A Mechanistic Neural Field Theory of How Anesthesia Suppresses Consciousness: Synaptic Drive Dynamics, Bifurcations, Attractors, and Partial State Equipartitioning

With the advances in biochemistry, molecular biology, and neurochemistry there has been impressive progress in understanding the molecular properties of anesthetic agents. However, there has been little focus on how the molecular properties of anesthetic agents lead to the observed macroscopic property that defines the anesthetic state, that is, lack of responsiveness to noxious stimuli. In this paper, we use dynamical system theory to develop a mechanistic mean field model for neural activity to study the abrupt transition from consciousness to unconsciousness as the concentration of the anesthetic agent increases. The proposed synaptic drive firing-rate model predicts the conscious-unconscious transition as the applied anesthetic concentration increases, where excitatory neural activity is characterized by a Poincare-Andronov-Hopf bifurcation with the awake state transitioning to a stable limit cycle and then subsequently to an asymptotically stable unconscious equilibrium state. Furthermore, we address the more general question of synchronization and partial state equipartitioning of neural activity without mean field assumptions. This is done by focusing on a postulated subset of inhibitory neurons that are not themselves connected to other inhibitory neurons. Finally, several numerical experiments are presented to illustrate the different aspects of the proposed theory.NPRP grant No. 4-187-2-060 from the Qatar National Research Fund (a member of the Qatar Foundation)Scopu

Cirurgia Com Tela Para Correção De Prolapso De Parede Anterior: Metanálise

Purpose Pelvic organ prolapse (POP) is a major health issue worldwide, affecting 6–8% of women. The most affected site is the anterior vaginal wall. Multiple procedures and surgical techniques have been used, with or without the use of vaginal meshes, due to common treatment failure, reoperations, and complication rates in some studies. Methods Systematic review of the literature and meta-analysis regarding the use of vaginal mesh in anterior vaginal wall prolapse was performed. A total of 115 papers were retrieved after using the medical subject headings (MESH) terms: ‘anterior pelvic organ prolapse OR cystocele AND surgery AND (mesh or colporrhaphy)’ in the PubMed database. Exclusion criteria were: follow-up shorter than 1 year, use of biological or absorbable meshes, and inclusion of other vaginal wall prolapses. Studies were put in a data chart by two independent editors; results found in at least two studies were grouped for analysis. Results After the review of the titles by two independent editors, 70 studies were discarded, and after abstract assessment, 18 trials were eligible for full text screening. For final screening and meta-analysis, after applying the Jadad score ( > 2), 12 studies were included. Objective cure was greater in the mesh surgery group (odds ratio [OR] = 1,28 [1,07–1,53]), which also had greater blood loss (mean deviation [MD] = 45,98 [9,72–82,25]), longer surgery time (MD = 15,08 [0,48–29,67]), but less prolapse recurrence (OR = 0,22 [01,3–0,38]). Dyspareunia, symptom resolution and reoperation rates were not statistically different between groups. Quality of life (QOL) assessment through the pelvic organ prolapse/urinary incontinence sexual questionnaire (PISQ-12), the pelvic floor distress inventory (PFDI-20), the pelvic floor impact questionnaire (PFIQ-7), and the perceived quality of life scale (PQOL) was not significantly different. Conclusions Anterior vaginal prolapse mesh surgery has greater anatomic cure rates and less recurrence, although there were no differences regarding subjective cure, reoperation rates and quality of life. Furthermore, mesh surgery was associated with longer surgical time and greater blood loss. Mesh use should be individualized, considering prior history and risk factors for recurrence. © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil.38735636

Cirurgia com tela para correção de prolapso de parede anterior: metanálise

Pelvic organ prolapse (POP) is a major health issue worldwide, affecting 6–8% of women. The most affected site is the anterior vaginal wall. Multiple procedures and surgical techniques have been used, with or without the use of vaginal meshes, due to common treatment failure, reoperations, and complication rates in some studies. Methods Systematic review of the literature and meta-analysis regarding the use of vaginal mesh in anterior vaginal wall prolapse was performed. A total of 115 papers were retrieved after using the medical subject headings (MESH) terms: ‘anterior pelvic organ prolapse OR cystocele AND surgery AND (mesh or colporrhaphy)’ in the PubMed database. Exclusion criteria were: follow-up shorter than 1 year, use of biological or absorbable meshes, and inclusion of other vaginal wall prolapses. Studies were put in a data chart by two independent editors; results found in at least two studies were grouped for analysis. Results After the review of the titles by two independent editors, 70 studies were discarded, and after abstract assessment, 18 trials were eligible for full text screening. For final screening and meta-analysis, after applying the Jadad score ( > 2), 12 studies were included. Objective cure was greater in the mesh surgery group (odds ratio [OR] = 1,28 [1,07–1,53]), which also had greater blood loss (mean deviation [MD] = 45,98 [9,72–82,25]), longer surgery time (MD = 15,08 [0,48–29,67]), but less prolapse recurrence (OR = 0,22 [01,3–0,38]). Dyspareunia, symptom resolution and reoperation rates were not statistically different between groups. Quality of life (QOL) assessment through the pelvic organ prolapse/urinary incontinence sexual questionnaire (PISQ-12), the pelvic floor distress inventory (PFDI-20), the pelvic floor impact questionnaire (PFIQ-7), and the perceived quality of life scale (PQOL) was not significantly different. Conclusions Anterior vaginal prolapse mesh surgery has greater anatomic cure rates and less recurrence, although there were no differences regarding subjective cure, reoperation rates and quality of life. Furthermore, mesh surgery was associated with longer surgical time and greater blood loss. Mesh use should be individualized, considering prior history and risk factors for recurrence.387356364Prolapso de órgãos pélvicos é problema de saúde públicas, sendo o mais comum o anterior. Para tratamento são utilizadas cirurgias, com ou sem telas. O uso de telas é para diminuir recidivas, mas não h á consenso. Métodos: Foi realizada revisão da literatura e metanálise, sobre uso de telas na correção do prolapso anterior. Base de dados foi PUBMED , com termos (MESH): “Anterior Pelvic Organ OR Cystocele AND Surgery AND (Mesh or Colporrhaphy)”. Critérios de exclusão foram: seguimento menor que 1 ano, telas biológicas ou absorvíveis. Resultados: foram avaliados 115 artigos. Após revisão dos títulos, 70 estudos foram descartados e 18 após leitura de resumos. Após critérios de Jadad (>2), 12 estudos foram incluídos. Análise estatística foi razão de risco ou diferença entre médias dos grupos, e as análises com grande heterogeneidade foram avaliadas através de análise de efeito aleatório. Resultados: Cura objetiva foi superior no grupo com tela - OR 1,28 (1,07-1,53, p ≤ 0,00001), maior perda sanguínea - diferença média (MD) 45,98 (9,72-82,25, p = 0,01), tempo cirúrgico mais longo - MD 15,08 (0,48-29,67, p = 0,04), porém menor recorrência - OR 0,22 (0,13-0,38, p = 0,00001), não apresentando maior resolução dos sintomas - OR 1,93 (0,83-4,51, p = 0,15). Dispareunia e taxa de reoperação também não foram diferentes entre grupos. Qualidade de vida não apresentou diferença. Conclusões: Cirurgia com tela para prolapso vaginal anterior apresenta melhor taxa de cura anatômica e menor recorrência, sem diferenças cura subjetiva, reoperação e qualidade de vida. Há maior tempo cirúrgico e perda sanguínea. Uso de telas deve ser individualizado

Universal Critical Behavior of Aperiodic Ferromagnetic Models

We investigate the effects of geometric fluctuations, associated with aperiodic exchange interactions, on the critical behavior of $q$-state ferromagnetic Potts models on generalized diamond hierarchical lattices. For layered exchange interactions according to some two-letter substitutional sequences, and irrelevant geometric fluctuations, the exact recursion relations in parameter space display a non-trivial diagonal fixed point that governs the universal critical behavior. For relevant fluctuations, this fixed point becomes fully unstable, and we show the apperance of a two-cycle which is associated with a novel critical behavior. We use scaling arguments to calculate the critical exponent $\alpha$ of the specific heat, which turns out to be different from the value for the uniform case. We check the scaling predictions by a direct numerical analysis of the singularity of the thermodynamic free-energy. The agreement between scaling and direct calculations is excellent for stronger singularities (large values of $q$). The critical exponents do not depend on the strengths of the exchange interactions.Comment: 4 pages, 1 figure (included), RevTeX, submitted to Phys. Rev. E as a Rapid Communicatio

The Harris-Luck criterion for random lattices

The Harris-Luck criterion judges the relevance of (potentially) spatially correlated, quenched disorder induced by, e.g., random bonds, randomly diluted sites or a quasi-periodicity of the lattice, for altering the critical behavior of a coupled matter system. We investigate the applicability of this type of criterion to the case of spin variables coupled to random lattices. Their aptitude to alter critical behavior depends on the degree of spatial correlations present, which is quantified by a wandering exponent. We consider the cases of Poissonian random graphs resulting from the Voronoi-Delaunay construction and of planar, ``fat'' $\phi^3$ Feynman diagrams and precisely determine their wandering exponents. The resulting predictions are compared to various exact and numerical results for the Potts model coupled to these quenched ensembles of random graphs.Comment: 13 pages, 9 figures, 2 tables, REVTeX 4. Version as published, one figure added for clarification, minor re-wordings and typo cleanu

