Electrophysiological Mechanisms and Validation of Ferritin-Based Magnetogenetics for Remote Control of Neurons.

Magnetogenetics was developed to remotely control genetically targeted neurons. A variant of magnetogenetics uses magnetic fields to activate transient receptor potential vanilloid (TRPV) channels when coupled with ferritin. Stimulation with static or radiofrequency (RF) magnetic fields of neurons expressing these channels induces Ca2+ transients and modulates behavior. However, the validity of ferritin-based magnetogenetics has been questioned due to controversies surrounding the underlying mechanisms and deficits in reproducibility. Here, we validated the magnetogenetic approach FeRIC using electrophysiological and imaging techniques. Previously, interference from RF stimulation rendered patch-clamp recordings inaccessible for magnetogenetics. We solved this limitation for FeRIC, and we studied the bioelectrical properties of neurons expressing TRPV4 (non-selective cation channel) and TMEM16A (chloride permeable channel) coupled to ferritin (FeRIC channels) under RF stimulation. We used cultured neurons obtained from rat hippocampus of either sex. We show that RF decreases the membrane resistance and depolarizes the membrane potential in neurons expressing TRPV4FeRIC RF does not directly trigger action potential firing but increases the neuronal basal spiking frequency. In neurons expressing TMEM16AFeRIC, RF decreases the membrane resistance, hyperpolarizes the membrane potential, and decreases the spiking frequency. Additionally, we corroborated the previously described biochemical mechanism responsible for RF-induced activation of ferritin-coupled ion channels. We solved an enduring problem for ferritin-based magnetogenetics, obtaining direct electrophysiological evidence of RF-induced activation of ferritin-coupled ion channels. We found that RF does not yield instantaneous changes in neuronal membrane potentials. Instead, RF produces responses that are long-lasting and moderate, but effective in controlling the bioelectrical properties of neurons.Significance statement Cell-specific and non-invasive stimulation can be a powerful tool for modulating neuronal circuits and functions. Magnetogenetic techniques that are fully genetically encoded provide such tools. However, there have been significant controversies surrounding the efficacy and underlying mechanisms of magnetogenetics. Here, we demonstrate that by employing a fully genetically encoded magnetogenetic approach called FeRIC, we can modulate neuronal voltage, inducing either depolarization or hyperpolarization through the activation of ion channels with magnetic fields; we validate this modulation mechanism with the gold-standard patch-clamp technique. We further discover that this neuronal modulation is not achieved by instantaneously triggering action potentials as previously assumed, but by modulating neuronal excitability.

Any-nucleus distributed active programmable transmit coil.

PURPOSE: There are 118 known elements. Nearly all of them have NMR active isotopes and at least 39 different nuclei have biological relevance. Despite this, most of today's MRI is based on only one nucleus-1H. To facilitate imaging all potential nuclei, we present a single transmit coil able to excite arbitrary nuclei in human-scale MRI. THEORY AND METHODS: We present a completely new type of RF coil, the Any-nucleus Distributed Active Programmable Transmit Coil (ADAPT Coil), with fast switches integrated into the structure of the coil to allow it to operate at any relevant frequency. This coil eliminates the need for the expensive traditional RF amplifier by directly converting direct current (DC) power into RF magnetic fields with frequencies chosen by digital control signals sent to the switches. Semiconductor switch imperfections are overcome by segmenting the coil. RESULTS: Circuit simulations demonstrated the effectiveness of the ADAPT Coil approach, and a 9 cm diameter surface ADAPT Coil was implemented. Using the ADAPT Coil, 1H, 23Na, 2H, and 13C phantom images were acquired, and 1H and 23Na ex vivo images were acquired. To excite different nuclei, only digital control signals were changed, which can be programmed in real time. CONCLUSION: The ADAPT Coil presents a low-cost, scalable, and efficient method for exciting arbitrary nuclei in human-scale MRI. This coil concept provides further opportunities for scaling, programmability, lowering coil costs, lowering dead-time, streamlining multinuclear MRI workflows, and enabling the study of dozens of biologically relevant nuclei.

