Due to its conservative morphology and allegedly primitive trunk tagmosis, we have utilized the centipede Strigamia maritima to study the correspondence between the expression of engrailed during late embryonic to postembryonic stages, and the development of the dorsal exoskeletal plates (i.e. tergites). The results corroborate the close correlation between the formation of the tergite borders and the dorsal expression of engrailed, and suggest that this association represents a symplesiomorphy within Euarthropoda. This correspondence between the genetic and phenetic levels enables making accurate inferences about the dorsoventral expression domains of engrailed in the trunk of exceptionally preserved trilobites and their close relatives, and is suggestive of the widespread occurrence of a distinct type of genetic segmental mismatch in these extinct arthropods. The metameric organization of the digestive tract in trilobites provides further support to this new interpretation. The wider evolutionary implications of these findings suggest the presence of a derived morphogenetic patterning mechanism responsible for the reiterated occurrence of different types of trunk dorsoventral segmental mismatch in several phylogenetically distant, extinct and extant, arthropod groups.Trilobites have a rich and abundant fossil record, but little is known about the intrinsic mechanisms that orchestrate their body organization. To date, there is disagreement regarding the correspondence, or lack thereof, of the segmental units that constitute the trilobite trunk and their associated exoskeletal elements. The phylogenetic position of trilobites within total-group Euarthropoda, however, allows inferences about the underlying organization in these extinct taxa to be made, as some of the fundamental genetic processes for constructing the trunk segments are remarkably conserved among living arthropods. One example is the expression of the segment polarity gene  Bergström, 1973.Trilobites comprise a very diverse and successful monophyletic group of well-known extinct arthropods characterized by the possession of a biomineralized dorsal exoskeleton, and include some of the oldest known macroscopic metazoans in the fossil record. All trilobites shared the same basic body construction; this consists of a head formed by  four limb-bearing segments covered by a cephalic shield, followed by a homopodous trunk with a highly variable number of segments that show a significant diversity in terms of the number of expressed tergites , as well as their degree of differentiation and fusion (i.e. tagmosis) There is a good understanding on the growth dynamics of the trunk in several trilobite species The main arguments utilized by Størmer Clarifying the correspondence between the tergites and the segments that constitute the trilobite trunk carries implications for understanding the origins and early evolutionary history of this important group, as it has been suggested that certain intrinsic aspects of trilobite trunk development show indications of significant variability and plasticity, particularly evident in Cambrian representatives relative to younger forms engrailed (en), which plays a pivotal role during segmentation, as it is essential for the formation and maintenance of the intersegmental borders in Drosophilaen was in all likelihood also involved in segment formation in these extinct arthropods The loss of biological information associated with the process of fossilization makes it impossible to examine directly the relationship of the trilobite’s tergites and their corresponding segmental units. However, several of the mechanisms responsible for the formation and patterning of the segments in extant arthropods are highly conserved, and thus enable making some inferences about the fundamental genetic processes required for the construction of a metameric trunk in these extinct representatives. A prime example can be found in the segment polarity gene en and the position of the tergite boundaries in the larval and adult abdomen of insects such as Oncopeltus fasciatus and Drosophila melanogasterGlomeris marginataen based on the position of the dorsal exoskeletal elements, even in cases in which there is a secondary modification on the exact expression domain of the en stripe, such as the dorsal side of Glomerisen and the formation of the tergite borders in these arthropods is representative of the ancestral state. To address this question, it is necessary to analyze the correspondence between en and the tergites in another extant arthropod model, ideally one that features a plesiomorphic trunk morphology.Some studies have also found a direct correlation between the expression of Strigamia maritima to study the correspondence between the formation of the tergites, during late embryonic to postembryonic development, and the dorsoventral expression of en. We then use the information on the correlation of en expression and tergite border formation as the theoretical foundation from which to make inferences about the expression domains of this segment polarity gene in the trunk of exceptionally well-preserved trilobites, and other closely related fossil arthropods. The trunk segments of Strigamia have several desirable traits for the aims of this study, such as the anteroposterior differentiation of the tergite into a pretergite and a metatergite, and the presence of lateral spiracles, as these morphological features can be utilized to follow the development of the tergites. Furthermore, the embryonic development of Strigamia has recently been described in detail Due to the conservative trunk morphology of centipedes, most notably the homonomy of the segments and direct correspondence between dorsal and ventral sclerites, we utilize the geophilomorph Strigamia were collected near Brora, northeastern Scotland . As noted by several workers In situ hybridizations were mostly performed as described by Chipman et al. Information on the morphology of the exoskeleton in trilobites and trilobite-like taxa was extracted from the primary literature, original photographs, and/or by direct inspection of catalogued specimens housed in scientific collections. The Smithsonian Institution (Washington D. C.), the Palaeontological Association (UK), and the Whittington Archives  granted permission for the study of collections and figure reproduction. Institutional abbreviations: Smithsonian Institution (USNM); National Museum of Wales (NMW); Early Life Research Centre, Nanjing Institute of Geology and Palaeontology, China (ELRC). No new material was collected for this study.Strigamia embryo develops as an extended flat germ band on the surface of the egg. In this flattened germ band, the ectoderm is on the surface, with the ventral component along the medial area and the right and left laterodorsal components symmetrically at the two sides Strigamia embryo faces the proctodeum, and the anterior part of the ventral ectoderm juxtaposes with the posterior part   1, C1. On tissues 1. This s tissues  [54]. A  tissues .en is very similar to that previously described for stage 7 embryos, including the correlation between the laterodorsal extent of the developing hemitergite and the corresponding stripe .Prominent changes observed in the cuticle of post-hatchling juveniles include the completed dorsal closure, forming a dorsal midline running longitudinally throughout the trunk , as wellMost of the features described before become more accentuated . The latAll the exoskeletal elements have acquired, or are close to, the mature morphology . The preen in embryos of Strigamiaen in embryonic stages, and represent valuable landmarks for estimating the approximate expression domains of this gene in hatched individuals. Thus it is possible to extrapolate the expression domain of en in the postembryonic trunk segments, which would be largely consistent with the pattern observed in the embryonic stages .The results confirm previous findings on the early expression of c stages . It is cen in the trunk segments of Strigamia is coincident with approximately the posterior third of each tergite. More specifically, the posterior edge of each en stripe is directly correlated with that of the posterior (meta)tergite boundary of its corresponding segment, and does not overlap with the adjacent (pre)tergite tergite 5; 8A. Asral side . While t al. see  that en f en see . Regardlen and the formation of the tergites in the trunk segments of phylogenetically distant representatives of Hexapoda  and Myriapoda  is indicative that this relationship represents a highly conserved, and almost certainly ancestral, patterning mechanism of the ectoderm derivates in Mandibulata. Amongst Chelicerata, detailed information on the expression of segment polarity genes is only available from a few araneaeid species. However, the pattern of hemitergite formation and dorsal closure in the opisthosoma of the cobweb spider Parasteatoda tepidariorumen observed in the posterior region of the orb weaving spider Cupiennius saleien expression and tergite formation represents the symplesiomorphic condition for the development of the laterodorsal exoskeletal elements in crown-group Euarthropoda.The close correspondence between the dorsal expression of PhacopsMisszhouiaMost aspects of the palaeobiology of trilobites are exclusively known from the morphology of their biomineralized dorsal exoskeletons. There are little more than 20 trilobite species from which the exceptionally preserved ventral tissues have been described, covering a considerable range of ages, taxonomic groups and preservation styles  [1]. AltKiisotoria saperi, an Early Cambrian non-trilobite arthropod from Greenland, show the presence of transverse ligament-like structures comparable to the tendinous bars of trilobites It is very unlikely that the peculiar trunk organization of trilobites is merely the result a taphonomic artefact caused by the decay of the internal tissues or compression after burial. Specimens with soft tissue preservation of “We will not enter into the detailed discussion on whether the tergite boundaries in these arthropods coincide with (segment) boundaries. Arbitrarily assuming that they do, the (segments) … must be obliquely inclined, with the ventral part more anterior than the dorsal”. Although the formation and maintenance of the body segments in arthropods is a complex process that requires a precise patterning of the ectodermal and mesodermal derivates, the interpretation for obliquely inclined segments in trilobites and their close relatives would imply a considerable morphogenetic rearrangement of the former. Instead, the plesiomorphic correlation between the position of the tergite borders and the expression of en in extant arthropods can provide an alternative explanation for this exoskeletal organization. The highly conserved ventral segmentation patterning and associated expression of en within Panarthropoda , insects Glomerisen stripe in the trilobite trunk would not have been located in the posterior region of the segment, but rather approximately in the middle of it, just above the site of limb attachment to the body. The same interpretation is also applicable for trilobite-like taxa in which most of the tergite boundaries have become fused into a single trunk  shield. In the case of nektaspidids, for example, the only functional articulation is found at the cephalo-thoracic boundary , a segment polarity gene that is normally active immediately anterior to the expression stripe of enwg-like anterior patterning signal could possibly be substituted by the interaction of hedgehog, a segment polarity gene with a similar expression domain to that of en, and a number of additional genes  that are also expressed in the dorsal segmental units of Glomeris. This proposed mechanism is largely based on analogy to a process that has been reported in the abdominal ventral pleurae Drosophila, which are characterized by similar patterns of gene and morphogen activity.The proposed dorsoventral mismatch of segment polarity gene expression in the trilobite trunk clearly deviates from the plesiomorphic arthropod condition consisting of a dorsoventrally continuous stripe of GlomerisGlomeris could be the result of evolutionary convergence that would have at least one parallel at the level of gene expression , which consequently results in a close morphological analogue . Indeed, among extinct and extant arthropods, genetic and phenetic differences in the dorsoventral segmental patterning of the trunk region can be found in several additional cases  is not expressed in the most ventral region of the germ band; however, it may be possible that the widespread dorsoventral expression of the gene Cs-Wnt5-1 is responsible for establishing the anteroposterior polarity of the germ band wg is apparently not expressed on the dorsal side of the notostracan Triops longicaudatus during post-embryonic segmentation , it has an additional morphological parallel with the diplosegments of Glomeris in that the posterior tergites are associated with more than one pair of legs  are associated with several pair of legs, unlike those that form anterior part of the trunk that only bear a single leg pair Fuxianhuia protensa, Shankouia shenghei), a controversial lower Cambrian group of rather primitive-looking arthropods that have been commonly interpreted as basal members of the euarthropod stem lineage This consideration can be further applied to extinct taxa that are also characterized by the presence of supernumerary pairs of limbs per tergite on the posterior region of the trunk. Among trilobite species with exceptional limb preservation, there are some confirmed cases in which there are several pairs of walking legs clustered in the posterior portion of the trunk, the so-called pygidium s eatoni   trilobites with soft-tissue preservation  that could be associated with the reduced body size that is characteristic of agnostids; alternatively, the trunk organization may provide indication that the position of agnostids lies outside Trilobita, and probably within the stem-lineage of Crustacea or even Mandibulata, but have acquired a similar dorsal morphology with eodiscid trilobites convergently. Haug et al. Agnostus pisiformis, coupled with the fact that the mode of trunk development in polymeroid trilobites and agnostids most likely represents an ancestral trait of total-group Mandibulata Within the context of our findings on trilobite segmentation, it is possible to provide two alternative interpretations for the affinities and trunk organization of Strigamia, it has been possible to corroborate the link between the development of the tergites and the associated dorsal expression of the segment polarity gene en, a relationship that can be readily considered as symplesiomorphic for Euarthropoda. The fact that this correlation is ubiquitous and persistent, even in extant representatives in which the trunk segmentation is clearly modified relative to the ancestral arthropod condition, enables to make precise inferences about the expression domains of en in the trunk of exceptionally preserved trilobites. This information leads to the conclusion that the segment and tergite borders of trilobites, as well as some of their close relatives, were not perfectly aligned with each other, which is indicative of a derived and widespread type of dorsoventral segmental mismatch in this diverse and early arthropod group. The interpretations on the segmental patterning of the trilobite trunk drawn from the ectodermal derivates of these arthropods are corroborated by additional information on further aspects of the exceptionally preserved internal anatomy, such as the structure of the digestive tract. Conversely, the metameric arrangement of the longitudinal musculature is deemed inadequate to address the segmental organization of the trilobite trunk due to the effect of potential postembryonic morphogenetic movements during ontogeny. These findings carry wider evolutionary implications for understanding the processes of arthropod segmentation in some of the oldest representatives of the group, and suggest the reiterated occurrence of a derived type of dorsal gene expression (i.e. anteriorly displaced en stripe) that is ultimately responsible for the morphological pattern of trunk segmental mismatch in several disparate groups of extinct (trilobites and closely related taxa) and extant (e.g. haplosegments Glomeris) arthropod throughout their long and successful evolutionary history.The difficulties associated with resolving the correlation, or lack thereof, of the segments that comprise the trilobite body with their respective exoskeletal elements stems from the fact that the morphological information available from the fossil record is inevitably incomplete, and thus poses unique challenges to the study of development and segmentation in extinct arthropods. Through the analysis of embryonic and postembryonic stages of


