al., Ramillien et al., Syed et al., Yeh et al., Rodell et al., Ramillien et al., Zaitchik et al., Rodell et al., Tiwari et al., Famiglietti et al., Reager and Famiglietti, Andersen et al., Yirdaw et al., Leblanc et al., Agboma et al., Chen et al., Swenson and Wahr, Wang et al., Satellite observations of time-variable gravity from the Gravity Recovery and Climate Experiment (GRACE) satellite mission [Wada et al. [Siebert and Döll [In this study, we used 84 months of GRACE data (January 2003 to December 2009) to examine the behavior of water storage in the north-central region of the Middle East, an area that includes most of the Tigris and Euphrates River Basins and western Iran. Additional data sets, including precipitation, evapotranspiration, streamflow, reservoir levels, and soil moisture, were compiled to help characterize the causes of observed variations and emerging trends. As an area that is well known for water scarcity and tension over transboundary waters, the Tigris-Euphrates region offers a compelling example of the power of satellite observations to provide insight into critical water resource issues in regions where hydrological observations are otherwise difficult to obtain. a et al.  and Sieband Döll  develope2. It includes most of the Tigris River Basin, the upper and middle section of the Euphrates River Basin, and western Iran. Consequently, we refer to the masked region in The specific study area within the Tigris-Euphrates region see  was seleGerman Federal Institute for Geosciences and Natural Resources (BRG) and United Nations Educational, Scientific, and Cultural Organization (UNESCO), The TEWI region spans the countries of Turkey, Syria, Iraq, and western Iran. Portions of Georgia and Azerbaijan, as well as all of Armenia, are also included in the study region, as are several large surface water bodies, namely, Lake Daryace, Lake Van, Lake Tharthar, the Asad Reservoir, and the Qadisiyah Reservoir. In addition to the area's surface water, a complex groundwater system [Siebert et al., Land use within the broader area surrounding the study region must also be considered. This broader area encompasses southeast Turkey, where most of the water management infrastructure—dams, reservoirs, and canals—of the GAP project is located. Additionally, there is extensive irrigation for agriculture in the study region and the broader surrounding [Chambers, Swenson and Wahr [Swenson and Wahr, Velicogna and Wahr, −1) was computed after removal of the annual signal. Note that the impact of contributions of the Caspian Sea, which abuts the TEWI region to the northeast, to variations in total water storage, were determined to be minor, accounting for less than 1.5% of the TEWI trend in total water storage.We used 84 months, from January 2003 to December 2009, of GRACE-derived variations in total terrestrial water storage computed at the Center for Space Research at the University of Texas at Austin [and Wahr , 2009 inRodell et al., Xie and Arkin, Derber et al., Pfaendtner et al., An extensive search for hydrological data in the region confirmed that in situ observations were publicly unavailable during the time period of interest. Consequently, to better understand the water balance dynamics in the study region, we used output from the NASA Global Land Data Assimilation System (GLDAS) [Liang et al., Chen et al., Koren et al., Dai et al., Kato et al., Koster et al., Syed et al., Zaitchik et al., In this study, we used the results of three land surface models from GLDAS—VIC [Observed precipitation and model outputs for evapotranspiration and streamflow were combined in the water balanceP is precipitation, E is evapotranspiration, Q is streamflow, and all are expressed in mm mo−1. Model-derived−1) of the anomalies of total water storage described above. GLDAS outputs for soil moisture and snow water equivalent were combined with satellite altimetry measurements of lake and reservoir heights (described below) in order to understand the respective contributions of each to the total water storage variations from GRACE. Outputs were prepared as monthly anomalies with respect to the study mean (mm) and as trends (mm yr−1) after removal of the annual signal.where Laboratoire d'Etudes en Géophysique et Océanographie Spatiales (LEGOS), Crétaux et al., Remotely sensed altimetry data from the Hydroweb database at Laboratoire d'Etudes en Géophysique et Océanographie Spatiales (LEGOS) were used to calculate variations in water storage from surface water bodies [−1) was also determined after the annual signal was removed. We used these data to ultimately infer the contribution of surface water variations to the total water storage variation observed by GRACE.Altimetry data for monthly water heights were converted to monthly changes in water volume using measurements of the mean surface area for the respective water bodies, as provided by