Análisis de la problemática resultante de los tipos de donación de sangre, producida en el Banco de Sangre de la Seguridad Social en La Paz durante la gestión 2020 / Analysis of the problems resulting from the types of blood donation, produced at the social security Blood Bank in La Paz during the 2020 administration

INTRODUCCIÓN: actualmente la sangre continúa siendo un elemento vital para la vida, su fabricación aún no ha sido optimizada, por lo tanto, solo puede obtenerse a través de donaciones humanas. Por ello, para los Bancos de Sangre, contar con personas de confianza que aporten sangre constituye uno de los principales problemas éticos. Actualmente existen tres tipos de donación de sangre: la donación voluntaria y altruista, la donación de reposición o familiar y la donación remunerada, siendo esta última inaceptable en términos económicos y sanitarios, además de estar prohibida en el marco legal vigente en nuestro país. OBJETIVOS: analizar la problemática de la donación de sangre, haciendo énfasis en los tipos de donaciones que existen en nuestro país, considerando cuál es el tipo de donación más seguro para el receptor y cuáles son los menores de las pruebas de tamizaje inmunoserológico. MATERIALES Y MÉTODOS: se realizó un estudio transversal analítico, retrospectivo, en el que se revisaron las historias clínicas y los formularios electrónicos de trabajo utilizados en la recolección de datos de las donaciones de sangre obtenidas en el Banco de Sangre. de la seguridad social. Para el análisis estadístico se realizó la media y la varianza. RESULTADOS: de un total de 7787 personas que se presentaron a donar sangre, solo 5166 realizaron una donación efectiva. El resto fueron diferidos temporalmente por causas subsanables, 147 fueron diferidos definitivamente por enfermedades e infecciones que pudieran suponer un riesgo para el receptor y en 19 de ellos la extracción de sangre fue difícil por dificultad de acceso venoso. Según el tipo de donaciones, el 52,8 % fueron donaciones solidarias de reposición, el 43,3 % donación exijida y el 3,71 % donación voluntaria. Finalmente, el 68 % del total de las donaciones de sangre provino de hombres. CONCLUIONES: los datos obtenidos demuestran porcentajes muy bajos de donantes voluntarios y valores altos de donantes obligados a donar, muy en relación a países con programas deficientes de donación voluntaria y altruista de sangre.

INTRODUCTION: currently blood is a vital element for life, its manufacture has not yet been optimized, therefore, it can only be obtained through human donations. For this reason, for Blood Banks, having reliable people who provide blood constitutes one of the main ethical problems. There are currently three types of blood donation: voluntary and altruistic donation, replacement or family donation, and paid donation, the latter being unacceptable in economic and health terms, as well as being prohibited under the current legal framework in our country. OBJECTIVES: analyze the problem of blood donation, emphasizing the types of donations that exist in our country, considering what is the safest type of donation for the recipient and what are the minors of immunoserological screening tests. MATERIALS AND METHODS: this was a retrospective, analytical cross-sectional study, in which, we reviewed clinical histories and electronic work forms used in the collection of data on blood donations obtained in the Blood Bank. of social security. For statistical analysis we performed the mean and variance. RESULTS: in a total of 7787 people who presented themselves to donate blood, only 5166 made an effective donation. The rest were temporarily deferred for rectifiable reasons, 147 were permanently deferred due to diseases and infections that could cause a risk to the recipient and in 19 of them it was difficult to draw blood due to difficult venous access. According to the type of donations, 52.8 % were solidarity replacement donations, 43.3 % required donation, and 3.71 % voluntary donation. Finally, 68 % of the total blood donations came from men. CONCLUSIONS: the data obtained show very low percentages of voluntary donors and high values of required donors, these results are in accordance with countries with deficient voluntary and altruistic blood donation programs.

Skin Testing With Peach Peel Extract Versus Serum IgE to Pru p 3 as a Stronger Predictor of Peach-Induced Anaphylaxis.

