Morphometric analysis of the foramen ovale in the Mexican population using computed tomography scan.

Background: The assessment of cranial foramina is an important part of the objective diagnostic and therapeutic study relevant to pathologies involving structures of the skull base. The study of the foramen ovale not only holds significance for anatomical development but also bears profound surgical importance, such as in trigeminal neuralgia, and diagnostic importance in tumors and various types of epilepsy. It becomes relevant in fine-needle aspiration techniques in perineural tumor procedures, for electroencephalographic analysis in seizures, and therapeutic procedures such as percutaneous trigeminal rhizotomy for trigeminal neuralgia. Methods: A cross-sectional study at the Department of Neurosurgery, Specialties Hospital, La Raza National Medical Center, Mexico City, involved 70 patients aged >18 years who underwent a single skull computed tomography scan between July 2023 and March 2024. Patients with sufficient scan quality and optimal visualization of skull base foramina were included in the study. Measurements of tomographic images were taken using Inobitec's DICOM file viewer. Data analysis in Microsoft Excel yielded mean, standard deviation, and 95% confidence interval (CI) for morphometric parameters of the foramen ovale. Results: Analysis of tomographies from 70 patients revealed a total of 140 foramen ovale, evenly split between 25 males (35.7%) and 45 females (64.3%). The measurements for the maximum anteroposterior diameter, transverse diameter, and surface area of all foramina were as follows: 6.61 ± 0.25 mm (95% CI), 3.97 ± 0.21 mm (95% CI), and 20.84 ± 1.58 mm2 (95% CI), respectively. Specific measurements for the right and left sides were obtained: for the right side, 6.59 ± 0.26 mm (95% CI) and 3.89 ± 0.21 mm (95% CI) for the maximum anteroposterior and transverse diameters, respectively, and 20.38 ± 1.62 mm2 (95% CI) for the surface area. For the left side, the measurements were 6.63 ± 0.24 mm (95% CI), 4.05 ± 0.21 mm (95% CI), and 21.31 ± 1.55 mm2 (95% CI) for the maximum anteroposterior diameter, transverse diameter, and surface area, respectively. The maximum and minimum dimensions for anteroposterior and transverse diameters were 10.67 mm, 4.41 mm, 7.09 mm and 2.36 mm, respectively, with a corresponding range for the surface area of 10.16 mm2-44.13 mm2. The average minimum distance between the foramen ovale and the foramen spinosum was 2.32 ± 0.24 mm (95% CI). In males, the average size of the foramen ovale was 23.66 ± 1.61, which was 22% larger than the average size in females (19.28 ± 1.45) (P = 0.0001). Conclusion: The foramen ovale is one of the main anatomical structures of the skull base, and besides that, it is complex and not directly accessible for clinical evaluation, useful information can be obtained through morphometric analysis. The present study provides specific anatomical data with morphological patterns to increase the understanding of the characteristics of the foramen ovale in the Mexican population. These are intended to be helpful in the pursuit of acknowledging the morphometrics and thus being able to plan neurosurgical procedures in the middle cranial fossa.

Genetic Variant of DNAM-1 rs763361 C>T Is Associated with Ankylosing Spondylitis in a Mexican Population.

DNAM-1 (CD226) is an activating receptor expressed in CD8+ T cells, NK cells, and monocytes. It has been reported that two SNPs in the DNAM-1 gene, rs763361 C>T and rs727088 G>A, have been associated with different autoimmune diseases; however, the role of DNAM-1 in ankylosing spondylitis has been less studied. For this reason, we focused on the study of these two SNPs in association with ankylosing spondylitis. For this, 34 patients and 70 controls were analyzed using endpoint PCR with allele-specific primers. Our results suggest that rs763361 C>T is involved as a possible protective factor under the CT co-dominant model (OR = 0.34, 95% CI = 0.13-0.88, p = 0.022) and the CT + TT dominant model (OR = 0.39, 95% CI = 0.17-0.90, p = 0.025), while rs727088 G>A did not show an association with the disease in any of the inheritance models. When analyzing the relationships of the haplotypes, we found that the T + A haplotype (OR = 0.31, 95% CI = 0.13-0.73, p = 0.0083) is a protective factor for developing the disease. In conclusion, the CT and CT + TT variants of rs763361 C>T and the T + A haplotype were considered as protective factors for developing ankylosing spondylitis.

The downregulation of Kv1 channels in Lgi1-/-mice is accompanied by a profound modification of its interactome and a parallel decrease in Kv2 channels.

