Chemistry Central Journal focusses on the genetically determined chemistry and biochemistry occuring in the cell.Molecular biology is an established interdisciplinary field within biology that deals fundamentally with the function of any nucleic acid in the cellular context. The molecular biology section in How can thousands of chemical reactions interact smoothly to maintain the life of cells, even in a variable environment? How is this self-sustaining system achieved? These are questions that should be answered in the light of molecular biology and evolution, but with the application of biophysical, physico-chemical, analytical and preparative technologies.Chemistry Central Journal, I hope to receive manuscripts that present new approaches aimed at better answering and shedding light upon these fascinating questions related to the chemistry of livings cells.As the Section Editor for the molecular biology section in  Chemistry Central Journal? Can molecular biology articles in this journal compete with contributions found in other excellent specialised molecular biology journals?At the outset, let me pose two important questions: Why is it necessary to have a molecular biology section within To answer these questions, let me start by first describing how the term molecular biology is understood today, before looking at the field in a chemical context.in situ or in vitro. The foundation of such techniques lies in the complementary nature of the genetic information contained in nucleic acids.Broadly, molecular biology aims to investigate the molecular genetics of all organisms, including man, by identifying mutants or genetic aberrations that are often the cause of diseases. Intense genetic studies on model organisms have cast light on the processes of morphological development, cell differentiation, and the control mechanisms governing organ (re)generation. Molecular biologists have generated their own specific methods to solve problems inherent in their field. Here of course I refer to techniques such as DNA recombination and nucleic acid amplification by PCR, whose functional basis is the manipulation of biological processes to gain deeper insight into complex molecular interactions either The specific goals of molecular biology research are the discovery and more detailed understanding of the structure and function of genetic material, namely DNA and RNA, and in particular, how these molecules determine the smooth running of metabolic processes. Such investigations are more or less independent of the organism studied, as the conserved function of DNA and RNA in all organisms guarantees the continuation of this self-sustaining chemical system from one generation to the next.In surveying the field of molecular biology one can only marvel at the fundamental similarities of many (bio)chemical reactions and processes – take, for example, the elaborate system of genes involved during the phase of early development. It is these similarities between complex processes that give us the possibility of categorizing molecular biology into several subdivisions. For example universal cellular processes like protein insertion and secretion or G-protein coupled signal transduction are self-dependent subdivisions of molecular biology.It is always fascinating to consider that in a cell, thousands of different biochemical reactions can proceed under constant temperatures, such as in homoiothermic mammals and birds. In contrast, the complex metabolic network of poikilothermic organisms, like fish or plants, also include the same metabolic chemical reactions!In cells several anabolic and catabolic reaction chains are separated from each other by 'compartments' like mitochondria, the endoplasmic reticulum, lysosomes, and many more. It is noteworthy that in all these separate locations, there occur different biochemical reactions, which are not however excluded from the intracellular mass transfer. For each 'compartment', transport proteins exist in the membranes responsible for the uptake and discharge of small molecules. Such transport can occur actively against the concentration gradient under ATP consumption or passively through protein channels in the membrane. Other organelles, such as the Golgi apparatus, exhibit a vesicular transport system for both generating new organelles like endosomes, and transporting proteins and small molecules within these vesicles. The directed transport processes between each 'compartment' occur in a finely tuned and controlled fashion. The genetic basis for these regulatory and control processes is one major source of interest in molecular biology research.Thus to return to our initial question, as I have outlined, it is clear that molecular biology, with its special emphasis on the self-sustaining capacity of the cell's complex chemical reaction network, has a close relationship with the field of chemistry. All (bio)chemical reactions, including their regulation, have been transferred from one generation to the next for millions of years. Selectivity has resulted in the existence of highly conserved molecular processes; whilst conversely and interestingly, some metabolic pathways cannot be traced back to any specific origin owing to their occuring in only a few recent organisms.The formative biological research activities of the last decade have been the genome sequencing projects of uni-cellular and multi-cellular organisms, including man. Surprisingly, the sequenced genomes have only shed limited light on increasing the understanding of the relationship between a gene and its expression and regulation. For instance, even the rudimentary question, 'what is a gene?', cannot yet be answered unambiguously.Genome sequences between several human individuals can vary drastically, so it is often impossible to predict from the DNA-sequence alone who will be susceptible to a disease and who will remain healthy. All cellular organisms have in common a high variability, which includes, for example, gene order, protein sequence, glycosylation patterns and membrane constitution. This variability is further complicated by the fact that many different organisms share conserved metabolic concepts, such as the low energy delivery glycolysis pathway, the Krebs cycle for high chemical energy production, the genetic code or the protein translation apparatus. I think it is this dialectic principle, resulting from the dichotomy of great variability coexisting with strict conservation – not only on the molecular level but also on the organism level – that makes molecular biology a particularly fascinating discipline. Almost every year, progress in the field of molecular biology provokes at least a significant modification of existing concepts, and sometimes even a paradigm change.I mentioned at the outset techniques native to molecular biology, such as recombinant DNA and several other techniques like nucleic acid amplification by PCR, high resolution microscopy and very sensitive protein detection systems. These have helped accelerate the growth of our vast, but scattered, knowledge. Furthermore, significant progress in microarray techniques has delivered data on complex expression profiles, including post-translational modifications like glycosylation and phosphorylation. Here the differences in the patterns observed for normal and cancerous cells allow one to perform a classification of cellular subtypes. The expression profiles of cells from different tissues may even identify the activity status of metabolic pathways and their phylogenetic conservation. A combination of expression profiling data with confocal fluorescent microscopy and imaging processing allows one to locate protein expression activities within the cell. By combining all these data, one will be able to construct an image of the cell in time and space that will deepen our understanding of molecular interactions.Metabolic processes can also be probed through the fine tuning of gene activities by silencing genes with small interfering RNA (siRNA) and microinterfering RNAi. Whilst the determination of the sequences and 3D structures of biological macromolecules have been significantly enhanced by many sophisticated biophysical techniques, also employed by chemists, such as MALDI and multidimensional NMR. Such techniques permit the identification and characterisation of many protein variants with unique catalytic centres and glycosylation/phosphorylation patterns that are specific for many different chemical reactions. Analytical techniques can now be performed almost quantitatively.Thousands of articles on molecular biology are published each year, meaning that inevitably experts can hardly keep a detailed track of research progress, even in their particular field. I am convinced that the principal benefits of open access publishing – that is to say, free and unhindered access to scientific research, rapid publication, authors' retention of copyright for their own work, free distribution and deposition of articles – will benefit the molecular biology community, and help cope with the huge flood of research in this field.Chemistry Central Journal's parent company, BioMed Central, already operates a number of successful journals in the field of molecular biology – notably Algorithms for Molecular Biology, BMC Molecular Biology, and the Journal of Molecular Signaling – and related disciplines. In addition, BMC Bioinformatics complements molecular biology by concentrating on data mining and computer-based simulation systems, concepts which can help significantly support molecular biologists' experimental work.Chemistry Central Journal, touch upon areas of interest to molecular biologists. Such overlap cannot be avoided, but rather serves to underline the interdisciplinary character of molecular biology.Of course a number of BioMed Central's other already-established open access titles, as well as the chemical biology section in Chemistry Central Journal it is inevitable that both themolecular biology and chemical biology sections will complement and enrich each other. Of course, when submitting a manuscript, an author can select up to 3 sections by which to classify the article.However, that said, each of these journals or sections have their own particular focal points. For example, the chemical biology section in this journal focusses on small organic molecules and their interactions with target proteins; while the aim of the molecular biology section, however, will be to publish research highlights whose focus is the innate chemistry of the cell and its evolution, as well as the fascinating theme of gene regulation and expression in all organisms. Thus, within Chemistry Central Journal because of the broad nature of our journal's audience – reaching from specialists in the field to those working in other fields but looking for cooperation partners to accelerate a common project – helped by the unhindered access to the journal's published research. All research presenting good science will be considered for publication and I am looking forward to receiving fresh and novel submissions.Finally, I also want to encourage molecular biologists to publish in the key to every biological problem must finally be sought in the cell" [nothing in biology makes sense except in the light of evolution" [I would like to close my commentary with two summatory statements: the first by Edmund B.Wilson: "he cell" ; and theolution" .