The most important peach fruit allergen is Pru p 3, followed by Pru p 1, Pru p 4, and Pru p 7. We aimed to assess their role in subjects with peach fruit-induced allergy (anaphylaxis and OAS) and compare skin prick tests (SPT) vs. specific immunoglobulin E (sIgE) for predicting anaphylaxis. We also selected a control group. SPT included prevalent inhalant and plant food allergens plus peach peel extract. The sIgE to Pru p 1, Pru p 3, Pru p 4, and Pru p 7 were quantified. Compared with controls (n = 42), cases (n = 41) were younger (P = 0.003), more frequently female (P < 0.05) and had higher SPT positivity to peach peel (44% vs. 2.4%, P < 0.0001). There were significant differences in sensitization to several pollens: Olea europaea, Artemisia vulgaris, Prunus persica, Platanus acerifolia (all P < 0.001); and fruits: apple (P < 0.04), peanut (P < 0.002), tomato (P < 0.005), and melon (P < 0.05). Pru p 3 sIgE was detected in 61% of all cases (85% anaphylaxis and 38% OAS; P < 0.01 each) and 5% of controls (P < 0.001). Pru p 4 sIgE was present in 19% of cases and 7% of controls. The sIgE to Pru p 1 and Pru p 7 were not found. The odds ratio to predict anaphylaxis for peach peel SPT was 113 (confidence interval [CI], 20-613; P < 0.0001); for sIgE to Pru p 3, 22 (CI, 5.3-93; P < 0.0001); and for SPT positivity to selected plant food allergens, 5 (CI, 1-19; P < 0.05). In our study group, SPT with peel peach extract was a better predictor of anaphylaxis than Pru p 3 sIgE or other variables considered. The role of sIgE to Pru p 1, Pru p 4, and Pru p 7 seemed negligible.

Evaluating methods and protocols of ferritin-based magnetogenetics.

FeRIC (Ferritin iron Redistribution to Ion Channels) is a magnetogenetic technique that uses radiofrequency (RF) alternating magnetic fields to activate the transient receptor potential channels, TRPV1 and TRPV4, coupled to cellular ferritins. In cells expressing ferritin-tagged TRPV, RF stimulation increases the cytosolic Ca2+ levels via a biochemical pathway. The interaction between RF and ferritin increases the free cytosolic iron levels that, in turn, trigger chemical reactions producing reactive oxygen species and oxidized lipids that activate the ferritin-tagged TRPV. In this pathway, it is expected that experimental factors that disturb the ferritin expression, the ferritin iron load, the TRPV functional expression, or the cellular redox state will impact the efficiency of RF in activating ferritin-tagged TRPV. Here, we examined several experimental factors that either enhance or abolish the RF control of ferritin-tagged TRPV. The findings may help optimize and establish reproducible magnetogenetic protocols.

Subjects develop tolerance to Pru p 3 but respiratory allergy to Pru p 9: A large study group from a peach exposed population.

Peach tree allergens are present in fruit, pollen, branches, and leaves, and can induce systemic, respiratory, cutaneous, and gastrointestinal symptoms. We studied the capacity of peach fruit/Pru p 1, Pru p 3, Pru p 4, Pru p 7 and peach pollen/Pru p 9 for inducing symptoms following oral or respiratory exposure in a large group of subjects. We included 716 adults (aged 21 to 83 y.o.) exposed to peach tree pollen and fruit intake in the study population. Participants completed a questionnaire and were skin tested with a panel of inhalant and food allergens, including peach tree pollen, Pru p 9 and peach fruit skin extract. Immunoglobulin E antibodies (SIgE) to Pru p 1, Pru p 3, Pru p 4 and Pru p 7 were quantified. Sensitised subjects underwent oral food challenge with peach fruit and nasal provocation test with peach tree pollen and Pru p 9. The prevalence of sensitisation to peach fruit was 5% and most of these had SIgE to Pru p 3, with a very low proportion to Pru p 4 SIgE and no SIgE to Pru p 1 and Pru p 7. In only 1.8%, anaphylaxis was the clinical entity induced. Cases with positive skin tests to peach and SIgE to Pru p 3 presented a good tolerance after oral challenge with peach fruit. The prevalence of skin sensitisation to peach tree pollen was 22%, with almost half recognising Pru p 9. This induced respiratory symptoms in those evaluated by nasal provocation. In a large population group exposed to peach fruit and peach tree pollen, most individuals were tolerant, even in those with SIgE to Pru p 3. A positive response to Pru p 9 was associated with respiratory allergy.

Lipid Oxidation Induced by RF Waves and Mediated by Ferritin Iron Causes Activation of Ferritin-Tagged Ion Channels.