LEGOS. We combined these values and divided by the total area of the region to calculate the anomaly of surface water storage (mm) with respect to the mean of the study period. The trend in surface water storage  and SW′ (6.4 mm), respectively, onto the least-squares-estimated trends and are 0.6 mm yr−1 and 0.4 mm yr−1, respectively. Errors for soil moisture and snow water equivalent trends are the standard deviations of the trends computed from the three land models used in the GLDAS simulations , using the methods based on the study by Kato et al. [−1 and 0.5 mm yr−1, respectively.o et al. , which sG′ is computed similarly to equation .Monthly error on equation  and plotGRACE observations of monthly terrestrial water storage anomalies were compared with the GLDAS-simulated anomalies for the study region, which were taken as the mean of the three land surface models . The comRodell and Famiglietti, Rodell et al., Rodell et al., Syed et al., Swenson and Wahr, Swenson et al., Yeh et al., Syed et al., Wahr et al., Swenson and Wahr, Swenson and Milly, Niu et al., Syed et al., Niu et al. [Lo et al. [First, numerous studies have demonstrated that the GRACE data capture natural water storage variations very well when compared with observations [u et al.  found tho et al.  used GRATiwari et al. [Famiglietti et al., Third, land surface model simulations of total water storage will deviate significantly from GRACE observations in areas where human water use and management  dominate the regional storage balance. For example, i et al.  subtractSwenson and Wahr, Wang et al., Famiglietti et al., Rodell et al., Syed et al., 2008; Yeh et al., Given the fact that the Tigris-Euphrates River Basin has extensive water infrastructure, the impacts of water management may significantly influence the trend in water storage anomalies in the TEWI region [−1 for the study region. This equates to a −20.5±0.4 km3 volume loss of water each year, for a total volume loss of approximately −143.6±2.8 km3 during the study period. This rate of water loss is among the largest liquid freshwater losses on the continents [Rodell et al., 3 loss during the 7-year study period is nearly equivalent in volume to the entire Dead Sea, which has an average volume of 147 km3.−1, and the trend in snow water equivalent was −0.9±0.5 mm yr−1, representing volumetric losses of −2.3±1.4 km3 yr−1 and −0.7±0.4 km3 yr−1, respectively. These negative trends are largely climate driven and reflect the regional drought mentioned above. Together they account for roughly one fifth of the observed water losses.−1 with an equivalent volume loss of −4.4±0.3 km3 yr−1, or nearly 20% of the total volume of water lost during the 84 month period studied. It is likely that our surface water trend underestimates the actual trend as only five water bodies comprised the calculation, Lakes Daryace, Van, and Tharthar and the Asad and Qadisiyah Reservoirs, and changes in the respective surface areas are not taken into account. As mentioned above, the five water bodies for which altimetry data were available likely represent approximately two-thirds of the actual surface water storage changes within the boundaries of the study area . By assuming a constant surface area, our estimate of monthly surface water storage is overestimated; however, with this assumption of constant surface area, the rate of decrease, or trend, is actually underestimated. Thus, in both cases (missing reservoirs and neglecting surface area shrinkage), we underestimate the surface water storage trend. Consequently, our estimates in the residual groundwater storage component may be overestimated. As discussed above, we acknowledge the shortcomings and additional uncertainties that this contributes to the study; however, we suggest that this work offers an example of a “best available” approach for regions where in situ data are inaccessible.Surface water storage anomalies are shown in −1 , a considerable loss that accounts for 63% of the total water storage change from 2003 to 2009. As seen in Following equation , groundw3 over the 7-year period studied. This loss is particularly alarming for regions such as the TEWI region, which is already facing severe water scarcity. The analyses presented here suggest that groundwater depletion is the largest single contributor to the observed negative trend, accounting for approximately 60% of the total volume of water lost, the majority of which occurred after the onset of drought in 2007. As we do not have in situ data to validate these conclusions, we acknowledge that there is uncertainty in this analysis, which we have attempted to quantify. However, we believe that this combination of remotely sensed and modeled data provides a very valuable alternative for understanding hydrologic changes occurring in data-scarce regions.The GRACE data indicate a total water volume loss of nearly 144 