In animal models of LGI1-dependent autosomal dominant lateral temporal lobe epilepsy, Kv1 channels are downregulated, suggesting their crucial involvement in epileptogenesis. The molecular basis of Kv1 channel-downregulation in LGI1 knock-out mice has not been elucidated and how the absence of this extracellular protein induces an important modification in the expression of Kv1 remains unknown. In this study we analyse by immunofluorescence the modifications in neuronal Kv1.1 and Kv1.2 distribution throughout the hippocampal formation of LGI1 knock-out mice. We show that Kv1 downregulation is not restricted to the axonal compartment, but also takes place in the somatodendritic region and is accompanied by a drastic decrease in Kv2 expression levels. Moreover, we find that the downregulation of these Kv channels is associated with a marked increase in bursting patterns. Finally, mass spectrometry uncovered key modifications in the Kv1 interactome that highlight the epileptogenic implication of Kv1 downregulation in LGI1 knock-out animals.

Evidence for two subpopulations of cerebrospinal-fluid contacting neurons with opposite GABAergic signaling in adult mouse spinal cord.

Spinal cerebrospinal fluid-contacting neurons (CSF-cNs) form an evolutionary conserved bipolar cells population localized around the central canal of all vertebrates. CSF-cNs were shown to express molecular markers of neuronal immaturity into adulthood, however the impact of their incomplete maturation on the chloride (Cl-) homeostasis as well as GABAergic signaling remain unknown. Using adult mice from both sexes, in situ hybridization revealed that a proportion of spinal CSF-cNs (18.3%) express the Na+-K+-Cl- cotransporter 1 (NKCC1) allowing intracellular Cl- accumulation. However, we did not find expression of the K+-Cl- cotransporter 2 (KCC2) responsible for Cl- efflux in any CSF-cNs. The lack of KCC2 expression results in low Cl- extrusion capacity in CSF-cNs under high Cl- load in whole-cell patch-clamp. Using cell-attached patch-clamp allowing recordings with intact intracellular chloride concentration, we found that activation of ionotropic GABAA receptors induced both depolarizing and hyperpolarizing responses in CSF-cNs. Moreover, depolarizing GABA-responses can drive action potentials as well as intracellular calcium elevations by activating voltage-gated calcium channels. Blocking NKCC1 with bumetanide inhibited the GABA-induced calcium transients in CSF-cNs. Finally, we show that metabotropic GABAB receptors have no hyperpolarizing action on spinal CSF-cNs as their activation with baclofen did not mediate outward K+ currents, presumably due to the lack of expression of G protein-coupled inwardly rectifying potassium (GIRK) channels. Together, these findings outline subpopulations of spinal CSF-cNs expressing inhibitory or excitatory GABAA receptors signaling. Excitatory GABA may promote maturation and integration of young CSF-cNs into the existing spinal circuit.Significant Statement Spinal CSF-contacting neurons (CSF-cNs) form a heterogeneous neural population with distinct maturation states in adult mice, but whether this reflects CSF-cNs with different GABAergic signaling remains unknown. Herein, we show that activation of GABAA receptors generates depolarization or hyperpolarization of CSF-cNs membrane potential in adult mouse spinal cord. Depolarizing GABA can trigger intracellular Ca2+ elevations through the activation of voltage-gated Ca2+ channels. Our results highlight a subpopulation of CSF-cNs in adult mice with depolarizing GABA that may promote their maturation and integration into the spinal cord.

Association between the Thickness of Lumbar Subcutaneous Fat Tissue and the Presence of Hernias in Adults with Persistent, Non-Traumatic Low Back Pain.

We aimed to analyze the association between the average lumbar subcutaneous fat tissue thickness (LSFTT) at each intervertebral level and the presence of hernias in patients with low back pain from an insurance network hospital in Mexico. This observational prospective study included 174 patients with non-traumatic lumbago who underwent magnetic resonance imaging with a 1.5T resonator. Two independent radiologists made the diagnosis, and a third specialist provided a quality vote when needed. The sample size was calculated with a 95% confidence interval using random order selection. Anonymized secondary information was used. Percentages and means with confidence intervals were tabulated. The area under the curve, specificity, and sensitivity of LSFTT were calculated. A regression analysis was performed to analyze the presence of hernias with LSFTT using each intervertebral level as a predictor. The odds of herniation at any intervertebral level increased directly with LSFTT. The average LSFTT predicted the overall presence of hernias; however, the LSFTT at each intervertebral level better predicted hernias for each intervertebral space. The area under the curve for LSFTT in predicting hernias was 68%. In conclusion, the average LSFTT was associated with the overall presence of hernias; patients with more hernias had higher LSFTT values.