One approach to magnetogenetics uses radiofrequency (RF) waves to activate transient receptor potential channels (TRPV1 and TRPV4) that are coupled to cellular ferritins. The mechanisms underlying this effect are unclear and controversial. Theoretical calculations suggest that the heat produced by RF fields is likely orders of magnitude weaker than needed for channel activation. Using the FeRIC (Ferritin iron Redistribution to Ion Channels) system, we have uncovered a mechanism of activation of ferritin-tagged channels via a biochemical pathway initiated by RF disturbance of ferritin and mediated by ferritin-associated iron. We show that, in cells expressing TRPVFeRIC channels, RF increases the levels of the labile iron pool in a ferritin-dependent manner. Free iron participates in chemical reactions, producing reactive oxygen species and oxidized lipids that ultimately activate the TRPVFeRIC channels. This biochemical pathway predicts a similar RF-induced activation of other lipid-sensitive TRP channels and may guide future magnetogenetic designs.

Tumor de Wilms: experiencia de 15 años en un Hospital de niños, Córdoba, Argentina / Wilms tumor: 15 years of experience at a children's hospital in Córdoba, Argentina

El objetivo de este trabajo fue describir la epidemiología, la presentación, el tratamiento y el seguimiento nefrológico de niños con tumor de Wilms. Se recopilaron datos de 46 pacientes. Se encontró baja edad de presentación (< 40 meses), con síntomas iniciales de dolor, masa abdominal y fiebre. La histología prevalente fue nefroblastoma tipo mixto. Todos los pacientes recibieron quimioterapia prequirúrgica seguida, en la mayoría de los casos, de nefrectomía unilateral. Los pacientes con alto riesgo histológico tuvieron un riesgo relativo de morir de 7,2 (IC 75 %: 1,5-33,7) con respecto al resto y de recidiva de 2,5 (IC 75 %: 1,0-6,4). La sobrevida libre de enfermedad a 5 años fue del 70 %. El 80 % mantuvo la función renal en estadio I al completar el tratamiento oncológico. El factor pronóstico más importante fue la histología. Estos pacientes requieren seguimiento nefrológico prolongado.

The objective of this study was to describe the epidemiology, clinical presentation, treatment and nephrology follow-up of children with Wilms tumor. Data from 46 patients were collected. The clinical presentation occurred at a young age (< 40 months old), with initial symptoms of pain, abdominal mass, and fever. The prevalent histology type was mixed nephroblastoma. All patients received pre-surgery chemotherapy followed by, in most cases, unilateral nephrectomy. Patients with a high histological risk had a 7.2 relative risk of death (75 % confidence interval: 1.5-33.7) compared to the rest, and a 2.5 relative risk of recurrence (75 % confidence interval: 1.0-6.4). Disease-free survival at 5 years was 70 %. Once cancer treatment was completed, 80 % of patients maintained a stage-I kidney function. The most important prognostic factor was histology. These patients required a long-term nephrology follow-up.

Wilms tumor: 15 years of experience at a children's hospital in Córdoba, Argentina. / Tumor de Wilms: experiencia de 15 años en un Hospital de niños, Córdoba, Argentina.

The objective of this study was to describe the epidemiology, clinical presentation, treatment and nephrology follow-up of children with Wilms tumor. Data from 46 patients were collected. The clinical presentation occurred at a young age (< 40 months old), with initial symptoms of pain, abdominal mass, and fever. The prevalent histology type was mixed nephroblastoma. All patients received pre-surgery chemotherapy followed by, in most cases, unilateral nephrectomy. Patients with a high histological risk had a 7.2 relative risk of death (75 % confidence interval: 1.5-33.7) compared to the rest, and a 2.5 relative risk of recurrence (75 % confidence interval: 1.0-6.4). Disease-free survival at 5 years was 70 %. Once cancer treatment was completed, 80 % of patients maintained a stage-I kidney function. The most important prognostic factor was histology. These patients required a long-term nephrology follow-up.

El objetivo de este trabajo fue describir la epidemiología, la presentación, el tratamiento y el seguimiento nefrológico de niños con tumor de Wilms. Se recopilaron datos de 46 pacientes. Se encontró baja edad de presentación (< 40 meses), con síntomas iniciales de dolor, masa abdominal y fiebre. La histología prevalente fue nefroblastoma tipo mixto. Todos los pacientes recibieron quimioterapia prequirúrgica seguida, en la mayoría de los casos, de nefrectomía unilateral. Los pacientes con alto riesgo histológico tuvieron un riesgo relativo de morir de 7,2 (IC 75 %: 1,5-33,7) con respecto al resto y de recidiva de 2,5 (IC 75 %: 1,0-6,4). La sobrevida libre de enfermedad a 5 años fue del 70 %. El 80 % mantuvo la función renal en estadio I al completar el tratamiento oncológico. El factor pronóstico más importante fue la histología. Estos pacientes requieren seguimiento nefrológico prolongado.

