Effect of Size and Location of Unruptured Intracranial Aneurysms on Self-Reported Headache.

AIM: To describe the relationship between aneurysm size and location with the prevalence of headache at diagnosis and three- and six-month follow-up in a sample of patients with UIA. MATERIAL AND METHODS: In this cohort study, patients were diagnosed with UIAs by digital subtraction angiography (DSA). Follow-up visits occurred three and six months after the diagnosis. Headache presence was registered, and headache was further classified by phenotypes. After DSA, the recorded variables were aneurysm number, morphology, location, and size (diameter [W], neck [N], and dome-neck distance [H]). The aspect ratio (H/N) and the dome/neck ratio (W/N) were calculated. The outcome of this study was the self-reported headache status at follow-up. RESULTS: Data from 42 patients and 46 aneurysms were available; 81.0% of patients were women, with a mean age of 57.4±14.3 years. Headache was reported by 61.9% of the patients. The pain phenotype was tension-type in 38.1%, migraine in 11.9%, neuralgia in 2.4%, and unclassifiable in 9.5%. The median (min-max) measurements were W=5.05 (0.89-22.9); N=3.02 (0.52-17.9); H=5.08 (0.92-23.0); aspect ratio 1.59 (0.68-17.69) and W/N ratio 1.65 (0.62-16.92). Thirty-three patients (37 aneurysms) received treatment, 47.8% by surgical clipping and 32.6% by endovascular occlusion. In the treated patients, headaches had persisted in 14.3% until the first visit and in 9.5% until the second visit. There were no differences in any registered variables between patients with and without headaches at follow-up. CONCLUSION: In this study, data was found that support that headaches in patients with UIAs improve after treatment and that such improvement is probably unrelated to the size and shape of the UIAs.

Evaluation of cytotoxic effect of siphonochilone from African ginger: an in vitro analysis.

Plants provide a wide array of compounds that can be explored for potential anticancer properties. Siphonochilone, a furanoterpene that represents one of the main components of the African plant Siphonochilus aethiopicus, shows numerous health benefits. However, to date, its antiproliferative properties have not been tested. The aim of this study was to analyze the cytotoxic effects of siphonochilone on a panel of cancer cell lines and its underlying mechanism of action. Our results demonstrated that siphonochilone exhibited significant cytotoxic effects on pancreatic, breast, lung, colon, and liver cancer cell lines showing a IC50 ranging from 22 to 124 µM at 72 h of treatment and highlighting its cytotoxic effect against MCF7 and PANC1 breast and pancreas cancer cell lines (22.03 and 39.03 µM, respectively). Cell death in these tumor lines was mediated by apoptosis by the mitochondrial pathway, as evidenced by siphonochilone-induced depolarization of the mitochondrial membrane potential. In addition, siphonochilone treatment involves the generation of reactive oxygen species that may contribute to apoptosis induction. In this work, we described for the first time the cytotoxic properties of siphonochilone and provided data about the molecular processes of cell death. Although future studies will be necessary, our results support the interest in this molecule in relation to their clinical application in cancer, and especially in breast and pancreatic cancer.

Signaling mechanisms underlying activity-dependent integration of adult-born neurons in the mouse olfactory bulb.

Adult neurogenesis has fascinated the field of neuroscience for decades given the prospects of harnessing mechanisms that facilitate the rewiring and/or replacement of adult brain tissue. The subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle are the two main areas in the brain that exhibit ongoing neurogenesis. Of these, adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and continued circuit integration within adult brain tissue. This review focuses on some of the recognized molecular and signaling mechanisms underlying activity-dependent adult-born neuron development. Notably, olfactory activity and behavioral states contribute to adult-born neuron plasticity through sensory and centrifugal inputs, in which calcium-dependent transcriptional programs, local translation, and neuropeptide signaling play important roles. This review also highlights areas of needed continued investigation to better understand the remarkable phenomenon of adult-born neuron integration.

Antitumor activity of bengamide ii in a panel of human and murine tumor cell lines: In vitro and in vivo determination of effectiveness against lung cancer.

