The demand for induced abortions in Uganda is high despite legal and moral proscriptions. Abortion seekers usually go to illegal, hidden clinics where procedures are performed in unhygienic environments by under-trained practitioners. These abortions, which are usually unsafe, lead to a high rate of severe complications and use of substantial, scarce healthcare resources. This study was performed to estimate the costs associated with induced abortions in Uganda.A decision tree was developed to represent the consequences of induced abortion and estimate the costs of an average case. Data were obtained from a primary chart abstraction study, an on-going prospective study, and the published literature. Societal costs, direct medical costs, direct non-medical costs, indirect (productivity) costs, costs to patients, and costs to the government were estimated. Monte Carlo simulation was used to account for uncertainty.The average societal cost per induced abortion (95% credibility range) was $177 ($140-$223). This is equivalent to $64 million in annual national costs. Of this, the average direct medical cost was $65 ($49-86) and the average direct non-medical cost was $19 ($16-$23). The average indirect cost was $92 ($57-$139). Patients incurred $62 ($46-$83) on average while government incurred $14 ($10-$20) on average.Induced abortions are associated with substantial costs in Uganda and patients incur the bulk of the healthcare costs. This reinforces the case made by other researchers--that efforts by the government to reduce unsafe abortions by increasing contraceptive coverage or providing safe, legal abortions are critical. Induced abortion is illegal in Uganda except to save the life of a pregnant mother and to preserve her physical and mental health . InducedYet the demand for induced abortion remains high, probably because of a high number of unintended pregnancies, at least 700,000 annually , which aWomen who decide to abort often resort to untrained and usually unskilled practitioners who practice in illegal and hidden clinics and often provide unsafe abortion procedures that result in a high rate of complications and sometimes death. Unsafe abortions are estimated to be the cause of 21% of all maternal deaths in Uganda  comparedIllegally-performed unsafe abortions in Uganda pose a large health risk for women because of inadequate skills of the providers, unsanitary environments, and hazardous techniques  which inPrevious studies of the cost of induced abortion in Uganda did not consider the consequences of failed induction and the impact of abortion provider on healthcare costs  or did nWe performed a descriptive cost-of-illness study to assess the economic burden of induced abortion in Uganda. A decision tree was developed to represent the consequences of induced abortion and to estimate the cost of an average case in Uganda from a societal perspective. Data to inform the model were obtained from a primary chart abstraction study, an on-going prospective study, and the published literature. The on-going prospective study is a cohort of women enrolled following discharge after post-abortion complications, discharge after child birth, and clinic visit for contraception. It was designed to compare the women discharged following post-abortion complications with the other women groups with regard to health and economic outcomes. The total national cost of induced abortion for 2010 was estimated by multiplying the average cost by an estimate of the annual incidence of induced abortion in Uganda.The decision tree showing the consequences of induced abortion is shown in Figure Women who receive abortion procedures from the different providers are further divided into those for whom induced abortion succeeds and those for whom it fails. Induced abortion rarely fails when performed by trained practitioners, and we found no studies that estimated its incidence in Uganda or similar countries, but studies in other settings have reported frequencies of 0.01% , 0.05% , and 0.0Women who have had successful induced abortions are divided in the model into those who develop complications and those who do not. The type of abortion provider has a direct influence on the probability of having abortion complications. A survey of health workers in Uganda estimated the proportion of induced abortion complications by provider ,28. It rWomen who develop complications following induced abortion were divided into those who need out-patient care and those who need hospital care. According to Prada et al . of the In the model, women who need and obtain hospital treatment following abortion complications both improve and are discharged alive, or they die in hospital. The in-hospital rate of abortion related mortality ranges from 1.3%  to 3.3% In the case of abortion failure after an attempt by a trained practitioner, the woman carries the pregnancy and faces the consequences of pregnancy. These include: a) miscarriage before 13 weeks gestation, b) miscarriage between 13 and 22 weeks which usually requires treatment, or c) birth of a child which includes preterm birth as well as term live or still birth. Miscarriages at 13-22 weeks account for 2.9% of all recognized pregnancies and live births account for 84.8% ,35. The We estimated the average cost of each outcome in the decision tree Figure . The oveThe cost of induced abortion was considered to include the following cost categories: 1) direct medical costs, 2) direct non-medical costs, and 3) indirect (productivity) costs. Direct medical costs included personnel, medical supplies, drugs, radiology tests, laboratory tests, and patient out-of-pocket costs. Direct non-medical costs included recurrent expenditures (such as utility bills) and capital expenditures , patient transportation, and patient upkeep while seeking healthcare. Indirect costs included lost productivity while seeking abortions and getting treatment for complications as well as productivity losses from abortion morbidity while convalescing and premature abortion-related maternal mortality. The total healthcare cost is the sum of the direct medical and direct non-medical costs.In a separate classification, the costs of induced abortion were also considered to include patient/family costs and government costs. Patient/family costs included the costs of procuring abortions, out-of-pocket costs, transportation, and upkeep while procuring abortions and seeking treatment for complications, and self-medication. Government costs included the costs of treating abortion complications and pregnancy-related costs when abortions fail, but excluded the healthcare costs associated with the procurement of abortions which are illegal in Uganda and are not provided by the national healthcare system.The societal cost estimate is the sum of all the different kinds of costs i.e. direct medical + direct non-medical + indirect/productivity costs or patient/family costs + government costs.The cost to women of abortion services by provider were obtained from a survey of health workers  costs of out-patient and hospital treatment of abortion complications were estimated from the World Health Organization Choosing Interventions that are Cost-Effective (WHO-CHOICE) database for Uganda . TranspoProductivity losses due to morbidity were estimated for both patients and caregivers using data from the prospective study by summing lost time spent in transit to hospitals (for patients and caregivers), seeking care, convalescing, and admitted to hospital (for patients and caregivers), and multiplying by wages. Wage data were obtained for formally-employed women in the same prospective study. The wage of the proportion of women who were unemployed (subsistence farmers) was valued at Uganda's gross domestic product per capita at the official exchange rate which was $474 in 2009 [Productivity losses due to mortality were estimated using the human capital approach  valuing The unit costs used in the analysis are summarized in Table All costs were converted into United States dollars ($US) using the Bank of Uganda official exchange rate on 1st June 2010  and wereThe average costs of induced abortion are shown in Table The annual incidence of induced abortion in Uganda is 362,000 cases. Therefore the national annual expenditure on induced abortion is projected to be $23.6 million in direct medical costs, $7.0 million in direct non-medical costs, $33.5 million in indirect/productivity costs, $5.1 million in costs to the government, $22.3 million in costs to patients, and $64.2 million in societal costs.Univariate sensitivity analysis Figure  showed tUsing a decision tree and data from multiple sources, we found that the average induced abortion in Uganda was associated with $177 in societal costs. This is over four times the per capita expenditure on health care in Uganda which is $44 . Given tThe annual abortion expenditure in Uganda is substantial and is a testament to the economic impact of abortion in countries where it is illegal (and likely to be unsafe), which has been previously described . The proThe largest contributor to the average societal cost of induced abortion was productivity costs 52%) but the healthcare component, of which direct medical costs were the largest, was also substantial (48%). The key driver of productivity costs is abortion-related mortality. The loss of young mothers from abortion exerts a substantial burden to society. The largest part of the healthcare costs can be attributed to the treatment of the complications of unsafe abortions. The majority of trained and untrained providers choose surgical techniques--such as evacuation and manual vacuum aspiration--to terminate pregnancies but not misoprostol combined with mifepristone which is the safest form of medical abortion [% but theThe average healthcare cost  of induced abortion was $85. This estimate included the cost of abortion procedures as well as the treatment of post-abortion complications. Levin et al . estimatVlassoff et al . estimatOne limitation of this study was the use of estimates of the proportion of abortions induced by different providers, the rate of complications, and costs of abortion procedures obtained from a survey of health workers  as opposAnother limitation of the study is that we did not include intangible societal costs of abortion such as the non-labor force value of women in taking care of children and the potential multi-generational effect of orphan hood. While these effects have been demonstrated previously, there is a need for Uganda-specific research to better inform policies aimed at reducing the impact of unsafe abortion. Additional data limitations to our study include the use of some resource use estimates from an on-going cohort study before completion of the protocol due to time and resource limitations, the failure to distinguish between the costs of legal and illegal induced abortions in the analysis as well as use of data on induced abortion failure from developed countries due to a lack of estimates from Uganda or similar countries. As mentioned above, the inherent uncertainty in these estimates was addressed by using Monte Carlo simulation.The results of the