Shunt technology for infants and a lifetime.

The use of cerebrospinal fluid (CSF) shunts remains a fundamental therapeutic modality in the management of hydrocephalus. Nowadays, neurosurgeons have an arsenal of different shunt technologies on their hands, with several companies producing many different configurations of them. The greatest difficulty of treating a child with hydrocephalus is to deal with a brain that will enormously change its size and hydrodynamic conditions and a body that will multiply its height and weight in a short time. Detailed knowledge of the hydrodynamic properties of shunts is mandatory for any neurosurgeon and much more for those taking care of pediatric patients. It is necessary to know that these properties of the valve may influence the evolution of the patient after shunting and it is recognized that a patient physiology-specific valve selection may yield better outcomes and decrease complications. This article provides a summary of the most common available CSF valves and overdrainage control devices, their technology, and possible combinations. The objective is to offer a quick overview of the armamentarium to facilitate the recognition of the implanted device and improve the selection of the most suitable valve for each patient.

Autochthonous Crimean-Congo Hemorrhagic Fever in Spain.

Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, viral, tickborne disease. In Europe, cases have been reported only in the southeastern part of the continent. We report two autochthonous cases in Spain. The index patient acquired the disease through a tick bite in the province of Ávila - 300 km away from the province of Cáceres, where viral RNA from ticks was amplified in 2010. The second patient was a nurse who became infected while caring for the index patient. Both were infected with the African 3 lineage of this virus. (Funded by Red de Investigación Cooperativa en Enfermedades Tropicales [RICET] and Efficient Response to Highly Dangerous and Emerging Pathogens at EU [European Union] Level [EMERGE].).

Genetic voltage indicators.

As a "holy grail" of neuroscience, optical imaging of membrane potential could enable high resolution measurements of spiking and synaptic activity in neuronal populations. This has been partly achieved using organic voltage-sensitive dyes in vitro, or in invertebrate preparations yet unspecific staining has prevented single-cell resolution measurements from mammalian preparations in vivo. The development of genetically encoded voltage indicators (GEVIs) and chemogenetic sensors has enabled targeting voltage indicators to plasma membranes and selective neuronal populations. Here, we review recent advances in the design and use of genetic voltage indicators and discuss advantages and disadvantages of three classes of them. Although genetic voltage indicators could revolutionize neuroscience, there are still significant challenges, particularly two-photon performance. To overcome them may require cross-disciplinary collaborations, team effort, and sustained support by large-scale research initiatives.

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins.

The control of neuronal protein homeostasis or proteostasis is tightly regulated both spatially and temporally, assuring accurate and integrated responses to external or intrinsic stimuli. Local or autonomous responses in dendritic and axonal compartments are crucial to sustain function during development, physiology and in response to damage or disease. Axons are responsible for generating and propagating electrical impulses in neurons, and the establishment and maintenance of their molecular composition are subject to extreme constraints exerted by length and size. Proteins that require the secretory pathway, such as receptors, transporters, ion channels or cell adhesion molecules, are fundamental for axonal function, but whether axons regulate their abundance autonomously and how they achieve this is not clear. Evidence supports the role of three complementary mechanisms to maintain proteostasis of these axonal proteins, namely vesicular transport, local translation and trafficking and transfer from supporting cells. Here, we review these mechanisms, their molecular machineries and contribution to neuronal function. We also examine the signaling pathways involved in local translation and their role during development and nerve injury. We discuss the relative contributions of a transport-controlled proteome directed by the soma (global regulation) versus a local-controlled proteome based on local translation or cell transfer (local regulation).

Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway.

Brain regions affected by Alzheimer disease (AD) display well-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment ß (C99), generated by cleavage of APP by ß-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement in AD and the earliest initiator of synaptic plasticity and long-term memory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosome formation or block the fusion of autophagosomes to endolysosomal compartments caused an increase in C99 levels. We also found that inhibition of autophagosome formation by depletion of Atg5 led to higher levels of C99 and to its massive accumulation in the lumen of enlarged perinuclear, lysosomal-associated membrane protein 1 (LAMP1)-positive organelles. In contrast, activation of autophagosome formation, either by starvation or by inhibition of the mammalian target of rapamycin, enhanced lysosomal clearance of C99. Altogether, our results indicate that autophagosomes are key organelles to help avoid C99 accumulation preventing its deleterious effects.-González, A. E., Muñoz, V. C., Cavieres, V. A., Bustamante, H. A., Cornejo, V.-H., Januário, Y. C., González, I., Hetz, C., daSilva, L. L., Rojas-Fernández, A., Hay, R. T., Mardones, G. A., Burgos, P. V. Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway.

