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.

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.

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.

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.

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.

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.

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.

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 Bayesian framework for cue integration in multistable grouping: Proximity, collinearity, and orientation priors in zigzag lattices.

Integration of proximity and good continuation cues is analyzed as a probabilistic inference problem in contour grouping. A Bayesian framework was tested in a multistable dot lattice experiment. In rectangular lattices, distance ratio and global orientation of rows and columns were manipulated. Discollinearity was introduced by imposing zigzag in one orientation, by either fixed or stochastic displacement of elements. Results indicate that proximity and good continuation are generally treated as independent sources of information, added to prior orientation log-odds to produce the odds of grouping percepts. Distance likelihood is well captured by a power law, and discollinearity likelihoods by generalized Laplace distributions, with higher kurtosis for stochastic zigzag. While observers prefer vertical over horizontal orientations, the exact prior distribution is idiosyncratic. Perceptual grouping along cardinal axes is less affected by distance, but more by discollinearity, than along oblique orientations. Results are qualitatively and quantitatively compared to ecological statistics of contours (J. H. Elder & R. M. Goldberg, 2002). The potential of hierarchically extended Bayes models for a better understanding of principles in cue integration is discussed.

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.

Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis.

This review covers recent advances of CD95 signaling. It focuses on CD95-interacting molecules, formation of the death inducing signaling complex and the role of caspases, particularly caspase-8, and their death substrates. We also discuss the relevance of mitochondria in the CD95-mediated apoptotic process and how viral proteins interfere with crucial steps of this signaling pathway.

Apoptosis signaling in lymphocytes.

Lymphocyte apoptosis is essential for proper function of the immune system. Among other functions, it is responsible for the homeostasis of immune cells and plays a key role in the elimination of autoreactive lymphocytes. Recently, progress has been made in the identification of genes that regulate apoptosis. Studies characterizing the basic apoptosis signaling machinery have begun to reveal the molecular control of processes that modulate lymphocyte apoptosis.

Identification of the cytolinker plectin as a major early in vivo substrate for caspase 8 during CD95- and tumor necrosis factor receptor-mediated apoptosis.

Caspase 8 plays an essential role in the execution of death receptor-mediated apoptosis. To determine the localization of endogenous caspase 8, we used a panel of subunit-specific anti-caspase 8 monoclonal antibodies in confocal immunofluorescence microscopy. In the human breast carcinoma cell line MCF7, caspase 8 predominantly colocalized with and bound to mitochondria. After induction of apoptosis through CD95 or tumor necrosis factor receptor I, active caspase 8 translocated to plectin, a major cross-linking protein of the three main cytoplasmic filament systems, whereas the caspase 8 prodomain remained bound to mitochondria. Plectin was quantitatively cleaved by caspase 8 at Asp 2395 in the center of the molecule in all cells tested. Cleavage of plectin clearly preceded that of other caspase substrates such as poly(ADP-ribose) polymerase, gelsolin, cytokeratins, or lamin B. In primary fibroblasts from plectin-deficient mice, apoptosis-induced reorganization of the actin cytoskeleton, as seen in wild-type cells, was severely impaired, suggesting that during apoptosis, plectin is required for the reorganization of the microfilament system.

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.

CD95 apoptosis resistance in certain cells can be overcome by noncanonical activation of caspase-8.

CD95 apoptosis resistance of tumor cells is often acquired through mutations in the death domain (DD) of one of the CD95 alleles. Furthermore, Type I cancer cells are resistant to induction of apoptosis by soluble CD95 ligand (CD95L), which does not induce efficient formation of the death-inducing signaling complex (DISC). Here, we report that tumor cells expressing a CD95 allele that lacks a functional DD, splenocytes from heterozygous lpr(cg) mice, which express one mutated CD95 allele, and Type I tumor cells stimulated with soluble CD95L can all die through CD95 when protein synthesis or nuclear factor kappa B is inhibited. This noncanonical form of CD95-mediated apoptosis is dependent on the enzymatic activity of procaspase-8 but does not involve fully processed active caspase-8 subunits. Our data suggest that it is possible to overcome the CD95 apoptosis resistance of many tumor cells that do not efficiently form a DISC through noncanonical activation of the caspase-8 proenzyme.

Induction of apoptosis in 9-nitrocamptothecin-treated DU145 human prostate carcinoma cells correlates with de novo synthesis of CD95 and CD95 ligand and down-regulation of c-FLIP(short).