TRPC1 and ORAI1 channels in colon cancer.

Colon cancer cells, like other types of cancer cells, undergo the remodeling of the intracellular Ca2+ homeostasis that contributes to cancer cell hallmarks including enhanced cell proliferation, migration, and survival. Colon cancer cells display enhanced store-operated Ca2+ entry (SOCE) compared with their non-cancer counterparts. Colon cancer cells display an abnormal expression of SOCE molecular players including Orai1 and TRPC1 channels, and the stromal interacting molecule (STIM) 1 and 2. Interestingly, upregulation of Orai1 and TRPC1 channels and their contribution to SOCE are associated with cancer malignancy in colon cancer cells. In a specific cellular model of colon cancer, whereas in non-cancer colon cells SOCE is composed of the Ca2+ release activated (CRAC) currents, in colon cancer cells SOCE is composed of CRAC- and cationic, non-selective store operated (SOC) currents. Former SOCs are mediated by TRPC1 channels. Moreover, colon cancer cells also display dysregulation of the expression of 1,4,5-triphosphate receptors (IP3R) that could contribute to the enhanced SOCE. Another important factor underlying the enhanced SOCE is the differential mitochondrial modulation of the CRAC and SOC currents in non-cancer and colon cancer cells. In colon cancer cells, mitochondria take up more Ca2+ that prevent the Ca2+-dependent inactivation of the SOCs, leading to sustained Ca2+ entry. Notably, the inhibition of SOCE in cancer colon cells abolishes their cancer hallmarks. Robust evidence has shown the efficiency of non-steroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO) to reverse the enhanced cell proliferation, migration, and apoptosis resistance of cancer cells. In colon cancer cells, both NSAIDs and DFMO decrease SOCE, but they target different molecular components of SOCE. NSAIDs decrease the Ca2+ uptake by mitochondria, limiting their ability to prevent the Ca2+-dependent inactivation of the SOCs that underlie SOCE. On the other hand, DFMO inhibits the expression of TRPC1 channels in colon cancer cells, eliminating their contribution to SOCE. The identification of players of SOCE in colon cancer cells may help to better understand the remodeling of the Ca2+ homeostasis in cancer. Importantly, the use of different pharmacological tools that target different SOCE molecular players in colon cancer cells may play a pivotal role in designing better chemoprevention strategies.

Composición química y calidad de la grasa contenida en frituras de maíz elaboradas y consumidas en Navojoa, estado de Sonora, México / Chemical Composition and Fat Quality in Fried Foods Made with Corn that Are Prepared and Consumed in Navojoa, State of Sonora, Mexico

Antecedentes: el consumo de frituras en México es alto, aunque las grasas se asocian con enfermedades crónicas no transmisibles. Objetivo: evaluar la composición química y calidad de la grasa obtenida de churros fritos de maíz elaborados y consumidos en Navojoa, estado de Sonora, México. Materiales y métodos: a cuatro muestras obtenidas en establecimientos comerciales se les realizó análisis químico proximal y determinación de índices de calidad de la grasa (acidez, peróxidos, yodo y anisidina), según normas mexicanas. Resultados: el aporte nutricional de las muestras estuvo en los siguientes rangos expresados en g %: grasas (23,7±0,2 y 35,2±1,0 g %), proteínas (2,5±0,0 y 8,1±1,4 g %), carbohidratos (54,1±0,3 y 64,40±0,5 g %) y energía (485±3 y 531±1 kcal %) con diferencias entre ellas (p<0,05). El mayor contenido de grasa y energía lo presentó B2 y el mejor perfil nutricional B4. La muestra B1 superó los límites máximos permitidos de acidez (4,8) y de peroxidación (10,6) con diferencias respecto a las otras muestras (p<0,05). Conclusiones: la densidad energética de los churros de maíz analizados es alta (superior a 4 kcal/g) al igual que el aporte de grasas, especialmente en la muestra B2. B4 presenta el mejor perfil nutricional y B1 el mayor deterioro oxidativo.