Since the WHO “Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)” was published in April 2010[In terms of the technical features, WHO guidelines are consistent with that of EU-4, head-Up to now, there are not yet specified regulations for SBPs in China. Based on “The Provisions for Drug Registration (SFDA Order 28)” , Part I Among the research projects of the "Twelfth Five-Year Plan" significant new drugs creation special, me too biothreapeutics are still the major part of the projects of biotechnology medicines. Therefore, accelerating the process of establishing our SBPs guidelines has great benefit for achieving the goal of ensuring the availability and affordability of public medicine and improving the development of our country’s biotechnology industry. Recently, our department has initiated the process of surveying the need to draft a specified SBP guideline. As some suggestions, due to very hard to obtain and very high costing of RBP would surely increase the difficulties of developing and evaluation of SBPs, how to define the requirement of RBP should be elaborately considered during the process of establishing our guidelines. Besides, special attention should be focused on how to perform the comparability exercise with RBP in the non-clinical and/or clinical study during the development of SBPs of therapeutic monoclonal antibodies. We believe that a SBPs guideline which considering both the actual situation of development of biomedicine in China and the general WHO framework would be established in the near future.


Anopheles gambiae and its underlying factors with an ultimate goal of designing mosquito rearing scheme that produce competitive mating males.The current works is focussed on ways in which the manipulation of mosquito mating behaviour has the potential to contribute to integrated programme for the control of malaria vectors. One line of investigation explores means of reducing vector populations by significantly reducing mating with lure-and-kill and mating disruption measures. The second line is looking at variation in mating success between and within swarms of An. gambiae mating system.A complete map of swarm distribution in Vallée du Kou was constructed and swarms were physically described. Overall swarms were tightly linked to specific man-made markers within the village and a significant difference in swarm numbers and size was observed between households. The pattern distribution of swarms across space was clustered and hotspots are clearly seen where most of the swarms aggregate. A multivariate analysis allowed identifying a subset of environmental parameters that best correlate to swarm structures and that includes, the number of swarm markers/surface unit, the exposition of the makers to sunlight, the contrast pattern and the openness of the marker to air circulation. Exploration of the energetic budget in relation to swarming and mating showed that sugars and glycogen are the main energetic sources that fuel males mating activities. The distribution of wing size of mated males was focused around a central value suggesting that intermediate size of males is advantageous in A better knowledge of key parameters that account for male mating success will be of significance to control strategies based on the release of genetically modified or sterilised males. Similarly, understanding the ecological parameters that are correlated with the presence or absence of swarms would be valuable for the implementation of mating disruption strategies.


The radiobiological effect of densely ionizing ends of primary or secondary charged particles may be influenced significantly by processes running in the chemical stage of radiobiological mechanism; especially the influence of present oxygen may be very important. The effect of its or of other species (radiomodifiers) present in water medium during irradiation may be studied with the help of corresponding mathematical models. The model based on the use of Petri nets will be proposed and described.Two parallel processes, i.e., diffusion of radicals and their chemical reactions, running in corresponding radical clusters formed during energy transfer may be represented with the help of the given model. A great number of chemical species may be easily taken into account. The model enables to study the concentrations of individual radicals changing during cluster diffusion and to estimate their damaging effects on corresponding DNA molecules in given cells. The results demonstrating the influence of oxygen under different concentrations will be presented.


The ATP-binding cassette (ABC) proteins represent a large family of transmembrane proteins that use the energy of ATP hydrolysis to transport a wide variety of physiological substrates across biological membranes . Of themThe ABCC2 transporter is a transmembrane protein expressed in the apical cell membrane of hepatocytes and epithelial cells of small intestine and kidney, where it is involved in the elimination of many endogenous and exogenous substrates from the cell, including compounds clinically relevant [in silico model based on the Gottesman database [In this scenario, the aim of the present work was the development of an database  able to database . Moleculdatabase . Feature


Parents of children with ASD are increasingly using special diets and dietary supplements, despite a lack of robust evidence of effectiveness. The most popular dietary intervention is the gluten free casein free (GFCF) diet which is not without risks for the child and family.To explore the attitudes of parents and health professionals towards dietary interventions and the use of the GFCF diet. To assess the feasibility of an RCT of this diet in preschool children with ASD.Short web-based questionnaire for parents and child health professionals.246/361 parents and 246/317 professionals responded. Of all parent respondents, 46% were currently using dietary supplements for their child, 84% were aware of the GFCF diet and 28% were currently using this diet. Three quarters of parent respondents said they would ‘definitely', or would ‘consider' participating in an RCT of the GFCF diet.72% of child health professionals had been approached by parents for advice about the GFCF diet. 50% of professionals reported they did not know enough about the efficacy of the diet to advise families. The majority of professionals strongly supported the need for evaluation of the GFCF diet and 75% would be prepared to recruit children to an RCT.The need to evaluate the GFCF diet has been confirmed. There is support amongst professionals and parents for an RCT of this diet and facilitators and barriers of recruitment and retention of families in a future RCT have been identified.Autism Speaks US.