sensitivity analysis showed that the estimate of costs of induced abortion in Uganda were most sensitive to the uncertainty surrounding in-hospital mortality from abortion complications and the rate of hospitalization for complications. The sensitivity of the societal cost to a relatively narrow range (1-3%) of in-hospital mortality, as well as the fact that productivity losses contribute over half (52%) of the total societal cost, point to the substantial economic burden of abortion-related mortality. Data on the rate of abortion complications were derived from surveys of health workers as opposed to prospective studies. It will require innovative research methods to improve on the quality of these estimates in the prevailing legal environment or a change in the abortion law which seems like a remote possibility at the current time.The substantial cost associated with the average induced abortion in Uganda, reinforces the case made by other researchers--that efforts to reduce unsafe abortions by increasing contraceptive coverage or providing safe, legal abortions, are critical. Such efforts would contribute to achieving Millennium Development Goal number 5  and are in line with the United States Global Health Initiative which places an emphasis on improving the health of women. The study may also be used as a basis for estimation of the potential economic gains of policies that increase contraceptive coverage or provide safe, legal abortions.The authors declare that they have no competing interests.JBB conceived of the study and participated in the design of the study, collecting data, performing the analysis and drafting the manuscript. AS participated in designing the study and revising the manuscript. DLV participated in designing the study and revising the manuscript. JSG participated in designing the study and revising the manuscript. JN participated in collecting data and revising the manuscript. PM participated in collecting data and revising the manuscript. LPG participated in designing the study and revising the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/904/prepub


The potential for a chemical to be reactive can be determined experimentally by a number of chemical tests and therefore can be captured computationally to form (Q)SARs. Providing a source of in chemico data for the reactivity of electrophiles with reference nucleophiles could assist in the non-animal based risk assessment of chemicals for regulatory purposes and in the application of integrated testing strategies (ITS). For this reason, we have compiled a database from a full range of chemical reactivity assays containing various reactivity data of numerous electrophiles forming peptide and DNA adducts. This includes reactivity data, kinetic rate constants, and qualitative information regarding the adducts formed. The data collection facilitates the in silico profiling of toxicologically relevant compounds by grouping and category approaches, and allows for the combination of the following information: the identification of electrophilic compounds; their mechanistic applicability domain and compound class; physical-chemical properties; reactivity data; and toxicological data. These experimental reactivity data were linked to the computational prediction of reactive mechanisms for different modes of toxic action (e.g. acute aquatic toxicity), at which the results indicated that physically meaningful parameters are suitable to explain the varying behaviour of electrophiles. This could be applied for screening purposes based on structural information and the reactivity data could be used to elucidate mechanisms of toxic effects. The funding of the EU FP6 InSilicoTox Marie Curie Project (MTKD-CT-2006-42328) is gratefully acknowledged.Covalent binding of xenobiotic electrophiles to nucleophilic endogenous biomolecules, e.g. peptides or DNA, is a common molecular initiating event, leading to potentially irreversible toxic effects such as enhanced acute toxicity, skin sensitisation, or mutagenicity. This knowledge provides the basis for the


Despite the limitation to two dimensions, the resulting images provide a unique depiction of white matter organization at resolutions currently unattainable with DWI. The method of analysis may be used to validate tissue properties derived from DTI and alternative models of the diffusion signal.Diffusion weighted imaging (DWI) has provided unparalleled insight into the microscopic structure and organization of the central nervous system. Diffusion tensor imaging (DTI) and other models of the diffusion MRI signal extract microstructural properties of tissues with relevance to the normal and injured brain. Despite the prevalence of such techniques and applications, accurate and large-scale validation has proven difficult, particularly in the human brain. In this report, human brain sections obtained from a digital public brain bank were employed to quantify anisotropy and fiber orientation using structure tensor analysis. The derived maps depict the intricate complexity of white matter fibers at a resolution not attainable with current DWI experiments. Moreover, the effects of multiple fiber bundles  and intravoxel fiber dispersion were demonstrated. Examination of the cortex and hippocampal regions validated-specific features of previous  The brain is a network with multiple levels of connectivity. The connections of each neuron determine its functional properties, and the functionality of the brain as a whole is determined by both these local and large-scale connections. Since anatomical and functional connectivity are intrinsically linked, a major goal of neuroscience has been to construct comprehensive maps of brain connectivity, or “connectomes”  has become an indispensible tool to investigate the large-scale anatomical connectivity in the brain. As a completely non-invasive modality, DWI has enabled unprecedented insights into brain microstructure and connectivity. Technological advances in the acquisition, analysis, and modeling of DWI data have propelled investigations of the normal brain architecture and the consequences of disease and injury. Despite these achievements, cross-validation of diffusion imaging and microscopy has been somewhat limited. Since DWI measures the mobility of water molecules, it is an indirect measure of structure. Inferences and mathematical models form the basis to derive structural information from the DWI signal. Diffusion tensor imaging (DTI) employs a single tensor model to obtain measures of primary fiber orientation and anisotropy. However, the DTI model has well-known limitations in brain regions that are composed of more than a single coherent fiber bundle, which occurs at high proportions in the human brain  images, respectively. Alternatively, downsampling was employed to mimic the resolutions achievable by MRI by summing f2x, fy2, and fxy from regularly spaced square subregions of a predetermined size  to derive J as shown above by omitting the outer scale. In this representation, the primary orientation and anisotropy were displayed as hue and brightness, respectively that mimic directionally encoded color (DEC) images derived from DTI. Additionally, fiber orientation distributions (FODs) were obtained for each voxel for visualization and quantification of the complete in-plane angular profile. The FODs were computed as histograms of pixel orientations, θ, within each voxel using 64 equally spaced bins. To quantify fiber dispersion, FODs were fit to a single Gaussian function Structure tensor analysis of histological sections was previously described for the rat brain  fiber populations.The effect of crossing fibers was further demonstrated in a region within the centrum semi-ovale, where fibers of the longitudinal fasciculus and corticospinal tract intersect with transcallosal fibers  has been identified in the human brain in vivo  agree with previous studies of the rat brain (14.4; 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.


Palmatolepis. Strikingly, both crises affected an already impoverished Palmatolepis disparity, increasing risks of random extinction. The major disparity signal rather emerged as a cycle of increase and decrease in disparity during the inter-crises period. The diversification shortly followed the first crisis and might correspond to an opportunistic occupation of empty ecological niche. The subsequent oriented shrinking in the morphospace occupation suggests that the ecological space available to Palmatolepis decreased through time, due to a combination of factors: deteriorating climate, expansion of competitors and predators. Disparity changes of Palmatolepis thus reflect changes in the structure of the ecological space itself, which was prone to evolve during this ancient period where modern ecosystems were progressively shaped.Early periods in Earth's history have seen a progressive increase in complexity of the ecosystems, but also dramatic crises decimating the biosphere. Such patterns are usually considered as large-scale changes among supra-specific groups, including morphological novelties, radiation, and extinctions. Nevertheless, in the same time, each species evolved by the way of micro-evolutionary processes, extended over millions of years into the evolution of lineages. How these two evolutionary scales interacted is a challenging issue because this requires bridging a gap between scales of observation and processes. The present study aims at transferring a typical macro-evolutionary approach, namely disparity analysis, to the study of fine-scale evolutionary variations in order to decipher what processes actually drove the dynamics of diversity at a micro-evolutionary level. The Late Frasnian to Late Famennian period was selected because it is punctuated by two major macro-evolutionary crises, as well as a progressive diversification of marine ecosystem. Disparity was estimated through this period on conodonts, tooth-like fossil remains of small eel-like predators that were part of the nektonic fauna. The study was focused on the emblematic genus of the period,  The Paleozoic (-550 to -250 Myrs) is a challenging period for paleobiological studies because ecosystems were increasing in complexity through the appearance and radiation of different groups of organisms, progressively colonizing and even creating ecological niches , up to building ecosystems close to those still existing today. These trends can be seen as emergent properties of supra-specific taxonomic units radiating, competing and going extinct ca. 15 myrs between the two successive F/F and D/C crises. We focused on conodont animals, small eel-like predators Palmatolepis, the most abundant conodont of the Late Devonian, disappearing during the D/C crisis. Using geometric morphometrics to quantify the shape of the tooth-like elements, the pattern of diversification of Palmatolepis was assessed through time. Questions addressed included (1) did the F/F crisis impoverish the morphological diversity within Palmatolepis, as expected based on macro-evolutionary patterns marking this mass extinction? (2) Was the screening of the crises random or not regarding ecomorphs