kmAlipour et al., Lashkaripour et al., Motagh et al., Michel et al., Although in situ hydrologic observations are nearly impossible to obtain, the results presented here are consistent with published reports from the region. Land subsidence due to overabstraction of groundwater near Tehran, Iran, is well documented [Famiglietti et al., Chulov [Chulov [Water use behavior in Iraq during the study period followed the typical pattern of increased groundwater abstraction in response to drought and declining surface water availability [, Chulov , by the  [Chulov  noted thSalman, UN Environmental Program (UNEP), Wolf and Newton, The water management response to the drought in the Tigris-Euphrates Basin portion of the study area, and the overall negative TEWI water storage trend, raises the critical issue of effective, science-informed transboundary water management strategies. Unfortunately, international water law fails to provide a guiding principle for transboundary management in the Tigris-Euphrates Basin as its application varies from nation to nation. Consequently, Turkey, Syria, and Iraq have foregone any legally binding water allocations or management practices for the two rivers. In the absence of binding agreements, downstream users—Syria and Iraq—are dependent on upstream water management decisions—by Turkey—which ultimately determine the downstream flows of the Tigris and Euphrates [Directorate of State Hydrolic Works (DSI), Harris, Ozdogan et al., FAO, Zawahri, Without an effective international water management strategy, each country is free to act unilaterally. Economically, each is dependent on Tigris and Euphrates water for agricultural irrigation, a core component of the national economies. In fact, the main purpose of the expansive GAP was to provide water resources for agriculture expansion in southeast Turkey [USDA, The consequences of this lack of transboundary management are clear from this study. The ultimate downstream user is left with little surface water availability and must deplete its nonrenewable reserves of groundwater. After the drought began in 2007, agricultural productivity declined for all three nations. Upstream, Turkey was least affected, with most crop yields slightly declining or remaining constant. However, downstream in Syria and Iraq, significant, larger declines occurred in all crops, particularly barley USDA, . The dec3 of water was lost in the TEWI region from 2003 to 2009. Using supplementary data sets from global hydrologic models and from satellite altimetry in a mass balance framework, we determined that the drivers of this trend were a combination of drought and corresponding increases in groundwater use. Approximately 91 km3 of the total amount of water lost during the study period came from groundwater.Our analysis highlights the role that the GRACE mission, and other recent and near future advances in hydrologic remote sensing, can play as important new tools for regional and transboundary environmental decision making. The study described here offers a valuable and unique opportunity to understand hydrologic trends in a data-inaccessible region such as the region of the Middle East studied here. Using GRACE data, we reported that nearly 144 kmOur analysis also placed this research in its regional economic and political context. Economically, this crisis resulted in the loss of agricultural yields, unemployment, emotional hardship, and mass migrations. Politically, the response to the drought represents a missed opportunity for cooperative transboundary water management.Swenson and Wahr, Tiwari et al., Rodell et al., Famiglietti et al., Famiglietti et al., Wood et al., Hopefully, we provided valuable insights for a region with little transparency in its water management decisions and few publicly available data sources. Although there is no substitute for ground-based observational data, GRACE and other emerging satellite water sensors will provide a unique tool for water management across the globe. Presented with a holistic picture of changing water availability, while confronted with the common problems of preserving and protecting this shared resource, nations and states may experience new incentives to collaborate on water management issues across political boundaries. Moreover, the synoptic view from space may ultimately render data denial and management opacity policies obsolete, as water management practices are being increasingly revealed from space [Emerging advances in hydrologic remote sensing and hydrological models, combined with enhanced access to observational data, suggest that the opportunity to construct the most accurate and holistic picture of freshwater availability, for a particular region or across the globe, is now on us. Such science-informed studies are essential for more effective, sustainable, and in transboundary regions, collaborative water management.