Lung cancer is the most commonly diagnosed cancer and the one that causes the most deaths worldwide, so there is a need for therapies that improve survival rates. Products derived from marine organisms are a source of novel and potent antitumor compounds, but they present the great obstacle of their obtaining from the natural environment and the problems associated with the synthesis and biological effects of chemical analogues. In this work, a Bengamide analogue (Bengamide II) was chemically synthesized and in vitro and in vivo studies were performed to determine its antitumor activity and mechanisms of action. It was shown to have potent antiproliferative activity in lung cancer lines in 2D and 3D models. In addition, Bengamide II-treated cells showed G2/M and G0/G1 cell cycle arrest, together with a decrease in the proliferation marker Ki67. As for the mechanism of action, the treatment was associated with increased LC3-II expression and production of acidic vesicles signaling autophagy. In addition, Bengamide II treatment was associated with caspase-3 activation and DNA fragmentation related to apoptosis. Furthermore, a reduction of VEGFA expression, related to angiogenesis, was also observed. In vivo studies showed that Bengamide II markedly reduced tumor volume and metastases increasing survival. Additionally, it revealed no systemic toxicity in in vivo models at the therapeutic doses used, which is essential for its future clinical use. Taken together, the chemically synthesized bengamide analogue Bengamide II, is a promising drug for lung cancer treatment showing relevant antitumor activity and significant safety.

An integrated microfluidic-based biosensor using a magnetically controlled MNPs-enzyme microreactor to determine cholesterol in serum with fluorometric detection.

This work provides a microfluidic-based biosensor to determine total cholesterol in serum based on integrating the reaction/detection zone of a microfluidic chip of a magnetically retained enzyme microreactor (MREµR) coupled with the remote fluorometric detection through a bifurcated fiber-optic bundle (BFOB) connected with a conventional spectrofluorometer. The method is based on developing the enzymatic hydrolysis and oxidation of cholesterol at microscale size using both enzymes (cholesterol esterase (ChE) and cholesterol oxidase (ChOx)) immobilized on magnetic nanoparticles (MNPs). The biocatalyst reactions were followed by monitoring the fluorescence decreasing by the naphtofluorescein (NF) oxidation in the presence of the previous H2O2 formed. This microfluidic biosensor supposes the physical integration of a minimal MREµR as a bioactive enzyme area and the focused BFOB connected with the spectrofluorometer detector. The MREµR was formed by a 1 mm length of magnetic retained 2:1 ChE-MNP/ChOx-MNP mixture. The dynamic range of the calibration graph was 0.005-10 mmol L-1, expressed as total cholesterol concentration with a detection limit of 1.1 µmol L-1 (r2 = 0.9999, sy/x = 0.03, n = 10, r = 3). The precision expressed as the relative standard deviation (RSD%) was between 1.3 and 2.1%. The microfluidic-based biosensors showed a sampling frequency estimated at 30 h-1. The method was applied to determine cholesterol in serum samples with recovery values between 94.8 and 102%. The results of the cholesterol determination in serum were also tested by correlation with those obtained using the other two previous methods.

Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition.

Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase gene USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients' primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients' sensitivity to mTOR inhibitors. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.

PBRM1 and KDM5C cooperate to define high-angiogenesis tumors and increased antiangiogenic response in renal cancer.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are key antiangiogenic drugs for renal cancer treatment. While Von Hippel-Lindau dysfunction constitutes the base for VEGFR-TKIs sensitivity, the role for individual and concurrent mutations in the genes encoding for the chromatin remodelers Polybromo-1 (PBRM1) and Lysine Demethylase 5C (KDM5C) is poorly understood. Here, we analyzed the tumor mutational and expression profiles of 155 unselected clear cell RCC (ccRCC) cases treated with first-line VEGFR-TKIs and the ccRCC cases of IMmotion151 trial were used for validation. We found that concurrent PBRM1 and KDM5C (PBRM1&KDM5C) mutations occurred in 4-9% of cases and were enriched in Memorial Sloan Kettering Cancer Center favorable-risk patients. In our cohort, tumors only mutated in PBRM1 or concurrently mutated in PBRM1 and KDM5C had increased angiogenesis (P=0.0068 and 0.039; respectively), and tumors only mutated in KDM5C showed a similar trend. Best response to VEGFR-TKIs corresponded to PBRM1&KDM5C mutated cases, followed by those mutated only in KDM5C or only in PBRM1 (P=0.050, 0.040 and 0.027 versus non-mutated cases, respectively), with a trend for longer progression free survival (PFS) in the group with only PBRM1 mutated (HR=0.64; P=0.059). Validation in the IMmotion151 trial revealed a similar correlation with increased angiogenesis and the PFS of patients in the VEGFR-TKI-arm was the longest in PBRM1&KDM5C mutated cases, intermediate for only PBRM1 or only KDM5C mutated patients and the shortest in non-mutated cases (P=0.009 and 0.025, for PBRM1&KDM5C and PBRM1 versus non-mutated cases). In conclusion, somatic PBRM1 and KDM5C mutations are common in patients with metastatic ccRCC and likely cooperate increasing tumor angiogenesis and VEGFR-TKI-based antiangiogenic therapy benefit.