within Palmatolepis? (3) Did Palmatolepis diversified subsequently to the F/F crisis in a random or selective way? (4) What is the timing of this diversification subsequent to a crisis? Was it mostly conditioned by the catastrophic mass extinction events, with a pattern of post-crisis diversification followed by a stable disparity, until facing the next mass extinction event? Alternatively, was the diversification dynamics mostly driven by long term climatic and/or ecological trends developing between the two crises?In such macro-evolutionary studies, the dynamics of a species is often summarized by the range of its temporal occurrence, or even summed up with other relatives into large taxonomic groups. This hinders to address how micro-evolutionary processes interplayed with macro-evolutionary trends. The present study aims at filling this gap by performing a fine-scale evolutionary analysis along the Late Devonian, a period of A composite record has been established based on samples from four sections, two located in the Montagne Noire in Southern France (Coumiac and Puech de la Suque) and two located in the Rhenish Massif in Germany (Schaumburg and Effenberg) . All theAccording to paleogeographic reconstructions rhenana and linguiformis) of this period are represented The Frasnian has only been recognized in Coumiac (France) where the last two zones  at that time. In order to provide a reliable estimate of its contribution to the morphological variance within Palmatolepis, its sampling has been increased by including Palmatolepis  linguiformis elements from other localities around the Protothetys The index species for the triangularis) has been documented in Coumiac rhenana and the triangularis zones have been subdivided into subzones. Only the latest of the triangularis subzone is documented in Schaumburg.Concerning the beginning of the Famennian, the first zone  have been documented in Schaumburg.The three following zones of the Famennian (trachytera zone praesulcata zone has been sampled in the Puech de la Suque section Samples from the Effenberg section document the postera and expansa) are missing in this study between trachytera and praesulcata.Unfortunately, two Famennian conodont zones  to the end-Famennian (360.7±2.7 Ma) Each rock sample along the composite section was dissolved in formic acid (10%) and rinsed through two sieves. The fraction between 100 µm and 1 mm was then picked for all conodont elements.Palmatolepis, the apparatus was composed of seven distinct elements (with right and left elements for six of them). The morphometric study focused on the so-called P1 platform element PalmatolepisPalmatolepis (Pa.) were picked over the composite section and measured, e.g. 5171 elements in total.The conodont animal had a complex feeding apparatus composed of several elements. In the case of Palmatolepis elements through time led to the description of numerous species and even subspecies. These (sub)species delivered valuable stratigraphic data Palmatolepis elements have been considered independently of any further taxonomic identification. (2) As a conservative approach, to be as close as possible to the current conodont taxonomy, Palmatolepis elements were attributed to the species (and subspecies whenever existing) level, a part of the samples being then let aside as non-identified specimens. (3) Palmatolepis elements were attributed to larger “groups” of specimens sharing a range of general characters species and by (sub)zones in the Palmatolepis throughout its record , each being weighted by two Fourier coefficients (FCs). The zero harmonic, proportional to the outline size, was used to standardize all other FCs so they represent shape variables only. Considering the first eleven harmonics has been shown to provide a satisfying compromise between the number of variables and the amount of shape information e.g. . One of a priori taxonomic attribution. The first two principal components define a morphospace on which the range of shape variation can be represented. The temporal variation in the occupation of this morphospace has been visualised by plotting each zone separately  the range encompassed by units along axes of a morphospace, or (2) the inter-unit variance triangularis zone to 1733 in the Late rhenana zone species and by group). Scores on the first principal axis were considered as a synthetic shape variable and provided estimates of shape variations along the record, either for all elements  or for (sub)species and for each group separately.18O values of conodont phosphate Disparity and shape variations were further compared with a paleotemperature proxy, represented by a composite record of ∂Relationships among morphological estimates, and between morphological and paleoenvironmental proxies were investigated. Several complementary tests were used. (1) Linear regressions were used to confront paleoenvironmental data (considered as independent variables) to morphological variables (dependent variables). Such an approach compares the raw data and the amount of variation between two successive samples impacts the regression. (2) Spearman-rank order correlations were used to further test the relationship between the variables. Values of each variable are ranked and these ranks are then compared among variables. This limits the impacts of extreme shifts that can be for instance due to a long time elapsed between two successive samples. (3) A correlation of paleoenvironmental and morphological variables could be due to the fact they both vary concomitantly through time. The data were thus detrended by considering the first difference  and thereafter compared using the above mentioned procedures (linear regression and Spearman rank-order correlation).Palmatolepis platform elements has been represented through time  defined a morphospace on which the distribution of all ugh time .rhenana zone), Palmatolepis elements were tightly clustered in the part of the morphospace corresponding to negative PC1 and positive PC2 scores. This cluster corresponded to conodonts attributed to the Manticolepis group. A limited diversification occurred during the latest zone of the Frasnian (linguiformis zone). A cluster occupied a formerly empty zone of the morphospace, towards slightly positive PC1 values. This cluster corresponded to the occurrence of the Palmatolepis group.Towards the end of the Frasnian (triangularis zone), was marked by a retraction of the morphological range towards the zone occupied during the rhenana zone. This corresponded to the occurrence of conodonts from the Perlobata and Subperlobata groups.The earliest Famennian, just after the Frasnian/Famennian crisis . Deflectolepis elements occupied then a limited zone of the morphospace, towards positive PC1 and PC2 values. This mirrored the situation that occurred during the end of the Frasnian, but with a cluster of elements in a completely different zone of the morphospace.During the Palmatolepis elements, (sub)species have been identified within groups. We investigated visually whether these units had a morphological coherence . Accordingly, (sub)species of a given group tended to cluster together in the morphospace . Noted that the increase in total disparity was slightly emphasized by the supplementary Pa. (Pa.) linguiformis specimens that had been added to the original sample. Disparity was back to a very low level just after the F/F crisis (lower triangularis zone), started increasing from the middle triangularis onward, up to culminate during the crepida zone. From this maximum it gradually decreased down to levels during the end Famennian (praesulcata zone) as low as during the end Frasnian.Patterns of disparity observed among the total assemblages of elements, among (sub)species and among groups were remarkably similar . Startin2 = 0.93, P<0.001). This result suggested that splitting groups in different species did not explain much of the morphological variance and it reinforced the use of the groups as relevant biological units. Considering the disparity among the total assemblage of specimens is a seldom used approach, because this estimate may vary depending on the relative abundance of the different taxonomic units. Our results showed that this approach provided the same trends as the disparity among species or groups . Disparity estimate based on the total assemblage of specimens appeared as quite robust to sampling issues as shown by the estimates based on rarefied samples that were similar to those based on the total sample. Furthermore variance among replicates of the rarefaction procedure was so reduced that error bars corresponding to a 95% standard error were not visible on curves (Disparity estimates based on (sub)species and based on groups provided highly similar results , supporting its definition as separate unit. Beyond this morphological coherence of the groups, the range they occupied often varied through time. Perlobata as well as Regularis displayed temporal variations, starting from negative PC1 close to those of the Frasnian Manticolepis to evolve towards positive scores similar to typical Famennian groups such as Panderolepis. Similarly, Deflectolepis displayed a trend towards more extreme shapes along the Famennian.Each group was characterized by a given range along PC1  started in crepida zone and continued up to the latest zone of the Famennian (praesulcata).Variation in the total average shape were further considered along PC1 . Overalltriangularis zone) followed by a trend of decreasing temperature until the end of the Famennian.Oxygen isotope data Palmatolepis, we compared the morphological parameters (average shape and disparity estimates) with this paleotemperature proxy. Combining all tests  linguiformis) also tended to present a reduced platform. This trait might thus have constituted a factor of increased risk of extinction. Although the conodont diet is still largely unresolved, a developed platform argues for the ability to handle robust food, whereas a reduced platform would better match the consumption of soft food. The ability to exploit a variety of resources, including robust prey, might have been a selective advantage at a time when resources were anyway decimated by the global crisis.A candidate explanation of this differential survival is that the set of related species constituting Palmatolepis presented two cases matching this scenario, since its disparity was at its lowest just before both the F/F and the D/C crisis. Hence, the typical macro-evolutionary pattern of depletion in diversity marking major crises cannot be recognised in the fine-scale evolutionary pattern of Palmatolepis. Far from being highly diversified before, and impoverished by the crises, it faced them with an – unfavourable – low diversity.Another, not mutually exclusive factor increasing risk of extinction, is to face the crisis with an already impoverished diversity. Then, extinction is more probable even when occurring at random Thus, at this scale of disparity, the driving force of disparity does not seem to be the major, punctual events of the crises. More progressive processes seem to have shaped conodont disparity during the period between