Laparoscopy was introduced more than 15 years ago into clinical practice. However, its role in colorectal surgery was not well established for want of better skills and technology. This coupled with high incidences of port site recurrences, prevented laparoscopic surgery from being incorporated into mainstream colorectal cancer surgery. A recent increase in the number of reports, retrospective analyses, randomized trials and multicentric trials has now provided sufficient data to support the role of laparoscopy in colorectal cancer surgery. We, thus, present a review of the published data on the feasibility, safety, short - and long-term outcomes following laparoscopic surgery for colorectal cancers. While the data available strongly favors the use of laparoscopic surgery in colonic cancer, larger well powered studies are required to prove or disprove its role in rectal cancer. The morbidity and mortality associated with surgical procedures performed on the colon and rectum have plagued surgeons since time immemorial. As surgeons began to perform open colorectal surgery with increasing confidence these very same problems assumed high significance until the principles of antisepsis and the refinements in surgical technique began to make a considerable dent in these negative outcomes. At this same time, surgeons had already explored the role of minimal invasiveness in treating colorectal problems, viz. the use of the sigmoidoscope to deflate a sigmoid volvulus, perineal procedures for prolapse in elderly persons, etc. The laparoscopic cholecystectomy in 1987 in France, performed by Philipe Mouret for the first time during a laparoscopic gynecologic surgery, rapidly established its role in place of open surgery.[Laparoscopy for colorectal cancers has not gained universal acceptance for a number of reasons3Questions on feasibility: Laparoscopic large bowel surgery is much more complicated than laparoscopic cholecystectomy with a steeper learning curve. It requires more advanced laparoscopic technique.Early reports of port-site recurrence / implantation in laparoscopic port sites.–8Presence of an anastomosis or stoma prevents rapid discharge from hospital.The efficacy of large bowel laparoscopic surgery for cancer with respect to factors like tumor clearance and the fear that laparoscopic surgery enhances tumor dissemination.Safety - this implies that laparoscopic surgery carries with it not only some of the general complications encountered with surgery on the bowel, but also a set of unique complications that can occur more or sometimes exclusively only in laparoscopic surgery, e.g., pneumothorax, gas embolism, port site hernias, etc.Advances in techniques of laparoscopy that have paved the way for a shift in the role of laparoscopic surgery in colorectal diseases from the initial intended role of an adjunct to open surgery, to an important operative modality have been, firstly, the realization of the benefit of such a procedure in elderly patients where the morbidity of the large incision of open surgery can be overcome by the reduction in pain and overall bacterial contamination. Videolaparoscopic techniques in colorectal surgery were used for the first time in 1990 by Moises Jacobs in Miami, Florida while performing a right hemicolectomy. The deveThe most important aspect if the feasibility of laparoscopy has to be assessed in case of colorectal malignancies is to unconditionally prove that the oncological resection, i.e., the margins of resection - proximal, distal and circumferential and the number of nodes harvested are comparable, if not better than in open surgery.et al also concluded that the distance of the tumor from resection margins and the number of lymph nodes harvested with the operative specimen did not vary from those obtained in open surgery.[et al, however, noted that the difference in distal resection margins (4.6 cm in the lap group versus 5.3 cm in the open group) were statistically significant in favor of open surgery. On the basis of correlation they concluded that laparoscopic surgery was as adequate as the conventional approach. Bretagnol et al, have shown that R0 resections could be achieved in 93% of patients undergoing laparoscopic low colorectal and coloanal surgeries.[Numerous studies313 in th3 surgery. A recent surgery. showed turgeries.et al[The introduction of laparoscopy into the armamentarium of surgery for colorectal cancer has brought, along with the novel idea of minimal access, a novel set of complications associated with the creation of pneumoperitoneum, port placement and diathermy use that require a considerable amount of skill as well as specialized training if they have to be prevented. et al concludeet al to 29%.[et al The concet alet al,[et al,[Braga et al, in theirl,[et al, have shol,[et al, on the sl,[et al, have beel,[et al, has concet al,[et al,[Laparoscopic colorectal surgeries have constantly been under scrutiny with respect to the long-term outcomes - survival data and recurrence rates. The data available–35 has s1836et al, have evel,[et al, have in l,[et al, has showl,[et al,40 have set al[et al,[et al,[After the first reported port site metastasis in 1978, numerouset al had stroal[et al, found noal[et al,44–46 foul,[et al, the incil,[et al, meticulol,[et al, wideningl,[et al,While the operative time for laparoscopic surgery is obviously more than that for open surgery, there are several beneficial outcomes resulting directly from the use of laparoscopy as compared with open surgery. As there is no large abdominal incision, the corresponding postoperative pain and the ensuing need for analgesia is reduced.23274748 23274729The incidence of small bowel related problems postoperatively including adhesive obstruction and the incidence of postoperative ventral hernias have also been seen to be on the lower side in the laparoscopically resected group of patients.The incidence of injuries to the pelvic autonomic nerves during dissection in rectal cancers has been associated with bladder and sexual dysfunction. An increased rate has been noted in some studies.–53 This Laparoscopy has been shown to have an important role in early colonic carcinomas viz, laparoscopic-assisted colonoscopic polypectomy, laparoscopic wedge resection and laparoscopic colostomies with a 67-100% success rate for avoiding a formal bowel resection. This can be achieved by preoperative colonoscopic tattooing for localization.According to the data available, laparoscopic surgery definitely appears to have a role in colonic malignancies. The short-term and long-term outcomes clearly favor this approach. It should be realized, though, that the benefits of laparoscopic surgery can be obtained only when performed by persons trained in the art of laparoscopy so as to avoid unnecessary morbidity and even the risk of mortality. As for rectal cancer, the present data on the role of laparoscopy is not mature enough, especially for anterior resections. At present, laparoscopic anterior resection should only be considered within the context of clinical trials.