Antibody-Drug Conjugates Containing Payloads from Marine Origin.

Antibody-drug conjugates (ADCs) are an important class of therapeutics for the treatment of cancer. Structurally, an ADC comprises an antibody, which serves as the delivery system, a payload drug that is a potent cytotoxin that kills cancer cells, and a chemical linker that connects the payload with the antibody. Unlike conventional chemotherapy methods, an ADC couples the selective targeting and pharmacokinetic characteristics related to the antibody with the potent cytotoxicity of the payload. This results in high specificity and potency by reducing off-target toxicities in patients by limiting the exposure of healthy tissues to the cytotoxic drug. As a consequence of these outstanding features, significant research efforts have been devoted to the design, synthesis, and development of ADCs, and several ADCs have been approved for clinical use. The ADC field not only relies upon biology and biochemistry (antibody) but also upon organic chemistry (linker and payload). In the latter, total synthesis of natural and designed cytotoxic compounds, together with the development of novel synthetic strategies, have been key aspects of the consecution of clinical ADCs. In the case of payloads from marine origin, impressive structural architectures and biological properties are observed, thus making them prime targets for chemical synthesis and the development of ADCs. In this review, we explore the molecular and biological diversity of ADCs, with particular emphasis on those containing marine cytotoxic drugs as the payload.

Advancements in the Quest to Map, Monitor, and Manipulate Neural Circuitry.

Neural circuits and the cells that comprise them represent the functional units of the brain. Circuits relay and process sensory information, maintain homeostasis, drive behaviors, and facilitate cognitive functions such as learning and memory. Creating a functionally-precise map of the mammalian brain requires anatomically tracing neural circuits, monitoring their activity patterns, and manipulating their activity to infer function. Advancements in cell-type-specific genetic tools allow interrogation of neural circuits with increased precision. This review provides a broad overview of recombination-based and activity-driven genetic targeting approaches, contemporary viral tracing strategies, electrophysiological recording methods, newly developed calcium, and voltage indicators, and neurotransmitter/neuropeptide biosensors currently being used to investigate circuit architecture and function. Finally, it discusses methods for acute or chronic manipulation of neural activity, including genetically-targeted cellular ablation, optogenetics, chemogenetics, and over-expression of ion channels. With this ever-evolving genetic toolbox, scientists are continuing to probe neural circuits with increasing resolution, elucidating the structure and function of the incredibly complex mammalian brain.

Co-transmitting neurons in the lateral septal nucleus exhibit features of neurotransmitter switching.

The lateral septal nucleus (LSN) is a highly interconnected region of the central brain whose activity regulates widespread circuitry. As such, the mechanisms that govern neuronal activity within the LSN have far-reaching implications on numerous brain-wide nuclei, circuits, and behaviors. We found that GABAergic neurons within the LSN express markers that mediate the release of acetylcholine (ACh). Moreover, we show that these vGATLSN neurons release both GABA and ACh onto local glutamatergic LSN neurons. Using both short-term and long-term neuronal labeling techniques we observed expression of the cholinergic neuron marker Choline Acetyltransferase (ChAT) in vGATLSN neurons. These findings provide evidence of cholinergic neurotransmission from vGATLSN neurons, and provide an impetus to examine dynamic co-neurotransmission changes as a potential mechanism that contributes to neuronal and circuit-wide plasticity within the LSN.

Neurological Disorders in Literary Fiction: A Single Author Case Series.