The past few decades have seen major advances in evaluation and treatment of fetal cardiovascular diseases. Largely due to advances in imaging, recognition of structural pathology in the developing human heart can now be performed as early as the 12th week of pregnancy and can be seen to develop and progress through gestation. Because of the observation that serious structural congenital heart disease may progress from seemingly minor disease if untreated, several centers are now intervening before birth to address such abnormalities and attempt to prevent the further development of structural disease. Furthermore, detailed assessment of cardiac rhythm, function, and myocardial mechanics is now also possible as early as the first trimester. Transplacental treatment for fetal rhythm abnormalities has dramatically changed the outcomes for affected pregnancies in the past decade. More recently, several centers have begun to incorporate routine fetal cardiovascular assessment in the evaluation of diseases such as congenital cystic adenomatiod malformation of the lung, twin-twin transfusion syndrome, and congenital diaphragmatic hernia where structural disease may impose significant comorbidity postnatally, and hemodynamic derangements and functional pathology secondary to the primary process may impact the fetus in utero. Recognition of potentially treatable fetal cardiac disease may alter the prognosis for these patients in the perinatal period as in utero treatment to address the primary abnormality has been shown to improve the hemodynamic derangements observed. Finally, prenatal recognition of fetal cardiac disease in general may be changing the natural history and incidence of disease in the postnatal population. Regardless of training and background, any healthcare professional involved in the diagnosis and management of diseases of the fetus and newborn now needs to be cognizant of the potential contribution of prenatal cardiac assessment and treatment in the congenitally malformed or unwell fetus. In this special issue on the fetus as a cardiac patient, we have invited a few papers addressing issues unique to this patient group.The first paper of this special issue addresses ethical issues relating to fetal diagnosis of a major abnormality with special emphasis on cardiac malformations. Presented are discussions of the ethical concept of beneficence and the principle of patient autonomy in the context of counseling expectant mothers and the complex ethical situation which arises in the consideration of the fetus as a patient.The second paper presents a comprehensive review of cardiac findings in twin-to-twin transfusion syndrome (TTTS), a condition which is a severe complication of monochorionic twin pregnancy. TTTS is characterized clinically on ultrasound by polyhydramnios in the “recipient” twin and oligohydramnios in the “donor” with varying degrees of cardiac dysfunction in the recipient. The pathophysiology of the syndrome itself and of the development of cardiomyopathic changes remains incompletely understood. The review discusses what is known with respect to the cardiac findings at presentation, natural history, and response to treatment and discusses current approaches to a comprehensive cardiac evaluation of affected fetuses. The third paper describes a large series of fetuses presenting with findings consistent with cardiomyopathy or myocarditis and represents a large natural history study of these entities, underlining the particularly high perinatal loss rate with diagnosis of dilated cardiomyopathy or myocarditis, as opposed to many of the hypertrophic myopathies.The issue concludes with two thought-provoking review articles regarding the intrauterine environment and the complex interaction the developing fetal brain and circulatory system have with each other and the placental circulation. In the first of these, the authors present a discussion of intrauterine hypoxia, its various causes, and mechanisms whereby disease in the fetus may result. The final paper presents a comprehensive review of the current understanding of pathologic findings in the developing brain of the fetus and infant with congenital heart disease. Methods for detection, potential etiologies, and implications for neurodevelopmental outcome are discussed. Intriguing speculation regarding the possibility of altering the natural history of developmental brain abnormalities via in utero intervention will leave the reader eagerly anticipating future developments in the rapidly advancing field of fetal cardiovascular assessment and treatment. Anita J. Moon-GradyAnita J. Moon-GradyShinjiro HiroseShinjiro HiroseGreg KesbyGreg KesbySamuel MenahemSamuel MenahemWayne TworetzkyWayne Tworetzky