In the Discussion of our paper, we mentioned that such abnormalities were not observed in an earlier study using long-term IUE of ChR2 under the same promoter (Huber et al., In our recent paper (Miyashita et al.,


Science by Liu and Imlay (Escherichia coli act via the production of reactive oxygen species (ROS). This hypothesis contradicts the view, proposed by Kohanski and colleagues  dye fluorescence. Furthermore, the authors assumed that this quenching was due to the production of hydroxyl radicals. This belief in an ROS-mediated bactericidal mechanism has now been challenged  initially formed by the Fenton reaction rather than the hydroxyl radical decomposition product.Recent articles in nd Imlay , and Kernd Imlay  questionlleagues , that balleagues  came to Pseudomonas putida is resistant to the bactericidal activity of ampicillin and the bacteriostatic activity of chloramphenicol. This resistance is achieved via TtgABC efflux pump-mediated extrusion of the antibiotics (Godoy et al., et al., et al., et al., et al., 2+ formed in the presence of bactericidal compounds enhances killing in addition to the direct inhibition of cell wall assembly, protein synthesis or interference with DNA metabolism.


OccasioDuring evolution, DNA base mutations occurred intracellulaly and not in extracellular environments. The DNA polymerase components that are involved in DNA replication directly influence the base composition of the genome (Zhao et al.,


In their valuable article, Knops et al.  challengWe take the liberty of adding own results in this commentary which further support these findings. We have also tested the OME in typically achieving children and a matched group with developmental dyscalculia (DD) Table . TypicalTogether with the findings of Knops et al., it seems that the left–right associations underlying the OME are dependent on development and experience. One might hypothesize that a complex interaction between visuo-spatial and attentional processes together with number related skills influence its development whereupon an early predisposition to relate representations of non-symbolic numerical magnitude to spatial length builds a core system (De Hevia and Spelke, According to the assumption of such a hierarchical and interwoven model of OME, the impairment of one or several aspects may affect the development of the OME negatively.DD is a specific learning disability of number processing and calculation. In addition to profound problems in numerical understanding, abnormalities in visuo-spatial, and attentional processes have also been associated with DD.As expected, no OME was observed in our tested group of children with DD Figure . TherefoIt is important to note that an adult control group is missing in our study. However, since Pinhas and Fischer  demonstrKnops et al. argue that the lack of an OME during childhood speaks against a flawed compression-uncompression mechanism as the driving factor of the operational momentum bias, which implies that the OME is caused by a systematic bias during uncompression of a logarithmic representation of the MNL. Furthermore, number representations change from a logarithmic mapping to a linear mapping scheme during development and familiarity in a number range (Siegler and Opfer, In contrast to the cohort of Knops et al., children in our study were older and showed a linear function describing the MNL representation like in adults, but exhibited no OME. Moreover, our results indicated that even after the completion of a specific number line training (Kucian et al., Findings reported by Knops et al. and our study corroborate that the OME is not necessarily present in childhood and unlikely to be caused by flawed uncompression of the MNL. In addition, our results further point to a possible negative impact of DD on the development of the OME. In conclusion, the OME is probably dependent on development and a complex interaction of the maturity of numerical skills, visuo-spatial, and attentional processes as well as cultural conventions.