Background: Across literary fiction, allusions to medical ailments are common. However, in the bibliography of Stephen King, neurological disorders appear to be present disproportionately. Objective: The objective of this study is to describe the epidemiology of neurologic disorders depicted in the writings of Stephen King. Methods: This study presents data from Stephen King's 60 published novels. The frequency, prevalence, lethality, and mortality of each neurological diagnosis found in the characters that appear in the novels are reported. Results: Forty-eight novels portrayed at least one character with a neurological diagnosis, and in total, 150 characters exhibited a neurological condition. The overall prevalence was 111.2 per 1,000 characters. Their median age was 20 years (range 76), and 61.7% were males. Headache was the most common symptom (35.3%), followed by stroke symptoms in 28.7%. Prevalence was 24.5, 17.8 for headache and epilepsy, respectively. Lethality was 28.7%. The overall mortality rate was 31.9. Conclusions: The epidemiology described in Stephen King's novels parallels that of the real world. The depiction of neurological disorders found in his novels showcases the elevated contribution of neurological disorders to the global burden of the disease, an important message for the readers of his fiction and interest to all neurologists.

Extended time window mechanical thrombectomy for pediatric acute ischemic stroke.

Endovascular thrombectomy (EVT) for the treatment of acute ischemic stroke (AIS) remains an off-label procedure seldom utilized in the pediatric population; this holds especially true for patients presenting outside the standard 6-hour time window. In this review we describe the published literature regarding usage of the extended time window EVT in pediatric stroke. We searched PubMed for all pediatric AIS cases and case series that included patients treated with extended time window EVT. We found data from 38 cases found in 27 publications (15 case reports and 12 case series). The median age was 10 years; 60.5% males. The median NIHSS before EVT was 13 with a median time-to-treatment of 11 hours. The posterior circulation was involved in 50.0%. Stent retrievers were used in 68.5%, and aspiration in 13.2%. Angiographic outcome TICI ≥2B was achieved in 84.2%, whereas TICI˂2B was reported in 10.6%. A favorable clinical outcome (NIHSS score ≤4, modified Rankin score ≤1, or Pediatric Stroke Outcome measure score ≤1) occurred in 84.2%. Eight cases that did not report the clinical outcome employing a standardized scale described mild to absent neurological residual deficits. This study found data that supports that extended window EVT produces high recanalization rates and good clinical outcomes in pediatric patients with AIS. Nevertheless, the source materials are indirect and contain substantial inconsistencies with an increased risk of bias that amount to low evidence strength.

Correlation between optic nerve sheath diameter and extracorporeal life support time.

INTRODUCTION: The objective of the study was to analyse the correlation between extracorporeal life support (ECLS) and aortic cross-clamp times and optic nerve sheath diameter (ONSD). PATIENTS AND METHODS: Study in a cohort of patients aged 0-15 years that underwent ECLS for cardiac surgery after obtention of signed informed consent. We calculated a sample size of 23 participants. First, we obtained 3 vertical and 3 horizontal measurements of the ONSD for each eye and calculated the mean of both eyes for each measurement to be used in the analysis. The measurements were made at admission and at 6 and 24 h post surgery. We retrieved the ECLS time and the aortic cross-clamp time were from the operative report. RESULTS: We analysed data for 23 participants, 52.2% female, with a median age of 14 months. The median ECLS time was 60 min; the median aortic cross-clamp time was 32 min. The median baseline ONSD was 3.1 mm. ONSD values had increased a median of 0.015 mm at 6 h post surgery (P = .03). We found a positive correlation between ECLS time and ONSD values (r = 0.476, P < 0,05). The ONSD values returned to baseline by 24 h post surgery. None of the patients developed signs or symptoms of increased intracranial pressure. CONCLUSION: Our study found a correlation between ECLS time and ONSD at 24 h post surgery. We found variations in the ONSD even in patients without signs or symptoms of increased ICP. Further research is required to identify the factors related to these variations.

Correlación del diámetro de la vaina del nervio óptico y el tiempo de circulación extracorpórea / Correlation between optic nerve sheath diameter and extracorporeal life support time