Deep learning-based image analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra.

Here we present a deep learning-based image analysis platform (DLAP), tailored to autonomously quantify cell numbers, and fluorescence signals within cellular compartments, derived from RNAscope or immunohistochemistry. We utilised DLAP to analyse subtypes of tyrosine hydroxylase (TH)-positive dopaminergic midbrain neurons in mouse and human brain-sections. These neurons modulate complex behaviour, and are differentially affected in Parkinson's and other diseases. DLAP allows the analysis of large cell numbers, and facilitates the identification of small cellular subpopulations. Using DLAP, we identified a small subpopulation of TH-positive neurons (~5%), mainly located in the very lateral Substantia nigra (SN), that was immunofluorescence-negative for the plasmalemmal dopamine transporter (DAT), with ~40% smaller cell bodies. These neurons were negative for aldehyde dehydrogenase 1A1, with a lower co-expression rate for dopamine-D2-autoreceptors, but a ~7-fold higher likelihood of calbindin-d28k co-expression (~70%). These results have important implications, as DAT is crucial for dopamine signalling, and is commonly used as a marker for dopaminergic SN neurons.

Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.

Leucine-rich glioma inactivated 1 (LGI1) is a glycoprotein secreted by neurons, the deletion of which leads to autosomal dominant lateral temporal lobe epilepsy. We previously showed that LGI1 deficiency in a mouse model (i.e., knock-out for LGI1 or KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release. However, it is not known whether normal excitability can be restored in epileptic neurons. Here, we show that the selective expression of LGI1 in KO-Lgi1 neurons from mice of both sexes, using single-cell electroporation, reduces intrinsic excitability and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the AIS. In addition, we show that the homeostatic-like shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons electroporated with the Lgi1 gene. Furthermore, we reveal a spatial gradient of intrinsic excitability that is centered on the electroporated neuron. We conclude that expression of LGI1 restores normal excitability through functional Kv1 channels at the AIS.SIGNIFICANCE STATEMENT The lack of leucine-rich glioma inactivated 1 (LGI1) protein induces severe epileptic seizures that leads to death. Enhanced intrinsic and synaptic excitation in KO-Lgi1 mice is because of the decrease in Kv1.1 channels in CA3 neurons. However, the conditions to restore normal excitability profile in epileptic neurons remain to be defined. We show here that the expression of LGI1 in KO-Lgi1 neurons in single neurons reduces intrinsic excitability, and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the axon initial segment (AIS). Furthermore, the homeostatic shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons in which the Lgi1 gene has been rescued. We conclude that LGI1 constitutes a critical factor to restore normal excitability in epileptic neurons.

Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states.

Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca2+ signaling in MDD are poorly understood. Here, we found that corticosterone-treated juvenile mice (Cort-mice) showed altered astrocytic Ca2+ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca2+ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca2+ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca2+ signaling with Gq-DREADDS restored to the control levels mood and cognitive abilities in Cort-mice. This study highlights the important role of astrocyte Ca2+ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states.

Insulin and the kidneys: a contemporary view on the molecular basis.

Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.

Advances in Osteosarcoma.

PURPOSE OF REVIEW: This article gives a brief overview of the most recent developments in osteosarcoma treatment, including targeting of signaling pathways, immune checkpoint inhibitors, drug delivery strategies as single or combined approaches, and the identification of new therapeutic targets to face this highly heterogeneous disease. RECENT FINDINGS: Osteosarcoma is one of the most common primary malignant bone tumors in children and young adults, with a high risk of bone and lung metastases and a 5-year survival rate around 70% in the absence of metastases and 30% if metastases are detected at the time of diagnosis. Despite the novel advances in neoadjuvant chemotherapy, the effective treatment for osteosarcoma has not improved in the last 4 decades. The emergence of immunotherapy has transformed the paradigm of treatment, focusing therapeutic strategies on the potential of immune checkpoint inhibitors. However, the most recent clinical trials show a slight improvement over the conventional polychemotherapy scheme. The tumor microenvironment plays a crucial role in the pathogenesis of osteosarcoma by controlling the tumor growth, the metastatic process and the drug resistance and paved the way of new therapeutic options that must be validated by accurate pre-clinical studies and clinical trials.