Background: Consumption of fried foods in Mexico is high, even though fats in fried foods are associated with noncommunicable chronic diseases. Objective: Evaluate the chemical composition and fat quality obtained from fried corn churros prepared and consumed in Navojoa, state of Sonora, Mexico. Materials and Methods: Four samples obtained from commercial establishments were subjected to proximal chemical analysis and determination of fat quality indices (acidity, alkalinity, iodine and anisidine), according to Mexican standards. Results: The nutritional breakdown of the samples is shown in the following ranges, expressed as grams % (g %): fats (23.7 ± 0.2 and 35.2 ± 1.0 g %), proteins (2.5 ± 0.0 and 8.1 ± 1.4 g %), carbohydrates (54.1 ± 0.3 and 64.4 ± 0.5 g %), and energy (kcal) (485 ± 3 and 531 ± 1) with significant differences between samples (p<0.05). The highest fat and energy content was presented by sample B2 and the best nutritional profile by sample B4. Sample B1 exceeded the maximum limits of acidity (4.8) and alkalinity (10.6) with a significant inter-sample difference (p <0.05). Conclusion: The energy density of the sampled fried corn churros is high (above 4 kcal/gram), as well as the fat content, especially in sample B2. Sample B4 presents the best nutrition profile and sample B1 the greatest oxidative deterioration.

Inhibition of Polyamine Biosynthesis Reverses Ca2+ Channel Remodeling in Colon Cancer Cells.

Store-operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non-excitable cells. Colorectal cancer (CRC) shows decreased Ca2+ store content and enhanced SOCE that correlate with cancer hallmarks and are associated to remodeling of store-operated channels (SOCs). Normal colonic cells display small, Ca2+-selective currents driven by Orai1 channels. In contrast, CRC cells display larger, non-selective currents driven by Orai1 and transient receptor potential canonical type 1 channels (TRPC1). Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), the limiting step in polyamine biosynthesis, strongly prevents CRC, particularly when combined with sulindac. We asked whether DFMO may reverse SOC remodeling in CRC. We found that CRC cells overexpress ODC and treatment with DFMO decreases cancer hallmarks including enhanced cell proliferation and apoptosis resistance. Consistently, DFMO enhances Ca2+ store content and decreases SOCE in CRC cells. Moreover, DFMO abolish selectively the TRPC1-dependent component of SOCs characteristic of CRC cells and this effect is reversed by the polyamine putrescine. Combination of DFMO and sulindac inhibit both SOC components and abolish SOCE in CRC cells. Finally, DFMO treatment inhibits expression of TRPC1 and stromal interaction protein 1 (STIM1) in CRC cells. These results suggest that polyamines contribute to Ca2+ channel remodeling in CRC, and DFMO may prevent CRC by reversing channel remodeling.

Cost Analysis of Endovascular Coiling and Surgical Clipping for the Treatment of Ruptured Intracranial Aneurysms.

BACKGROUND: Cost-effectiveness analyses for the treatment of aneurysmal subarachnoid hemorrhage are necessary to determine health policy, treatment guidelines, and screening protocols for cerebral aneurysms. To perform these modeling studies, detailed cost data are necessary and are currently lacking. OBJECTIVE: The goal of this study was to determine detailed inpatient cost of aneurysmal subarachnoid hemorrhage. METHODS: A retrospective review of our ruptured subarachnoid hemorrhage database was performed to identify consecutive patients between January 2013 and December 2015. Patients were searched by International Classification of Disease 9 diagnosis and procedure codes. Patient demographics and clinical characteristics were acquired. The cost breakdown was compiled into a comprehensive itemized list encompassing all aspects of hospitalization. A mean cost based on resource used per patient was obtained. RESULTS: There were 269 patients treated, 209 were coiled and 60 were clipped. Mean age in the clipping group was 49 years and 55 years in the coil group (P = 0.006). Other patient demographics and clinical characteristics were found to be statistically similar for both groups. Total cost per patient for treatment and hospital stay was $74,192 for clipping and $85,553 for coiling (P = 0.06). Cost amplified with increasing Hunt and Hess grade in both clipping and coiling groups. CONCLUSIONS: The detailed cost information reported in this article can be used to help establish appropriate, standardized costs nationally by improving transparency. It can also help provide critical information necessary to develop cost-effective treatment algorithms and screening protocols.

Mitochondrial control of store-operated Ca2+ channels in cancer: Pharmacological implications.