Introducción: El objetivo de este estudio es establecer la correlación entre los tiempos de circulación extracorpórea (CEC) y pinzamiento aórtico y el diámetro de la vaina del nervio óptico (DVNO). Pacientes y métodos: Se estudió una cohorte de pacientes con edad de 0 a 15 años, sometidos a cirugía cardíaca con CEC. Se calculó un tamaño muestral de 23 participantes. Primero se obtuvo el promedio de tres mediciones verticales y tres horizontales del DVNO. Después, se utilizó para los análisis la media de los valores de ambos ojos. Las mediciones ocurrieron al ingreso y a las 6 y 24 horas poscirugía. Los tiempos de CEC y pinzamiento aórtico se obtuvieron del informe quirúrgico. Resultados: Se analizaron datos de 23 participantes, el 52,2% mujeres, con edad mediana de 14 meses. La mediana del tiempo de CEC fue 60 minutos; la mediana de tiempo de pinzamiento aórtico fue 32 minutos. La mediana del DVNO basal fue 3,1mm. Los valores de DVNO aumentaron por una mediana de 0,015mm a las 6 horas poscirugía (p=0,03). Encontramos una correlación positiva entre el tiempo de CEC y los valores de DVNO (r=0,476; p<0,05). Los valores de DVNO regresaron al valor basal a las 24 horas poscirugía. Ningún paciente desarrolló signos o síntomas de incremento de la presión intracraneal. Conclusión: El estudio encontró una correlación entre el tiempo de CEC y el DVNO medido 24 horas poscirugía. Hubo variaciones del DVNO incluso en pacientes sin signos o síntomas de incremento de la presión intracraneal. Se requiere más investigación para identificar los factores relacionados con estas variaciones. (AU)

Introduction: The objective of the study was to analyse the correlation between extracorporeal life support (ECLS) and aortic cross-clamp times and optic nerve sheath diameter (ONSD). Patients and methods: Study in a cohort of patients aged 0 to 15 years that underwent ECLS for cardiac surgery after obtention of signed informed consent. We calculated a sample size of 23 participants. First, we obtained 3 vertical and 3 horizontal measurements of the ONSD for each eye and calculated the mean of both eyes for each measurement to be used in the analysis. The measurements were made at admission and at 6 and 24hours post surgery. We retrieved the ECLS time and the aortic cross-clamp time were from the operative report. Results: We analysed data for 23 participants, 52.2% female, with a median age of 14 months. The median ECLS time was 60minutes; the median aortic cross-clamp time was 32minutes. The median baseline ONSD was 3.1mm. ONSD values had increased a median of 0.015mm at 6hours post surgery (P=.03). We found a positive correlation between ECLS time and ONSD values (r=0.476, p<,05). The ONSD values returned to baseline by 24hours post surgery. None of the patients developed signs or symptoms of increased intracranial pressure. Conclusion: Our study found a correlation between ECLS time and ONSD at 24hours post surgery. We found variations in the ONSD even in patients without signs or symptoms of increased increased intracranial pressure. Further research is required to identify the factors related to these variations. (AU)

Awareness of Oral Disorders Among Community-Dwelling Elderly Spaniards.

Introduction: Oral status has a clear impact on systemic health, a key component of successful aging. Awareness of oral disorders permits early diagnoses and treatments. This study investigates oral disorders awareness among community-dwelling elders. Methods: Community-based survey through face-to-face interviews undertaken in four cities at busy commercial and administrative areas. Results: A total of 789 people were recruited, mostly nonsmoker (60.3%) males (56.9%) with basic education (65.6%). The most frequently recalled disorder was bruxism, followed by periodontal diseases and ulcerations/aphthae. Caries was mentioned by 3.91%. Dentate participants were more aware of dental-related disorders, such as bruxism (p = .001) and periodontitis (p = .010), except for caries (p = .100). Caries awareness was related to educational level (p = .018) and smoking (p = .020), as was oral cancer (p = .019) with former smokers more aware of this neoplasm. Education was strongly related with periodontal awareness (p = .001). Conclusion: Awareness of the main oral disorders is worryingly poor among the elderly population and immediate action is required by taking advantage of the position of family nurses in the treatment of systemic chronic disorders and through educational interventions on this population subgroup to ease preventive behaviors, favor early diagnoses, and promote simpler, more effective treatments with a lower financial burden.

Oxytocin signaling is necessary for synaptic maturation of adult-born neurons.

Neural circuit plasticity and sensory response dynamics depend on forming new synaptic connections. Despite recent advances toward understanding the consequences of circuit plasticity, the mechanisms driving circuit plasticity are unknown. Adult-born neurons within the olfactory bulb have proven to be a powerful model for studying circuit plasticity, providing a broad and accessible avenue into neuron development, migration, and circuit integration. We and others have shown that efficient adult-born neuron circuit integration hinges on presynaptic activity in the form of diverse signaling peptides. Here, we demonstrate a novel oxytocin-dependent mechanism of adult-born neuron synaptic maturation and circuit integration. We reveal spatial and temporal enrichment of oxytocin receptor expression within adult-born neurons in the murine olfactory bulb, with oxytocin receptor expression peaking during activity-dependent integration. Using viral labeling, confocal microscopy, and cell type-specific RNA-seq, we demonstrate that oxytocin receptor signaling promotes synaptic maturation of newly integrating adult-born neurons by regulating their morphological development and expression of mature synaptic AMPARs and other structural proteins.