A non-clinical and clinical IUCLID database for 530 pharmaceuticals (part I): Methodological aspects of its development.

A new IUCLID database is provided containing results from non-clinical animal studies and human information for 530 approved drugs. The database was developed by extracting data from pharmacological reviews of repeat-dose, carcinogenicity, developmental, and reproductive toxicity studies. In the database, observed and no-observed effects are linked to the respective effect levels, including information on severity/incidence and transiency/reversibility. It also includes some information on effects in humans, that were extracted from relevant sections of standard product labels of the approved drugs. The database is complemented with a specific ontology for reporting effects that was developed as an improved version of the Ontology Lookup Service's mammalian and human phenotype ontologies and includes different hierarchical levels. The developed ontology contains novel and unique standardized terms, including ontological terms for reproductive and endocrine effects. The database aims to facilitate correlation and concordance analyses based on the link between observed and no-observed effects and their respective effect levels. In addition, it offers a robust dataset on drug information for the pharmaceutical industry and research. The reported ontology supports the analyses of toxicological information, especially for reproductive and endocrine endpoints and can be used to encode legacy data or develop additional ontologies. The new database and ontology can be used to support the development of alternative non-animal approaches, to elucidate mechanisms of toxicity, and to analyse human relevance. The new IUCLID database is provided free of charge at https://iuclid6.echa.europa.eu/us-fda-toxicity-data.

[Brain aneurysms treatment with pCONus2 device. Initial experience at IMSS]. / Aneurismas cerebrales tratados con dispositivo pCONus2. Experiencia inicial en el IMSS.

Background: pCONus2 device has been used in some countries as coadyuvant in the treatment of wide-neck bifurcation aneurysms with coils. Objective: To present the first series of brain aneurysms treated with pCONus2 in the Mexican Institute for Social Security (IMSS). Material and methods: We retrospectively present the first 13 aneurysms treated from October 2019 to February 2022 with pCONus2 device at a third level hospital. Results: 6 aneurysms located at anterior communicating artery, 3 at middle cerebral artery bifurcation, 2 at internal carotid artery bifurcatión, and 2 at the tip of basilar artery were treated. Device deployment was performed without complications and it was possible to embolize aneurysms with coils in 12 patients (92%), while on an internal carotid bifurcation aneurysm (8%) there was an incident of a pCONus2 petal migration toward vascular lumen caused by coils mesh pressure, situation that was solved by placing an nitinol self-expandable microstent. In 7 cases (54%) we performed coiling technique after microcatheter passage through pCONus2, while in 6 cases (46%) we used the jailing technique without complications. Conclusions: pCONus2 is a useful device for wide-neck bifurcation aneurysms embolization. In Mexico our experience is yet limited; however, the first cases have been successful. Furthermore, we showed the first cases treated using jailing technique. Much more cases are required in order to carry out a statistically conclusive analysis and to establish the effectiveness and safety of the device.

Introducción: el dispositivo pCONus2 ha sido usado en algunos países como coadyuvante en el tratamiento con coils de los aneurismas de cuello ancho localizados en las bifurcaciones. Objetivo: presentar los primeros aneurismas tratados con pCONus2 en el Instituto Mexicano del Seguro Social (IMSS). Material y métodos: se exponen retrospectivamente 13 casos de pacientes tratados con pCONus2 de octubre de 2019 a febrero de 2022 en un hospital de tercer nivel del IMSS. Resultados: se trataron 6 aneurismas de la arteria comunicante anterior, 2 de la bifurcación de la arteria carótida interna, 3 en la bifurcación de la arteria cerebral media y 2 del tope de la arteria basilar. El uso del pCONus2 se hizo sin complicaciones ni incidentes en 12 pacientes (92%), mientras que en un aneurisma de la bifurcación de carótida interna (8%) ocurrió la migración de un pétalo del dispositivo hacia la luz vascular, motivado por la presión de la malla de coils, que se solucionó con un microstent. Siete aneurismas (54%) fueron embolizados con coils después del paso del microcatéter a través del pCONus2, mientras que en 6 (46%) se utilizó la técnica jailing, sin complicaciones ni incidentes. Conclusiones: el pCONus2 es un dispositivo útil en la embolización de aneurismas localizados en bifurcaciones arteriales. En México la experiencia todavía es poca, pero los primeros casos han sido exitosos. Mostramos, además, los primeros casos tratados con la técnica de jailing. Se requieren más casos en nuestro país para hacer un análisis estadísticamente concluyente y determinar la efectividad y seguridad del dispositivo.