Many women in Sub-Saharan African countries do not receive key recommended interventions during routine antenatal care (ANC) including information on pregnancy, related complications, and importance of skilled delivery attendance. We undertook a process evaluation of a successful cluster randomized trial testing the effectiveness of birth plans in increasing utilization of skilled delivery and postnatal care in Ngorongoro district, rural Tanzania, to document the time spent by health care providers on providing the recommended components of ANC.The study was conducted in 16 health units . We observed, timed, and audio-recorded ANC consultations to assess the total time providers spent with each woman and the time spent for the delivery of each component of care. T-test statistics were used to compare the total time and time spent for the various components of ANC in the two arms of the trial. We also identified the topics discussed during the counselling and health education sessions, and examined the quality of the provider-woman interaction.The mean total duration for initial ANC consultations was 40.1 minutes (range 33-47) in the intervention arm versus 19.9 (range 12-32) in the control arm p < 0.0001. Except for drug administration, which was the same in both arms of the trial, the time spent on each component of care was also greater in the intervention health units. Similar trends were observed for subsequent ANC consultations. Birth plans were always discussed in the intervention health units. Counselling on HIV/AIDS was also prioritized, especially in the control health units. Most other recommended topics (e.g. danger signs during pregnancy) were rarely discussed.Although the implementation of birth plans in the intervention health units improved provider-women dialogue on skilled delivery attendance, most recommended topics critical to improving maternal and newborn survival were rarely covered. Antenatal care (ANC) visits provide an opportunity to reach pregnant women with important preventive and treatment interventions as well as counselling on a variety of topics such as birth and complication readiness and the importance of skilled delivery and immediate postnatal care . An addiThe amount of time spent on health education, advice and counselling during ANC consultations is key to the effectiveness of ANC in improving health behaviours and care seeking during pregnancy, labour and delivery and in the immediate postpartum period . The infThe scope of health education and counselling on pregnancy and related complications provided to women during ANC visits in most Sub-Saharan African countries where over half of all maternal deaths occur, however, is often inadequate or nonexistent,7. This Maternal mortality is very high in Tanzania, estimated at 454 deaths/100,000 live births. Ninety-The focused ANC package based on the WHO model was introduced in Tanzania in 2002, althoughStudies on the content of ANC provided to women are needed in low-resource countries to improve the quality of ANC. Although some information on the quality of ANC services is collected through national surveys such as Demographic and Health (DHS) and health service assessment, detailed data on counselling, health education or promotion of skilled delivery and postnatal care are often missing.This paper reports the scope and quality of ANC services provided to women in Ngorongoro, a rural district in northern Tanzania. It compares time spent for various components of ANC and quality of care provided in the control and intervention arms of a cluster randomized controlled trial (RCT) that aimed at examining the effectiveness of birth plans in improving utilization of skilled delivery and postnatal care . Although a component of the recommended focused ANC in Tanzania, birth plans are rarely implemented during routine ANC consultations in the study district.Sixteen dispensaries offering maternal and child health (MCH) services in Ngorongoro district, rural northern Tanzania were included in the study. According to the 2002 Tanzania national census, the total district population was 129,362 of which 29,489 were women in the reproductive age group. Given tThe study was descriptive and used mixed methods of data collection. Quantitative methods were combined with direct observation of ANC consultations. For the purposes of the cluster randomized control trial, the 16 participating health units were randomly grouped into either the intervention arm where birth plans were introduced or the control arm where the standard of ANC as per district protocol was offered . Antenatal and post natal care services were generally available at all clinics . Providers worked more than eight hours a day in some clinics because women would frequently arrive close to the end of official hours. Clinic attendees included a mixture of women seeking antenatal and postnatal care.Between October-December 2008, providers in the intervention units were trained for a total of two half working days at a training workshop, followed by a second training for two half working days at their respective health units. The training covered the implementation of birth plans during ANC and the importance of involving male partners or others identified by women as participants in their care. Providers were also instructed to encourage women to bring their male partners for future ANC visits if they did not accompany them at the time of study recruitment. Major components of the birth plans included: 1) plans for a place of delivery , 2) calculation of the expected costs and money saving strategies for delivery, 3) plans for identifying someone to accompany the woman to the delivery site and another to look after her household, 4) plans for identifying possible blood donors, and 5) plans for addressing any complications arising during pregnancy, labour, delivery, and in the postnatal period (for mother and newborn), and 6) strategies for overcoming any other barriers to accessing skilled delivery care. One copy of the birth plans was retained by the woman so that she could present it to providers at the delivery site, and a second copy was kept at the health unit.Providers' performances during practical training sessions were timed and recorded on a video camera and later jointly reviewed by trainers and providers. Follow-up training to re-enforce skills learned was conducted at each health unit on clinic days.Providers in the control units were trained for one half working day at a workshop in the concept of the study in their arm followed by another one half working day in their respective health units supervised by MM. Topics covered included general concepts of focused ANC, and collection and recording of study-related data from study participants and participants' follow-up. Health care providers in both arms of the study were also informed of the process evaluation during the training sessions and before data collection commenced.Providers in both the intervention and control arms of the study had previously undergone basic and in-depth training on the concepts and implementation of focused ANC by the district MCH team and various NGOs involved in MCH care. All had at least one year experience in implementing focused ANC.The process evaluation was conducted over a period of approximately ten weeks from January to March 2009 at all 16 health units and took place during the implementation of the cluster randomized trial. ANC consultations were observed, recorded using a digital voice recorder, and timed using a stopwatch. The total time spent on the consultation and on each component of care delivered was recorded.A health unit assessment form was used to collect information on clinic characteristics, provider adherence to the focused ANC model in all clinics, and on provider implementation of the birth plans in the intervention clinics. Some of the questions in the assessment form were adapted from the Tanzania Service Provision Assessment Survey, 2006 questionnaire, and theThe health units were visited unannounced. Each unit was visited once or twice for observation of the ANC consultations and once for postnatal care. Information was collected on a maximum of five consultations during any single visit to a health unit. Systematic random sampling was used to select up to five consultations depending upon the volume of patient flow at the health unit. The data collected were reviewed with providers after health unit working hours.Health care providers were asked to hang a digital voice recorder around their necks to record the entire consultation. This strategy was used to protect the woman's privacy during physical examinations. After seeking consent from both care providers and women, MM and one trained assistant, both familiar with Kiswahili and the two major local languages (Ma and Kitemi) observed the consultations except the physical examinations. The total duration of the consultations and the time allotted for delivering each component of care was recorded on the health unit assessment form. The components of care assessed included: history taking, examination for maternal and foetal well being, drug administration, and counselling and health education. Counselling and health education included time spent explaining the importance of skilled delivery care for all women, voluntary counselling and testing (VCT) for HIV, health education for HIV/AIDS, birth plans and other topics as stipulated in the focused ANC guidelines for Tanzania Figure . At the On the same day of the visit or immediately after leaving the health unit, MM recorded the observations of the quality of provider-client interaction findings in a diary. Information on the availability of essential supplies (e.g. drugs and equipment) and other items needed to support for the delivery of quality ANC was collected.The recorded information was analyzed by the principal investigator (MM) assisted by an experienced MCH nurse who reached consensus on the amount of time allotted to each component of care and on the quality of care delivered.The average total time spent for antenatal consultations for each clinic was calculated by dividing the sum of the time for each component of care delivered divided by the number of consultations assessed to obtain a cluster level summary that was entered in the health unit assessment form. Cluster level summaries on the time spent for providing specific components of care were also calculated. The summaries were later used to calculate the time spent for total consultation in each arm of the study as well as for specific components of ANC.The quality of the provider-client interaction was ranked good if the provider allowed women to ask questions and responded to their questions. The quality was ranked fair if the provider allowed women to ask questions but did not respond to their concerns nor try to ascertain if the women understood what was discussed. The discussions were ranked bad if the provider neither allowed women to ask questions, nor tried to determine if women understood what they were being told. The interactions were categorized as undetermined if for any reason the ANC sessions were too short to allow assessment of the provider-women interaction. A health unit was categorized to have "good" provider-client interaction if all consultations in the particular health unit were ranked fair or good.Quantitative data was entered into SPSS statistical package (version 16.0) and later transferred into STATA (version 9) statistical package for cleaning and analysis. The average time for initial and revisit ANC (2nd visit or higher), and postnatal care consultations were calculated and compared between the two study arms using unpaired t-test statistic. Times for components of ANC were similarly calculated.Ethical approval was obtained from the Institutional Review Boards of the World Health Organization, London School of Hygiene and Tropical Medicine, and the National Institute for Medical Research in Tanzania. Permission was also granted from Arusha region and Ngorongoro district administrative and health authorities and staff at participating health units. Informed verbal consent was obtained from all providers and women who participated in the process evaluation.A total of 23 service providers were observed (11 in the intervention arm and 12 in the control): nursing officers (2), midwives (5), MCH nurses (8), nurse auxiliaries (4) and clinical officers (4).73 initial ANC consultations were observed (36 in the intervention arm and 37 in the control). A total of 35 re-visit ANC consultations were observed (18 in the intervention and 17 in the control). Since not all women were given drugs or immunized at each ANC consultation, a total of 20 consultations were observed for this component of care . The reported average number of pregnant women seen per working day in each clinic did not differ between the two study arms .Table Table Providers in all intervention health units consistently counselled women on the importance of delivering at the available health units when helping them formulate their birth plans. In contrast, providers in only one control health unit briefly counselled women on skilled delivery care (information not shown). Providers in both the intervention and control health units consistently provided VCT for HIV/AIDS during initial ANC visits, and blood test results were communicated to the women before they left the clinics. Some aspects of prevention of maternal to child transmission of HIV (PMTCT) were also discussed during all ANC consultations.Tanzania's focused ANC guidelines recommend that women make plans for postpartum care during the third visit (at 28-32 weeks gestation). The importance of postnatal care was consistently emphasized in 5 out of the 8 health units in the intervention arm of the study. It was not consistently emphasized in three of the intervention health units because women typically initiated ANC late. Consequently, there was insufficient time to cover this topic along with all other recommended topics. In contrast, women in only one control health unit were informed about postnatal care and the amount of information provided was brief and inconsistent across consultations.All health units in the intervention arm and all except one in the control arm received a good score for provider-client interaction. Women asked questions freely and even participated in some health unit activities like weighing other women and recording this information on the ANC cards. Providers in all health units spoke the local language and needed interpreters only occasionally.All health units experienced stock-outs of drugs and equipment needed for the delivery of routine ANC Table . For exaThe implementation of the birth plan intervention significantly improved the total time for consultations and for most components of ANC including health promotion and counselling. The increased time spent on counselling in the intervention units suggests that training of providers on birth plans can translate into measurable improvements in provider practices.The study did not improve the quality of care as measured by provider-patient interactions since consultations in both arms of the study were generally rated as "good". This is a somewhat surprising finding because a logical assumption is that spending more time with women should translate into improved provider-patient communication between providers and clients. The fact that most providers were able to speak the local languages, were willing to work past regular hours to accommodate women's needs, had served in the health units for sufficient time to build a sense of trust with the surrounding communities, and knew most of the women attending their clinics, however, suggests that the rapport between providers and patients in the study health units was strong prior to the implementation of the intervention. Our findings are consistent with results from a previous study in an urban setting in Tanzania.The average time for the initial ANC consultation of 40 minutes in the intervention health units compares favourably with WHO recommendations  but is sTraining of providers on birth plans alone did not result in significant changes in the implementation of other aspects of the focused ANC model. Providers need more training on adequately delivering all components of the model, appropriate supportive supervision and regular evaluation of their performances to improve the quality of care. Arguably, the full implementation of the Tanzania's focused ANC model in health units with heavy workloads might require an increase in the number of providers or office hours to cope with increased time requirements to deliver ANC. The re-organization of health unit activities enabling MCH providers more time and resources to provide quality ANC services may be a pragmatic interim solution. Staffing each health unit with an MCH provider responsible for delivering only clinical services could be a long term objective.This study found that counselling in both control and intervention units was not provided on many topics recommended in Tanzania's national essential health intervention package and focuThe time spent for counselling in this study in relationship to client flow raises some questions about the time providers will need to spend to cover all recommended topics. If more time than is currently spent is needed to deliver all components of recommended care, this may present a challenge for providing individualized counselling in clinics with heavy workloads. Although group counselling for some topics such as danger signs in pregnancy, labour, delivery and postpartum may be an option, other topics such as birth plans may not be amenable to group discussion. Women's lack of autonomy and decision making ability in the study setting plus the sensitivity of some issues  also mean that a group approach cannot completely replace the need for individualized counselling.This study showed that some clinics experienced stock-outs of essential drugs and equipment needed to provide routine ANC. For example, blood pressure was not routinely checked among women in health units which lacked functioning blood pressure machines, and those with elevated levels could be missed with serious consequences to both the women and their unborn babies. Such stock-outs may contribute to women's perceptions of services at health clinics in the district to be of poor quality and discourage them from utilizing available services for delivery and emergency care. If women choose to bypass the health clinics for hospitals to receive skilled delivery care, they may not reach them fast enough because the hospitals are located far from most women's residences.Process evaluation is a useful technique for understanding how well programmes are being implemented, and can be useful for identifying factors that contribute to or detract from smooth implementation,24. ThisThe process evaluation had some limitations. The evaluation was not designed to be a comprehensive assessment of the quality of ANC care in the study setting, but focused on evaluating the implementation of the counselling component of routine ANC. The Hawthorne effect-the possibility that some providers modified their behaviour by spending more time with their clients than they would have done in the evaluator's absence may have influenced the study findings given that providers in both study arms knew that they were being assessed. In a study on the quality of ANC in Tanzania, Boller et al 2003 found that providers delivered free ANC services to women who were usually told to pay for some services in the absence of the researchers. In contNgorongoro is a remote district and consists of a predominantly pastoralist population. Care seeking behaviours in the district are likely to differ from other districts in Tanzania. The relatively low volume of women attending ANC clinics on a given day also allows providers time to give individualized attention to women. This type of individualized care may not be possible in other settings where the number of ANC attendees is higher. The methodological approach used did not allow for blinding of the principal investigator regarding which health units were in the intervention or control arm. His interpretation of the recorded findings might have been influenced by the knowledge of the arm of the study to which the health units were allocated, thereby introducing bias. To reduce this risk, the recorded materials were reviewed by an experienced MCH nurse who was not aware of the health units' allocation to the two study arms, and the final interpretation of the recorded material depended on consensus of the two investigators. The process evaluation commenced a month after the trial implementation and continued for only three months. Repeat assessment at a later date would help determine if results can be sustained in the longer term.Most topics recommended in the ANC guidelines are not routinely discussed during ANC consultations in the study setting. Provider competency and willingness to implement all components of Tanzania's focused ANC model including all recommended health education/promotion topics needs further examination. The need for more training, supportive supervision and monitoring should be addressed to improve the quality of care. The limited time allocated for providing the various components of the focused ANC model in the control arm; the fact that not all recommended health education and counselling topics are being discussed despite prior training on the focused ANC model; and the lack of emphasis on explaining to women the importance of early postnatal care are missed opportunities to realize the full potential of antenatal care to improve obstetrical outcomes in the study setting.The authors declare that they have no competing interests.MM designed the study, collected and analyzed the data, drafted the initial manuscript and reviewed subsequent drafts. JR participated designing the study, developing the data collection tools and reviewing the draft manuscripts at all stages. VF, OMRC and SC participated in designing the study, developing the data collection tools and reviewing the initial and final manuscripts. All authors approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/11/64/prepub