IRE1 signaling exacerbates Alzheimer's disease pathogenesis.

Altered proteostasis is a salient feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid ß oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.

Transport along the dendritic endoplasmic reticulum mediates the trafficking of GABAB receptors.

In neurons, secretory organelles within the cell body are complemented by the dendritic endoplasmic reticulum (ER) and Golgi outposts (GOPs), whose role in neurotransmitter receptor trafficking is poorly understood. γ-aminobutyric acid (GABA) type B metabotropic receptors (GABABRs) regulate the efficacy of synaptic transmission throughout the brain. Their plasma membrane availability is controlled by mechanisms involving an ER retention motif and assembly-dependent ER export. Thus, they constitute an ideal molecular model to study ER trafficking, but the extent to which the dendritic ER participates in GABABR biosynthesis has not been thoroughly explored. Here, we show that GABAB1 localizes preferentially to the ER in dendrites and moves long distances within this compartment. Not only diffusion but also microtubule and dynein-dependent mechanisms control dendritic ER transport. GABABRs insert throughout the somatodendritic plasma membrane but dendritic post-ER carriers containing GABABRs do not fuse selectively with GOPs. This study furthers our understanding of the spatial selectivity of neurotransmitter receptors for dendritic organelles.

Spike transmission failures in axons from mouse cortical pyramidal neurons in vivo.

The propagation of action potentials along axons is traditionally considered to be reliable, as a consequence of the high safety factor of action potential propagation. However, numerical simulations have suggested that, at high frequencies, spikes could fail to invade distal axonal branches. Given the complex morphologies of axonal trees, with extensive branching and long-distance projections, spike propagation failures could be functionally important. To explore this experimentally in vivo, we used an axonal-targeted calcium indicator to image action potentials at axonal terminal branches in superficial layers from mouse somatosensory cortical pyramidal neurons. We activated axons with an extracellular electrode, varying stimulation frequencies, and computationally extracted axonal morphologies and associated calcium responses. We find that axonal boutons have higher calcium accumulations than their parent axons, as was reported in vitro. But, contrary to previous in vitro results, our data reveal spike failures in a significant subset of branches, as a function of branching geometry and spike frequency. The filtering is correlated with the geometric ratio of the branch diameters, as expected by cable theory. These findings suggest that axonal morphologies contribute to signal processing in the cortex.

Robot-assisted implantation of a microelectrode array in the occipital lobe as a visual prosthesis: technical note.

The prospect of direct interaction between the brain and computers has been investigated in recent decades, revealing several potential applications. One of these is sight restoration in profoundly blind people, which is based on the ability to elicit visual perceptions while directly stimulating the occipital cortex. Technological innovation has led to the development of microelectrodes implantable on the brain surface. The feasibility of implanting a microelectrode on the visual cortex has already been shown in animals, with promising results. Current research has focused on the implantation of microelectrodes into the occipital brain of blind volunteers. The technique raises several technical challenges. In this technical note, the authors suggest a safe and effective approach for robot-assisted implantation of microelectrodes in the occipital lobe for sight restoration.

Role of the unfolded protein response in organ physiology: lessons from mouse models.

The endoplasmic reticulum (ER) is a key subcellular compartment involved in the folding and maturation of around one-third of the total proteome. Accumulation of misfolded proteins in the ER lumen engages a signal transduction pathway known as unfolded protein response (UPR) that feedback to recover ER homeostasis or to trigger apoptosis of irreversible damaged cells. The UPR is initiated by three main stress sensors including protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein 1α (IRE1α), which reprogram the genome through the control of downstream transcription factors. In this article, the authors have reviewed most relevant studies uncovering the physiological function of the UPR in different organs and tissues based on the phenotypes observed after genetic manipulation of the pathway in vivo. Biomedical applications of targeting the UPR on a disease context are also discussed.