Kaposi sarcoma (KS) flare may occur following therapy with corticosteroids, as part of the immune reconstitution inflammatory syndrome seen with highly active antiretroviral therapy (HAART), and after rituximab therapy. The exact mechanism responsible for iatrogenic KS flare is unclear.A case of AIDS-associated cutaneous KS flare following rituximab therapy was compared to similar controls by means of immunohistochemistry using vascular makers , monoclonal antibodies to Human Herpesvirus 8 (HHV8) gene products , as well as B-lymphocyte (CD20) and T-lymphocyte  markers.CD20+ B-cell depletion with rituximab in KS flare occurred concomitantly with activation of the HHV8 immediate early gene protein K5. KS flare in this patient was successfully treated with liposomal doxorubicin and valganciclovir.Rituximab-induced KS flare appears to be related to HHV8 activation. Effective management of iatrogenic KS flare therefore depends upon the control of HHV8 viremia in conjunction with specific chemotherapy for KS. Kaposi sarcoma (KS) is a multifocal, angioproliferative tumor related to Kaposi's Sarcoma Herpesvirus/Human Herpesvirus-8 (KSHV/HHV8) infection. HHV8 is a member of the gamma-herpesvirinae sub-family, in which gene expression and viral replication are regulated by latent, immediate early, early, and late viral gene transcription . During Histologically, KS lesions are comprised of spindled shaped tumor cells, abnormal vessels and a variable chronic lymphoplasmacytic inflammatory infiltrate. KS lesions grow from an early patch stage, to form plaques, which ultimately develop into a nodular (tumor) stage. Most of the cells found in both KS lesions and HHV8-infected cultures are latently infected , althougKS exacerbation (flare or recrudescence) has been documented following therapy with corticosteroids -6, as paWe present, for the first time, the pathology of rituximab-induced KS flare. By means of immunohistochemistry, we set out to study the potential role of host immunity, as well as that of specific HHV8 gene products, in the pathogenesis of KS flare.Institutional Review Board approval from Baystate Medical Center and Beth Israel Deaconess Medical Center was obtained for this study. Informed consent was obtained from the patient to perform this study and publish the findings.3 and his HIV viral load was greater than 100,000 copies/ml. His physical examination was notable for massive lymphadenopathy involving cervical, occipital, supraclavicular, axillary, groin and epitrochlear areas with lymph nodes measuring up to 1 cm in diameter. A CT scan also demonstrated marked lymphadenopathy of his chest, abdomen, and pelvis. Biopsy of an axillary node confirmed MCD, containing HHV8 (LNA-1) immunoreactive lymphoid cells. Treatment was begun with prednisone 1 mg/kg to control his symptoms, and rituximab 375 mg/m2 once weekly for 4 consecutive weeks as definitive treatment for MCD. One week after starting rituximab, he developed a biopsy-proven KS plaque lesion on his leg , chills, drenching night sweats, lassitude, diffuse myalgias and arthralgias. He had been started on HAART several months prior to this presentation, which was discontinued due to the development of a rash. Prior to the initiation of HAART, his CD4 T-cell count was 363 cells/mm04°F, chiThe aforementioned patient's biopsy was compared to similar (control) cutaneous plaque-stage KS lesions from two AIDS patients with stable KS disease. Formalin fixed, paraffin embedded routinely processed tissue was studied. The antibodies and dilutions used are summarized in Table The histomorphology of the KS flare case and that of the controls was unremarkable. In all specimens, CD34 and CD31 similarly highlighted spindled tumor cells and the abnormal vasculature within these lesions. LNA-1 nuclear granular immunoreactivity was of equal intensity and proportion in scattered KS tumor cells of all specimens. However, K5 staining was identified only in occasional cells , thereby facilitating KS development . Other rLymphocytes are an integral component of KS tumors. Peripheral lymphocytes, particularly B-cells, are also the major latent reservoirs of HHV8. As compared to normal skin, KS tumors typically contain a high density of CD3+ T-lymphocytes, and fewer CD20+ B-lymphocytes . In factExactly how B-cell depletion causes KS growth is most likely related to HHV8. Rituximab has previously been noted to cause Hepatitis B reactivation with related fulminant hepatitis . In vivoOur data demonstrate that B-cell depletion with rituximab in patient's at risk for KS development may activate HHV8, resulting in unwanted KS flare. Given the expanding therapeutic use of rituximab, caution is required when using this monoclonal antibody in patients at risk for developing KS. Nevertheless, in HHV8+ patients with MCD we feel that rituximab is still the treatment of choice. Finally, based upon the resolution of our patient's KS flare following appropriate therapy, effective management of iatrogenic KS flare appears to depend upon the control of HHV8 viremia in conjunction with chemotherapy for KS. Valganciclovir, when administered for 8 weeks, has been demonstrated in a randomized placebo-controlled trial to suppress HHV8 replication . AlthougThe authors declare that they have no competing interests.All authors contributed equally to the manuscript. LP coordinated the study and interpreted all immunostains. KF and AVM provided monoclonal antibodies. SM performed all stains. BJD was the treating physician. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS.Participants were enrolled into one of four groups on the basis of HIV and KS status . Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR).78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men , persons with KS  and persons with HIV infection . Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected . Genital HHV-8 detection was rare (9 (3%) of 272 swabs).HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda. African (“endemic”) Kaposi sarcoma (KS) was originally described in Uganda in the 1960s Human herpesvirus-8 (HHV-8) is the causative agent of all forms of KS Lytic HHV-8 replication in the vascular compartment is thought to play an essential role in the pathophysiology of epidemic KS To gain insight into the pathophysiology of HHV-8 replication in association with endemic and epidemic KS in Uganda, we conducted a prospective cohort study using detailed sampling methods among HIV-infected and HIV-uninfected persons with or without KS to describe the sites and patterns of HHV-8 mucosal and plasma replication in a region where both HHV-8 and KS are highly prevalent.Eighty-seven participants were enrolled in the study: one participant did not have histological confirmation of KS, and another participant enrolled but was lost to follow up before collecting any oral swabs: these participants were excluded from further analyses . Eighty-The remaining cohort consisted of 78 participants who were distributed across four groups: 17 HIV negative/KS negative, 19 HIV positive/KS negative, 20 HIV negative/KS positive and 22 HIV positive/KS positive . EighteeOverall, 2969 (89%) of 3354 expected samples were collected and available for analysis, and subjects attended 377 (97%) of 390 protocol visits. From the 78 subjects, a total of 2063 oral swabs were collected on a median of 29 days per person and of these, 428 (21%) had HHV-8 DNA detected by PCR. The quantity of HHV-8 detected in oral swabs was highly correlated between participant-collected and clinician-collected oral swabs  participants had HHV-8 DNA detected from oral swabs (“shedding”) on ≥1 day. The proportion of participants with oral HHV-8 shedding was significantly higher in persons with KS as compared to those without KS (p = 0.002). Three (18%) HIV negative/KS negative persons and 5 (26%) HIV positive/KS negative persons had HHV-8 DNA detected from the oral mucosa. In contrast, 10 (50%) HIV negative/KS positive and 14 (64%) HIV positive/KS positive persons had oral HHV-8 shedding , Table 2Three hundred fifty eight plasma samples were collected from the 78 participants (median of 5 separate samples per participant). Of these, 96 (27%) were positive for HHV-8 DNA. Thirty-eight (49%) participants had HHV-8 detectable in ≥1 plasma sample , Table 2Of the 272 swabs collected from the genital tract, only 9 (3%) were positive for HHV-8 DNA and 5 (56%) of 9 came from one study subject who had genital KS. The median per person shedding rate and amount of genital HHV-8 DNA detected did not differ in KS positive and KS negative persons.Individual patterns of HHV-8 oral shedding differed by HIV and KS status. Interestingly, we identified several KS negative subjects who shed HHV-8 from their oropharynx at high frequency. HHV-8 was shed from the oral mucosa on greater than 70% of days in 2 of 3 HIV negative/KS negative and 3 of 5 HIV positive/KS negative participants who had oral HHV-8 detection . Six  of 13 participants with endemic KS were viremic on less than 30% of days, and two (15%) of 13 had HHV-8 viremia on 100% of days sampled. In contrast, ten (82%) of 17 participants with epidemic KS were viremic on greater than 70% of the days sampled, and 6 (35%) of these were viremic on 100% of days sampled.We examined the association between HHV-8 oral shedding and viremia on a per person basis, and found that oral