Angiotensin II and nitric oxide (NO) can modulate the sensitivity of the TGF mechanism. However, the interaction among these substances in regulating the TGF resetting phenomenon has been debated. Studies in isolated perfused AA have shown a biphasic response to accumulating doses of adenosine alone. In the nanomolar range adenosine has a weak contractile effect (7%), whereas vasodilatation is observed at high concentrations. However, a synergistic interaction between the contractile response by adenosine and that of angiotensin II has been demonstrated. Adenosine in low concentrations strongly enhances the response to angiotensin II. At the same time, angiotensin II in physiological concentrations increases significantly the contractile response to adenosine. Moreover, addition of a NO donor (spermine NONOate) to increase NO bioavailability abolished the contractile response from combined application of angiotensin II and adenosine. These mutual modulating effects of adenosine and angiotensin II, and the effect of NO on the response of AA can contribute to the resetting of the TGF sensitivity.Adenosine, via activation of A The tubuloglomerular feedback (TGF) is a negative-feedback system operating within the juxtaglomerular apparatus that can regulate glomerular filtration rate (GFR) by changing arteriolar resistance and hence blood flow and pressure into the glomerular capillaries. In this control system the tubular load to the distal parts of the nephron is detected via changes in tubular sodium chloride concentration at the macula densa site. This information is then used to determine the contractile state of the afferent arteriole (AA) that is the main effector link of this controller. The sensitivity and reactivity of the TGF system can be modulated via several different factors and via those changing the effector response. Exactly where and how this modulation of the TGF response occurs has not been clear. Recent work from our laboratory has indicated that this modulation to some extent can be carried out by the arterioles themselves.Figure 1 and A2 receptors are expressed on afferent arterioles, and can regulate preglomerular resistance. Adenosine in physiological concentrations constricts afferent arterioles via a prominent effect on purinergic A1-receptors  and increasing concentrations of adenosine  completely abolished the contractile response to angiotensin II and adenosine  with L-NAME further amplified the contractile response when added to the combined solution of angiotensin II , oxidative stress (increased) and NO bioavailability (reduced).We suggest that these interactions of vasoactive substances on the afferent arteriolar contractions can explain at least a part of the phenomenon of resetting of the TGF by angiotensin II, ROS and NO. Increased arteriolar reactivity and TGF responses have been described in several models for hypertension, which may be associated to the abnormal regulation of renal angiotensin II 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.


A 34-year-old right-hand-dominant man sustained an electrical injury to his left hand while handling a 450-volt cable. He presented with deep burns to the first web space and the dorsal aspect of the index finger. The excision of the eschar resulted in exposure of bare tendons .What is the initial management of an electrical burn?What is the management of the hand injury?What are the reconstructive options?A first dorsal metacarpal artery flap was performed on this patient. What are the common advantages and pitfalls?Electrical injury often causes deep burns involving underlying soft tissue and bone. A careful history should be taken noting voltage and current involved, duration of contact with source, and related events . Other associated complications include vascular and neurologic injuries, fracture, subluxation of joints, rhabdomyolysis and myoglobinuria, renal failure and cardiac arrhythmias.The general appearance of the hand is noted. Any deficit in range of motion, sensation, and regular neurovascular assessment is carried out. Whether or not immediate and definitive reconstruction should be attempted is clearly dependent on the circumstances of the accident, health of the patient, and consideration taken of the zone of injury.,6Rapid resurfacing of the wound is essential to enable early mobilization and optimum recovery of hand function. Early reconstruction is favored when excision of all necrotic tissue is completed and allows for good wound coverage.5The first dorsal metacarpal artery (FDMA) flap has become popular for this injury. This is an axial pattern skin flap extending proximally from the level of the metacarpophalangeal joint and distally to the level of proximal interphalangeal joint. The course of the artery is determined by Doppler and then marked. The flap is outlined on the proximal phalanx of the index finger extending between the mid lateral lines. A line is then drawn along the radial border of the second metacarpal in a lazy-S fashion, beginning from the lateral margin of the proximal base of the skin island to the tip of the first webspace. This represents the pivot point and the arc of rotation of the flap . The useSkin flaps are raised on both sides of the incision. Superficial veins that have the same course as the pedicle and the terminal branch of the dorsal sensory branch are incorporated with a cuff of superficial subcutaneous tissue. The fascia is then incised on the radial half of the first dorsal interosseous muscle proceeding toward the ulnar side in which the FDMA comes into view. Dissection proceeds to the periosteum at the dorsal radial edge of the second metacarpal including soft tissue around the FDMA to protect the pedicle. The skin island is elevated just above the extensor hood on the proximal phalanx of the index finger leaving the paratenon intact . The fla


This issue of the Stem Cell International journal contains papers from many of the leading scientists in the emerging field: ex vivo expansion of hematopoietic progenitor cells into erythrocytes for transfusion.immunology of transfusion and transplantation began with the discovery of the heterogeneity of human blood group antigens by Dr. Karl Landsteiner in 1901 (recognized with a Nobel Prize in 1930). The discovery of clinically relevant infectious diseases transmitted by transfusion played an important role in the development and advancement of virology. The inheritance of certain form of anemias was discovered during blood transfusion practice and led to development of the genetics of human red cell disorders. In the 1940–1950s, the establishment of blood banks followed by the development of rigorous donation criteria and standardization of blood manufacturing processes has made transfusion safe and widely available and has provided a paradigm for the development of emerging therapies using ex vivo expansion and differentiation of many cell types. An example of one such therapy is represented by the tumor immunotherapy described by Lapteva and Vera.Blood transfusion, the first form of successful cell therapy and, at least to some, “transplantation”, was inspired by the discovery of the circulation by Richard Harvey in the 1600s . In vivo functional studies of human red blood cells in animal models will likely allow more complete characterization in many ways [in vivo imaging and cell fate determination of human erythroid cells by labeling the cells before transfusion with a fluorescent reporter gene by retroviral technology.Reprogramming technology is still under development. Therefore, red blood cells expanded lleagues , who havAlthough red blood cells do not have nuclei, their immediate precursors the erythroblasts do. The terminal maturation of erythroblasts into functional red cells requires a complex remodeling process which ends with extrusion of the nucleus and the formation of an enucleated red blood cell . These lAs represented by all the information, data, and in fact vision contained in this issue, we are clearly at the beginning of a rapidly expanding field. The papers herein provide a broad and comprehensive overview of the most relevant areas of research which have been pursued and are needed to advance the field. Still, as state of the art as this issue is presently, the field is moving so rapidly that one may predict that new knowledge will rapidly follow.Anna Rita MigliaccioAnna Rita MigliaccioGiuliano GrazziniGiuliano GrazziniChristopher D. HillyerChristopher D. Hillyer


The use of lung ultrasound in the detection of pneumothorax is becoming routine in emergency departments and intensive care units in the United States and Europe . The intTo evaluate the sensitivity and specificity of diagnosis of medical students compared with emergency physicians (experts) in identifying pneumothorax by lung ultrasound.n = 40) and emergency physicians (n = 11) with training in emergency medicine and intensive care, called experts, were invited to participate. The study subjects were assessed for the correct diagnosis of 20 cases of pneumothorax after training through classroom teaching of lung ultrasound lasting 2 hours addressing the recognition of artifacts in the lung and identification of pneumothorax Lung Sliding Lines B. Prior to training, medical students and emergency physicians had no prior knowledge or practice in emergency ultrasonography. We used video-clips of 10 positive and 10 negative real cases of pneumothorax obtained by an experienced examiner in lung ultrasound. The comparison between the two groups was described by the mean and standard deviation of hits in each group and tested by the nonparametric Mann-Whitney test. The agreement between raters overall and in each group was estimated by the kappa correlation coefficient. The difference between the agreement observers in each group was tested by Z test for proportions.Students of 3 years of medical graduation participating in the module Radiology Emergency Medicine (Students and experts did not have statistically different test scores as shown in Table Medical students and medical experts are able to accurately identify pneumothorax, despite an abbreviated training time with no previous knowledge of ultrasound lung. Therefore the use of a simulation model based on lung ultrasound videos can be implemented in a systematic way to help health professionals and medical students in their training.