Transport and localization on dendrite-inspired flat band linear photonic lattices.

The capacity of a physical system to transport and localize energy or information is usually linked to its spatial configuration. This is relevant for integration and transmission of signals as performed, for example, by the dendrites of neuronal cells. Inspired by recent works on the organization of spines on the surface of dendrites and how they promote localization or propagation of electrical impulses in neurons, here we propose a linear photonic lattice configuration to study how the geometric features of a dendrite-inspired lattice allows for the localization or propagation of light on a completely linear structure. We show that by increasing the compression of the photonic analogue of spines and thus, by increasing the coupling strength of the spines with the main chain (the "photonic dendrite"), flat band modes become prevalent in the system, allowing spatial localization in the linear - low energy - regime. Furthermore, we study the inclusion of disorder in the distribution of spines and show that the main features of ordered systems persist due to the robustness of the flat band states. Finally, we discuss if the photonic analog, having evanescent interactions, may provide insight into linear morphological mechanisms at work occurring in some biological systems, where interactions are of electric and biochemical origin.

An analysis of the cecum microbiome of three breeds of the guinea pig: Andina, Inti, and Peru.

This study investigated the effect of host genetics on the structure and composition of the cecum microbiota of three breeds of guinea pigs: Andina, Inti, and Peru. Fifteen guinea pigs were distributed into three groups according to their breed: Andina (5), Inti (5), and Peru (5). We discovered that four main phyla were shared between the three breeds: Bacteroidota, Firmicutes, Spirochaetota, and Synergistota. Although there were no significant differences in the alpha and beta diversity analysis, we found that the Linear discriminant analysis effect size and the heat tree analysis showed significant differences between the abundance of several taxa present in the cecum microbiome of the three breeds. These results suggest that host genetics could be a factor in the structure and composition of the guinea pig cecum microbiome. In addition, we found unique genera for each breed that have fermentation capacity and, therefore can be analyzed in further studies to determine if there is a functional relationship between them and the breed and its industrial profile.

Comparative analysis of fasting effects on the cecum microbiome in three guinea pig breeds: Andina, Inti, and Peru.

Guinea pigs have historically been used as a food source and are also an important model for studying the human intestines. Fasting is the act of temporarily stopping the intake of food. This process can alter the microbiota of various animals. This study is the first to investigate the impact of fasting on the cecum microbiome of three guinea pig breeds. We investigated the impact of fasting on the microbiome population structure in the cecum of three guinea pig breeds. This was done by sequencing and analyzing the V4 hypervariable region of the 16S rRNA gene in bacterial communities found in cecum mucosa samples. To achieve this, we established two treatment groups (fasting and fed), for each of the three guinea pig breeds: Andina, Inti, and Peru. The study involved twenty-eight guinea pigs, which were divided into the following groups: Andina-fed (five), Andina-fasting (five), Inti-fed (four), Inti-fasting (five), Peru-fed (five), and Peru-fasting (four). The results indicated a significant difference in beta diversity between the treatment groups for the Peru breed (P-value = 0.049), but not for the treatment groups of the Andina and Inti breeds. The dominant phyla across all groups were Firmicutes and Bacteroidetes. We observed variations in the abundance of different taxa in the cecum microbiota when comparing the treatment groups for each breed. Additionally, there was a higher number of unique taxa observed in the fasting groups compared to the fed groups. We discovered that the genus Victivallis was the only one present in all fasting groups across all breeds. Despite the findings, the resilience of the gut microbiome was not challenged in all three breeds, which can lead to disruptive changes that may affect the overall maintenance of the cecum microbiome. Based on the observed differences in the treatment groups of the Peru breed, it can be suggested that fasting has a greater impact on this particular breed.

Erratum to "Development and evaluation of a 3d printed training model for endoscopic third ventriculostomy in low-income countries" [Brain and Spine 3 (2023) 101736].

[This corrects the article DOI: 10.1016/j.bas.2023.101736.].

Development and evaluation of a 3d printed training model for endoscopic third ventriculostomy in low-income countries.