the crises. Such processes went largely unnoticed because that period deserved little interest among researchers due to the overall stability of fauna in terms of diversity.Palmatolepis morphological evolution. In contrast, a progressive diversification occurred shortly after the crisis. This pattern matches the expectation of a “recovery period” during which the impoverished ecosystem is increasing again in complexity. The crisis, by decimating many groups, is supposed to have let vacant many ecological niches that the post-crisis organisms progressively re-occupied Palmatolepis matched, at this fine evolutionary scale, the expected macro-evolutionary pattern of recovery. The diversification occurred in few million years, along the first zone consecutive to the crisis. It also occurred in a selective manner, with an oriented trend corresponding to the progressive occupation of morphospace areas corresponding to slender elements with a more and more reduced platform. Based on an ecomorphological interpretation of these variations, this suggests a diversification of the food resources exploited by Palmatolepis, a process favoured by the decimation of the ecosystem that occurred shortly before, towards the consumption of other, presumably softer preys.The expected pattern of impoverished disparity consecutive to the major event of a biotic crisis was not documented along the record of A more surprising feature is that this diversification did not continue until the next major biotic crisis punctuating the D/C boundary. It did not even reach a plateau of stable disparity, associated with a subsequent increase in diversity: such a pattern is the sign of rapid morphological innovations allowing the conquest of new ecological niches, followed as a subsequent step by a finer resource partitioning between related species Palmatolepis was characterized by warm-water preferences, being restricted to tropical and sub-tropical areas Palmatolepis were shrinking towards the end of the Devonian. This may be due to a decrease in primary productivity itself, but the composition and dynamics of the primary producers, and even more the feedbacks between the carbon cycle and the climate change, are far from being understood in this deep past Palmatolepis might have been deprived of access to resources it formerly consumed by changes in the ecosystem itself. First, each group had its own timing of post-crisis recovery, and possibly Palmatolepis acted as an opportunistic taxon rapidly colonizing empty niches but thereafter outcompeted by more specialist groups Palmatolepis has been suggested to be an opportunistic taxa investing much in early reproduction and achieving a rapid turnover Bispathodus, another conodont genus that increased in diversity along the Famennian to represent the dominant component of the conodont fauna towards the end of the period PalmatolepisThis decrease in disparity appears to be related to the cooling trend characterizing the time period. This may be due to coincident trends without causal relationship. Yet, Palmatolepis may have interfered with processes occurring at a longer time pace. During the Late Paleozoic, the ecosystems were increasing in complexity because of the diversification of major groups. This is the case of ammonoids and chondrychthians Beyond the dynamics of post-crisis recovery, the evolution of Palmatolepis disparity could thus be the result of an unfavourable combination: deteriorating climate, diversification of predators, and increasing competition at different paces, from the F/F recovery to long-term increase in complexity of the ecosystems. All could have contributed to its decrease in diversity and disparity predating the D/C crisis. Without being the direct cause of Palmatolepis extinction, all of these factors could have thus increased the risk of extinction; similar dynamics seems probable just before the F/F crisis, although this part of the record is not documented here. In this context, the major events constituted by the crises do not emerge as the key factors driving disparity dynamics within Palmatolepis. Rather, the progressive change in the structure of the ecological space seems to have conditioned the diversification and subsequent impoverishment of Palmatolepis.The selective impoverishment of Palmatolepis illustrates this interaction in the deep past. Understanding the emerging patterns of biodiversity is difficult because of such subtle interplay between ranges of processes that were usually considered separately, and even more by the interaction of different scales and paces of processes. Palmatolepis disparity illustrates this intermingling of scales. It appears as the combined product of long-term trends in ecosystem complexity, middle-term trends in climate and dynamics of related groups, and even short-term evolutionary trends within each group composing Palmatolepis. Indeed, several Palmatolepis groups displayed oriented trends that mirrored, within each lineage, the trend followed by the genus as a whole. Fine-scale evolutionary analyses also demonstrated the ability of Palmatolepis species to track and adapt rapid temperature changes during the F/F crisis This interplay of evolutionary and ecological processes is emerging as crucial to understand the dynamics of perturbed ecosystems


The present paper documents the uses of plants in traditional herbal medicine for human and veterinary ailments, and those used for dietary supplements, religious purpose, local beverage, and plants used to poison fish and wild animals. Traditional botanical medicine is the primary mode of healthcare for most of the rural population in Arunachal Pradesh.IC) to determine the homogeneity of informant's knowledge on medicinal plants.Field research was conducted between April 2006 and March 2009 with randomly selected 124 key informants using semi-structured questionnaire. The data obtained was analyzed through informant consensus factor (FIC (0.56) and the gastro-intestinal diseases have FIC (0.43). FIC values indicated that there was high agreement in the use of plants in dermatological and gastro-intestinal ailments category among the users. Gymnocladus assamicus is a critically rare and endangered species used as disinfectant for cleaning wounds and parasites like leeches and lice on livestocks. Two plant species (Illicium griffithii and Rubia cordifolia) are commonly used for traditional dyeing of clothes and food items. Some of the edible plants recorded in this study were known for their treatment against high blood pressure (Clerodendron colebrookianum), diabetes mellitus (Momordica charantia), and intestinal parasitic worms like round and tape worms . The Monpas of Arunachal Pradesh have traditionally been using Daphne papyracea for preparing hand-made paper for painting and writing religious scripts in Buddhist monasteries. Three plant species  were frequently used to poison fish during the month of June-July every year and the underground tuber of Aconitum ferrox is widely used in arrow poisoning to kill ferocious animals like bear, wild pigs, gaur and deer. The most frequently cited plant species; Buddleja asiatica and Hedyotis scandens were used as common growth supplements during the preparation of fermentation starter cultures.We documented 50 plants species belonging to 29 families used for treating 22 human and 4 veterinary ailments. Of the medicinal plants reported, the most common growth form was herbs (40%) followed by shrubs, trees, and climbers. Leaves were most frequently used plant parts. The consensus analysis revealed that the dermatological ailments have the highest FThe traditional pharmacopoeia of the Monpa ethnic group incorporates a myriad of diverse botanical flora. Traditional knowledge of the remedies is passed down through oral traditions without any written document. This traditional knowledge is however, currently threatened mainly due to acculturation and deforestation due to continuing traditional shifting cultivation. This study reveals that the rural populations in Arunachal Pradesh have a rich knowledge of forest-based natural resources and consumption of wild edible plants is still an integral part of their socio-cultural life. Findings of this documentation study can be used as an ethnopharmacological basis for selecting plants for future phytochemical and pharmaceutical studies. Goswami et al [et al [et al [al [et al [Wancho tribe of Tirap district, Arunachal Pradesh.Medicinal plants have been used as sources of medicine in many indigenous communities throughout the world. According to WHO, herbal medicines serve the health needs of about 80% of the world's population, especially for millions of people in the rural areas of developing countries . India het al  reportedet al  documentl [et al  while stmi et al  reportedl [et al  reportedl [et al  reportedt al [al  documentl [et al  reportedl [et al  have stuAlthough the rich indigenous knowledge on the medicinal use of plants has been relatively well documented in other ethnic groups of Arunachal Pradesh -21, studThe Kalaktang region 417 sq. km.) is located approximately between 91° 30'-92° 40' East longitudes and 26° 54'-28° 01' North latitudes with an estimated total population of 6,391 . It shares an international border with the Tibet region of China in the North, Bhutan in the West, Tawang district and East Kameng districts of Arunachal are in the northwest and northeast, respectively. The southern boundary adjoins the Sonitpur district of Assam  are daily rituals. They believe in transmigration of soul and reincarnation. The Monpas perform many pantomime dances of which "Achilamu", a group of five member dance is the most unique and popular form of dance perform throughout the day to complete the process in special occasions. Festival forms essential aspects of socio-religious life of the Monpas. Lossar and Choskar are the major religious festival of Monpa celebrated once in a year. Lossar, usually celebrated in the month of March before the start of agriculture is the local new year of the Monpa community. In Choskar festival , the lamas or Monks read religious scriptures in the Gonpa (monastery) for a number of days (3-4 days). Thereafter, the villager's particularly female folk (both married and unmarried) carry the religious books on their back in the procession under the guidance of senior most Monk and the procession (1 day) covers throughout the cultivation fields. The significance of this performance is to ensure bumper harvest and crop/grains protection from insects and wild animals and for overall prosperity of the village people. The Monpas are agriculturist, practice both shifting and permanent types of cultivation. The commonly grown field crops include maize, paddy, beans, bajra, millets, barley, wheat, mustard, cabbage, potato, cauliflower, and pumpkin, etc. Livestock's like yaks, cows, pigs, sheep, seasonal fishing, and hunting of wild animals are the primary source of income. The Monpas are well known for wood curving, painting religious scrolls called Thankas, carpet and paper making, and weaving.The west kameng district is inhabited by five different tribes such as the Akas, Khowas, Mijis, Sherdukpens, and Monpa. The entire population of the west kameng district can be divided into two cultural groups on the basis of their socio-religious affinities, of which the Monpas and Sherdukpens follow the lamaistic tradition of Mahayana Buddhism. The second groups of the people are Akas, Mijis, and Buguns, who worship the Sun and the Moon as God, locally called as "Donyi-Polo" and "Abo-Tani", respectively. Due to slight variations in dialects, Monpa can be divided into six linguistic groups, namely Tawang Monpa, Dirang Monpa, Lish Monpa, Boot Monpa, Panchen Monpa, and Kalaktang Monpa. The Monpa have castes and clans with no social hierarchy. Monogamy (follow strictly endogamy) is a general rules though polygamy is also practiced in the present generation. The Monpa belongs to the Tibeto-Mongoloid racial stock and their houses are built of stones and timber decorated with a small altars and chapels with statues of Lord Buddha. Offering water in seven little cups and burning butter lamps and some leaves of herbal species  were conducted amongst Monpa community during the study period from April 2006 and March 2009 to document an indigenous traditional knowledge on medicinal plants. Male and female respondents with age ranging from 20-60 years were included during interview. All collections were made by the first author (NDN) who grew up and belonged to Monpa community of Kalaktang and was familiar with the local language and some of the traditional plants used by the local people of the region. The ethno- botanical information was collected using semi-structured questionnaires ,22 to ad1. Document the medicinal plants used in the traditional healthcare system of Kalaktang study area-parts used and method of preparation,IC) was calculated in order to estimate use variability of medicinal plants,2. The informant consensus factor  for testing homogeneity on the informant's knowledge was followed by the method provided by Trotter and Logan [IC is given by:Only the plants indicated by at least 20 independent informants were considered. The acquired data were confirmed by repeated queries and field surveys made among the general local people, experienced elderly people and 20 male respondents that constitute the traditional herbal practitioners. The taxonomic identification of the collected plant specimens was made with the help of herbarium materials, experts and taxonomic keys at Botanical Survey of India, Arunachal Pradesh. The botanical nomenclature followed that of the Flora of Arunachal Pradesh -25. The nd Logan . A conseur is the number of use-reports of informants for particular illness usage, where a use-report is a single record for use of a plant mentioned by an individual, and Nt refers to the number of species used for a particular illness category for all informants. The use of "general categories" is adopted here as recommended by other ethnobotanical researchers [The factor provides a range of 0 to 1, where a high value acts as a good indicator for a high rate of informant consensus. Nearchers ,28. ThesThis study identified fifty ethnobotanical species, 36 species (60%) were used as herbal medicines for treating 22 different human ailments. Some of the reported plants were used for other functions: rituals (14%) and religions, fish feeds and poisoning (10%), veterinary healthcare (7%) and local beverage or fermentation purpose (7%). The surveyed plants contained the following ethno-botanical elements: botanical name, voucher specimen number, local name, parts used, and method of preparations and ailments treated , indicating greater homogeneity among informants. The highest FIC value for dermatological and gastro-intestinal diseases categories could be related to the high occurrence of skin-related and gastritis problems in the study area. The FIC of local knowledge for disease treatment depended on the availability of plant species and the occurrence of diseases in the study area. In the literature, high informant consensus (FIC 0.875) was also recorded among the snakebite healers of Kamba in Africa [IC 0.80) among Northwestern Ethiopia [Artemisia nilagirica, Azadirachta indica, Allium sativum, Cannabis sativa, Clerodendrum colebrookianum, Gymnocladus assamicus, Lindera neesiana, Ocimum sanctum, Psidium guajava, and Saccharum officinarum, for wound healing and scabies, stomach disorder and diarrhea, bone fracture, diarrhea in cattle, high blood pressure, soap and ethno-veterinary, intestinal worms, wounds, diarrhea, and jaundice, respectively, indicated the 100% choice of most healers or plant practitioners for treating such diseases. The literature search on ethnopharmacological use showed that many of the species of plants with 100% FL were used to treat ailments in other parts of the world  were interviewed in the study area with their age ranged between 20-60 years. Large number of informants reported that most ailments were treated at a household level. On average, significantly higher numbers of medicinal plants were claimed by illiterate village men than women (91 (73.4%) men; 33 (26.6%) women; aged between 40 and 60 years). Ethno-pharmacological survey work in India also indicated that information on the medicinal uses of plants was being confined mostly to elderly people (above 40 years of age) ,47. LiteAlocasia indica (Roxb.), Dioscorea alata L., Ipomoea batatas (leaves and tuber) L., Mannihot esculentum Crantz, Momordica charantia L., Phaseolus vulgaris L., Pouzolzia bennettiana Wight, Diplazium esculentum (Retz.) Sw., Centella asiatica L., Houttuynia cordata Thunb. , Gynura crepedioides (BTH.) Moore , Spilanthus oleraceae Murr., Litsea cubeba (Lour) Pers. (spice), Clerodendron viscosum Vent., Solanum indicum L. , Solanum torvum Sw. , Solanum etiopicum, Allium sativum Linn., and Allium hooleri L. . These plant species are generally sold in the local market at reasonable price. The tender shoots of selected bamboo species like Dendrocalamus hamiltonii Hook. f. collected in bulk was prepared by cutting it into strips or pieces and boiled. The boiled shoots are chopped finely and packed in jars, bamboo tubes (Chunga) or even in plastic buckets and was kept for 5-10 days for fermentation. After fermentation, the taste of chopped shoots becomes sour. Fresh bamboo shoots and its fermented products were sold in the local market as edible foodstuffs. Important domestic uses concerned presently cultivated species of Livistona jenkensiana Griff. used for thatching and Bambusa tulda Roxb. and B. pallida Munro., for house building work. Traditional dyeing of clothes and food items were derived from plant species namely Illicium griffithii Hook. and Rubia cordifolia L. These plant species are currently cultivated in the gardens to meet regular use due to their less accessibility. Some of the plant parts used as a food source was also ingested as a remedy: Clerodendron colebrookianum (blood pressure), Momordica charantia (diabetes mellitus), Lindera neesiana, Solanum etiopicum, and Solanum indicum  Wall. Flowering twigs of Thysanolaena maxima has traditionally been used for broom making and to support the cotton wick to offer daily butter lighting in monastery. However, under the influence of modern society, today D. papyracea was not being used for making paper for writing Buddhist scripts as revealed during field survey work. Gymnocladus assamicus ripe pods are soaked in water and used to rubbed palms when preparing torma, a kind of sweet made of rice flour offered to the Lord Buddha during various festival ceremonies at Monasteries. The Monpa houses are built of stones and timber decorated with a small altars and chapels with statues of Lord Buddha. Offering water in little seven cups and burning butter lamps and herbal incense sticks with few herbal leaves  (Cupressaceae) are daily rituals. These plant species are cultivated within the premises of monasteries for their use during religious festival called Choskar. It was of common belief that burning of such herbal leaf create clean and refreshing atmosphere inside the Gonpa. The heart wood of pine tree was used for lighting of the street at night and ignition of firewood at home in olden days where there was no supply of electricity and kerosene. The resins extracted from pine wood are used as adhesives. Bulbs of Allium sativum and Allium hookeri are used in rituals and to protect against the evil spirit. A leaf of banana has long been used during festival ceremony in monastery to offer foodstuffs to local participants. The rhizomes of Zingiber officinale and Mannihot esculentum remains an integral component of daily rituals among the Monpas religious life.The Monpa community in the eastern Himalayan province of Arunachal Pradesh follow Mahayana sect of Buddhism and are famous for hand-made paper for writing religious scripts in Monasteries  from stem bark of Oryza sativa L.), finger millet (Eleusine coracana Geartn.), maize (Zea mays L.) and buckwheat (Fagopyrum esculentum Moench). "Bhangchang" has traditionally been used and served in all festive occasions, birth and marriage ceremonies. A diverse knowledge system exists among the Monpa women to prepare the nutritionally rich foods and fermented beverages, which play an important role in their day to day socio-cultural and spiritual occasions. A Monpa woman uses some of the wild plants as anti-microbial and they believed that these plants are responsible for the healthy growth of yeast during the process of fermentations. During the field study, we have documented the use of young leaves and twigs of certain species like Piper betle, Solanum indicum, Buddleja asiatica and Hedyotis scandens as common growth supplements during the preparation of fermentation starter cultures containing brewer's yeast . The most frequently cited species were Buddleja asiatica and Hedyotis scandens. They believed that consumption of rice beer is good for health and act as a remedy for various ailments may be attributed to medicinal properties of the herbs used in the preparation of starter cultures.The traditional consumption of a variety of alcoholic beverages since time immemorial is still an integral part of different ethnic communities in the north-eastern region of India. Popular traditional beer, locally known as "bhangchang", was prepared from rice (Cannabis sativa was given to the cattle and goat to cure dysentery and diarrhoea (These diseases were identified by the presence of watery stool and blood). The stem of wild Musa paradisica L., was regularly given to cattle particularly during pregnancy to enhance the yield of milk. A paste powder obtained from the whole plant of Plantago major and Ageratum conyzoides are commonly tied to the affected portions of cattle and goat to relieve from severe pain and inflammations. Gymnocladus assamicus ripe pods are soaked in water and used as disinfectant for cleaning wounds and parasites like leeches and lice on the skin of livestocks. The fully ripe pods soaked in water are used as soap for bathing because it does not cause harm to soft skin and burning sensation to eyes. Leaves are used as green manure in agricultural field crops. Gymnocladus assamicus is a critically rare and endangered plant species and also endemic to the north-eastern region of India [A few plants were used to improve the health state and growth of livestocks. The leaves of of India .Castanopsis indica, Derris scandens, Aesculus assamica, Polygonum hydropiper, Spilanthes acmella, Ageratum conyzoides, and Cyclosorus extensus were used to poison fish during the month of June-July every year and leaves of three species like Ipomoea batatas, Mannihot esculenta, and Zea mays were used as common fish foodstuffs. The two main molecular groups of fish poisons in plants (the rotenones and the saponins) as well as a third group of plants which liberate cyanide in the water account for nearly all varieties of fish poisons [Aconitum ferrox was widely used in arrow poisoning to kill ferocious animals like bear, wild pigs, gaur and deer. The killing of Himalayan bear was very common practice among the tribal people and the gall bladders are highly priced in the local market. The dried gall bladders of bear are given orally in low doses to cure malaria since ancestral times.Community seasonal fishing and hunting are of great economic activities of many tribal people including Monpa ethnic group in addition to agriculture. The study revealed a wealth of indigenous knowledge and procedures related to poison fishing with the aid of poisonous plants. This easy and simple method of fishing are forbidden in urban areas but still practiced in remote tribal areas. The active ingredients were released by macerating the appropriated plant parts with the help of wooden stick or hammer, which were then introduced into the water environment. Depending upon time and conditions, the fish begin to float to the surface where they can easily be collected with bare hand. A total of seven plant species, namely  poisons . The undThis ethno-botanical survey results probably revealed the rich wealth of indigenous knowledge and usage custom of traditional plants associated with rural people of Arunachal Pradesh. Despite their use in traditional medicines, plant species documented in the present field work have been extensively used for improving the health of livestock, fish foodstuffs, ethno-fishing technology, local fermentation technologies, religious and food plants as well. There was no written document of traditional healing knowledge and transmission to the future generation take place only through oral communication. The immediate and serious threat to the local medical practice in the study area seems to have come from the increasing influence of modernization, deforestation due to anthropogenic activities and migration of the younger generations to urban areas leaving a gap in the cultural beliefs and practices of indigenous society. However, there was a potential threat to the medicinal flora of the area as a result of the increasing trend of shifting cultivation  and cultural changes signaling the need for serious efforts to create public awareness so that the appropriate measures are taken to conserve the suitable environments required to protect the medicinal plants in the natural ecosystems. More detailed ethnopharmacological investigations need to be conducted in this area particularly in regard to conservation strategies and sustainable use of medicinal plants.The authors declare that they have no competing interests.NDN developed and designed the research study and conducted field survey work data and wrote the manuscript. ST helped in preliminary identification of plant species and corrected the manuscript. MM and SCM read, supervised and approved the final manuscript. All authors have read and approved the final manuscript.


Throughout life new neurons are continuously added to the hippocampal circuitry involved with spatial learning and memory. These new cells originate from neural precursors in the subgranular zone of the dentate gyrus, migrate into the granule cell layer, and integrate into neural networks encoding spatial and contextual information. This process can be influenced by several environmental and endogenous factors and is modified in different animal models of neurological disorders. Neuroinflammation, as defined by the presence of activated microglia, is a common key factor to the progression of neurological disorders. Analysis of the literature shows that microglial activation impacts not only the production, but also the migration and the recruitment of new neurons. The impact of microglia on adult-born neurons appears much more multifaceted than ever envisioned before, combining both supportive and detrimental effects that are dependent upon the activation phenotype and the factors being released. The development of strategies aimed to change microglia toward states that promote functional neurogenesis could therefore offer novel therapeutic opportunities against neurological disorders associated with cognitive deficits and neuroinflammation. The present review summarizes the current knowledge on how production, distribution, and recruitment of new neurons into behaviorally relevant neural networks are modified in the inflamed hippocampus. In the adult mammalian brain, the subgranular zone of the dentate gyrus (DG) is one of the brain regions where robust neurogenesis continues throughout life . Adult-bArc (activity-regulated cytoskeleton-associated protein) or IEGs encoding transcription factors such as cfos  and cellular debris . By producing neurotrophic and growth factors that are pivotal for tissue repair and renewal they contribute to resolve infection or injury and to restore normal tissue homeostasis . On the One of the brain regions most densely populated with microglia is the hippocampus ; microglFigure 1).Both macrophages  and micrFigure 1).Proliferation, differentiation, and survival of neurons in the adult brain has been shown to be modulated in pathological conditions associated with inflammation . Animal in vivo following irradiation  is expressed in neurons and peripheral endothelia cells . CX3CL1 Available data indicate that the generation, migration, and functional integration of adult-born neurons can be modulated in the inflamed hippocampus, and this modulation appears to differ depending on the activation phenotype of microglia and the specific factors that they release. It is now clear that the range of impact of microglia on adult-born neurons is wider than previously thought, as demonstrated by the anti-neurogenic and pro-neurogenic effects of opposite pro-inflammatory and anti-inflammatory polarized microglia. Previous strategies aimed to maintain functional neurogenesis have mainly focused on decreasing microglia activation. While recent data highlight the potential neuroprotective role of microglia following brain injury, it appears that transforming their phenotype toward alternative activation states could optimize the production, migration, and integration of neurons. Future studies are needed to: (i) characterize the phenotype of microglia activation and the microglia-released factors following brain injury, taking into account the nature of the injury and the timing following the injury; (ii) understand how specific microglia activation states and microglia-released factors impact functional neurogenesis, including migration and functional integration; (iii) identify ways to induce activation of microglia that would support functional neurogenesis in the injured brain. These steps are of critical importance to develop immune-mediated strategies to promote efficient adult-born neurons integration for the maintenance or improvement of hippocampus-dependent cognitive function.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.


Every year more than 20 million infants are born with low birth weight worldwide. About 3.6 million infants die during the neonatal period. More than one third of child deaths are thought to be attributable to maternal and child under nutrition.To systematically review the effect of supplementing various combinations and types of micronutrients on the course and outcomes of pregnancy.Electronic search of Medline, Pub Med, Health Internetwork access to Research Initiative, and Google Scholar databases was conducted. Outcomes of interest were birth weight, low birth weight, small size for gestational age, prenatal mortality and neonatal mortality. After exclusion of irrelevant /incomplete ones, 17 out of 115 articles were considered for the final analysis.Majority of the articles reviewed favored the supplementation of micronutrients to pregnant mother. Some studies suggested calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia. The remaining articles reviewed, showed significant benefit of Multiple Micronutrients supplementation during pregnancy in reducing low birth weight, small for Gestational Age births as compared to the usual iron-folate supplements.Supplying micronutrients, mainly multiple micronutrients have beneficial effect in reducing the risk of low birth weight and other complications. Further studies at various combination and doses of micronutrient supplements are recommended. Every year more than 20 million infants are born with low birth weight worldwide. About 3The World Health Organization (WHO) currently recommends iron and folic acid supplementation to reduce the risk of iron deficiency anemia among pregnant women. Since many developing countries already have systems in place for the delivery of iron and folic acid supplements, micronutrient supplements could be provided at little additional cost.Several systematic reviews of trials examining the effects of maternal multiple micronutrient supplementation have been conducted-10 but tIn addition, most of the studies and literature reviews dealing with maternal nutrition and birth outcomes have approached the issue by investigating single nutrients in isolation. On one level, this is necessary for an in-depth study of the complex issues involved. However, nutrient deficiencies are generally found in low-Socio-economic populations, where they are more likely to involve multiple rather than single deficiencies; and stuThe effects of maternal micronutrient supplementation on perinatal mortality and other pregnancy outcomes can differ depending on trial characteristics and study population. An updated systematic review is essential to provide the basis for future research and for a discussion of policy implications. Hence, this manuscript examines the effect of micronutrient supplements on the progress and outcomes of pregnancy by reviewing high quality literatures/articles.The published results from high-quality human observational and experimental studies which analyzed the effects of supplying Multiple Micro Nutrients (MMN) on the course of pregnancy and pregnancy outcomes were all included to this literature based analysis. Electronic search of Medline, Pub Med, Health Internetwork Access to Research Initiative (HINARI), and Google Scholar databases up to the end of 2011 was conducted. Search was done in keywords:  AND (“Micronutrients” OR “multiple micronutrient*” OR multivitamin OR micronutrient*) AND (supplement*) AND . A function extracting related articles as well as reference lists from research, reviews and