Intracellular Ca2+ is a pleiotropic second messenger involved in control of different cell and physiological functions including long-term processes such as cell proliferation, migration and survival. Agonist-induced Ca2+ entry in most cells, especially in non-excitable cells including epithelial cells, is mediated by store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway activated by agonist-induced release of Ca2+ from intracellular stores in the endoplasmic reticulum (ER). This pathway is modulated also by mitochondria which, acting as Ca2+ sinks, take up Ca2+, thus limiting Ca2+-dependent inactivation of Ca2+-release activated Ca2+ channels (CRAC). Compelling evidence shows that SOCE is upregulated in a large variety of cancer cells and this change contribute to cancer hallmarks. Mechanisms for enhanced SOCE include changes in expression of members of the Orai, Stromal interaction molecule (STIM) and canonical transient receptor potential channel (TRPc) gene families. Tumor cell mitochondria may contribute to SOCE upregulation in cancer as well. Molecular players involved in enhancing mitochondrial Ca2+ uptake are upregulated in tumor cells whereas negative modulators are repressed. Furthermore, mitochondrial potential, the driving force for mitochondrial Ca2+ uptake, is enhanced in tumor cells due to the Warburg effect. Finally, SOCE in tumor cells may be sustained further by the gain of function of non-selective TRPC channels permeable to Na+ that favour Ca2+ exit from mitochondria in exchange for Na+, thus limiting Ca2+-dependent inactivation of Orai1 channels. Therefore, tumor cell mitochondria may efficiently contribute to enhance and sustain SOCE in cancer. Interestingly, this effect could be counterbalanced by selected non-steroidal anti-inflammatory drugs (NSAIDs) reported to prevent colorectal cancer and other forms of cancer.

Comparative myology of the ankle of Leopardus wiedii and L. geoffroyi (Carnivora: Felidae): functional consistency with osteology, locomotor habits and hunting in captivity.

Leopardus wiedii (margay) is the only arboreal Neotropical felid able to climb head-first down trees, due to its ability to rotate its tarsal joint 180°. A closely related, similar-sized species, L. geoffroyi (Geoffroy's cat) exhibits more typical terrestrial habits and lacks the arboreal capabilities of L. wiedii. There is osteological evidence that supports a mechanical specialization of L. wiedii's tarsal joint for inversion, but there have been no studies on the myology of this specialization. Based on comparative gross-anatomy dissections of zeugo- and autopodial muscles related to the ankle joint of one margay specimen and two Geoffroýs cats, we identified myological specializations of L. wiedii that support its arboreal abilities. In addition, we documented both species hunting the same prey (domestic pigeon Columba livia, Aves: Columbidae) in captivity, to complement. We report differences in the origin, insertion and belly in 8 of the 10 dissected muscles. At least 3 of these interspecific variations can be associated with strengthening of the main muscles that command inversion/eversion movements of the tarsal joint and support the body weight in the head-down climbing position typical of L. wiedii. Frame-by-frame video reconstructions depict the sequence of movements in these species while hunting and highlight the advantages of the arboreal abilities of L. wiedii.

Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.

Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency-controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.

Mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells: reversal by non-steroidal anti-inflammatory drugs.

Tumor cells undergo a critical remodeling of intracellular Ca2+ homeostasis that contribute to important cancer hallmarks. Store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway modulated by mitochondria, is dramatically enhanced in colon cancer cells. In addition, most cancer cells display the Warburg effect, a metabolic switch from mitochondrial metabolism to glycolysis that provides survival advantages. Accordingly, we investigated mitochondria control of store-operated currents (SOCs) in two cell lines previously selected for representing human normal colonic cells and colon cancer cells. We found that, in normal cells, mitochondria are important for SOCs activity but they are unable to prevent current inactivation. In contrast, in colon cancer cells, mitochondria are dispensable for SOCs activation but are able to prevent the slow, Ca2+-dependent inactivation of SOCs. This effect is associated to increased ability of tumor cell mitochondria to take up Ca2+ due to increased mitochondrial potential (ΔΨ) linked to the Warburg effect. Consistently with this view, selected non-steroidal anti-inflammatory drugs (NSAIDs) depolarize mitochondria, inhibit mitochondrial Ca2+ uptake and promote SOC inactivation, leading to inhibition of both SOCE and cancer cell proliferation. Thus, mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells and this effect is counteracted by selected NSAIDs providing a mechanism for cancer chemoprevention.