HHV-8 DNA predicted the detection of HHV-8 in the blood. HHV-8 was detected significantly more often from plasma samples collected when HHV-8 was shed from the oropharynx during the week prior than during periods when HHV-8 was not shed from the oropharynx . Overall, 31 (62%) of 50 days with HHV-8 detected in plasma had HHV-8 oral shedding on at least one day during the prior week. Conversely, HHV-8 viremia did not predict oral HHV-8 detection in the following week .Correlates of HHV-8 detection in the oral mucosa were determined by univariate and multivariate modeling . In the In univariate analyses, correlates of HHV-8 plasma viremia included male sex , HIV infection , plasma HIV RNA level above 4.5 log  and having KS . In multivariate models, male sex, HIV infection, and KS status remained significantly associated with HHV-8 viremia. In addition, being a member of the Baganda tribe was associated with HHV-8 viremia  and having more than one sex partner during the past year was associated with a reduced risk of viremia . A sensitivity analysis, which included those participants without laboratory evidence of HHV-8 infection by either HHV-8 seropositivity, HHV-8 DNA detection from mucosal surfaces or blood, or biopsy proven KS, did not change the results of multivariate models for oral HHV-8 detection or viremia (data not shown).We conducted a comprehensive study of the natural history of HHV-8 infection in an area where HHV-8 infection and KS are endemic and demonstrated; 1) HHV-8 DNA detection in the oropharynx and peripheral blood is common and highly correlated; 2) individual patterns of oral and plasma HHV-8 replication differ in persons with and without endemic and epidemic KS; and 3) HHV-8 viremia is more frequent among men and among persons with KS or HIV-infection.While daily home collection of mucosal samples for herpesvirus culture and PCR has been validated in multiple studies in resource-rich settings, We found that oral HHV-8 detection was associated with multiple recent sex partners, and that remote sexual debut and consistent condom use with sexual activity were associated with reduced risk of oral HHV-8 shedding. These results are consistent with potential acquisition of HHV-8 in adults, as previously described in a cohort of Kenyan men HHV-8 viremia occurred frequently among persons with both epidemic KS and endemic KS. In addition, HHV-8 viremia appeared sustained throughout the 28 day study period in nearly 30% of persons with KS. While sustained and frequent viremia has been reported in patients with epidemic KS, our data in endemic KS provide further evidence that disseminated and persistent viral replication may be important to the pathophysiology of development of KS, independent of HIV status.Our finding that HHV-8 viremia was associated with a greater than 3-fold increased risk of HHV-8 oral detection during the prior week suggests that a loss of control of HHV-8 replication in the mucosal compartments may contribute to the development of viremia and progression of KS. Our data are consistent with a model that lytic HHV-8 replication in the oral compartment precedes HHV-8 viremia, and that HHV-8 dissemination to the vascular compartment is necessary for development of KS. The high frequency of HHV-8 viremia in epidemic KS may also be a factor in sustaining and seeding areas of established KS The observation of a dichotomous oral replication pattern in Ugandans with asymptomatic HHV-8 infection, between those with frequent and high quantity detection or infrequent and low quantity detection, is similar to results seen in a US based population of asymptomatic HHV-8 infected MSM 3 may have led to an underestimation of the relationship between HIV and HHV-8 replication, though previous work from our group and others has shown HHV-8 oral replication to be more common in HIV-positive persons with higher CD4+ T-cell counts We were surprised that HIV infection did not have a more profound influence on HHV-8 oral replication and viremia in our cohort. In previous studies of women in Kenya, HIV seropositivity was associated with a 2-fold increased risk of HHV-8 detection from any mucosal surface This study is limited by a short follow up period. Longer prospective studies of HIV-infected persons with high rates of oral HHV-8 detection and viremia are ongoing to determine if sustained HHV-8 replication is associated with the development of KS. If HHV-8 viremia does precede KS, as suggested by other cohorts In summary, we demonstrate that intensive virologic studies can be carried out in resource limited settings, and that lytic replication of HHV-8 in both the oral and vascular compartments is highly associated with the presence of endemic as well as epidemic KS. Detection of HHV-8 in these compartments is highly correlated, suggesting that mucosal HHV-8 replication may be an important antecedent of HHV-8 viremia. Understanding the cofactors that influence HHV-8 acquisition, reactivation and persistence is likely to lead to novel strategies to reduce HHV-8 associated KS.3 or were taking antiretroviral medication (ARV) were ineligible. All participants gave informed consent for study participation and, when performed, HIV testing. Verbal consent was obtained in place of written consent if participants were unable to read and understand the consent form. Ethical approval for all study procedures, including verbal and written informed consenting procedures, was obtained from the Makerere University Research and Ethics Committee, the Uganda National Council for Science and Technology, and the University of Washington Human Subjects Division.The study was conducted at the Uganda Cancer Institute (UCI), Mulago Hospital, Makerere University, Kampala, Uganda between May 2005 and July 2006. Participants between the ages of 18 and 65 were recruited from the UCI, the Infectious Disease Institute (IDI) and through word of mouth. Eighty-seven participants were enrolled into one of four groups on the basis of HIV and KS status: HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive and HIV positive/KS positive. Participants unable to give written or verbal informed consent or taking acyclovir or ganciclovir were ineligible for the study. In addition, HIV positive participants who had a CD4+ T-cell count less than 200/mmAt the screening visit, a questionnaire which collected information about demographic, sexual, and behavioral practices was administered. At enrollment, past medical history, current symptoms and medications were obtained, and a physical examination was performed, including detailed documentation of location and size of KS lesions. All participants with KS had histologically-confirmed disease. Participants were taught oral swab collection techniques, which included vigorously swabbing the buccal mucosa, gums, tongue, hard palate and tonsils with a Dacron swab. The swab was placed in a vial containing 1 ml of filter sterilized 1× digestion buffer orf73 gene, with positive and negative controls as previously described For those who could not provide written documentation of HIV test results within the past 6 months, HIV serostatus was ascertained using the Determine HIV ½ lateral flow qualitative rapid immunoassay on whole blood  Positive results were confirmed with the Clearview Stat-Pak . CD4+ T-cell count was determined in HIV-positive persons at the MUJHU laboratory using standard cell sorting techniques. HHV-8 serostatus was determined at the University of Washington, using an immunofluorescence assay (IFA) to detect serum antibodies to latent and lytic proteins as previously described 10 transformed for analysis. Detection of HHV-8 in participant- and clinician-collected oral samples was evaluated with a Spearman-rank correlation coefficient. Oral shedding rates were calculated using participant-collected daily oral swabs only, unless such swabs were unavailable on clinic visit days, in which case the results from clinician-collected oral swabs were used. Summary shedding rates for oral, anogenital and plasma samples were calculated per participant  and per sample .Chi-square tests or non-parametric Kruskal-Wallis (KW) tests were used to assess the homogeneity of demographic and virologic characteristics according to KS and HIV status. Quantity of HHV-8 DNA (copies/ml) was logAll regression models used generalized estimating equations (GEE) with an exchangeable correlation structure to adjust for intra-individual correlation of repeated measures per person, and the Huber-White variance estimator. Two sided p-values≤0.05 were considered statistically significant.The difference in HHV-8 DNA copy number among clinician- and participant-collected oral swabs and among groups was determined using GEE Gaussian regression with an identity link. Correlates of HHV-8 oral mucosal and plasma detection were identified via univariate and multivariate GEE Poisson regression. All covariates that were associated with HHV-8 detection at the p<0.1 and p<0.2 levels in univariate analyses were assessed as significant predictors or confounders of HHV-8 detection. Confounders were retained if they changed the beta coefficients of predictors by greater than 10%. The association between HHV-8 viremia and oral HHV-8 detection was assessed using GEE binomial regression with a log link. Statistical analyses were performed using Stata, version 10.0.