Stimulation of CD95 leads to oligomerization of this receptor and the recruitment of the Fas-associated death domain (FADD) and procaspase-8 to form the death-inducing signaling complex (DISC). Subsequent proteolytic activation of caspase-8 at the DISC leads to the activation of downstream caspases and execution of apoptosis. The anticancer drug 9-nitrocamptothecin (9NC) inhibits the nuclear enzyme topoisomerase I (Top1), an event followed by apoptosis of cancer cells. We investigated whether other mechanisms downstream of the DNA-Top1-9NC complexing step regulate the apoptotic ability of 9NC in DU145 cells. We demonstrate that induction of apoptosis in DU145 cells, upon exposure to 9NC, is associated with de novo expression of CD95 and CD95L, suggesting that 9NC-induced apoptosis is mediated by the CD95 system. In this line, we observed early activation of procaspase-3, -7, and -8, but not -1, -9, and -10. Moreover, 9NC treatment resulted in the dramatic down-regulation of c-FLIP(short) expression, but not that of c-FLIP(long) or FADD. Furthermore, incubation of DU145 cells with a neutralizing antibody (NOK-1) to CD95L or transient transfection of a c-FLIP(short) expression vector into DU145 cells partially abrogated 9NC-triggered apoptosis. We propose that 9NC triggers apoptosis by driving DU145 cells from a nonapoptotic status (c-FLIP(short)(high), CD95(low), CD95L(low)) toward a proapoptotic status (c-FLIP(short)(low), CD95(high), CD95L(high)). These findings indicate that in addition to a Top1-mediated effect, 9NC can additionally activate a CD95/CD95L-dependent apoptotic pathway.

Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors.

Betulinic acid (BA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases). FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-XL conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, Bax and Bcl-xs, two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.

ICE-proteases mediate HTLV-I Tax-induced apoptotic T-cell death.

The Tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is important for the T-cell immortalizing properties of this virus in vitro and is considered to be responsible for the early stages of leukemogenesis in infected hosts. Tax can upregulate expression of TNF-alpha and TNF-beta, as well as potentiate apoptosis in activated T-cells and in serum starved murine fibroblasts. To examine the role of CD95 (APO-1/Fas) and ICE-proteases in Tax-mediated active T-cell death, Jurkat T cells expressing (APO(S)) or lacking (APO(R)) cell surface expression of CD95 (APO-1/Fas) were genetically modified to express hormone-inducible HTLV-1 Tax constructs. Hormone-inducible action of Tax alone was sufficient to promote programmed cell death in CD95-expressing Jurkat T-cell clones. In contrast, clones lacking CD95 surface expression were resistant to the antiproliferative action of Tax. Both APO(S) and APO(R) clones exhibited Tax-dependent upregulation of CD95 ligand and TNF-alpha. Blocking experiments suggested that while the apoptotic action of Tax critically required ICE-protease function it was largely independent of cell surface interaction of CD95 ligand or TNF-alpha with their corresponding receptors. These observations strongly implicate ICE-proteases in Tax-induced T-cell death, and suggest a possible involvement of CD95 in this process.

CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases.

Triggering of CD95 (APO-1/Fas) on different T- and B-cell lines resulted in the induction of a number of kinases (35 kDa, 38 kDa, 46 kDa and 54 kDa) that phosphorylate c-Jun and to a lesser extent Histone H1. Activation of these kinases was independent of protein biosynthesis and preceded apoptotic DNA degradation. The kinase activation pattern was specific for CD95 triggering since a variety of physical or chemical inducers of T- and B-cell apoptosis activated different kinases. The kinase activities at 46 and 54 kDa contained members of the stress-activated family of protein kinases (JNK/SAPK). Activation of the CD95-specific set of kinases was prevented by treating cells with the ICE-inhibiting peptide N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) or by overexpression of the cow pox virus serpin CrmA. However, despite inhibition of ICE-like proteases the death signal was readily initiated at the cell membrane since a CD95 death-inducing signaling complex (DISC) was formed. Thus, our results demonstrate that ICE-like proteases in the CD95 pathway function downstream of the DISC but upstream of SAP kinases.

The CD95(APO-1/Fas) DISC and beyond.

CD95 (APO-1/Fas) is a prototype death receptor characterized by the presence of an 80 amino acid death domain in its cytoplasmic tail. This domain is essential for the recruitment of a number of signaling components upon activation by either agonistic anti-CD95 antibodies or cognate CD95 ligand that initiate apoptosis. The complex of proteins that forms upon triggering of CD95 is called the death-inducting signaling complex (DISC). The DISC consists of an adaptor protein and initiator caspases and is essential for induction of apoptosis. A number of proteins have been reported to regulate formation or activity of the DISC. This review discusses recent developments in this area of death receptor research.