Physical interactions between MCM and Rad51 facilitate replication fork lesion bypass and ssDNA gap filling by non-recombinogenic functions.

The minichromosome maintenance (MCM) helicase physically interacts with the recombination proteins Rad51 and Rad52 from yeast to human cells. We show, in Saccharomyces cerevisiae, that these interactions occur within a nuclease-insoluble scaffold enriched in replication/repair factors. Rad51 accumulates in a MCM- and DNA-binding-independent manner and interacts with MCM helicases located outside of the replication origins and forks. MCM, Rad51, and Rad52 accumulate in this scaffold in G1 and are released during the S phase. In the presence of replication-blocking lesions, Cdc7 prevents their release from the scaffold, thus maintaining the interactions. We identify a rad51 mutant that is impaired in its ability to bind to MCM but not to the scaffold. This mutant is proficient in recombination but partially defective in single-stranded DNA (ssDNA) gap filling and replication fork progression through damaged DNA. Therefore, cells accumulate MCM/Rad51/Rad52 complexes at specific nuclear scaffolds in G1 to assist stressed forks through non-recombinogenic functions.

[Correlation between optic nerve sheath diameter and extracorporeal life support time]. / Correlación del diámetro de la vaina del nervio óptico y el tiempo de circulación extracorpórea.

INTRODUCTION: The objective of the study was to analyse the correlation between extracorporeal life support (ECLS) and aortic cross-clamp times and optic nerve sheath diameter (ONSD). PATIENTS AND METHODS: Study in a cohort of patients aged 0 to 15 years that underwent ECLS for cardiac surgery after obtention of signed informed consent. We calculated a sample size of 23 participants. First, we obtained 3 vertical and 3 horizontal measurements of the ONSD for each eye and calculated the mean of both eyes for each measurement to be used in the analysis. The measurements were made at admission and at 6 and 24hours post surgery. We retrieved the ECLS time and the aortic cross-clamp time were from the operative report. RESULTS: We analysed data for 23 participants, 52.2% female, with a median age of 14 months. The median ECLS time was 60minutes; the median aortic cross-clamp time was 32minutes. The median baseline ONSD was 3.1mm. ONSD values had increased a median of 0.015mm at 6hours post surgery (P=.03). We found a positive correlation between ECLS time and ONSD values (r=0.476, p<,05). The ONSD values returned to baseline by 24hours post surgery. None of the patients developed signs or symptoms of increased intracranial pressure. CONCLUSION: Our study found a correlation between ECLS time and ONSD at 24hours post surgery. We found variations in the ONSD even in patients without signs or symptoms of increased increased intracranial pressure. Further research is required to identify the factors related to these variations.

Scaling Laws in the Diffusive Release of Neutral Cargo from Hollow Hydrogel Nanoparticles: Paclitaxel-Loaded Poly(4-vinylpyridine).

We study the nonequilibrium diffusive release of electroneutral molecular cargo encapsulated inside hollow hydrogel nanoparticles. We propose a theoretical model that includes osmotic, steric, and short-range polymer-cargo attractions to determine the effective cargo-hydrogel interaction, ueff*, and the effective diffusion coefficient of the cargo inside the polymer network, Deff*. Using dynamical density functional theory (DDFT), we investigate the scaling of the characteristic release time, τ1/2, with the key parameters involved in the process, namely, ueff*, Deff*, and the swelling ratio. This effort represents a full study of the problem, covering a broad range of cargo sizes and providing predictions for repulsive and attractive polymer shells. Our calculations show that the release time through repulsive polymer networks scales with q2eßueff*/Deff* for ßueff* ≫ 1. In this case, the cargo molecules are excluded from the shell of the hydrogel. For attractive shells, the polymer retains the cargo molecules on its internal surface and its interior, and the release time grows exponentially with the attraction strength. The DDFT calculations are compared to an analytical model for the mean first passage time, which provides an excellent quantitative description of the kinetics for both repulsive and attractive shells without fitting parameters. Finally, we apply the method to reproduce experimental results on the release of paclitaxel from hollow poly(4-vinylpyridine) nanoparticles and find that the slow release of the drug can be explained in terms of the strong binding attraction between the drug and the polymer.

Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.

Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants.