Neurocritical Care in Nigeria.

Nigeria is the most populous country in Africa with an estimated 206 million inhabitants served by less than 300 neurologists and 131 neurosurgeons. Neurological conditions account for approximately 18% of all medical emergencies. Neurocritical care challenges in Nigeria are as complex as they are in other low-to-middle-income countries (LMICs). These include high burden of neurological diseases, poor pre-hospital care, delays in transfer, lack of neurocritical care equipment, and inadequate rehabilitative capacity. Neurocritical care units in Nigeria offer mostly limited multimodal monitoring due to out-of-pocket payment, and the success of repeat radiological imaging and blood work is low. Data gathering and outcome research in neurocritical conditions can help in clinical decision-making and enhance cost-effective clinical care. The concept of allocation requires that when medical resources are scarce, they must be efficiently utilized in the most judicious way so as to achieve the greatest possible benefit. A high degree of transparency is needed with regard to the principles, values and criteria employed to facilitate such triage decisions. Proper funding will help improve availability of equipment and drugs resulting in a higher quality of care and, subsequently, improvement in mortality. There is ample evidence that neurocritical care improves overall prognosis in neurocritically-ill patients. Neurocritical care units (NCCUs) are mostly unavailable in Nigeria, often resulting in poorer prognosis for patients. What is already known: Nigeria has an unacceptably huge deficit in the overall capacity for neurocritical care. The inadequacies affect a wide range of components - facilities, quantity and quality of personnel, and the unbearably high cost, among others. What this study adds: This article attempts to condense the challenges in one piece while highlighting previously obscure ones, with the aim of providing possible solutions to the lingering challenges in neurocritical care in Nigeria and, invariably, other LMICs. How this study might affect practice, policies or research: We envisage this article will stimulate the initial steps in a multipronged and data-driven approach to bridging the gap by government and relevant healthcare administrators.

Le Nigeria est le pays le plus peuplé d'Afrique avec une population estimée à 206 millions d'habitants et à peine moins de 300 neurologues et 131 neurochirurgiens au service de cette population. Les urgences neurologiques représentent environ 18 % de toutes les urgences médicales. Les défis posés par les soins neurocritiques au Nigeria sont aussi complexes que dans d'autres pays à revenu faible ou intermédiaire (PRFI). Il s'agit notamment du lourd fardeau des maladies neurologiques, de la médiocrité des soins préhospitaliers, des retards de transfert, du manque d'équipements de soins neurocritiques et d'une capacité de réadaptation réduite. Les unités de soins neurocritiques au Nigeria disposent d'une surveillance multimodale limitée en raison du paiement direct, et le succès de la répétition de l'imagerie radiologique et des analyses sanguines est faible. La collecte de données et la recherche sur les résultats dans les conditions neurocritiques peuvent aider à la prise de décision clinique et améliorer la rentabilité des soins cliniques. Selon le concept d'allocation, lorsque les ressources médicales sont rares, elles doivent être utilisées efficacement et de la manière la plus judicieuse possible afin d'obtenir le plus grand bénéfice possible. Un degré élevé de transparence est nécessaire en ce qui concerne les principes, les valeurs et les critères utilisés pour faciliter ces décisions de triage. Un financement adéquat permettra d'améliorer la disponibilité des équipements et des médicaments, ce qui se traduira par une meilleure qualité des soins et, par la suite, par une réduction de la mortalité. Il existe de nombreuses preuves que les soins neurocritiques améliorent le pronostic général des patients en état neurocritique. Les unités de soins neurocritiques (NCCU) sont pour la plupart indisponibles au Nigeria, ce qui entraîne un pronostic plus défavorable. Ce que l'on sait déjà : Le Nigeria souffre d'un déficit inacceptable en matière de capacité globale de soins neurocritiques. Les insuffisances touchent un large éventail d'éléments - installations, quantité et qualité du personnel, et coût insupportablement élevé, entre autres. Ce que cette étude apporte : Cet article tente de condenser les défis en un seul élément tout en mettant en lumière ceux qui étaient auparavant obscurs, dans le but de fournir des solutions possibles aux défis persistants des soins neurocritiques au Nigeria et invariablement dans les pays à faible revenu intermédiaire. Comment cette étude pourrait-elle affecter la pratique, les politiques ou la recherche ? Nous pensons que cet article stimulera les premières étapes d'une approche multidimensionnelle et axée sur les données pour combler le fossé par le gouvernement et les administrateurs de soins de santé concernés. Mots-clés: Soins Neurocritiques, Nigeria, Maladies neurologiques.

The regulation of a pigmentation gene in the formation of complex color patterns in Drosophila abdomens.

Changes in the control of developmental gene expression patterns have been implicated in the evolution of animal morphology. However, the genetic mechanisms underlying complex morphological traits remain largely unknown. Here we investigated the molecular mechanisms that induce the pigmentation gene yellow in a complex color pattern on the abdomen of Drosophila guttifera. We show that at least five developmental genes may collectively activate one cis-regulatory module of yellow in distinct spot rows and a dark shade to assemble the complete abdominal pigment pattern of Drosophila guttifera. One of these genes, wingless, may play a conserved role in the early phase of spot pattern development in several species of the quinaria group. Our findings shed light on the evolution of complex animal color patterns through modular changes of gene expression patterns.

Oxygen isotope (δ18O, Δ'17O) insights into continental mantle evolution since the Archean.

Oxygen isotopic ratios are largely homogenous in the bulk of Earth's mantle but are strongly fractionated near the Earth's surface, thus these are robust indicators of recycling of surface materials to the mantle. Here we document a subtle but significant ~0.2‰ temporal decrease in δ18O in the shallowest continental lithospheric mantle since the Archean, no change in Δ'17O is observed. Younger samples document a decrease and greater heterogeneity of δ18O due to the development and progression of plate tectonics and subduction. We posit that δ18O in the oldest Archean samples provides the best δ18O estimate for the Earth of 5.37‰ for olivine and 5.57‰ for bulk peridotite, values that are comparable to lunar rocks as the moon did not have plate tectonics. Given the large volume of the continental lithospheric mantle, even small decreases in its δ18O may explain the increasing δ18O of the continental crust since oxygen is progressively redistributed by fluids between these reservoirs via high-δ18O sediment accretion and low-δ18O mantle in subduction zones.

Effect of Presentation Format on Judgment of Long-Range Time Intervals.

Investigations in the temporal estimation domain are quite vast in the range of milliseconds, seconds, and minutes. This study aimed to determine the psychophysical function that best describes long-range time interval estimation and evaluate the effect of numerals in duration presentation on the form of this function. Participants indicated on a line the magnitude of time intervals presented either as a number + time-unit (e.g., "9 months"; Group I), unitless numerals (e.g., "9"; Group II), or tagged future personal events (e.g., "Wedding"; Group III). The horizontal line was labeled rightward ("Very short" = >"Very long") or leftward ("Very long" = >"Very short") for Group I and II, but only rightward for Group III. None of the linear, power, logistic or logarithmic functions provided the best fit to the individual participant data in more than 50% of participants for any group. Individual power exponents were different only between the tagged personal events (Group III) and the other two groups. When the same analysis was repeated for the aggregated data, power functions provided a better fit than other tested functions in all groups with a difference in the power function parameters again between the tagged personal events and the other groups. A non-linear mixed effects analysis indicated a difference in the power function exponent between Group III and the other groups, but not between Group I and II. No effect of scale directionality was found in neither of the experiments in which scale direction was included as independent variable. These results suggest that the judgment of intervals in a number + time-unit presentation invoke, at least in part, processing mechanisms other than those used for time-domain. Consequently, we propose the use of event-tagged assessment for characterizing long-range interval representation. We also recommend that analyses in this field should not be restricted to aggregated data given the qualitative variation between participants.

A common representation of time across visual and auditory modalities.

Humans' and non-human animals' ability to process time on the scale of milliseconds and seconds is essential for adaptive behaviour. A central question of how brains keep track of time is how specific temporal information across different sensory modalities is. In the present study, we show that encoding of temporal intervals in auditory and visual modalities are qualitatively similar. Human participants were instructed to reproduce intervals in the range from 750 ms to 1500 ms marked by auditory or visual stimuli. Our behavioural results suggest that, although participants were more accurate in reproducing intervals marked by auditory stimuli, there was a strong correlation in performance between modalities. Using multivariate pattern analysis in scalp EEG, we show that activity during late periods of the intervals was similar within and between modalities. Critically, we show that a multivariate pattern classifier was able to accurately predict the elapsed interval, even when trained on an interval marked by a stimulus of a different sensory modality. Taken together, our results suggest that, while there are differences in the processing of intervals marked by auditory and visual stimuli, they also share a common neural representation.

Individual differences in long-range time representation.

On the basis of experimental data, long-range time representation has been proposed to follow a highly compressed power function, which has been hypothesized to explain the time inconsistency found in financial discount rate preferences. The aim of this study was to evaluate how well linear and power function models explain empirical data from individual participants tested in different procedural settings. The line paradigm was used in five different procedural variations with 35 adult participants. Data aggregated over the participants showed that fitted linear functions explained more than 98% of the variance in all procedures. A linear regression fit also outperformed a power model fit for the aggregated data. An individual-participant-based analysis showed better fits of a linear model to the data of 14 participants; better fits of a power function with an exponent ß > 1 to the data of 12 participants; and better fits of a power function with ß < 1 to the data of the remaining nine participants. Of the 35 volunteers, the null hypothesis ß = 1 was rejected for 20. The dispersion of the individual ß values was approximated well by a normal distribution. These results suggest that, on average, humans perceive long-range time intervals not in a highly compressed, biased manner, but rather in a linear pattern. However, individuals differ considerably in their subjective time scales. This contribution sheds new light on the average and individual psychophysical functions of long-range time representation, and suggests that any attribution of deviation from exponential discount rates in intertemporal choice to the compressed nature of subjective time must entail the characterization of subjective time on an individual-participant basis.