Quality Programs in Neurosurgery: The Memorial Hermann/University of Texas Experience.

The importance of outcome measures is steadily increasing due to the rise of "pay for performance" and the advent of population health. In 2007, a quality initiative was started due to poor performance on rankings such as the University Health Consortium (UHC) report card. Inherent to all such efforts are common challenges: how to engage the providers; how to gather and ensure the accuracy of the data; how to attribute results to individuals; how to ensure permanent improvements. After analysis, a strategy was developed that included an initial focus on 3 metrics (mortality, infection rates, and complications), leadership from practicing neurosurgeons, protocol development and adherence, and subspecialization. In addition, it was decided that the metrics would initially apply to attending physicians only, but that the entire team would need to be involved. Once the fundamental elements were established, the process could be extended to other measures and providers. To support this effort, special information system tools were developed and a support team formed. As the program matured, measured outcomes improved and more metrics were added (to a current total of 48). For example, UHC mortality ratios (observed over expected) decreased by 75%. Infection rates decreased 80%. The program now involves all trainee physicians, advanced practice providers, nurses, and other staff. This paper describes the design, implementation, and results of this effort, and provides a practical guide that may be useful to other groups undertaking similar initiatives.

Calcium remodeling in colorectal cancer.

Colorectal cancer (CRC) is the third most frequent form of cancer and the fourth leading cause of cancer-related death in the world. Basic and clinical data indicate that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may prevent colon cancer but mechanisms remain unknown. Aspirin metabolite salicylate and other NSAIDs may inhibit tumor cell growth acting on store-operated Ca2+ entry (SOCE), suggesting an important role for this pathway in CRC. Consistently, SOCE is emerging as a novel player in different forms of cancer, including CRC. SOCE and store-operated currents (SOCs) are dramatically enhanced in CRC while Ca2+ stores are partially empty in CRC cells. These features may contribute to CRC hallmarks including enhanced cell proliferation, migration, invasion and survival. At the molecular level, enhanced SOCE and depleted stores are mediated by overexpression of Orai1, Stromal interaction protein 1 (STIM1) and Transient receptor protein channel 1 (TRPC1) and downregulation of STIM2. In normal colonic cells, SOCE is mediated by Ca2+-release activated Ca2+ channels made of STIM1, STIM2 and Orai1. In CRC cells, SOCE is mediated by different store-operated currents (SOCs) driven by STIM1, Orai1 and TRPC1. Loss of STIM2 contributes to depletion of Ca2+ stores and enhanced resistance to cell death in CRC cells. Thus, SOCE is a novel key player in CRC and inhibition by salicylate and other NSAIDs may contribute to explain chemoprevention activity. SUMMARY: Colorectal cancer (CRC) is the third most frequent form of cancer worldwide. Recent evidence suggests that intracellular Ca2+ remodeling may contribute to cancer hallmarks. In addition, aspirin and other NSAIDs might prevent CRC acting on remodeled Ca2+ entry pathways. In this review, we will briefly describe 1) the players involved in intracellular Ca2+ homeostasis with a particular emphasis on the mechanisms involved in SOCE activation and inactivation, 2) the evidence that aspirin metabolite salicylate and other NSAIDs inhibits tumor cell growth acting on SOCE, 3) evidences on the remodeling of intracellular Ca2+ in cancer with a particular emphasis in SOCE, 4) the remodeling of SOCE and Ca2+ store content in CRC and, finally, 5) the molecular basis of Ca2+ remodeling in CRC. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

Remodeling of Calcium Entry Pathways in Cancer.

Ca(2+) entry pathways play important roles in control of many cellular functions, including long-term proliferation, migration and cell death. In recent years, it is becoming increasingly clear that, in some types of tumors, remodeling of Ca(2+) entry pathways could contribute to cancer hallmarks such as excessive proliferation, cell migration and invasion as well as resistance to cell death or survival. In this chapter we briefly review findings related to remodeling of Ca(2+) entry pathways in cancer with emphasis on the mechanisms that contribute to increased store-operated Ca(2+) entry (SOCE) and store-operated currents (SOCs) in colorectal cancer cells. Finally, since SOCE appears critically involved in colon tumorogenesis, the inhibition of SOCE by aspirin and other NSAIDs and its possible contribution to colon cancer chemoprevention is reviewed.