Substantial changes in large parts of the developing world have materialised in the last three decades. These are extremely diverse countries with respect to culture, societal values and political arrangements, but sharing one feature - prevalent poverty and limited resources to protect the health of individuals. The control of emerging chronic diseases in low-resource countries is a formidable challenge. For this reason any intervention should be kept logistically simple and incorporated into a general plan aiming at building gradually the infrastructure that is necessary to bring care to the population at large. The present contribution summarizes some of the priorities in cancer prevention in developing countries and the underlying evidence base, and addresses some of the challenges. Many countries in sub-Saharan Africa still struggle with endemic tuberculosis, malaria, AIDS, nutritional deficiencies and perinatal conditions that cause high rates of premature death and permanent disability, a disease burden at least one order of magnitude greater than cancer. But even where substantial economic development has taken place, as in Thailand, Malaysia, China, India or Brazil, it has failed to benefit society at large; rather, new health threats are on the rise with limited control of the long-term burden of prevalent diseases. Moreover, the lack of comprehensive planning of health systems has led to wider inequalities in access to health care.Cancer control encompasses a package of diverse interventions  aiming aChoices should be driven primarily by the quantification of the problem combined with the feasibility and cost of different interventions. Means to monitor the occurrence of cancer in developing countries are still very limited, therefore planning relies largely on estimates. Based on the comprehensive GLOBOCAN2008 [Smoking of commercial cigarettes used to be uncommon in developing countries where tobacco smoking is a recent aspect of Westernization of life styles. While interventions to reduce the habit in rich countries is now showing positive results, the tobacco industry is pursuing new markets in the developing world ,4. Of alImmunization of infants against hepatitis B virus (HBV) is probably the second most cost-effective option in regions where the infection is still endemic. Lorenzo Tomatis at the International Agency for Research on Cancer saw the potential of such public health measure in the early eighties when he promoted the establishment of The Gambia Hepatitis Intervention Study (GHIS). The main objective of the study was to prove the feasibility of such interventions and quantify the efficacy of immunization in preventing chronic liver diseases and hepatocellular cancer in an African country. Several more years of observation are needed to measure the full impact of the intervention; but high coverage and reduced incidence of chronic hepatitis have been achieved  promisinOne of the most celebrated successes of cancer research is the recognition that virtually all cervix cancers are caused by certain types of the Human Papilloma Virus (HPV) with types 16 and 18 accounting for about 80% of the burden [Compared with classical cytology-based screening, the HPV technology offers a valid and possibly more cost-effective strategy in secondary prevention of cervix cancer in low-resource settings, because the sensitivity and specificity of available HPV tests in exfoliated cells are much more reproducible than those of cytology which strongly depends on human expertise and skill . In factIn a large randomised trial in Kerala, India, Sankaranayan and colleagues  assessedThere is no single strategy to develop cervix cancer control programmes from scratch. With a careful analysis of the size of the problem, feasibility, costs and expected outcomes against the background of existing infrastructure, plans can be gradually built from a minimal level —e.g. one life-time HPV-based screening test with timely treatment accessible to all women from age 35 years— and expanded on the medium- or long-term with immunization programmes and repeated screening. The condition for any intervention to be successful and cost-effective is to reach high coverage of the target population; therefore, much attention must be paid to the logistics of how the services are delivered in order to ensure access and high compliance.Other preventive interventions that are the object of much research and activities in the West focus on nutritional habits and energy balance, clearly an increasing problem in emerging economies as shown by rising rates of diabetes  . TackliThe increased risk of breast cancer in emerging economies is seen as the direct expression of economical development; yet, our understanding of the modifiable causes of the disease is still very limited leaving little room for primary prevention beyond avoiding excessive body weight. Improving access to timely treatment of early palpable tumours is likely to result in a greater benefit to the population. Etiological research in populations still at low or intermediate risk for the disease offer instead powerful opportunities to test hypotheses based on observations made in the high-risk Western world.Finally, an area that is often overlooked among preventive actions in low-resource countries is the uncontrolled use of carcinogens in industrial processes and economical activities, often imported from technologically advanced economies where regulations impose uses that are safe for workers and the environment, but less profitable. Any attempt to estimate the magnitude of the current and future disease burden due to potential carcinogens newly introduced under uncontrolled conditions would be highly controversial as lack of regulations implies also lack of monitoring of the amount, usage and disposal of hazardous substances. Nonetheless, whatever the size of the problem, ethical principles impose the inclusion in any cancer control programme of actions to prevent occupational exposure and environmental contamination with carcinogens. As a first step in this direction both rich and poor countries should be encouraged to sign up to the Rotterdam Convention whose objectives are to promote shared responsibility in the international trade of hazardous chemicals and to contribute to their sound use . Bodies In rich countries the combination of early detection and new treatments that can improve disease outcomes have contributed to a modest but constant decline in cancer mortality rates that started in the 1980s . The maiThe author declare no competing financial or non-financial interests.


In his book Marc Rodwin, Professor of Law at Suffolk University, analyses the regulation of medical interests. He looks more precisely at doctors’ conflicts of interest that can have an influence on their therapeutic choices which are not necessarily in the patients’ best interest. While society and regulators usually expect doctors to be objective in their therapeutic choices, regulating (or the lack thereof) entrepreneurship of private practitioners, their ownership of medical facilities, their type of employment , and forms of remuneration for medical services can create incentives for preferring one medical treatment over another. The initial chapter of the book illustrates these choices by presenting fictional patients from France, the US and Japan who share the same diagnosis, but receive a variety of treatments depending on the economic and regulatory incentive structure of medical practice.The book’s main research question is a normative one, namely how regulation can minimize conflicts of interest between the patients’ interest and physicians’ entrepreneurial goals. On the basis of a political economic perspective, the book sets out to analyse the interplay between several variables: medical associations’ oversight and medical self-regulation, market competition mechanisms, insurance companies’ influence over medical practice, and the state’s practice of regulation. This analytical framework is developed in chapter 1.Chapters 2 and 3 deal with France. The development of the relationship between the organized medical profession, insurance companies and the role of the state are traced back from the medieval times onwards in chapter 2. The last section of the chapter also looks at the influence of European law. Chapter 3 analyses how France aims at avoiding conflicts of interest. The author shows the unusual strength of the French Medical Association and how certain relationships between the pharmaceutical industry and doctors are still tolerated. Rodwin concludes that France only shows limited success in dealing with doctors’ conflicts of interest.Chapters 4–7 form the core of the book and deal with the US. Rodwin distinguishes four phases of the development of the medical economy showing a high variation in tackling medical conflicts of interest. Chapter 4 covers the period before 1950, chapter 5 the period until 1980 and chapter 6 the logic of medical markets from the 1980s onwards. Chapter 7 deals with the ways in which the US cope with conflicts of interests today. The author shows how insurance companies have come to set incentives to reduce medical services and thus create conflicts of interest. Also, the market orientation of the American healthcare system has reinforced ties between physicians and the pharmaceutical industry. Rodwin recommends federal regulation of medical care and health insurance, in order to develop a coherent approach to coping with conflicts of interest.The following chapters focus on Japan. Chapter 8 depicts the historical development of Japan’s medicine and chapter 9 analyses how Japan copes with conflicts of interest. Rodwin exposes the coexistent roles of Japanese doctors as private and hospital practitioners leading to a situation in which Japanese patients stay longer in hospitals than in other nations and also receive more drugs for medical treatment.Chapter 10 (‘Reforms’) deals with the implications of the previous findings for regulation. Neither market competition nor pure public employment of physicians alone does necessarily mitigate conflicts of interests of doctors. Hence, both should coexist. Some of the other suggested solutions are strict regulation of entrepreneurship of private practitioners, of ties between doctors and the pharmaceutical industry, and avoiding intervention of insurance companies in medical standard setting.Chapter 11 is a more sociology-inspired chapter dealing with the concept of professionalism of physicians and its role to play in reducing conflicts of interest. Rodwin argues that the state, doctors and market mechanisms alike should have authority to regulate conflicts of interests, thus effectively providing for the possibility of ‘checks and balances’ between them.The book provides overall a very detailed analysis of the historical and structural sources for conflicts of interest in the three countries presented. The chapter on professionalism complements the political economic perspective and avoids an overly functionalist view of coping with conflicts of interests. The detailed analysis shows that the state and insurance funds are also no ‘neutral’ actors and develops therefore to the convincing conclusion that conflicts of interest are best dealt with by a mix of market-driven, professional and public regulation. The detailedness of some chapters complicates however the readability and leaves the reader with the question if the same conclusions and recommendations could not have been developed with a more structured presentation of some developments. from a regulatory perspective. These interests are not necessarily congruent with the individual patient’s interest of receiving the best medical care. From a regulator’s perspective patients are one interest group among others, even if they are certainly one of the most important groups given their role as future electors. Yet, their interest has to be reconciled with other legitimate interests. Since the medical profession is the main object of interest for the book, it would also be desirable to inquire about the belief structures of physicians about what their own and what patients’ interests are. Using regulatory incentive structures alone does not necessarily explain why certain doctors themselves criticize the ties between the pharmaceutical industry and their profession, even though the same regulatory incentive structures apply.While the ‘patients’ interest’ plays a key role for analysis, the book falls short of defining what the patients’ interests would beThanks to its comprehensive analysis of the three countries and their different regulatory frameworks this book is not only useful for legal or economic scholars/experts who are interested in dealing with conflicts of interest, but also for those who would like to study the healthcare systems of France, Japan and the USA. It is also useful as a starting point for sociologists and political scientists for studying the role of the medical profession.