Introduction: Pediatric hydrocephalus is highly prevalent and therefore a major neurosurgical problem in Africa. In addition to ventriculoperitoneal shunts, which have high cost and potential complications, endoscopic third ventriculostomy is becoming an increasingly popular technique especially in this part of the world. However, performing this procedure requires trained neurosurgeons with an optimal learning curve. For this reason, we have developed a 3D printed training model of hydrocephalus so that neurosurgeons without previous experience with endoscopic techniques can acquire these skills, especially in low-income countries, where specific techniques training as this, are relatively absent. Research Question: Our research question was about the possibility to develop and produce a low-cost endoscopic training model and to evaluate the usefulness and the skills acquired after training with it. Material and Methods: A neuroendoscopy simulation model was developed. A sample of last year medical students and junior neurosurgery residents without prior experience in neuroendoscopy were involved in the study. The model was evaluated by measuring several parameters, as procedure time, number of fenestration attempts, diameter of the fenestration, and number of contacts with critical structures. Results: An improvement of the average score on the ETV-Training-Scale was noticed between the first and last attempt (11.6, compared to 27.5 points; p<0.0001). A statistically significant improvement in all parameters, was observed. Discussion and Conclusion: This 3D printed simulator facilitates acquiring surgical skills with the neuroendoscope to treat hydrocephalus by performing an endoscopic third ventriculostomy. Furthermore, it has been shown to be useful to understand the intraventricular anatomical relationships.

[Do differences exist in the neurosurgical handling of intracranial lesions of pregnant patient? Outcomes of our experience and literature review]. / ¿Existen diferencias en el manejo neuroquirúrgico de las lesiones intracraneales en la paciente gestante? Resultados de nuestra experiencia y revisión de la literatura.

OBJECTIVE: The main objective of our work is to revise our neurosurgical experience in pregnant patient and to carry out a revision of the related literature in order to optimize the neurosurgical handling of these kind of patients. METHOD: Retrospective study between august 1993 and June 2010. We included patients who were pregnant at the time and who presented any trace of cranial neurosurgical or spinal disease. RESULTS: The research includes the cases of 12 patients aged between 17 and 37 years old with an average age of 28.8 years old. The average gestation period was of 24.17 weeks, finding 50% of the patients within their third three-month period of pregnancy at the moment of diagnosis, 25% in their second three-month period and the remaining 25% in their first three-month period. The mean follow-up duration for this series was 84 months. 4 of them presented brain vascular lesions, 5 presented brain tumor lesions, 1 of them presented Chiari malformation, one lumbar disc herniation and 1 patient suffered from traumatic intracraneal hemorrhage. 8 of the 12 patients were subjected to neurosurgical procedures under general anesthetic, 2 for aneurysm embolizations and 2 for conservative treatments. Between the neurosurgical procedures 6 craniotomies were done, of wich 4 were to resection of the tumor and 2 for aneurysm clippings. There were done a transesfenoidal approach and a lumbar microdiscectomy. 2 of the 6 patients given craniotomies required external ventricular drainage before the operation. 5 elective cesareans were done in the group of patients given the craniotomies whilst of the rest the pregnancy was allowed to bring to term for reasons of pulmonary maturity. In our patients there were no cases of therapeutic abortion. There was found no morbidity no mortality neither in the mother nor in the fetus related to surgery. CONCLUSIONS: In our experience with pregnant patients who suffered from neurosurgical lesion and in the experience we got from the revision of the related literature, the surgery of intracranial lesions is well tolerated by the mothers and the fetus. It must though be considered, the possibility of labor through cesarean depending on the fetus' lung maturity.

Voltage compartmentalization in dendritic spines in vivo.

Dendritic spines mediate most excitatory neurotransmission in the nervous system, so their function must be critical for the brain. Spines are biochemical compartments but might also electrically modify synaptic potentials. Using two-photon microscopy and a genetically encoded voltage indicator, we measured membrane potentials in spines and dendrites from pyramidal neurons in the somatosensory cortex of mice during spontaneous activity and sensory stimulation. Spines and dendrites were depolarized together during action potentials, but, during subthreshold and resting potentials, spines often experienced different voltages than parent dendrites, even activating independently. Spine voltages remained compartmentalized after two-photon optogenetic activation of individual spine heads. We conclude that spines are elementary voltage compartments. The regulation of voltage compartmentalization could be important for synaptic function and plasticity, dendritic integration, and disease states.