Environmental Health Perspectives (EHP). Anniversaries and new years always tend to promote reflection on the year just past and provide an opportunity to look toward the future. Readers of EHP are no doubt aware of the instability that the journal endured in recent years related to the proposal made in 2005 to privatize this federally funded publication. Fortunately, the negative response of the environmental health science community led to a rejection of that proposal. Future support for the journal was articulated in a congressional hearing in 2007, at which time Samuel H. Wilson, acting director of the National Institute of Environmental Health Sciences (NIEHS), pledged renewed and ongoing support of the institute for the journal and its programs.January marks the completion of my first year as editor-in-chief of EHP obviously relies on words and images. However, it has been the restoring, renewing, and expanding of the journal’s resources that have demonstrated the institute’s long-term commitment to EHP ’s mission to provide the highest-quality and most timely environmental health research and information to people around the world. Over the last several months, many people including the EHP staff, interim editors, consulting editors, and NIEHS senior management have worked hard to ensure the integrity of the journal and the quality of its news and science content. The following describes some major milestones met by the journal during the last year.As a tool for communication, Year’s end is neither an end nor a beginning but a going on, with all the wisdom that experience can instill in us.—Hal Borland (1900–1978)In July 2008, we were able to put into place a renewed 5-year contract to provide production, design, and web-site support for the journal. Given this renewed long-term commitment to the journal, we expect to embark on new and exciting paths for presenting and distributing our content that will take advantage of innovative technologies and the latest trends in scientific publishing.EHP’s Associate Editor and Editorial Review Boards were reconstituted to maximize our access to and engagement with research leaders across the broad spectrum of scientific fields that contribute to our understanding of environmental health. Second, in July the journal implemented Manuscript Central, an online manuscript management system. The use of this software has already allowed for more diverse and direct involvement by our associate editors in the journal’s peer-review process and resulted in an approximate 20% decrease in time from submission to publication, a boon for both authors and the research community.On the editorial side of the equation, two extremely important activities have already begun to bear fruit for the journal’s continued growth and success. First, EHP is pleased to welcome a new science editor to our permanent staff. Jane Schroeder, an epidemiologist who came to EHP from the University of North Carolina at Chapel Hill, is poised to reinvigorate our search for the best papers on the most important findings in environmental health research.In addition to these editorial improvements, EHP has renewed the relationship with Shanghai CDC to translate and distribute selected EHP content to a broad audience of environmental scientists and managers in China. In addition, we will continue to work in partnership with Ciencia & Trabajo, Ciência & Saúde Coletiva, and Mali Médical; recently we created a new content-sharing partnership with the Instituto Nacional de Salud Publica in Mexico. We have also redesigned our International Program webpage and resumed translations of selected content into Spanish, Chinese, and French. EHP is now in a position to seek new partnerships with other journals and to contribute to improving the infrastructure of other journals by providing access to publication expertise and experience concerning the peer-review process.Throughout the past year, much attention and effort has been given to restoring several key outreach areas de-emphasized previously due to budget and resource constraints. Some of these were specifically identified during the congressional hearing and include our international and science education programs. With regard to the former, We are also excited to announce that science education lesson development and distribution has resumed and has been greeted with great enthusiasm by high school teachers and others in the education community. In a new international effort, we will provide these lessons to Spanish-speaking students in Mexico City. For the future, it is our goal to expand our Science Education Program to reach more educational levels, increase awareness and access to these tools by foreign teachers and students, and engage students using more contemporary learning tools and approaches.EHP is in the process of redesigning its website. This process has led us to think about ways to improve navigation of the website and upgrade our search engine. Such improvements will help those who use our journal for research and those seeking information to develop and support environmental health policies and practices. We are also thinking about ways to take advantage of technological trends to make information available in formats that are the most engaging and familiar to a younger generation of environmental health scientists and students.Finally, EHP—and publications like it—has never been greater. More than ever, as we face environmental health problems, including old foes such as toxic exposures and even more daunting new ones such as global climate change, the world’s citizens require open, accessible, and most importantly, credible scientific information from their governments and other public institutions. EHP has long been at the forefront of this effort, and I am proud to have the opportunity and responsibility of shepherding our efforts into the future. EHP and its staff look forward with great enthusiasm and hopefulness to the next year, and we thank everyone for their continued support.All of the activities described above have taken place with the express support and encouragement of senior management at NIEHS. Such “in-house” support for the journal is gratefully acknowledged and appreciated by the journal. Moreover, as I have met and talked with people throughout the environmental research, public health, and scientific publishing communities over the last year, it has become increasingly clear that the need for


EHP has revised its Instructions to Authors. The new version became available on the journal’s website on 19 September 2008, and a print version is provided on page A444. The instructions now provide background information (Who We Are) and describe the type of multidisciplinary research of interest to the journal (What We Publish). Sections are organized to address the various phases of publication . The instructions also include a section on the publication style preferred by the journal (EHP Style).EHP editors. For the first time, we have described EHP ’s policy concerning potential nonfinancial conflicts of interest. This policy pertains primarily to reviewers and editors.Please note that the journal remains committed to the full disclosure of all potential competing interests for authors, reviewers, and http://mc.manuscriptcentral.com/ehp). Authors should also note the new page charges and costs for color figures effective 1 August 2008.The new Instructions to Authors also describes in considerable detail the process for using the new Manuscript Central (ScholarOne) tracking system that we announced in the August issue of the journal [Environ Health Perspect 116:A328 (2008)]. New manuscripts should be submitted using this system (


The current approach to screen for drug-like molecules is to sieve for molecules with biochemical properties suitable for desirable pharmacokinetics and reduced toxicity, using predominantly biophysical properties of chemical compounds, based on empirical rules such as Lipinski's "rule of five" (Ro5). For over a decade, Ro5 has been applied to combinatorial compounds, drugs and ligands, in the search for suitable lead compounds. Unfortunately, till date, a clear distinction between drugs and non-drugs has not been achieved. The current trend is to seek out drugs which show metabolite-likeness. In identifying similar physicochemical characteristics, compounds have usually been clustered based on some characteristic, to reduce the search space presented by large molecular datasets. This paper examines the similarity of current drug molecules with human metabolites and toxins, using a range of computed molecular descriptors as well as the effect of comparison to clustered data compared to searches against complete datasets.We have carried out statistical and substructure functional group analyses of three datasets, namely human metabolites, drugs and toxin molecules. The distributions of various molecular descriptors were investigated. Our analyses show that, although the three groups are distinct, present-day drugs are closer to toxin molecules than to metabolites. Furthermore, these distributions are quite similar for both clustered data as well as complete or unclustered datasets.The property space occupied by metabolites is dissimilar to that of drugs or toxin molecules, with current drugs showing greater similarity to toxins than to metabolites. Additionally, empirical rules like Ro5 can be refined to identify drugs or drug-like molecules that are clearly distinct from toxic compounds and more metabolite-like. The inclusion of human metabolites in this study provides a deeper insight into metabolite/drug/toxin-like properties and will also prove to be valuable in the prediction or optimization of small molecules as ligands for therapeutic applications. To search for biologically active compounds, with favorable ADMET   among drugs, human metabolites and toxin molecules are available from Table While there is a multitude of molecular descriptors available for carrying out comparison studies, given the large size of the datasets, we need a set of rapidly computable molecular descriptors, for efficient analysis. Furthermore, to account for 70% of the drugs, Oprea et al.  used simMetabolites follow a bimodal distribution in molecular weight, with the first peak at 100-400  and the second and larger peak at 700-1000, containing 48% of the dataset. On the other hand, the molecular weight of drugs follows a Gaussian distribution with the majority of drugs (82%) under the range of 500. This is in accordance with the Lipinski restriction of weight less than or equal to 500. Despite the Ro5 restriction, 18% of the drug molecules possess a molecular weight in excess of 500. Toxin molecules more or less follow the same pattern as drugs, with the gradual decrease in number of compounds as molecular weight increases from 100 to 500 Fig. .From the calculated mean and median values for the molecular weight, it appears that the metabolite data is skewed towards high molecular weight compounds whereas drugs and toxin molecules prefer a lower molecular weight distribution. The statistics of the molecular weight property for the three datasets are available in Table Lipid solubility is a direct measure of transport abilities of the compound across biological membranes . Drug moLipinski hydrogen bond donors (LHBDs) are determined by counting the numbers of OH and NH bonds in each molecule . ApproxiOnly a fraction of molecules in all the datasets  do not possess Lipinski hydrogen bond acceptors (LHBAs), computed by summing the numbers of nitrogen and oxygen atoms in each molecule [The distribution of the total number of atoms in metabolites follows a bimodal pattern Fig. , with thAlmost half of the molecules in the metabolite dataset have carbon atoms in the range 35-55 while 32% have 5-25 carbon atoms per molecule Fig. . The carApproximately 40% of metabolites do not have any nitrogen atom Fig. , while 4For the three datasets, there is a clear reversal of the trend for the oxygen atom distribution compared to the nitrogen atom