editorials was used during the search process. The full version of the English-language analyzed articles and abstracts of most found papers were available during the selection process except for pubmed search.All literatures, including: observational studies, quasi-randomized trials and prospective randomized controlled trials (RCTs) evaluating multiple micronutrient supplementation in women during pregnancy, published in English language, were included. There were no limits on gestational age at the time of enrolment in the study and the duration of supplementation. Other than the assessment of Small for Gestational Age and neonatal mortality, we did not specifically evaluate minor adverse effects of the supplements such as nausea and vomiting among the mothers and newborns.In the primary search 115 records were found. After exclusion of studies/reviews which did not examine the effect of micronutrient supplements on pregnancy outcomes duplicated and outdated (published before 2005) data, 64 articles were selected. During the second selection we evaluated 17 of them as potentially relevant articles considering the effect of multiple micro nutrient supplementations on pregnancy and birth outcomes. Studies that failed to meet our criteria were not taken into consideration (FigureWe defined a “multiple micronutrient supplement” as a single tablet containing more than three different micronutrients; however micronutrient-fortified powders, foods and beverages were not included in the definition.We identified 115 potentially relevant articles for detailed review (FigureThough some degrees of variation by type and amount of micronutrients supplied are observed, the results of the final analysis of the most articles reviewed, favored the supplementation of micronutrients to pregnant mothers.The systematic review of clinical trials by Buppasiri P et al. from Thailand, with the objective of determining the effect of calcium supplementation on maternal, fetal and neonatal outcomes revealed that Calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia and improving mean infant birth weight. The same study also confirmed lack of additional benefits for calcium supplementation in prevention of preterm birth or low infant birth weight.Another study with a similar finding by Hofmeyr GJ et al. concluded that Calcium supplementation appears to almost halve the risk of pre-eclampsia, and to reduce the rare occurrence of the composite outcome ‘death or serious morbidity’, with no other clear benefits, or harms.The thesis based study by Melody B. on maternal vitamin D status during pregnancy as a predictor of offspring bone mass at three years of age shows that maternal vitamin D status during pregnancy did not predict for the child at 3 years of age. AnotherSimilarly, the study by Dror DK et al. shows the existence of recent evidence supporting the role of maternal vitamin D status, particularly early in pregnancy, in modulating the risk of pregnancy complications and in sustaining fetal growth, bone development, and immune maturation.On the other hand, according to the findings of the many of the final articles reviewed; though few disfavored the beneficial outcomes of supplementing MMN to pregnant mothers; majority of the others in one way or another supported the presence of significant association and benefit of MMN supplementation with at least one birth outcome.Among the studies against the added role of supplying MMN to pregnant mothers, the study by Parul Christian, which was about the Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal, revealed that Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight but MMN confer no additional benefit over folic acid-iron in reducing this risk,18. AnotConversely, the remaining RCT and observational studies reviewed from various parts of the world confer that oral supplementation of MMN for pregnant woman benefits the mother and the growing fetus as well as the newborn.In line with this, the reviews and RCT studies by Prakesh S., Zulfiqar A Bhutta, Michael B Zimmermann and other scholars across the globe unanimously reported that supplementing pregnant mothers with MMN immensely benefits both the mother and the growing fetus in reducing maternal morbidity conditions and morbid neonatal birth outcomes-23.Similarly, the systematic review by Prakesh S. et al. also indicates that prenatal MMN supplementation is associated with a significantly reduced risk of low birth weight and with improved birth weight when compared with iron–folic acid supplementation. However, there was no significant effect of MMN supplementation on the risk of preterm birth or small-for-gestational-age infants,22.Additionally, the review by Zulfiqar A Bhutta et al. also provides evidence on significant benefit of MMN supplementation during pregnancy on reducing SGA births as compared to iron-folate, with no significant increase in the risk of neonatal mortality in populations where skilled birth care is available and majority of births take place in facilities.Furthermore, other review by Kosuke Kawai et al. discusses the safety, efficacy and effective delivery of maternal micronutrient supplementation requiring further research. The other study by Dr. Kathleen Abu-Saad on the other side, declares that maternal nutrition is a modifiable risk factor of public health importance that can be integrated into efforts to prevent adverse birth outcomes, particularly among economically developing/low-income populations,25.On the other hand, RCT by Philip N Baker et al. revealed that Poor micronutrient intake and status increases the risk of SGA births in pregnant adolescents and hence mothers should get prenatal micronutrient supplementation in addition to the customary iron folic acid supplementation.In addition, in a poor population, the effects of maternal MMN supplementation on the fetus persisted into childhood, with increases in both weight and body size. Maternal MMN supplementation might therefore be an important part of overall strengthening of prenatal-care programmes-28.Therefore, it is clear to see that given comparability of impacts on maternal anemia, the decision to replace iron-folate with MMN during pregnancy may be taken in the context of available services in health systems and birth outcomes monitored.It was possible to learn that almost all available studies of RCT and other observational studies conducted in various parts of the world revealed that it is beneficial for the mother and the neonate and even to childhood with supplementation of MMN than ordinarily iron folic acid supplementation; nonetheless, there are still some equivocal findings related to the effect of MMN supplementation on the risk of preterm birth, small-for-gestational-age infants and neonatal mortality. Therefore, further studies at various combination and doses of micronutrient supplements particularly in areas where there is high prevalence of malnutrition are recommended.The authors declare that they have no competing interests.TA developed the review parameters and secured support. He also undertook partial literature search, data extraction and analysis. HT made detailed and extensive literature search and involved in the write up and synthesis of the findings. He also reviewed and standardized the study. Both authors read and approved the final manuscript.


Suberites domuncula we show that the axial growth of the spicules proceeds in three phases: (I) formation of an axial canal; (II) evagination of a cell process into the axial canal, and (III) assembly of the axial filament composed of silicatein. During these phases the core part of the spicule is synthesized. Silicatein and its substrate silicate are stored in silicasomes, found both inside and outside of the cellular extension within the axial canal, as well as all around the spicule. The membranes of the silicasomes are interspersed by pores of ≈2 nm that are likely associated with aquaporin channels which are implicated in the hardening of the initial bio-silica products formed by silicatein. We can summarize the sequence of events that govern spicule formation as follows: differential genetic readout (of silicatein) → fractal association of the silicateins → evagination of cells by hydro-mechanical forces into the axial canal → and finally processive bio-silica polycondensation around the axial canal. We termed this process, occurring sequentially or in parallel, bio-inorganic self-organization.The enzymatic-silicatein mediated formation of the skeletal elements, the spicules of siliceous sponges starts intracellularly and is completed extracellularly. With  They are made of silica  analysis primmorph sections were transferred onto coated copper grids and analyzed with a Tecnai 12 microscope . Slices were prepared as described The detailed procedure was given previously Primmorph samples were embedded in epoxy resin as described S. domuncula were tylostyles  from the middle part (ii) from the region close to the apex (ii) At the more terminal end, closer to the apex of the axial canal, the cell membrane ended before the silica rim leaving an open extracellular space. There, “extracellular” vacuoles, silicasomes, of sizes between 50 and 200 nm existed the apex . (i) In the apex . The ves existed . In thisFrom these data we propose that into each growing spicule one cell process protrudes. At the entrance of the cellular extension into the axial canal the diameter of the canal was much larger (1 to 3 µm) while it decreased steadily in size towards the apex which was surrounded by the siliceous mantel.EDX analyses were performed to prove whether the organic material existing in the axial canal contains silicic acid which could serve as substrate for the polycondensation reaction catalyzed by silicatein. Therefore, primmorphs were sectioned and especially areas where spicules were cut transversely or longitudinally were selected for the spectroscopic analyses. Areas from the extra-spicular space (spectrum 1), from the siliceous mantel surrounding an axial canal (spectrum 2), and finally from the axial canal itself (spectrum 3) were selected and analyzed by EDX. The spectra show  that in The ultrastructural analysis by TEM revealed that vesicles, silicasomes, were abundant within the axial canal of developing spicules. Those vesicles displayed pores in their membranes . The 50–Cryosections were prepared and reacted with antibodies raised against silicatein, aquaporin and arginine kinase. The reaction of the anti-silicatein antibody was very strong on the surfaces and also in the center of the spicules . Since tTEM analysis has been combined with immunostaining to localize silicatein, aquaporin and arginine kinase within the axial canal . ArgininIn a parallel series of experiments slices were reacted either with the respective antibodies or with the preimmune serum . A longiUntil this study it remained enigmatic which morphogenetic events trigger and control extracellular axial growth of the siliceous spicules of sponges. Surely the answer to this question will help not only to understand the development of sponge spicules, but may also contribute to the understanding of morphogenesis of