A recent review paper, published online on April 24 2012 in Frontiers in Psychology, argues that antidepressants interfere with the normal homeostatic response of the body and cause more harm than good  improve both mental and physical health outcomes (Katon et al., Finally, the argument that evidence from randomized control trials that show little difference between antidepressants and placebos proves that antidepressants are not effective is a simplistic interpretation of the data. Recent work has demonstrated that these trials show small mean differences between the two groups because they lump responders together with non-responders. When looking at subgroups of responders, there are large differences between antidepressants and placebo (Thase et al.,


Chronic fatigue syndrome (CFS) is characterized by fatigue, sleep dysfunction, and cognitive deficits (Fukuda et al.,  Myalgic Encephalomyelitis/chronic fatigue syndrome (CFS) is an illness characterized by persistent excessive fatigue , post-exertional malaise, flu-like symptoms, and cognitive impairments  is a disease characterized by orthostatic tachycardia without orthostatic hypotension. In other words, patients with POTS often experience an excessive increase in heart rate when they stand up. POTS is known to be comorbid with CFS. In particular, POTS is often commonly found to be comorbid with adolescents with CFS  contributes to orthostatic intolerance (OI), a symptom of both CFS and POTS  (Demitrack et al., It is clear that understanding cognitive impairments and symptoms in CFS and POTS is not a simple task. However, the common theme suggests some sort of impairment within the central nervous system. Further research should focus on the central nervous system as a possible gateway of understanding the etiology of these disorders further.Patients with CFS and POTS suffer from cognitive impairments that could lead to difficulties with daily functioning. Although there are studies that question the presence of cognitive impairments in CFS (Altay et al., Patients with POTS experience a mental clouding known as “brain fog” (Raj et al., Cognitive impairments in both CFS and POTS have the potential to create problems with daily functioning, including difficulties with school and employment. Cognitive impairment is a core symptom of CFS, and the presence of cognitive impairments is part of the definition of CFS (Fukuda et al., 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.


Curiosity about the numerical abilities of non-human animals has been a topic in experimental psychology for about as long as such a science has existed. Some of the earliest comparative work looked at how well animals could use number as a cue in making different kinds of judgments. Early results were mixed, and in some cases were incredibly controversial . After the “fall” of behaviorism and the “rise” of cognitive psychology, the question of numerical competence became one of the dominant research areas in the new field of comparative cognition. The present series of papers in this special topic represents the newest additions to that research area. This special topic also serves as an anniversary of sorts, as it comes 25 years after one of the most influential papers on the subject of numerical competence in animals . Subitizing remains an interesting phenomenon, sometimes evident in animal research but other times not evident (see Murofushi, Davis and Perusse  and the This special topic encompasses 16 novel studies, including mammals (e.g., Beran et al., The special topic also includes theoretical and research studies on human infants. In particular, attention has been focused on number-space interaction (de Hevia et al.,


Crystal structures of a membrane protein transporter in three different conformational states provide insights into the transport mechanism. Microbacterium liquefaciens, has been determined in three conformational states; from this a mechanism is proposed for switching from the outward-facing open conformation through an occluded structure to the inward-facing open state.Secondary active transporters move molecules across cell membranes by coupling this process to the energetically favourable downhill movement of ions or protons along an electrochemical gradient. They function by the alternating access model of transport in which, through conformational changes, the substrate binding site alternately faces either side of the membrane. Owing to the difficulties in obtaining the crystal structure of a single transporter in different conformational states, relatively little structural information is known to explain how this process occurs. Here, the structure of the sodium-benzylhydantoin transporter, Mhp1, from  Many of these integral membrane proteins can be broadly categorized into two classes, primary and secondary transporters. Primary transporters are energized by the hydrolysis of ATP, redox reactions or light. Secondary transporters, on the other hand, harness the energy stored in electrochemical gradients across the membrane to the transport process (Crane et al., 2008et al., 2010Many transporters are thought to work by an alternating access mechanism. The principle of this mechanism, which was first proposed in 1966 (Jardetzky, 1966Microbacterium liquefaciens is a member of the nucleobase-cation symport-1 family of transporters (Suzuki & Henderson, 2006et al., 2010l-hydantoins into l-amino acids (Suzuki & Henderson, 2006Mhp1 from 2.et al., 2008et al., 2005et al., 2008et al., 2009et al., 2010et al., 2009et al., 2009et al., 2009The crystal structure of Mhp1 was solved initially at a