distribution presented in the previous section. Only 1% of the metabolite molecules do not have an oxygen atom as compared to 8% of drugs and 15% of toxin molecules Fig. . FurtherThe fraction of molecules with a single negatively charged atom in the metabolite dataset (16%) is almost the same as that containing one positively charged atom (17%). While the metabolite dataset contains molecules with more than one negatively charged atom, there are no molecules with more than one positively charged atom. The percentage of negatively charged atoms is smaller in the drug dataset as compared to metabolite dataset Fig. . Only 5%The distribution of number of rings is shown in Fig. After removing the non-ring bonds from a molecule the remaining backbone is termed as the ring assembly. As shown in the Fig. The number of rotatable bonds is a measure of molecular flexibility and is important in determining oral bioavailability of the drugs . Only 4%More than 80% of metabolites do not possess any aromatic bond. The remaining metabolites have several aromatic bonds, usually as multiples of five or six. As shown in Fig. In contrast to metabolites, only 29% molecules of drugs have no any aromatic bonds. Of the remaining, 12% and 36%, respectively, of drug molecules have aromatic bonds as multiple of five and six. The maximum number of aromatic bonds in the drug dataset is 62. On the other hand, toxin molecules are predominantly aromatic (61%) with 7% and 42% having aromatic bonds as multiples of five and six, respectively. The maximum number of aromatic bonds in the toxin dataset is 46. The order of aromatic bond distribution is Drugs ≈ Toxin molecules > Human metabolites, with almost half the aromatic bonds in all the three datasets being multiples of five or six.For solutes that can ionize, the distribution coefficient (D) is the ratio of the sum of the concentrations of all forms of the compound (ionized plus un-ionized) in each of the two solution phases. logD is thus considered a better measure of lipophilicity that Alog P. However, for all three datasets, logD follows the same distribution as Alog P Fig .in vivo (aqueous media).Human metabolites have large range of molecular solubility values for example more than 85% of the molecules in metabolite dataset have molecular solubility in the range of -20 to 0. Drug molecules have a smaller range of molecular solubility as compared to metabolites, with 87% of the molecules in drug dataset having molecular solubility values spanning -10 to 0. Similarly, more than 90% of toxin molecules have a solubility value in the range -10 to 0. Thus, the most preferred and common range of molecular solubility among the three datasets is -10 to 0, which comprises ~85% of the drug and toxin datasets but only 38% of the metabolite dataset  are chiral. Chirality falls sharply in drugs and toxic compounds to 31% and 14%, respectively.As expected, toxin molecules have the highest number of halogen atoms per molecule compared to metabolites and drugs. 31% of molecules in toxin dataset possess a single halogen atom  per molecule while in case of drugs close to 18% contain halogen atoms. In sharp contrast, to these two datasets, metabolites have far fewer halogen atoms per molecule. Only 15 out of 4568 molecules, i.e. only 0.3% of the molecules, studied are reported to have any halogen atom. The trend for halogens is Toxin molecules > Drugs >> Metabolites. The statistics provided in Table Only 5% of the molecules in metabolite dataset, 20% of the drugs and almost the same percentage (16%) of toxin molecules contain one or more sulphur atoms in their molecule. For sulphur atoms, the trend is Drugs ≈ Toxin molecules > Metabolites. The trend gets reversed in the case of phosphorus atoms, with 46% of molecules in metabolites, 13% of drug molecules and only 3% of the toxic dataset having one or more phosphorus atoms. So the trend in phosphorus atom distribution is Metabolites >> Drugs > Toxin molecules.The metabolite molecules form two groups, with 48% having a mean value of 0.82 Å bond length, while another 51% have 0.83 Å. The majority of drug molecules (65%) also have either 0.82 or 0.83 Å bond length. In sharp contrast to the other two datasets, the average bond length for 92% of molecules in toxic dataset is 1.33 Å, while another 7% of the molecules have 1.40 Å as the average bond length. As far as average bond length is concerned, metabolites and drugs have a much shorter average bond length compared to toxin molecules, the trend being Toxin molecules > Metabolites ≈ Drugs.2, containing 37% of the molecules and the second larger peak at 700-1100 Å2, with 53% of the molecules. On the other hand, 83% of drugs molecules have molecular surface area between 100-500 Å2. A similar distribution is obtained for toxin molecules with 89% of the compound in the toxin dataset having a molecular surface area in the range 100-500 Å2 and only 4% are in the range 0-100 Å2. From these values and the statistics in Table Molecular surface area distribution in metabolites is bimodal Fig.  with the3. The majority of molecular volume distribution of the drug dataset is narrow compared to that of human metabolites with 81% of the molecules are in the range form 100-400 Å3, although the tails extend further, with some molecules found to have volumes above 1700 Å3. The molecular volume range is even more restricted in toxic compounds with 90% of the molecules in the range 0-300 Å3 with ~49% of these having a molecular volume of 100-200 Å3. So, the trend for molecular volume distribution is the same as that observed for molecular weight distribution among the three datasets: Metabolites > Drugs > Toxin molecules.The results of molecular volume distribution in three datasets are reflected in the related property of molecular weight distribution. As depicted in Fig. 2 , including the attached hydrogen atoms. It is often correlated with drug transport capabilities and is important for penetrating the blood-brain barrier (BBB). As most of the metabolites do not need to be shuttled through barriers like BBB, they can afford to have more polar surface area than drugs and toxins. More than 95% of the metabolites have polar surface area in the range 0-350 Å2 Fig.  while 923 and a larger peak containing 46% of the molecules around 1000-1300 Å3. However, there is no molecule with accessible volume less than or equal to 100 Å3. Unlike metabolites, drugs molecules have only one peak covering almost the entire dataset. About 91% of the drug molecules have solvent accessible volume from 200 to 800 Å3. Like metabolites there is no molecule with solvent accessible volume less than or equal to 100 in drug dataset. The distribution of solvent accessible volume in toxin molecules is even thinner with 89% of the molecules in the range 200-600 Å3. Other 7% are present in the range 600-1000 Å3. According to the statistics shown in Table Molecular solvent accessible volume distribution is similar to the distribution of the molecular volume. In the case of metabolites Fig. , it also2 while for drugs the range is 0-350 Å2. On the other hand maximum numbers of metabolites are covered in between 100-250 Å2. The statistics in Table Drugs and toxin molecules follow a perfect Gaussian distribution for polar solvent accessible surface area while metabolites follow a bimodal pattern Fig. . The max2 while drugs peak at 400-600 Å2. Metabolites, on the other hand, form a lower peak at 300-400 Å2 with a second larger peak at 1200-1500 Å2. Form Table Differences among metabolites, drugs and toxin molecules are readily observable for molecular solvent accessible surface area. Metabolites follow a bimodal distribution whereas drugs and toxins follow a Gaussian distribution Fig. . Toxin mThe frequency of functional group occurrence among the three datasets was carried out in this study with the Scitegic Pipeline pilot software (details in the Methods section). The occurrence of specific functional groups of interest to drug design is given in Table viz. Alog P, molecular weight, the number of oxygen atoms, the number of nitrogen atoms, molecular polar surface area, molecular solubility, the number of rings and the number of aromatic bonds  datasets (data not shown). Correlation coefficients were calculated for all the properties and eight properties which are not significantly correlated are presented here, ds Figs. , 7, 8, 9ds Figs.  do not dThere is an exception at five oxygen atoms per molecule in the unclustered metabolite dataset Fig. .The number of molecules with zero rings drops for drugs (~8% decrease) and toxins (~9% decrease) whereas metabolites follow a similar distribution in clustered and unclustered dataset comparison Fig. .2 while clustered toxins show a 15% increase in the number of molecules with polar surface area between 0 to 50 Å2. Drugs, on the other hand, follow a similar distribution for clustered and unclustered datasets  as well as reduced or clustered datasets. We note that, in the main, the distributions for the two data groups, clustered and unclustered, are very similar, supporting the use of clustered datasets, except in the case of the number of oxygen atoms, the molecular polar surface area and the number of rings. Based on this result, these properties should be treated with caution for lead discovery in drug discovery pipelines with unclustered datasets.From the analyses of clustered datasets, we find that two-thirds of the human metabolites lie outside the Lipinski universe. On the other hand, over 90% of the toxin molecules abide by Lipinski's rule, implying that since Ro5 does not explicitly take toxicity into account, present-day drugs are consequently similar to toxins than to metabolites.Results from the analysis of 1D and 3D molecular properties consolidate our finding of drugs and toxins sharing a larger property space, than drugs and metabolites. 1D properties such as the total number of atoms advocate that metabolites are bulky, with more carbon and hydrogen atoms than drug and toxins. This is consistent with the idea that metabolites are produced at the required subcellular location and thus do not need to be transferred from one location to another. In order to design metabolite-like drugs, it would be beneficial to attempt alternative ways for drug delivery, since traditionally, drugs are required to pass through the blood-brain-barrier, which limits the size of drug molecules. Considering the numbers of nitrogen and oxygen atoms, metabolites prefer oxygen over nitrogen containing groups. Above 50% of the metabolites are acyclic while only 9% of the drugs and 19% of the toxin molecules are acyclic. The number of rotatable bonds measuring molecular flexibility and consequently, oral bioavailability, suggests that metabolites are far more flexible than drugs and toxin molecules. Over 70% of the drugs and 62% of toxin molecules are aromatic while only 20% of the metabolites are aromatic. This result is in accordance with the fact that drugs are derived from various sources including NPs which are mostly aromatic in nature. In all the datasets examined, the majority of molecules have negative solubility values, suggesting that a large proportion of these compounds are soluble in aqueous solutions. Chirality falls sharply from metabolites to drugs and toxin molecules while as expected, the number of halogen atoms are found to be higher in toxins than in drugs and metabolites. The average bond length of 90% metabolites and more than 65% of drugs is much smaller than majority of toxins, suggesting multiple bonds in the former datasets. The analysis results from 3D descriptors such as molecular volume and molecular surface area are reflected in the related property of molecular weight and confirm that present day drugs are more like toxins than metabolites.The analysis also shows that although drugs share a relatively larger property space with toxins than with metabolites, drugs and toxins are two different classes of compounds as reflected in specific physicochemical characteristics. Drugs tend to have higher values for properties such as