more complex skeletal elements, e.g. bone in vertebrates. During bone formation the hydroxyapatite mineral is deposited by osteoblasts apparently in the extracellular space aquaporin gene is expressed during spicule formation and contributes to the hardening/aging of the bio-silica product of silicatein (EMBL accession number FR773712 i) the removal of water from the site of its formation during the synthesis of bio-silica. In turn, elimination of reaction water causes a shift of the equilibrium towards enhanced silica condensation, resulting in (ii) an aging process of the formed bio-silica Recently we discovered for the first time that the Based on the TEM studies presented here it is obvious that the silicasomes, both in the extra-spicular and in the intra-spicular space, comprise pores with an approximate size of 1–2 nm. Surely those pores do not reflect aquaporin pores which have a size of around 3 Å In none of the TEM images clear evidence for the existence of mitochondria could be detected in the cell processes. However, the fast polycondensation reactions S. domunculasilicateins and of collagen, as described Based on the TEM analyses of diagonal and longitudinal sections through growing spicules the most plausible explanation for the dynamics of the extension of the cellular processes into the axial canals of the spicules is to propose hydrodynamic forces that drive an evagination process. Evagination is a frequently occurring process in metazoans, which can be explained by an interplay of movement, intercalation, and division of cells as well as by changes in the cell polarization and shape i) Initial stage of gene expression, primarily of the major spicule-forming gene, silicatein, and subsequent association of the formed silicatein molecules following a fractal mechanism (ii) Extrusion of the primordial spicule into the extracellular space  Exar space . There, ar space . This moar space . The remgenetic readout  → fractal association of the silicateins → evagination of cells by hydro-mechanical forces → and finally processive polycondensation of bio-silica. We term the interactions of these two processes, biologically driven events and chemically occurring processes that run sequentially or in parallel, as bio-inorganic self-organization. This term should express that the bio-genetic self-organization mechanisms, characteristic for the arrangement of cells within tissue, also are under the control of processes that originate from chemical and/or physical processes.In turn we can summarize the sequence of events that governs spicule formation by the following chain of processes: differential


Recent studies suggest that subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) may exert at least part of its therapeutic effect through the antidromic suppression of pathological oscillations in the cortex in 6-OHDA treated rats and in parkinsonian patients. STN-DBS may also activate STN neurons by initiating action potential propagation in the orthodromic direction, similarly resulting in suppression of pathological oscillations in the STN. While experimental studies have provided strong evidence in support of antidromic stimulation of cortical neurons, it is difficult to separate relative contributions of antidromic and orthodromic effects of STN-DBS. The aim of this computational study was to examine the effects of antidromic and orthodromic activation on neural firing patterns and beta-band (13-30 Hz) oscillations in the STN and cortex during DBS of STN afferent axons projecting from the cortex. High frequency antidromic stimulation alone effectively suppressed simulated beta activity in both the cortex and STN-globus pallidus externa (GPe) network. High frequency orthodromic stimulation similarly suppressed beta activity within the STN and GPe through the direct stimulation of STN neurons driven by DBS at the same frequency as the stimulus. The combined effect of both antidromic and orthodromic stimulation modulated cortical activity antidromically while simultaneously orthodromically driving STN neurons. While high frequency DBS reduced STN beta-band power, low frequency stimulation resulted in resonant effects, increasing beta-band activity, consistent with previous experimental observations. The simulation results indicate effective suppression of simulated oscillatory activity through both antidromic stimulation of cortical neurons and direct orthodromic stimulation of STN neurons. The results of the study agree with experimental recordings of STN and cortical neurons in rats and support the therapeutic potential of stimulation of cortical neurons. Deep brain stimulation (DBS) is an established surgical therapy for treating the symptoms of medically refractory Parkinson's disease. The mechanisms by which DBS exerts its therapeutic influence, at both the cellular and system level, however, remain unclear. Excessively synchronized neural activity throughout the cortico-basal ganglia network is a characteristic hallmark of Parkinson's disease , STN and GPe. The model used in this study is based on the network model developed by Kang and Lowery , with siIDBS was delivered to a homogeneous extracellular medium of conductivity σ. The extracellular potential, Ve at each point i located a distance  from the point source positioned at the origin was calculated as:The extracellular potential in the surrounding white matter tissue during DBS was estimated by modeling the applied stimulus as a point current source under the assumption of quasistatic conditions  = 0 for x < 0, and H(x) = 1 for x ≥ 0, ρD is the interstimulus interval, ID is the maximum pulse amplitude, and δD is the duration of the positive phase of the stimulus pulse.where i, Vmisoma is described byThe cortical neuron model consisted of a soma, AIS, main axon and axon collateral situated in 3-dimensional space. The cortical soma model is based on regular spiking cortical neurons developed by Pospischil et al. . It reprCmisoma is the membrane capacitance, Vmisoma is the membrane potential, INaisoma is the sodium current, IKdisoma is the potassium current and IMisoma is a slow voltage-dependent potassium current responsible for spike-frequency adaptation. Iisomaleak indicates a leak current. Details of the parameter values for the cortical neurons are as presented in Pospischil et al. . Preliminary studies using the model indicated that this number is sufficient to capture the network effects of interest while maintaining a reasonable level of computational efficiency. For simplicity the same number of neurons was assumed in each nucleus was used. In reality, however, the number of neurons varies across the different nuclei. In particular, the ratio of cortical neurons to interneurons is about approximately 200:20  antidromic, (2) orthodromic, and (3) simultaneous antidromic and orthodromic excitation of collaboratoral axons due to extracellular DBS were each examined. Definition of antidromic and orthodromic activation of STN-DBS used in the model was illustrated in Figure To simulate the effect of pure orthodromic activation due to STN-DBS, action potentials traveling toward the cortical soma were blocked by setting the axon conductance of the last node connected to the axon collateral close to zero. This resulted in orthodromic activation of the axon during STN-DBS. As propagation was blocked in the direction toward the cortical soma only, action potentials generated within the cortex were allowed to reach the axon collaterals but no antidromic propagation was allowed. Simultaneous antidromic and orthodromic excitations were simulated by allowing bi-directional propagation of action potentials during STN-DBS as in the physiological situation.Simulations were performed on a personal computer with Intel(R) Core(TM)2 CPU 6600, 2.39 GHz and 3 GB RAM using C++. The simulation was performed for a duration of 5 s with DBS applied for 1 s in five separate simulation experiments and the power of the sum of the membrane potentials of the populations of STN and cortical neurons in the frequency band of interest was examined. User developed programs using Welch's method in Matlab  and low frequency (20 Hz) DBS on simulated beta frequency oscillations among the simulated STN neurons with both orthodromic and antidromic propagation facilitated was first examined. DBS with an amplitude of 2.5 mA and pulse duration of 60 µs for both conditions was applied, Figure The effects of simultaneous antidromic and orthodromic activation of the cortical axon collaterals during DBS on the power spectrum of the STN neurons in the beta frequency range is shown in Figure The combined effect of antidromic and orthodromic activation resulted in stimulus-driven firing in the STN neurons, Figure Firing of STN neurons in response to each DBS stimulus was also observed under the simulated condition of pure orthodromic activation, Figure In contrast to the results with combined orthodromic-antidromic activation and orthodromic activation alone, an irregular firing pattern was observed in the STN neurons under conditions of pure antidromic DBS activation, Figure As the effect of orthodromic activation during DBS resulted in a similar effect on neural firing in the STN to the combined effect of antidromic and orthodromic activation, the propagation of action potentials along the axon collaterals during DBS was examined to better understand the responses elicited by the different simulation conditions, Figure At a stimulation frequency of 10 Hz, antidromic cortical excitation was reliably elicited, as over 90% of stimuli were followed by antidromic firing in all cortical neurons, Figure The aim of this study was to develop a computational model of the cortico-STN-GPe network to examine the effects of antidromic and orthodromic activation on neural firing and beta-band oscillatory activity among cortical and STN neurons during STN-DBS. By providing a method with which to separately stimulate cortical neurons antidromically and STN neurons orthodromically, as well to simultaneously elicit antidromic and orthodromic activation as likely occurs physiologically, the model enables the relative contributions of orthodromic and antidromic activation of STN afferent axons projecting from the cortex to the STN to be explored. The results provide new insights into the possible mechanisms by which STN-DBS modulates and disrupts abnormal neural activity in both the cortex and STN to exert its therapeutic effects.In this study, based on the findings of the most recent experimental studies, STN afferent axons originating from the cortex were the chosen target for DBS. This is in contrast to previous simulation studies in which DBS was either intracellularly applied to single-compartment models of STN neurons  that may be reasonably requested by others for the purpose of academic and non-commercial research. In regards to deposition of data and data sharing through databases, Frontiers urges authors to comply with the current best practices within their discipline.This work was supported by Irish Research Council for Science, Engineering and Technology Grant RS/2009/1330.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.