Visual Causality Judgments Correlate with the Phase of Alpha Oscillations.

The detection of causality is essential for our understanding of whether distinct events relate. A central requirement for the sensation of causality is temporal contiguity: As the interval between events increases, causality ratings decrease; for intervals longer than approximately 100 msec, the events start to appear independent. It has been suggested that this effect might be due to perception relying on discrete processing. According to this view, two events may be judged as sequential or simultaneous depending on their temporal relationship within a discrete neuronal process. To assess if alpha oscillations underlie this discrete neuronal process, we investigated how these oscillations modulate the judgment of causality. We used the classic launching effect with concurrent recording of EEG signal. In each trial, a disk moved horizontally toward a second disk at the center of the screen and stopped when they touched each other. After a delay that varied between 0 and 400 msec after contact, the right disk began to move. Participants were instructed to judge whether or not they had a feeling that the first disk caused the movement of the second disk. We found that frontocentral alpha phase significantly biased causality estimates. Moreover, we found that alpha phase was concentrated around different angles for trials in which participants judged events as causally related versus not causally related. We conclude that alpha phase plays a key role in biasing causality judgments.

MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment.

Cancer cells grow in an environment comprised of multiple components that support tumor growth and contribute to therapy resistance. Major cell types in the tumor microenvironment are fibroblasts, endothelial cells and infiltrating immune cells all of which communicate with cancer cells. One way that these cell types promote cancer progression is by altering the expression of microRNAs (miRNAs), small noncoding RNAs that negatively regulate protein expression, either in the cancer cells or in the associated normal cells. Changes in miRNA expression can be brought about by direct interaction between the stromal cells and cancer cells, by paracrine factors secreted by any of the cell types or even through direct communication between cells through secreted miRNAs. Understanding the role of miRNAs in the complex interactions between the tumor and cells in its microenvironment is necessary if we are to understand tumor progression and devise new treatments.

Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis.

The cross-talk between ovarian cancer (OvCa) cells and the metastatic microenvironment is an essential determinant of successful colonization. MicroRNAs (miRNAs) have several critical roles during metastasis; however, the role of microenvironmental cues in the regulation of miRNAs in metastasizing cancer cells has not been studied. Using a three-dimensional culture model that mimics the human omentum, one of the principal sites of OvCa metastasis, we identified and characterized the microenvironment-induced downregulation of a tumor suppressor miRNA, miR-193b, in metastasizing OvCa cells. The direct interaction of the OvCa cells with mesothelial cells, which cover the surface of the omentum, caused a DNA methyltransferase 1-mediated decrease in the expression of miR-193b in the cancer cells. The reduction in miR-193b enabled the metastasizing cancer cells to invade and proliferate into human omental pieces ex vivo and into the omentum of a mouse xenograft model of OvCa metastasis. The functional effects of miR-193b were mediated, in large part, by the concomitant increased expression of its target, urokinase-type plasminogen activator, a known tumor-associated protease. These findings link paracrine signals from the microenvironment to the regulation of a key miRNA in cancer cells. Targeting miR-193b, which is essential for metastatic colonization of cancer cells could prove effective in the treatment of OvCa metastasis.

The role of CD95 and CD95 ligand in cancer.

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.

Modulation of perceived contrast in the brightness comparison of asynchronous stimuli.

Comparative judgment is a crucial task in ecological settings, as well as in many experimental studies about basic aspects of perceptual processes. It has long been known that sequential comparison is prone to order effects. This phenomenon has received little attention and has often been discounted as a type of response bias. In the present study, we investigated brightness discrimination of two brief (100 ms) spatially disjoint luminance stimuli. In the first and second experiments, stimuli were presented against a dark background with a stimulus onset asynchrony (SOA) from 0 to 200 ms, in a paradigm controlling for response bias. In the third experiment, stimuli were presented against a bright background. We demonstrate that the time interval between stimuli modulates and even inverts their perceived brightness difference, enhancing the second stimulus relative to the first. When the background is brighter than the target stimuli, the sign of the effect is inverted, suggesting that the underlying mechanism operates on contrast rather than brightness. The magnitude of this effect is shown to depend on SOA and average luminance level of the target stimuli. Hypotheses in terms of neural and attentional dynamics are proposed.