molecular weight, the number of oxygen atoms, the number of rotatable bonds and molecular polar surface area whereas toxin molecules have considerably higher Alog P and Log D values.Additionally, empirical rules like the "rule of five" can be refined to increase the coverage of drugs or drug-like molecules that are clearly not close to toxic compounds, because toxicity reduction is one of the key aspects of drug discovery programs. Our results have implications for the analysis of novel compounds in lead discovery pipelines, to uncover novel target molecules.Three publicly available databases, relevant to human diseases and their treatment have been used in this study. The human metabolome database  containsPreliminary datasets containing 6668 human metabolites from the human metabolome database (as on 23-Dec-2008), 4883 drugs from DrugBank (as on 6-Jan-2009) and 1547 toxin molecules from DSSTox (as on 16-Jan-2009) were extracted.From these preliminary datasets duplicates and inorganic molecules  were removed. Any "missing" compounds (either with no or incomplete structure) were also removed. The "cleaned" collections of unique compounds were compiled into analysis datasets containing 6582 metabolites, 4829 drug molecules and 1448 toxin molecules. Finally, clusters were generated from each dataset, using the Cluster "Clara" algorithm embedded in the Scitegic Pipeline Pilot software , which iThe overlap among the three clustered datasets  was calculated and it was found that more compounds are common in between drugs and toxin molecules than any other combination. The results are displayed in Figure The calculation of all the molecular properties was carried out through the Scitegic pipeline pilot  and in-hTwo types of hydrogen bond acceptors and donors were taken into account. Firstly, the Lipinski type donors (sum of OH and NH) and acceptors (sum of N and O atoms) were calculated as defined by Lipinski et al.  and thenThe octanol-water partition coefficient was either retained if provided with the data, or was calculated from Scitegic software. The hydrophobicity measure, Alog P, was calculated using the Ghose-Crippen method  which taOther simple count-based molecular descriptors enumerating aromatic bonds, atoms, carbon atoms, nitrogen atoms, oxygen atoms, hydrogen atoms and rings were also calculated. Beside these, one-dimensional (1D) descriptors calculated include molecular weight and molecular solubility. Three-dimensional (3D) descriptors like molecular volume, molecular surface area, molecular polar surface area and molecular solvent accessible surface area were also computed. The molecular polar surface area is defined as the sum of all the polar atoms . This descriptor is often correlated with drug transport capabilities and is important in penetrating the blood-brain barrier.The authors declare that they have no competing interests.VK curated the dataset and conducted the analysis work; SR directed the study and both authors prepared and approved the manuscript.BMC Genomics Volume 10 Supplement 3, 2009: Eighth International Conference on Bioinformatics (InCoB2009): Computational Biology, available online at http://www.biomedcentral.com/1471-2164/10?issue=S3.Other papers from the meeting have been published as part of Table S1. Occurrence of discriminatory functional groups in the three datasets.Click here for file


Molecular Autism - a new open-access journal published by BioMed Central. Autism and associated conditions are now recognized as major disabilities with major implications for the public purse. A recent economic analysis of the total annual cost of autism in the UK estimated this to be £28 billion, assuming a prevalence of 1% of the population [Molecular Autism reflects this broad perspective, from molecular to cellular to systems to neural, cognitive and behavioral level analyses, and back again [We are delighted to announce the launch of Molecular Autism joins other journals targeting autism and associated conditions but differs in key ways. First, Molecular Autism is both online and open access. In a field where dissemination of accurate information has become so important, where internationally, scientists, educators, clinicians, and families are tracking the developments and are looking for up-to-date, definitive and accessible sources of scientific information, Molecular Autism will provide such a forum. Open access means that the articles are freely available to all, worldwide, and at no cost to the reader. Online publication also allows for no restriction on number or length of articles and for the inclusion of all available digital technologies: large data sets, unlimited use of color, slide shows, animation, video clips, and links to other web pages, all at no additional charge. Articles are published online on the day of acceptance and, very soon after, are listed in bibliographic databases and full-text article repositories [sitories . BioMed Molecular Autism these costs are defrayed by the author via article processing charges (APCs). However, APCs can typically be covered by grants. In addition, individual APCs are waived in institutions that have full membership to BioMed Central. A discounted APC is provided for institutions with supporting membership and authors from countries in low or low-middle income categories defined by the World Bank may also have APC charges waived. Beyond this, we will also consider individual waivers on a case-by-case basis, making every effort to ensure that lack of funds does not impede the overall objective of publishing the best science, irrespective of authorship or country of origin [Publication costs in subscription journals are paid by the reader; in f origin .Molecular Autism differs from other journals in the autism science field is by having a focus on the molecular level. Whereas other journals have a broad remit, from clinical and educational psychological studies through cognitive experiments to neuroimaging and genetics, Molecular Autism will publish articles that have a bearing on the molecular basis of autism and related conditions. This does not preclude a behavioural or cognitive or neural study, so long as there is also a molecular measure in the study or the implications for the molecular basis of autism are considered. Our reason for this requirement is that part of our mission statement is to accelerate research into the fundamental determinants of the condition [The second way in which ondition . The firMolecular Autism differs from other autism journals is that it aims to achieve integration across the multiple levels that these syndromes affect. We now recognize that autism will not be understood by a single discipline, be it genetics or neurology or psychology. Rather, each level has to be mapped on to the next, to reveal how mechanisms give rise to the phenotype within each system. This makes autism and related syndromes complex but the response to such a challenge has to be scientific articles that attempt to tackle such multi-level complexity.The third way in which Molecular Autism are peer-reviewed by at least two, and most typically more, experts, drawn from the Editorial Board and the wider scientific community. Manuscript review and processing is rapid while, with the assistance of the Editorial Board, we shall ensure that the highest standards are maintained, including fair refereeing and editorial decision-making [We are committed to publishing the highest quality articles in the field. Since we made our first call for manuscripts, we have attracted manuscripts from leaders in the field and have sustained a constant rate of submissions. Articles in n-making .Molecular Autism is also a forum for timely reviews of topics of interest and will be a site for discussion of open questions in the field. After the launch of the journal, we will review the state-of-the-art in association studies in psychiatric genetics and define the criteria for the highest quality studies, and will commit to this level of rigor in all articles published in Molecular Autism.Molecular Autism will be at the forefront of these breakthroughs.We are in a transformative period in autism research. Behavioral interventions have been shown to be effective, and earlier diagnosis, using molecular and behavioral methods, becomes critical to take advantage of these interventions. In parallel, identification of etiological causes of autism has led to novel drug targets, and several large-scale clinical trials are being carried out based on these findings. We underline the important ethical issue that research into efficacy of medications should evaluate not only improvements in areas of known disability, but the lack of unwanted side-effects (particularly ensuring that areas of strength in autism are not compromised).


Important advances in science often result from research that is novel or contrary to accepted paradigms. Often, the existing literature may be incomplete or inconsistent. Unfortunately, it is extremely difficult to review this type of work objectively—if we reject such papers we may be suppressing important ideas or concepts, but if we accept them we may be promoting “junk science.” The problem is exacerbated when the work in question is strongly associated with an individual, because it can be difficult, if not impossible, to separate the idea from the person. Also, in the absence of an objective basis or precedent for judgment, arguments “for” and “against” can become increasingly polarized to the point where there seems to be no middle ground between the two sides.EHP has a section devoted to Commentaries that are intended to “present information and insight on a particular topic” [see EHP’s Instructions to Authors available online (http://www.ehponline.org/docs/admin/ita.html)]. EHP Commentaries therefore provide an effective and highly visible forum for discourse on new ideas and emerging issues. On rare occasions, Commentaries also serve as a platform for airing opposing sides of an argument. Such is the case with two Commentaries in this month’s issue .Like many journals, EHP Commentaries can advance environmental health by promoting open and constructive discussions about controversial topics and ideas. We reserve the right, however, to reject without review Commentaries we view as too polemic or personal in nature. We also reserve the right to propose that Commentaries be reviewed as one side of a “point–counterpoint” debate. If the original author agrees, we would ask another author to address the opposite side of the argument; if both papers were accepted, we would publish them together, as with this month’s articles by Mushak and Calabrese. After paired Commentaries are published, any additional rebuttals and critiques will be considered for publication only as Correspondence and would need to be formatted accordingly.We believe We look forward to publishing Commentaries that help us achieve our goal of advancing environmental health. As always, we welcome your feedback.EHP is pleased to announce a significant redesign of the journal’s website starting in September. The new website utilizes an open source platform for publishing our news and research articles. In addition to advanced search capabilities, we have included the ability to browse articles by subject category and publication date. There are RSS feeds for newly published articles by date and subject category. The website also includes community features such as threaded discussions; ratings for news articles; user profiles; formal correction and retraction annotations by EHP staff; and TrackBack support. We have improved capability to link to related articles and issues and to access recently published, most viewed, and featured discussion material. The new website also includes new features for article citation, as well as PDF and XML downloads. EHP welcomes your feedback and suggestions as you begin to explore the new features and layout of the new website. We consider the website to be a dynamic feature of the journal and intend to institute modifications and updates as needed.