The last decade has seen an exponential increase in research directed to the field of regenerative medicine aimed at using stem cells in the repair of damaged organs including the brain. The therapeutic use of stem cells for neurological disorders includes either the modulation of endogenous stem cells resident in the brain or the introduction of exogenous stem cells into the brain. The final goal of these attempts is to replace damaged dysfunctional cells with new functional neurons. Nevertheless, there are multiple concerns regarding the therapeutic efficacy of the cellular replacement approach both from endogenous and exogenous sources. Indeed the extensive heterogeneity of neuronal subtypes in the brain makes it difficult to drive stem cells to differentiate to specific neuronal subtypes  pharmacological or genetic modulation of endogenous neural stem cells (NSCs) and (ii) transplantation of exogenous stem cells.NSCs resident in the adult brain are characterized by the ability to self-renew their own pool through cell proliferation and by the potential to differentiate into the three main cell types of Central nervous system (CNS): neurons, astrocytes, and oligodendrocytes Gage, .Active neurogenesis occurs throughout adulthood in primates and various mammals including; rodents, rabbits, monkeys, and humans  increase in the number of newborn neurons in the neurogenic niches as compared to physiological conditions, (ii) migration of new neurons from the neurogenic niches to the damaged area, or (iii) production of the new neurons from local progenitor cells in the vicinity of the damaged brain. Indeed, various reports have demonstrated the occurrence of these three phenomenona following brain damage. Specifically, it has been shown that neurogenesis can be upregulated in neurogenic niches in response to different brain insults including ischemia   directed migration of the new neurons to the proper site of integration and (ii) directed neurite-growth over long distances, which have not been demonstrated in the adult brain outside the neurogenic niches.Therefore, the introduction of new neurons directly to the site of damage in the brain either by exogenous or endogenous sources faces major challenges such as differentiation to the correct subtype and integration. This leaves to date the newborn neurons in the neurogenic niches as the only cell type shown to be able to functionally integrate in the adult brain circuitry.Consequently, one fundamental question is how we can make use of the reactive pool of neural precursor cells residing in the neurogenic niches to take over the function of a remote damaged brain region. In order to address this question it will be important to gain knowledge from the plastic properties of the older brothers of neural stem cells, the postmitotic neurons.Postmitotic neurons exhibit a certain degree of plasticity following brain ischemia and traumatic brain injuries. Indeed, despite the permanent structural damage and cellular loss, functional recovery is observed to a certain extent following brain damage (Chollet et al., Neuroplasticity is defined as the brain's ability to reorganize itself by forming new functional synaptic connections throughout life. Continuous remodeling of neuronal connections and cortical maps in response to our experiences occurs to enable neurons to adapt to new situations Taupin, . ReorganDespite the consistent reports confirming circuitry reorganization in the brain following injury, the molecular and electrophysiological mechanisms controlling this fascinating phenomenon remain still elusive.Another unexplored aspect of compensatory plasticity includes the question of whether newborn neurons are involved in the reorganization of brain circuitry that occurs following brain injury. However, because of their peculiar cellular and plastic properties, we believe that newborn neurons in the neurogenic niches are important players in this phenomenon.Indeed it has been shown that newly generated neurons, as compared to mature granule cells, exhibit a lower threshold for induction of LTP (Schmidt-Hieber et al., Importantly, following brain ischemia, newborn neurons react with a plastic response enhancing not only their proliferation rate but also exhibiting increased spine density and dendritic complexity as compared to resident hippocampal neurons (Liu et al., So far it has not been investigated whether this plastic response includes changes in the pattern of brain connectivity of newborn neurons. However the recent application of retrograde monosynaptic tracing to study the connectome of the newly generated neurons (Deshpande et al., The next step following the demonstration of the involvement of newborn neurons in brain reorganization would be to increase their plastic potential by increasing their number. This may be achieved, taking advantage of the increase in the proliferation rate of NPCs that normally occurs upon brain damage (Liu et al., Previous work has described a number of intrinsic and extrinsic factors required for newborn neurons survival (see Table The vast amount of information that have been gathered in the recent years about the use of neural stem cells in brain repair indicates that cellular replacement alone cannot lead to effective restoration of function due to the complex anatomical, histological, and functional organization of the brain.In this perspective, due to their plastic potential and their innate ability to functionally integrate in brain circuits, newborn neurons produced inside the neurogenic niches are the most suitable targets for brain repair. Moreover, the importance of neurogenesis-related plasticity is further supported by the finding that hippocampal neurogenesis occurs in humans throughout adulthood with a modest decline during aging (Spalding et al., In this scenario strategies that enhance the survival and the plasticity of newly generated neurons in the dentate gyrus may be the most effective to foster the functional reorganization of brain circuits following injury.