resolution of 2.85 Å (Weyand i.e. the structure was outward-open in the definition of the alternating access model (Fig. 3et al., 2005E. coli in defined media in the presence of selenomethionine (Shimamura et al., 2010In the initial structure of Mhp1 a large cavity was present extending from the extracellular face of the protein into the centre, el Fig. 3 and did 3.et al., 2010The conformational changes that take place as the protein goes from outward-open through the occluded to the inward-open state can be described best by considering the core ten TMs in three parts Fig. 4 (ShimamuIn going from the outward-open structure to the occluded structure the N-terminal half of TM 10 bends, closing over the substrate in its binding site. At this resolution there are no other significant movements that can be assigned unambiguously. However, there is a small but definite shift of the hash motif and C-terminus towards the bundle. To switch the substrate binding site from facing outward to facing inward a surprisingly simple rigid body rotation of 30° of the hash motif relative to the bundle occurs around an axis roughly in line with TM 3. This simultaneously blocks further the substrate binding site from the outside and opens it to the inside. This rotation is accompanied by two other main changes to the protein. Firstly, TM 5, the N-terminal equivalent of TM 10, flexes in a similar manner to TM 10 to open the cavity further to the exterior. Secondly, a small extracellular helix moves to seal the extracellular face of the protein completely.4.et al., 2009The mechanism of converting between the different states of the protein has also been described in terms of two sets of gates: thick and thin (Krishnamurthy 5.et al., 2008et al., 2010The sodium and substrate binding sites are located at the interface of the bundle and the hash motif. In the outward-facing structures both are intact with the sodium ion interacting with residues on TM 1 and TM8 and the benzylhydantoin fitting snugly between the indole rings of Trp 117 on TM 3 and Trp 220 in TM 6 Fig. 5. In the 6.et al., 2008et al., 2008et al., 2005et al., 2005et al., 2010The derivation of the mechanism above was enabled by our knowledge of the three structures of Mhp1. Since Mhp1 is part of the LeuT superfamily the question arises as to whether this mechanism is also relevant for the other members. This superfamily contains proteins with very different substrates that are regulated by sodium or by protons and both symporters and antiporters. For the sodium-coupled symporters it seems likely that the switching between the outward- and inward-facing structures is based on the same principle. A similar mechanism of the switching between outward- and inward-facing conformations caused by a rigid-body movement of the four-helix bundle relative to the rest of the protein was, in fact, first proposed for LeuT based on the asymmetry of the crystal structure and investigated more thoroughly using a mutational analysis of the serotonin transporter (Forrest


In a nomenclature proposal published in 2010 monocytes were subdivided into classical and non-classical cells and in addition an intermediate monocyte subset was proposed. Over the last couple of years many studies have analyzed these intermediate cells, their characteristics have been described, and their expansion has been documented in many clinical settings. While these cells appear to be in transition from classical to non-classical monocytes and hence may not form a distinct cell population in a strict sense, their separate analysis and enumeration is warranted in health and disease. Human monocyte subsets are typically analyzed in multi-color flow cytometry using antibodies to CD14 (the LPS receptor) and CD16  was not significantly increased in the intermediates but antibody staining showed a specific twofold higher expression for TIE2 protein.Zawada et al.  used SupThese data show that delineation of monocyte subsets cannot be restricted to the transcript level but will have to take on board all the other levels of gene expression including the proteome.TIE2-expressing monocytes strongly overlap with and may be identical to the intermediate cells.The Zawada findings of high TIE2 protein expression in the intermediates is in line with earlier work by Murdoch et al.  and receThere have been transcriptome studies into intermediate monocytes in non-human primates by Kim et al.  and theyMost functional studies into monocyte subsets have looked at two types of cells  with intermediate monocytes being excluded or allotted to one or the other of the two main monocyte types. However, a few studies specifically addressing functions of the intermediates have been published.Looking at cytokine production Skrzeczynska-Moncznik et al.  isolatedEarlier functional studies by Grage-Griebenow et al.  defined in vitro model revealed a selective cluster formation for the intermediate monocytes. Together with the selective increase of TIE2 protein expression and a similar increase of endoglin and VEGF receptor 2 by the intermediates (Zawada et al., TIE2-expressing monocytes in the mouse has shown that among blood mononuclear cells only these cells are capable of inducing a capillary network (De Palma et al., Also, studies in an angiogenesis in vitro culture they develop into non-classical monocytes or into a unique progeny, which is different from the progeny of classical or non-classical monocytes. If it can be demonstrated that intermediate monocytes give rise to a unique type of DC or macrophage then this would support the concept that they are a biologically meaningful