MicroRNAs regulate both epithelial-to-mesenchymal transition and cancer stem cells.

Concepts and experimental models derived from basic research have been successfully applied to the field of molecular oncology, tremendously increasing our knowledge of the nature and the progression of tumors. The process of epithelial-to-mesenchymal transition, the cancer stem cell hypothesis, and their functional association and interdependence represent some of the most significant examples. The molecular determinants underlying the plasticity of cancers are currently the object of extensive research efforts, and a substantial body of evidence suggests that these models can be connected by the regulatory role of microRNAs, small noncoding RNA molecules with a fundamental role in many cellular functions. This review will highlight and discuss this link and its possible implications for the fight against cancer.

Bias and learning in temporal binding: intervals between actions and outcomes are compressed by prior bias.

It has consistently been shown that agents judge the intervals between their actions and outcomes as compressed in time, an effect named intentional binding. In the present work, we investigated whether this effect is result of prior bias volunteers have about the timing of the consequences of their actions, or if it is due to learning that occurs during the experimental session. Volunteers made temporal estimates of the interval between their action and target onset (Action conditions), or between two events (No-Action conditions). Our results show that temporal estimates become shorter throughout each experimental block in both conditions. Moreover, we found that observers judged intervals between action and outcomes as shorter even in very early trials of each block. To quantify the decrease of temporal judgments in experimental blocks, exponential functions were fitted to participants' temporal judgments. The fitted parameters suggest that observers had different prior biases as to intervals between events in which action was involved. These findings suggest that prior bias might play a more important role in this effect than calibration-type learning processes.

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012.

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

The relation between action, predictability and temporal contiguity in temporal binding.

Previous studies have documented a subjective temporal attraction between actions and their effects. This finding, named intentional binding, is thought to be the result of a cognitive function that links actions to their consequences. Although several studies have tried to outline the necessary and sufficient conditions for intentional binding, a quantitative comparison between the roles of temporal contiguity, predictability and voluntary action and the evaluation of their interactions is difficult due to the high variability of the temporal binding measurements. In the present study, we used a novel methodology to investigate the properties of intentional binding. Subjects judged whether an auditory stimulus, which could either be triggered by a voluntary finger lift or be presented after a visual temporal marker unrelated to any action, was presented synchronously with a reference stimulus. In three experiments, the predictability, the interval between action and consequence and the presence of action itself were manipulated. The results indicate that (1) action is a necessary condition for temporal binding; (2) a fixed interval between the two events is not sufficient to cause the effect and (3) only in the presence of voluntary action do temporal predictability and contiguity play a significant role in modulating the effect.These findings are discussed in the context of the relationship between intentional binding and temporal expectation.

Sudden death of a 7-year-old boy due to undiagnosed glioblastoma.

We present a case of sudden death of a 7-year-old boy who at autopsy was found to have an undiagnosed glioblastoma. The boy was asymptomatic until 2 hours before death complaining of a headache and was later found unresponsive in bed. A medicolegal autopsy was notable for a large hemorrhagic mass of the right frontal lobe, which on analysis was diagnostic of a glioblastoma. We feel that this is a unique case for 2 main reasons; high-grade gliomas of the cerebral cortex are rare in the pediatric population, and it is unusual for a large neoplasm to remain asymptomatic until 2 hours prior to death.

Targeting of mRNAs by multiple miRNAs: the next step.

Micro(mi)RNAs are small noncoding RNAs that regulate expression of the majority of the genes in the genome at either the messenger RNA (mRNA) level (by degrading mRNA) or the protein level (by blocking translation). miRNAs are thought to be components of vast regulatory networks. Currently, the field is focused primarily on identifying novel targets of individual miRNAs. This focus is about to undergo a dramatic change. In a new paper by Wu et al. (2010) it is experimentally confirmed that multiple miRNAs target the same gene, suggesting that it is the combination of all these activities that determines the expression of miRNA target genes. This study ushers in a new era of miRNA research that focuses on networks more than on individual connections between miRNA and strongly predicted targets.

Voluntary action and causality in temporal binding.

Previous studies have documented temporal attraction in perceived times of actions and their effects. While some authors argue that voluntary action is a necessary condition for this phenomenon, others claim that the causal relationship between action and effect is the crucial ingredient. In the present study, we investigate voluntary action and causality as the necessary and sufficient conditions for temporal binding. We used a variation of the launching effect proposed by Michotte, in which participants controlled the launch stimulus in some blocks. Volunteers reported causality ratings and estimated the interval between the two events. Our results show dissociations between causality ratings and temporal estimation. While causality ratings are not affected by voluntary action, temporal bindings were only found in the presence of both voluntary action and high causality. Our results indicate that voluntary action and causality are both necessary for the emergence of temporal binding.

Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009.

Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.