19-base Pair Deletion Polymorphism Of The Dihydrofolate Reductase (dhfr) Gene: Maternal Risk Of Down Syndrome And Folate Metabolism [polimorfismo De Deleção De 19 Pares De Bases Do Gene Dihidrofolato Redutase (dhfr): Risco Materno Para Síndrome De Down E Metabolismo Do Folato]

Context and objective: Polymorphisms in genes involved in folate metabolism may modulate the maternal risk of Down syndrome (DS). This study evaluated the influence of a 19-base pair (bp) deletion polymorphism in intron-1 of the dihydrofolate reductase (DHFR) gene on the maternal risk of DS, and investigated the association between this polymorphism and variations in the concentrations of serum folate and plasma homocysteine (Hcy) and plasma methylmalonic acid (MMA). Design and setting: Analytical cross-sectional study carried out at Faculdade de Medicina de São José do Rio Preto (Famerp). Methods: 105 mothers of individuals with free trisomy of chromosome 21, and 184 control mothers were evaluated. Molecular analysis on the polymorphism was performed using the polymerase chain reaction (PCR) through differences in the sizes of fragments. Folate was quantified by means of chemiluminescence, and Hcy and MMA by means of liquid chromatography and sequential mass spectrometry. Results: There was no difference between the groups in relation to allele and genotype frequencies (P = 0.44; P = 0.69, respectively). The folate, Hcy and MMA concentrations did not differ significantly between the groups, in relation to genotypes (P > 0.05). Conclusions: The 19-bp deletion polymorphism of DHFR gene was not a maternal risk factor for DS and was not related to variations in the concentrations of serum folate and plasma Hcy and MMA in the study population.1284215218Freeman, S.B., Allen, E.G., Oxford-Wright, C.L., The National Down Syndrome Project: Design and implementation (2007) Public Health Rep, 122 (1), pp. 62-72Ramírez, N.J., Belalcázar, H.M., Yunis, J.J., Parental origin, nondisjunction, and recombination of the extra chromosome 21 in Down syndrome: A study in a sample of the Colombian population (2007) Biomedica, 27 (1), pp. 141-148James, S.J., Pogribna, M., Pogribny, I.P., Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome (1999) Am J Clin Nutr, 70 (4), pp. 495-501Patterson, D., Folate metabolism and the risk of Down syndrome (2008) Downs Syndr Res Pract, 12 (2), pp. 93-97Biselli, J.M., Goloni-Bertollo, E.M., Zampieri, B.L., Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: Maternal risk factors for Down syndrome in Brazil (2008) Genet Mol Res, 7 (1), pp. 33-42Meguid, N.A., Dardir, A.A., Khass, M., MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children (2008) Dis Markers, 24 (1), pp. 19-26Coppedè, F., Migheli, F., Bargagna, S., Association of maternal polymorphisms in folate metabolizing genes with chromosome damage and risk of Down syndrome offspring (2009) Neurosci Lett, 449 (1), pp. 15-19Pozzi, E., Vergani, P., Dalprà, L., Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome (2009) Am J Obstet Gynecol, 200 (6), pp. 636e1-636e6Stanislawska-Sachadyn, A., Brown, K.S., Mitchell, L.E., An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women (2008) Hum Genet, 123 (3), pp. 289-295Johnson, W.G., Stenroos, E.S., Spychala, J.R., New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): A risk factor for spina bifida acting in mothers during pregnancy? (2004) Am J Med Genet A, 124 A (4), pp. 339-345Parle-McDermott, A., Pangilinan, F., Mills, J.L., The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population (2007) Am J Med Genet A, 143 A (11), pp. 1174-1180Xu, X., Gammon, M.D., Wetmur, J.G., A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users (2007) Am J Clin Nutr, 85 (4), pp. 1098-1102Gellekink, H., Blom, H.J., van der Linden, I.J., den Heijer, M., Molecular genetic analysis of the human dihydrofolate reductase gene: Relation with plasma total homocysteine, serum and red blood cell folate levels (2007) Eur J Hum Genet, 15 (1), pp. 103-109Miller, S.A., Dykes, D.D., Polesky, H.F., A simple salting out procedure for extracting DNA from human nucleated cells (1988) Nucleic Acids Res, 16 (3), p. 1215Dulucq, S., St-Onge, G., Gagné, V., DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL (2008) Blood, 111 (7), pp. 3692-3700Haddad, R., Mendes, M.A., Höehr, N.F., Eberlin, M.N., Amino acid quantitation in aqueous matrices via trap and release membrane introduction mass spectrometry: Homocysteine in human plasma (2001) Analyst, 126 (8), pp. 1212-1215de Andrade, C.R., Fukada, S.Y., Olivon, V.C., Alpha1D-adrenoceptor-induced relaxation on rat carotid artery is impaired during the endothelial dysfunction evoked in the early stages of hyperhomocysteinemia (2006) Eur J Pharmacol, 543 (1-3), pp. 83-91Carvalho, V.M., Kok, F., Determination of serum methylmalonic acid by alkylative extraction and liquid chromatography coupled to tandem mass spectrometry (2008) Anal Biochem, 381 (1), pp. 67-73Fenech, M., The role of folic acid and Vitamin B12 in genomic stability of human cells (2001) Mutat Res, 475 (1-2), pp. 57-67Wang, X., Thomas, P., Xue, J., Fenech, M., Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21 (2004) Mutat Res, 551 (1-2), pp. 167-180Beetstra, S., Thomas, P., Salisbury, C., Turner, J., Fenech, M., Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei (2005) Mutat Res, 578 (1-2), pp. 317-326Finkelstein, J.D., Martin, J.J., Homocysteine (2000) Int J Biochem Cell Biol, 32 (4), pp. 385-389Coppedè, F., Marini, G., Bargagna, S., Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women (2006) Am J Med Genet A, 140 (10), pp. 1083-1091Wang, S.S., Qiao, F.Y., Feng, L., Lv, J.J., Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China (2008) J Zhejiang Univ Sci B, 9 (2), pp. 93-99Kalmbach, R.D., Choumenkovitch, S.F., Troen, A.P., A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate (2008) J Nutr, 138 (12), pp. 2323-2327van der Linden, I.J., Nguyen, U., Heil, S.G., Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida (2007) Mol Genet Metab, 91 (1), pp. 98-103Barkai, G., Arbuzova, S., Berkenstadt, M., Heifetz, S., Cuckle, H., Frequency of Down's syndrome and neural tube defects in the same family (2003) Lancet, 361 (9366), pp. 1331-1335Guéant, J.L., Guéant-Rodriguez, R.M., Anello, G., Genetic determinants of folate and vitamin B12 metabolism: A common pathway in neural tube defect and Down syndrome? (2003) Clin Chem Lab Med, 41 (11), pp. 1473-1477Klee, G.G., Cobalamin and folate evaluation: Measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate (2000) Clin Chem, 46 (8 PART 2), pp. 1277-1283Galloway, M., Rushworth, L., Red cell or serum folate? Results from the National Pathology Alliance benchmarking review (2003) J Clin Pathol, 56 (12), pp. 924-926Bunduki, V., Dommergues, M., Zittoun, J., Maternal-fetal folate status and neural tube defects: A case control study (1995) Biol Neonate, 67 (3), pp. 154-159Kilbride, J., Baker, T.G., Parapia, L.A., Khoury, S.A., Iron status, serum folate and B(12) values in pregnancy and postpartum: Report from a study in Jordan (2000) Ann Saudi Med, 20 (5-6), pp. 371-376Zhang, T., Xin, R., Gu, X., Maternal serum vitamin B12, folate and homocysteine and the risk of neural tube defects in the offspring in a high-risk area of China (2009) Public Health Nutr, 12 (5), pp. 680-686Eser, B., Cosar, M., Eser, O., 677C>T and 1298A>C polymorphisms of methylenetetrahydropholate reductase gene and biochemical parameters in Turkish population with spina bifida occulta (2010) Turk Neurosurg, 20 (1), pp. 9-1

Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data

Bodily tides near spin-orbit resonances

Spin-orbit coupling can be described in two approaches. The method known as "the MacDonald torque" is often combined with an assumption that the quality factor Q is frequency-independent. This makes the method inconsistent, because the MacDonald theory tacitly fixes the rheology by making Q scale as the inverse tidal frequency. Spin-orbit coupling can be treated also in an approach called "the Darwin torque". While this theory is general enough to accommodate an arbitrary frequency-dependence of Q, this advantage has not yet been exploited in the literature, where Q is assumed constant or is set to scale as inverse tidal frequency, the latter assertion making the Darwin torque equivalent to a corrected version of the MacDonald torque. However neither a constant nor an inverse-frequency Q reflect the properties of realistic mantles and crusts, because the actual frequency-dependence is more complex. Hence the necessity to enrich the theory of spin-orbit interaction with the right frequency-dependence. We accomplish this programme for the Darwin-torque-based model near resonances. We derive the frequency-dependence of the tidal torque from the first principles, i.e., from the expression for the mantle's compliance in the time domain. We also explain that the tidal torque includes not only the secular part, but also an oscillating part. We demonstrate that the lmpq term of the Darwin-Kaula expansion for the tidal torque smoothly goes through zero, when the secondary traverses the lmpq resonance (e.g., the principal tidal torque smoothly goes through nil as the secondary crosses the synchronous orbit). We also offer a possible explanation for the unexpected frequency-dependence of the tidal dissipation rate in the Moon, discovered by LLR

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types