monocyte subpopulation.Monocytes are precursors for dendritic cells and macrophages. For the non-classical monocytes a higher propensity to become DCs with a higher capacity to induce T-cell proliferation and IL-4 in CD4 T-cells has been reported (Randolph et al., In clinical settings the intermediate monocytes have been noted to increase in number in several diseases (for a detailed review, see Wong et al., For rheumatoid arthritis Cooper et al.  noted a In adult survivors of childhood acute lymphoblastic leukemia intermediate monocytes were found increased along with increases of several inflammatory markers (Sulicka et al., When testing M-CSF in preclinical trials Weiner et al.  have notIn a model of viral infection, injection of the TLR7/8 ligand R-848 into non-human primates was shown to lead to a strong increase in intermediate monocytes on day 1 followed by a peak of non-classical monocytes on day 2 (Kwissa et al., Whether or not the intermediate monocytes, induced by various stimuli, go on to develop into non-classical monocytes may be dependent on the type and on the strength of the stimulus.When comparing gene expression patterns in classical and non-classical monocytes for man versus mouse it was noted that a differential gene expression between the two subsets was reverse in man and mouse for a number of biologically relevant genes (Ingersoll et al., Since the discovery of the CD16-positive monocytes by flow cytometry this approach has been used to distinguish these cells from the major population of classical monocytes. A third population of intermediate monocytes initially had been overlooked because of its low number and transitional nature. Now clinical studies have demonstrated that these cells can strongly expand and laboratory analyses have shown intermediate but also unique features for these cells. Specific markers for the intermediate monocytes will be required in order to unequivocally identify and enumerate these cells.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.


TO THE EDITOR: The recent article by Demir et al.  in your For instance, artemin enhances transcription of bcl2 – leading to it's up regulation and thereby augments tumor growth in human non-small cell lung carcinomas (Tang et al., Increased expression of artemin is also seen in esophageal carcinomas. Interestingly transfection with a mir-223 vector decreases expression of artemin and thereby suppresses tumor growth in esophageal carcinomas (Li et al., The above examples clearly illustrate the significant enhancement of oncogenicity secondary to artemin in tumors ranging from lung carcinomas to endometrial carcinomas. There is a clear and urgent need to identify inhibitors of artemin function in order to improve the prognosis in these tumors.


Diabetes is a major threat to global public health. According to the latest data from the International Diabetes Federation (IDF), at least 366 million people are living with diabetes and this number is projected to be 552 million by 2030. At least 50% of people with diabetes suffer from one or two major diabetic complications such as diabetic cardiomyopathy, nephropathy, neuropathy, retinopathy, and diabetic foot diseases. Development of an authentic model of each type of diabetes and their associated complications, which exactly mimic the human pathogenesis, is very crucial not only for a better understanding of the core causes of the diseases but also for the development and routine pharmacological screening of novel anti-diabetic drugs. A number of genetic and nongenetic animal models of the different types of diabetes and their associated complications have been developed in last three decades but none of them are without limitations.This special issue of the Journal of Diabetes Research has been designed to publish original and review articles with novel approaches of the development of animal model of diabetes and its associated complications. Almost all areas of the animal models of diabetes and its associated complications have been covered by this issue. Among the reviews: the animal models of diabetic retinopathy by A. K. W. Lai and A. Lo, animal models of diabetic neuropathy by M. S. Islam, murine models of diabetic neuropathy by L. L. Kong et al., methods and models for metabolic assessment by G. Pacini et al., and porcine models of accelerated coronary atherosclerosis by D. Hamamdzic et al. contributed significantly by summarizing the advantages, disadvantages, and suitability of animal models developed to study the above-mentioned diabetic complications. Many other original papers such as role of adrenomedulin in the renal NADPH oxidase and (pro)renin in diabetic mice by M. Hayashi et al., development of glomerulopathy in the KK.Cg-Ay/J mouse with the pathology of diabetic nephropathy by P. Stephen et al., and the role of ERK/MAPK and TGF-beta/Smad signaling pathways in the kidney fibrosis of diabetic mice by X. Cheng et al. contributed novel information in the pathogenesis of diabetic nephropathy, a major and common complications of diabetes mellitus. Finally, an exceptional paper has been contributed by E. Hillhouse et al. on the effect of nearby construction on the progress to overt autoimmune diabetes in NOD mice. As a whole, papers from almost every aspects of the animals models of diabetes and its associated complications have been published in this special issue so it can be a special interest of diabetes researchers particularly those who are working in the different areas of diabetic complications.Md.  Shahidul  IslamMd.  Shahidul  IslamDaisuke  KoyaDaisuke  KoyaBernard  PorthaBernard  Portha