A Modified Method for the Quantification of Immune Checkpoint Ligands on Exosomes from Human Serum using Flow Cytometry.

Objectives: Exosomes are the smallest of the extracellular vesicles and can contain a variety of different cargos, including nucleic acids, lipids, and proteins. Ultracentrifugation followed by electron microscopy has historically been used for the isolation and visualization of exosomes; Western blot and ELISA have also been used, but these techniques are only semiquantitative and are unable to distinguish different exosome markers in the same sample. To resolve some of these issues, we propose a modification of a bead-based flow cytometry method. Methods: Peripheral blood serum was mixed with a commercial exosome separation reagent and incubated for 30 min at 4°, centrifuged, exosome pellet was isolated and resuspended in PBS. Exosomes were then added to magnetic beads, incubated 18 h, then incubated with exosome-specific antibodies for 1 h. The resulting bead:exosome complexes were centrifuged and then washed, then washed again using a magnetic separator, resuspended in PBS, and analyzed via flow cytometry. Results: Using commercial magnetic beads bound with anti-CD63, our protocol modifies starting conditions, washing steps, and magnetic separation and uses the FSC and SSC determination of the flow cytometer to result in increased yield and identification of the exosome populations of interest. Our modified protocol increased the yield of specific populations approximately 10-fold. Conclusion: The new protocol was used to identify exosomes positive for 2 immune checkpoint ligands in serum-derived exosomes from cervical cancer patients. We suspect that this protocol can also be used for the identification of other exosome proteins since we also quantified the exosome membrane-enriched tetraspanins CD9 and CD81. Identification of proteins rarely expressed in exosomes is complicated in this technique as serum is an inherently dirty source of exosomes, and great care must be taken in the washing and gating of the exosome:bead populations.

Pharmacological options in the treatment of osteogenesis imperfecta: A comprehensive review of clinical and potential alternatives.

Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The severity of these manifestations makes it possible to classify OI into different subtypes based on the main clinical features. This review aims to outline and describe the current pharmacological alternatives for treating OI, grounded on clinical and preclinical reports, such as antiresorptive agents, anabolic agents, growth hormone, and anti-TGFß antibody, among other less used agents. The different options and their pharmacokinetic and pharmacodynamic properties will be reviewed and discussed, focusing on the variability of their response and the molecular mechanisms involved to attain the main clinical goals, which include decreasing fracture incidence, improving pain, and promoting growth, mobility, and functional independence.

Non-fitness status of peripheral NK cells defined by decreased NKp30 and perforin, and increased soluble B7H6, in cervical cancer patients.

The NKp30 receptor is one of the three natural cytotoxic receptors reported in NK cells. This receptor is codified by the NCR3 gene, which encodes three isoforms, a consequence of the alternative splicing of exon 4. A greater expression of the three isoforms (A, B, and C), along with low levels of the NKp30 ligand B7H6, has been reported as a positive prognostic factor in different cancer types. Here, in patients with cervical cancer and precursor lesions, we report an altered immune-phenotype, characterized by non-fitness markers, that correlated with increased disease stage, from CIN 1 to FIGO IV. While overall NK cell numbers increased, loss of NKp30+ NK cells, especially in the CD56dim subpopulation, was found. Perforin levels were decreased in these cells. Decreased expression of the NKp30 C isoform and overexpression of soluble B7H6 was found in cervical cancer patients when compared against healthy subjects. PBMCs from healthy subjects downregulated NKp30 isoforms after co-culture with B7H6-expressing tumour cells. Taken together, these findings describe a unique down-modulation or non-fitness status of the immune response in cervical cancer, the understanding of which will be important for the design of novel immunotherapies against this disease.

Intracranial aneurysms in pediatric population treated with flow diverters: A single-center experience.