The data from DNA microarrays are increasingly being used in order to understand effects of different conditions, exposures or diseases on the modulation of the expression of various genes in a biological system. This knowledge is then further used in order to generate molecular mechanistic hypotheses for an organism when it is exposed to different conditions. Several different methods have been proposed to analyze these data under different distributional assumptions on gene expression. However, the empirical validation of these assumptions is lacking.Best fit hypotheses tests, moment-ratio diagrams and relationships between the different moments of the distribution of the gene expression was used to characterize the observed distributions. The data are obtained from the publicly available gene expression database, Gene Expression Omnibus (GEO) to characterize the empirical distributions of gene expressions obtained under varying experimental situations each of which providing relatively large number of samples for hypothesis testing. All data were obtained from either of two microarray platforms - the commercial Affymetrix mouse 430.2 platform and a non-commercial Rosetta/Merck one. The data from each platform were preprocessed in the same manner.a priori assumption of any of these distributions across all probe sets is not valid. The pattern of null hypotheses rejection was different for the data from Rosetta/Merck platform with only around 20% of the probe sets failing the logistic distribution goodness-of-fit test. We find that there are statistically significant (at 95% confidence level based on the F-test for the fitted linear model) relationships between the mean and the logarithm of the coefficient of variation of the distributions of the logarithm of gene expressions. An additional novel statistically significant quadratic relationship between the skewness and kurtosis is identified. Data from both microarray platforms fail to identify with any one of the chosen theoretical probability distributions from an analysis of the l-moment ratio diagram.The null hypotheses for goodness of fit for all considered univariate theoretical probability distributions  are rejected for more than 50% of probe sets on the Affymetrix microarray platform at a 95% confidence level, suggesting that under the tested conditions  The current biological literature makes extensive use of gene mRNA expression data from experimental systems called gene chips/gene micro-arrays. These data are used to infer genomic level conclusions. For example, to infer the response of an organism or cell culture under treatment or perturbation. Microarrays as an experimental system are very valuable in that they provide a genome-wide picture  genes). Unfortunately, because of costs of collecting microarray data, the number of samples per treatment is quite small (~2-10).The data from microarrays are noisy. There are a number of reasons to expect variability in the measurements of the expressions of the genes in mammalian organisms. These include biological causes, or the noise associated with the steps involved in the measurement of the gene expression. Depending on the question that the researcher is trying to answer, he/she would have to control for many of these sources of variation of gene expression. This paper is interested in understanding the variation in the expression data after the known/reported sources of variation have been controlled for.The biological variability could be due to genetic or non-genetic factors  studies Among the non-genetic factors explaining the variation in gene expression include the gender of the organism -   have been termed intrinsic, extrinsic and pathway-specific or global noises  being normalized and preprocessed to get estimates of gene expressions. RNA are isolated from the cells obtained from the tissue sample has been drawn from the organism. The RNA are then subjected to the process of reverse transcription (RT) to obtain cDNA that are then subjected to the vitro transcription (IVT) process to obtain cRNA using polymerases. The cRNA are then hybridized to probes on the microarray platform . The facMost of the current journals require the microarray data to be deposited on a database  if thesOne of the main areas where microarray data has had its application is in the identification of differentially expressed genes across varying treatment conditions. The approaches used could be classified based on whether they use parametric assumptions about the underlying distribution the gene expression or not. Kerr et al  used a AThe above paragraph describes a snapshot of the analysis done using gene expression data, some of the analyses make use of distributional assumptions and some do not. Since distributional assumptions are made frequently, it appears prudent to validate this assumption. As mentioned above Newton et al  and KerrSince 2002 a significant amount of data from sources like the Gene Expression Omnibus GEO  and ArraThis paper focuses on identifying and validating empirical distribution fits of genome-wide gene expressions as measured by microarrays. In addition to the normal distribution we empirically tested the empirical fit for a number of well established probability distributions.We analyzed four microarray data sets from the GEO database . They weThe microarray samples used in the analyses in this manuscript were based in part on six separate data sets  were analyzed in a number of papers -54 whereFor each of the four Affymetrix data sets used, raw CEL format data from GEO was normalized using the R Bioconductor  implemenFor the data set of 6219 microarray samples RAM memory limitations prohibit normalizing all samples together. To normalize these, the following steps were followed:1. The samples were partitioned into sets of 75.2. The gene expression data for each of these 75 samples were obtained after running the GCRMA routine.Unpublished manuscript 2001.).3. Using the data from step 2, the gene expression across the whole data set of 6219 samples were normalized with respect to each other using the quantile normalization method as described in with these active genes were also chosen. This combined set of genes is what is used in the analysis in this paper. In the interest of having a relatively large number of genes for analysis, further criteria used by Yang et al [Yang et al  that useng et al  like preFor each of the data sets "Craniofacial", "Liver" and "Brain", "Housekeeping", "Male" and "Female", Kolmogorov-Smirnov (KS) and Anderson-Darling (AD) hypothesis tests were used to test distributional assumptions. Both test the null hypothesis that a set of data comes from a given distribution, with distributional parameters possibly unknown. The AD test is more sensitive to differences in the tails of the data than the KS distribution. In testing for Normality, the AD test is known to be more powerful than the KS test . Normal,F, each of identified  probe sets were tested in the following manner:For each of the data sets and each distribution F1. Use maximum likelihood estimation (MLE) to estimate 2. Use the KS and AD tests at the 90% and 95% to test whether the probe data comes from For each of these distributions, MATLAB version R2009B Statistics Toolbox MLE functions were used. Critical values can be found in .In addition, for housekeeping genes, KS and AD tests were used to test for gamma and Pareto distributions across a set of 6219 samples. For these distributions, tables of critical values do not exist, but a method for generating p-values for KS tests with unknown distribution parameters from  was usedThe l-moment ratio diagram ,64 of l-The "Male" and "Female" data were fitted to mixture of normal distributions using the "mixdist" package  in the RThe Kruskal Wallis test was used on the logarithm of expression of the probe sets in each of the "Craniofacial", "Liver" and "Brain" data sets in order to identify those that were most likely unaffected by any of the conditions involved in the generation of these data sets. The results in Table The results of the goodness of fit Anderson-Darling distribution tests for the "Male" and "Female" data sets showed different characteristics from those of the other data sets. Only around 43-46% of the probe sets rejected the normal hypothesis (as compared with 72-82% for the previous data sets). The logistic distribution was rejected less often than the previous data sets (21-24% as compared with 69-79%). The fit of the extreme value distributions were equally bad for both sets of data. This difference in characteristics of the goodness of fit test results between two different microarray platforms indicates the contribution of technology and/or of the normalization methodology to the distribution characteristics of microarray data.2 values for different polynomial fits . So the mean values of skewness and kurtosis are plotted by the red lines in Figure The dependence of the mean on the higher order product moments are shown in Figures K) and the skewness (denoted by S) have to satisfy the following inequality ,The data in Table Further validation of the lack of fit of gene expression to any of the standard theoretical univariate probability distributions can be seen in the L-moment ratio diagram in Figure The samples from the "Male" and "Female" datasets could be considered more or less homogenous with respect to sex, tissue, diet and experimental conditions. One reason we could be seeing poor fits to standard distributions could be that there are different modes to the distribution of the expression of a given gene reflecting the genetic variation in the F2 cross animals or a stochastic network influence  of its expression . Hence iIn the past several years, there has been an explosion in amount of quantitative biological data either in terms of transcriptomics, sequencing data, genetic structure variation, proteomics or metabolomics. DNA microarrays have been important and valuable resource for understanding perturbations to biological systems in terms of identifying affected gene expressions. The standard statistical methods are being either directly used or modified to work with gene expression data. Unfortunately, only a small number of replicate samples per treatment (2-10) are used for analysis owing to the cost of the experimentsal system. This point plus the fact that the probability distributions of gene expressions as measured by these arrays were not characterized leads one of logically question the use various statistical methods that are based on distributional assumptions. Heuristics are being proposed that attempt to relax the reliance on this distributional assumption. One example of this would be the method of jointly using the p-value from a two sample t-test along with the gene expression fold-change to identify differentially expressed genes. Alternately, there is an increased use of non-parametric methods or permutation-based methods ,38.The essential question that we address in this manuscript is whether the distribution of the logarithm of gene expression as measured by DNA microarrays can be approximated by any of the standard theoretical univariate probability distributions. The results in Table The observed distributional characteristics of gene expression data in this manuscript suggest either the need for the use of non-parametric statistical methods or a need to develop newer statistical/mathematical approaches that are capable of and are optimal for working with these kinds of distributions.Because of the nature of the data used in this paper, we are unable to separate the contribution to the variation of the data due to biological reasons from those induced by the microarray technology. The noise we observe is probably the result of the convolution of these two factors. In light of the increasing use of newer technologies like those based on Next Generation Sequencing  and despThe analyses of the empirical probability distribution of gene expressions from five publicly available data sources with relatively large number of samples have been described in this manuscript. The failure of the distributions to follow any of the known theoretical univariate probability distributions has been demonstrated though the data suggests consistent relationships between the different moments of the distributions. These moment relationships should motivate the development of Bayesian methods with appropriately chosen priors.RT and SM designed the study. LdT carried out the all goodness of fits analyses and contributed to the write-up. XC contributed in checking the annotations of the entire microarray data samples used and also in the interpretation of the results. RT performed the l-moment analysis and drafted the manuscript. SM also contributed to the drafting of the manuscript. All authors read and approved the final manuscript.Table S8: Detailed description of the data in Table Click here for fileTable S3: List of housekeeping genes [ng genes  analyzedClick here for fileTable S1: GEO [ S1: GEO  microarrClick here for fileTable S2: GEO [ S2: GEO  microarrClick here for fileTable S6: Results of goodness of fit tests for the Anderson-Darling tests for the six analyzed probability distributions obtained by the varying the cutoff for the Kruskal-Wallis test.Click here for fileTable S4: Best fit distribution Kolmogorov-Smirnov test results for "Craniofacial", "Liver", "Brain", "Male" and "Female" data setsClick here for fileTable S5: Probe set level best fit distribution results for the Anderson Darling (AD) and the Kolmogorov-Smirnov test (KS) tests at 90 and 95 percent confidence levelsClick here for fileFigure S1: Diagnostic plot for the linear model between the logarithm of the coefficient of variation (CV) and the mean of the distribution of the logarithm of gene expression for the "Craniofacial" data set. Note the residual plots (subplots (b) and (c)) also provide the pearson correlation (denoted by ρ) between the absolute value of the residuals and the mean and logarithm of the CV respectively.Click here for fileFigure S2: Diagnostic plot for the linear model between the logarithm of the coefficient of variation (CV) and the mean of the distribution of the logarithm of gene expression for the "Liver" data set. Note the residual plots (subplots (b) and (c)) also provide the pearson correlation (denoted by ρ) between the absolute value of the residuals and the mean and logarithm of the CV respectively.Click here for fileFigure S3: Diagnostic plot for the linear model between the logarithm of the coefficient of variation (CV) and the mean of the distribution of the logarithm of gene expression for the "Brain" data set. Note the residual plots (subplots (b) and (c)) also provide the pearson correlation (denoted by ρ) between the absolute value of the residuals and the mean and logarithm of the CV respectively.Click here for fileFigure S4: Diagnostic plot for the quadratic model between the kurtosis and the skewness of the distribution of the logarithm of gene expression for the "Craniofacial" data set. Note the residual plots (subplots (b) and (c)) also provide the pearson correlation (denoted by ρ) between the absolute value of the residuals and the skewness and kurtosis respectively.Click here for fileFigure S5: Diagnostic plot for the quadratic model between the kurtosis and the skewness of the distribution of the logarithm of gene expression for the "Liver" data set. Note the residual plots (subplots (b) and (c)) also provide the pearson correlation (denoted by ρ) between the absolute value of the residuals and the skewness and kurtosis respectively.Click here for fileFigure S6: Diagnostic plot for the quadratic model between the kurtosis and the skewness of the distribution of the logarithm of gene expression for the "Brain" data set. Note the residual plots (subplots (b) and (c)) also provide the pearson correlation (denoted by ρ) between the absolute value of the residuals and the skewness and kurtosis respectively.Click here for fileFigure S7: l-moment ratio diagram for the four data sets as in Figure 6 but including all probe sets including those with mean expression less than 6.Click here for fileFigure S8: l-moment ratio diagram for the four data sets as in Figure 7 but including all probe sets including those with absolute value of mean of log expression ratio less than 0.05.Click here for fileTable S7: Spearman rank correlation between the mean and standard deviation of the measured data for "Craniofacial", "Liver", "Brain", "Male" and "Female" data sets.Click here for file


We analyzed the dynamics of cumulative severe acute respiratory syndrome (SARS) cases in Singapore, Hong Kong, and Beijing using the Richards model. The predicted total SARS incidence was close to the actual number of cases; the predicted cessation date was close to the lower limit of the 95% confidence interval.