The objective of this study is to evaluate the cost effectiveness of exenatide versus insulin glargine using RCT data and a previously published model of Type 2 diabetes disease progression that is based on the United Kingdom Prospective Diabetes Study; the perspective of the health-payer of the United Kingdom National Health Service.Exenatide belongs to a new therapeutic class in the treatment of diabetes (incretin mimetics), allowing glucose-dependent glycaemic control in Type 2 diabetes. Randomised controlled trial data suggest that exenatide is as effective as insulin glargine at reducing HbAThe study used a discrete event simulation model designed to forecast the costs and health outcome of a cohort of 1,000 subjects aged over 40 years with sub-optimally-controlled Type 2 diabetes, following initiation of either exenatide, or insulin glargine, in addition to oral hypoglycaemic agents. Sensitivity analysis for a higher treatment discontinuation rate in exenatide patients was applied to the cohort in three different scenarios; (1) either ignored or (2) exenatide-failures excluded or (3) exenatide-failures switched to insulin glargine. Analyses were undertaken to evaluate the price sensitivity of exenatide in terms of relative cost effectiveness. Baseline cohort profiles and effectiveness data were taken from a published randomised controlled trial.The relative cost-effectiveness of exenatide and insulin glargine was tested under a variety of conditions, in which insulin glargine was dominant in all cases. Using the most conservative of assumptions, the cost-effectiveness ratio of exenatide vs. insulin glargine at the current UK NHS price was -£29,149/QALY (insulin glargine dominant) and thus exenatide is not cost-effective when compared with insulin glargine, at the current UK NHS price.This study evaluated the relative cost effectiveness of insulin glargine versus exenatide in the management of Type 2 diabetes using a published model. Given no significant difference in glycaemic control and applying the additional effectiveness of exenatide over insulin glargine, with respect to weight loss, and using the current UK NHS prices, insulin glargine was found to be dominant over exenatide in all modelled scenarios. With current clinical evidence, exenatide does not appear to represent a cost-effective treatment option for patients with Type 2 diabetes when compared to insulin glargine. Typically, lifestyle modifications such as diet and exercise fail to achieve and give way to the administration of oral hypoglycaemic agents (OHAs) in order to maintain glucose control. In addition to tolerability issues for patients, the inability of OHAs to stem the decline in β-cell function  [The progression of Type 2 diabetes is driven by progressive unction   commonlyunction  ,4. Whils• an inability to control mealtime glucose excursion ,• increased risk of severe hypoglycaemia ,7,• the need for complicated dose-titration , and• weight gain .Hypoglycaemia of any severity has a profound effect on patients' quality of life  and is rInsulin glargine (Lantus™) is an analogue of human insulin with a prolonged duration of action and once-daily dosing. In Type 2 diabetes, the principal emergent benefit is significantly reduced risk of all forms of hypoglycaemia over Neutral Protamine Hagedorn (NPH) . However2, specific problems arising from high weight, inadequate blood glucose control (glycosylated haemoglobin (HbA1c) >7.5 %), prescribed conventional oral therapy and where other high cost therapies would otherwise be commenced. Using their own model (based on UKPDS 68 [The incretin mimetics are emerging as a significant new class of hypoglycaemic agents that regulate glucose homeostasis similarly to endogenous glucagon-like peptide-1 (GLP-1). Exenatide (Byetta™), the first such compound to be licensed by the European Medicine Agency (EMEA) , enhanceUKPDS 68 ), NICE eUKPDS 68  and, furUKPDS 68 .The only published head-to-head randomised controlled trial (RCT)  of exenaThe increasing global financial burden of chronic health conditions is fuelling a rising demand for value for money when introducing new health technologies. In line with many other countries, in the United Kingdom (UK), NICE currently accepts as cost-effective, "those interventions with an incremental cost-effectiveness ratio of less than £20,000 per QALY  and that there should be increasingly strong reasons for accepting as cost effective interventions with an incremental cost-effectiveness ratio of over £30,000 per QALY ." A receThe objective of this analysis was to prospectively evaluate the cost-effectiveness of exenatide from a UK NHS perspective, using insulin glargine as a comparator and the current UK NHS price for exenatide and also applying the cohort profiles and published data from the Heine trial . The modThis evaluation was undertaken within the context of the UK National Health Service (NHS), and used the NHS as its perspective (payer's perspective). The method used was a cost-utility analysis (CUA) intended to determine the cost per quality adjusted life years gained (QALYs gained) comparing exenatide to insulin glargine as adjunct therapy to maximal doses of metformin and sulphonylurea in Type 2 diabetes.The modelling approach used was a discrete event simulation (DES) model of people with Type 2 diabetes using UKPDS-derived risk functions for development of vascular complications  and a mu2).The model simulates a cohort of 1000 subjects over a 40-year time horizon. The specific events modelled were ischaemic heart disease (IHD), myocardial infarction (MI), congestive heart failure (CHD), stroke, blindness in one eye, end stage renal disease (ESRD) and amputation, in addition to diabetes-related and all-cause mortality; furthermore, the model additionally predicts severe, nocturnal, and symptomatic hypoglycaemic events. The results presented represent an average of one hundred first order Monte Carlo simulations. The baseline characteristics of the subjects from Heine trial   over time (weeks) had begun to plateau by the study endpoint, a pattern echoed by the long-term extension trials of exenatide . Thus, tFinally, discontinuation rates due to adverse events (Δ 8.9% of intention-to-treat (ITT) patients) were modelled using three approaches: either completely ignored; exenatide-discontinuations removed from analysis; and exenatide discontinuations switched to insulin glargine.The financial costs applied to the simulation model are detailed in Table Treatment and comparator Insulin glargine cost was calculated on a per kilogram basis, costed at the current UK weighted average wholesale prices for Lantus across the different preparations [st line sulphonyureas) administered were modelled at their respective maximum daily dosages [arations  to reflearations . In commarations , where darations . As neitarations . 5 microarations . In both dosages . The modMacrovascular event costs Macrovascular event costs are split into either fatal or non-fatal costs and were applied in the year in which the event occurred. Maintenance costs for those subjects surviving were applied in all subsequent years until either the end of the simulation time horizon or until the subject died.Blindness (in one eye) Subjects were assumed to incur blindness in one eye only. The initial cost related to the event was assumed to be equal to zero, with subsequent maintenance costs applied annually thereafter from published data [hed data .Nephropathy Dialysis costs were annual weighted mean costs for peritoneal dialysis  and haemodialysis  [16; 29%) .Peripheral vascular disease was modelled as the occurrence of an amputation and had a single cost associated with the event and a subsequent annual maintenance cost.Severe hypoglycaemia costs are applied to severe hypoglycaemia events only and are based on the costs of hospitalised treatment reported in Tayside, UK. The Diabetes Control and Complications Trial (DCCT), estimated that 20% of all severe hypoglycaemic episodes result in a hospital intervention, either emergency room attendance or inpatient hospitalization. The most comprehensive data relating to treatment modality of severe hypoglycaemic episodes is reported by Leese et al. [e et al. , from the et al. , the aveUtility estimates were taken from either the UKPDS study , or geneImportant differences exist between exenatide and glargine that may also affect quality of life; in particular, changes in weight and a different side effect profile. A number of studies have shown exenatide to be associated with weight reduction ,44 whilsThe results presented here did not accommodate any utility changes associated with gastrointestinal side effects or weight change. Furthermore, consistent with longitudinal studies assessing health utility and insulin initiation, no utility decrement was applied to therapy type .All prices are all adjusted to 2007 values (UK£) using the UK Treasury gross domestic product (GDP) deflator formula . Where nThe model was designed to output the frequency  in each of a range of pertinent vascular events and mortality that are listed in Table In the first scenario where no exenatide treatment discontinuations was considered, there was an overall difference of 21,359 nocturnal episodes of hypoglycaemia, in favour of exenatide, but 38,808 more daytime episodes of hypoglycaemia for patients treated with exenatide. Overall 24.5 severe hypoglycaemic events were predicted for patients treated with exenatide. The biggest difference in vascular endpoints occurred for congestive heart failure (CHF), where use of exenatide results in 7.7 fewer events on average; this difference being driven by the improved BMI profile associated with exenatide.With exenatide treatment discontinuations excluded from the analysis, the number of clinical endpoints predicted are fewer in the exenatide group (with the exception of daytime hypoglycaemic events); however, this observation is due to fewer patients available in the model to experience clinical endpoints.Switching exenatide discontinuations to insulin glargine produces similar results to ignoring discontinuation rates altogether. The number of nocturnal hypoglycaemic events with exenatide reduces to 19,465 and the number of additional daytime hypoglycaemic events increases by 35,402. The number of expected CHF events avoided with exenatide is 6.87 when compared with insulin glargine. Under these conditions, mortality due to macrovascular events is still favourable to exenatide with 4.0 deaths avoided, but this scenario is the least positive result to exenatide compared with 4.7 macrovascular deaths saved in the baseline scenario and 43.0 macrovascular deaths saved when exenatide treatment failures are excluded.Applying the current UK price of exenatide, total treatment costs over the simulation period associated with exenatide use were significantly higher than for insulin glargine. Ignoring discontinuations rates resulted in the discounted total costs  of £14,567,526 and £9,280,312 