Background: Pediatric intracranial aneurysms (PIAs) are uncommon. Flow diverters (FDs) have shown to be effective on treatment of selected aneurysms. Methods: We describe 10 cases of PIAs treated with FDs at one medical center in Mexico, from April 2015 to April 2020. Results: Out of 230 patients treated with FDs, 10 (4.3%) were pediatric. Average age was 9.4 years old (R: 6-15). Two patients (20%) had subarachnoid hemorrhage, 3 had epilepsy (30%), 3 (30%) had clinical signs of cranial nerve compression, and 4 (40%) had only headache. Two patients were in 1a grade of Hunt and Kosnik scale. Out of the nonruptured aneurysms, 7 (70%) were in 15 points of Glasgow Coma Scale and 1 patient (10%) was in 13 points. Treatment was performed without complications; nevertheless, appropriate distal deployment was not achieved in one case. At discharge, nine patients had 5 points of Glasgow Outcome Scale. All patients underwent computed tomography angiography or digital subtraction angiography at 1, 3, 6, and 12 months, 2 patients (20%) had a 2-year follow-up, and 3 patients (30%) had a 3-year follow-up. According to Kamran grading scale, 9 patients (90%) were classified as Grade 4 and 1 patient (10%) as Grade 3. Conclusion: Even though it is a small series, as this is an uncommon disease, we may suggest that FDs are useful to treat properly selected PIAs. Our study has consecutive imaging assessment at least a year of follow-up in which aneurysm stable occlusion was observed in 90% of patients.

Molecular landscape of BoNT/B bound to a membrane-inserted synaptotagmin/ganglioside complex.

Botulinum neurotoxin serotype B (BoNT/B) uses two separate protein and polysialoglycolipid-binding pockets to interact with synaptotagmin 1/2 and gangliosides. However, an integrated model of BoNT/B bound to its neuronal receptors in a native membrane topology is still lacking. Using a panel of in silico and experimental approaches, we present here a new model for BoNT/B binding to neuronal membranes, in which the toxin binds to a preassembled synaptotagmin-ganglioside GT1b complex and a free ganglioside allowing a lipid-binding loop of BoNT/B to interact with the glycone part of the synaptotagmin-associated GT1b. Furthermore, our data provide molecular support for the decrease in BoNT/B sensitivity in Felidae that harbor the natural variant synaptotagmin2-N59Q. These results reveal multiple interactions of BoNT/B with gangliosides and support a novel paradigm in which a toxin recognizes a protein/ganglioside complex.

Association of MIR3117 and MIR612 Genes Polymorphisms with Childhood Acute Lymphoblastic Leukemia in the Mexican Population.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world, which is associated with a wide spectrum of factors that play an important role in epidemiology, risk stratification, and therapeutic intervention. Several studies have shown the role of microRNAs (miRNAs) in the development of the disease. Genetic variations such as single-nucleotide polymorphisms (SNPs) in miRNAs can alter their function and lead to alter the expression of their target genes. OBJECTIVE: The aim of this study was to evaluate the association of rs12402181 in MIR3117 and rs12803915 in MIR612 with the risk of childhood preB-ALL in Mexican population. MATERIAL AND METHODS: DNA from 148 children (<18 years old) diagnosed with preB-ALL and 172 samples from participants in control group were included in the present study. Genotyping of the rs12402181 and rs12803915 polymorphisms was carried out by Real-Time PCR. To estimate the risk factor, the multiple genetic models co-dominant, dominant, and recessive were determined in both polymorphisms. RESULTS: In dominant genetic model from rs12402181, a high risk of susceptibility to ALL was observed (OR = 2.03, 95% CI = 1.27-3.22, p = 0.003). In the analysis adjusted for gender, a significant increase in the risk of ALL was maintained (OR = 2.03, 95% CI = 1.28-3.24, p = 0.003). The rs12803915 polymorphism was no associated with the risk of susceptibility to preB-ALL in any of the genetic models using in this study. CONCLUSIONS: Our data indicated that the A allele of the rs12402181 polymorphism may be considered as a genetic biomarker of preB-ALL susceptibility. Likewise, it was identified that the A allele of the rs12402181 polymorphism is an independent risk factor for ALL.

Intramedullary cervical spinal cord and cerebellar hemangioblastoma: A case report.

Background: Hemangioblastomas are benign tumors that develop in the central nervous system. They represent 1.5-2.5% of all intracranial tumors, and about 2-15% of all spinal cord tumors. They are highly associated with von Hippel-Lindau disease. Case Description: A 36-year-old female presented with a 4-year history of progressive right upper extremity distal weakness and cervical pain. The magnetic resonance imaging demonstrated a homogeneously, contrast enhancing intradural/intramedullary tumor at C6-C7 with perilesional edema and a syrinx accompanied by a cerebellar cyst with a mural nodule. Surgery included excision of the spinal lesion and decompression and excision of the cerebellar cyst and mural nodule (i.e., median suboccipital craniectomy and cervical C5-C7 laminectomy). Conclusion: Surgery is the gold standard treatment for symptomatic hemangioblastomas, and surgical approaches should minimize risk.