for exenatide and insulin glargine, respectively  was-£29,149 per QALY gained, with insulin glargine being less costly and more effective than exenatide. Under the most conservative scenario of excluding exenatide failures, the dominance of insulin glargine persisted with a mean ICER of -£4,579 per QALY gained. The scenario where exenatide failures were switched to insulin glargine produced similar results with insulin glargine remaining cheaper and more effective than exenatide .1c. On the other hand weight increased on average by 3.0 kg and nocturnal hypoglycaemic events increased on average to 3.55 events/patient-year and symptomatic events on average to 5.65 events/patient-year. Using the same hypoglycaemic rates for exenatide as reported in the Heine trial, the nocturnal hypoglycaemia rate would be 75% lower in the exenatide group than the insulin glargine group, and incidence of daytime hypoglycaemia would be 17% higher in the exenatide group than in the insulin glargine group. Applying this evidence of glycaemic control, weight control and dosage to the model showed that exenatide in comparison to glargine was still estimated to be more costly and a less effective option with a cost-effectiveness ratio of £6,365 (glargine dominant). Using the evidence of increased hypoglycaemic events when using a higher dosage of glargine the results were similar and exenatide in comparison to glargine was still estimated to be more costly and a less effective option with a cost-effectiveness ratio of £6,884 (glargine dominant). The complete results of the two sensitivity scenarios are shown in Table As a sensitivity analysis, the input factors for the model were varied to reflect long term outcomes and clinical practice for glargine and exenatide. Open label extension of exenatide trials showed that the glycaemic control in the long term was similar to the effect shown in the Heine trial. However weight reduction was continuing up to a maximum of 5.3 kg over 3 years. There was no evidence of the rate of hypoglycaemic events in published the open label extensions -51. GlarFor this analysis, a previously published UK diabetes Type 2 model was used to evaluate the introduction of exenatide in patients with sub-optimally controlled Type 2 diabetes to the UK NHS. As a comparator, insulin glargine, a long-acting once daily human insulin analogue, was chosen. The results of the study reflect the long-term projection of the findings of the Heine trial . Using tA recently published study of Ray et al.  evaluatiThe main difference between the outcomes reported by Ray et al.  and our The major drawback of the Heine trial  was thatAs with all modelling simulations, our economic evaluation has a number of strengths and weaknesses. The model can only be as reliable as the predictive algorithms and other data that were used in its construction. The model was based on contemporary data largely drawn from the same source – the United Kingdom Prospective Diabetes Study; however, the dependence of our findings on the UKPDS model is not without drawbacks. In particular, the UKPDS outcomes model does not completely capture the complexities of all diabetes related complications. For example, complications such as peripheral neuropathy, ulceration, gross proteinuria or proliferative retinopathy and macular oedema are handled crudely, primarily due to insufficient patient numbers experiencing these events in the UKPDS study. This is largely due to the inclusion criteria of the UKPDS study in which patients were newly diagnosed with Type 2 diabetes with no pre-existing cardiovascular complications. Type 2 diabetes, however, is primarily characterised by macrovascular complications and the equations published from this study represent a robust approach to describing the relationship between the major complications occurring in Type 2 diabetes and modifiable risk factors. No modelled economic evaluation can ever provide point estimates that are demonstrably precise; nevertheless, the fact that exenatide is significantly more costly than insulin glargine, but provides only marginal benefits with respect to BMI provides some degree of confidence that the conclusions presented here are reliable.This study strictly applied those statistically significant differences between exenatide and insulin glargine emergent reported by Heine et al . AlthougThis study could have a number of implications for policy makers. Given therapeutic equivalence of exenatide and insulin glargine concerning glycaemic control it is likely that a forthcoming NICE appraisal of exenatide possibly would apply the lower £20,000 threshold. This economic evaluation showed that glargine, when used in the treatment of Type 2 diabetes patients, was dominant in comparison to exenatide. Maintaining the current UK price difference between insulin glargine and exenatide, the recommendation of exenatide should be considered cautiously as a cost-effective alternative to insulin glargine for tertiary treatment of Type 2 diabetes given the evidence present for exenatide.The authors declare that they have no competing interests.PMc conceived the study. AW and TT prepared the model. All authors contributed to the design of the protocol. AW drafted the manuscript. All authors have read and approved the final manuscript.


Kaposi Sarcoma (KS) is a multifocal angioproliferative neoplasm characterized by inflammation, oedema, neoangiogenesis and spindle cell proliferation. The pathogenesis of human immunodeficiency virus (HIV)-associated KS (HIV-KS) is multifactorial. HHV-8 is an essential factor but not in itself sufficient to cause HIV-KS, the development of which is influenced by HIV, by increased production of cytokines and by growth factors. Whether HIV-KS is a true malignancy or a reactive hyperplastic inflammatory condition is debatable.Oedema of the face, legs and hands is a prominent feature of HIV-KS and is probably caused by lymphoedema related to the HIV-KS lesions. The cases of two HIV-seropositive subjects with KS-associated facial lymphoedema are reported. Extensive oral HIV-KS in association with facial oedema in the absence of anti-retroviral treatment appears to be an indication of a poor prognosis. Kaposi sarcoma (KS) is an endothelial tumour of lymphatic endothelial origin that affects mucocutanous sites, but may also involve internal organs . Human iThe natural course of HIV-KS is unpredictable. It may be either a mild or a life-threatening disease but the overall prognosis without treatment is poor. Aggressive HIV-KS is associated with extensive intraoral exophytic lesions, sometimes with oedema and sometimes as in the case of aggressive HIV-KS at any site, with pulmonary involvement -5.Lymphoedema associated with HIV-KS commonly affects the face, the neck, the external genitalia and the lower extremities. It may be present before the appearance of clinically overt KS lesions and the lymphoedematous site is predisposed to secondary bacterial infections .Oral HIV-KS lesions are single or multifocal, initially present as macules that may progress to papulo-nodular lesions and eventually become confluent to form large exophytic masses . The lesThe aim of this paper is to report that the onset of facial lymphoedema in two subjects with extensive HIV-KS of the mouth of some duration who had not received antiretroviral treatment was rapidly followed by death. We suggest that the onset of facial lymphoedema under circumstances comparable to those mentioned above, may have serious prognosticatory significance. As far as we are aware this observation has not previously been reported.A 28-year-old black male with an unremarkable medical history presented with numerous nodules on the face Fig , and witKS was provisionally diagnosed. Serological tests confirmed HIV infection, and microscopic examination of a biopsy specimen from the palate showed pronounced vascular and spindle cell proliferation, slit-like vascular spaces with extravasated red blood cells. These findings provided confirmation of the provisional diagnosis of KS.The patient refused anti-retroviral treatment and systemic cytotoxic chemotherapy, and was temporarily lost to follow-up but returned to our clinic three months later. He now presented with severe oedema of the face, an increase in number of the facial KS lesions Fig , and ext6/l and CD4+ T cell and a percentage of total lymphocytes of 2.11%, had extensive cutaneous and oral lesions as well as pronounced oedema of the face  together with cytotoxic chemotherapy is the treatment of choice for the management of HIV-KS. At times this may also improve the associated lymphoedema. The lymphoedema should be treated in parallel to the treatment of HIV-KS with diuretic agents, and in cases where the lower extremities are involved, by elevation of the limbs and compressive dressings. The preservation of skin integrity is important to prevent secondary bacterial and fungal infections. Application of emollients to the affected lymphoedematous skin may prevent cutaneous breakdown. If breakdown does occur, application of topical antimicrobial agents is necessary .According to the AIDS clinical trial group staging classification for AIDS-associated Kaposi sarcoma, lymphoedema and exophytic HIV-KS oral lesions are independently associated with poor prognosis ,4. The tIn sub-Saharan Africa, the natural course of HIV-KS in the absence of HAART is characterized by rapid disease progression associated with high HHV-8 burden and short life expectancy. In this geographic region, HIV-KS has reached epidemic proportions ,23. HIV-Since there is no cure for HIV-KS, conventionally its treatment focused on control of tumour growth and palliation. HAART should always be instituted in HAART-naïve HIV-seropositive subjects with KS, since it promotes regression of KS lesions. However, in about 6,5% of these subjects HIV-KS may flare up shortly after the introduction of HAART as an immune reconstitution inflammatory syndrome (IRIS) .In light of the cases presented here and our personal experience, it might be advisable to treat oral HIV-KS with cytotoxic chemotherapy at early maculo-papular stages when the lesions are still asymptomatic. Such a treatment protocol might have several advantages. Firstly, systemic cytotoxic chemotherapy might prevent or at least delay the development of extensive exophytic oral lesions that have a poor prognosis; secondly it might prevent the development of lymphoedema associated with late stages of HIV-KS; and thirdly, in the early stages of oral HIV-KS, limited cytotoxic chemotherapy is sufficient to control tumour growth compared to more extensive chemotherapy regimen needed to treat advanced oral HIV-KS. Indeed, systemic chemotherapy given to HIV-seropositive subjects has the risk of exaggerating the existing state of immuno-suppression, thus further increasing the susceptibility to opportunistic infections and neoplasms, however, limited doses of cytotoxic chemotherapy is not usually associated with such adverse effects.