Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces

Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction A Prespecified Analysis of DAPA-HF

BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events. METHODS: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction RESULTS: Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65-0.82]; P CONCLUSION: In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin

Internationalization within networks: Exploring the relationship between inward and outward FDI in China’s auto components industry

This is the accepted manuscript. It is currently embargoed pending publication.We explore how the outward FDI strategies of Chinese auto component MNCs are\ud shaped by sub-contracting supply relationships established with developed market MNCs.\ud We argue the strong presence of foreign MNC business networks developed through prior\ud inward FDI constitutes an important home country effect influencing the outward FDI\ud strategies of emerging market MNCs. Using the updated internationalization process model,\ud we show how commitment to business networks is a critical mechanism driving the\ud internationalization trajectories of Chinese auto component MNCs. This includes geographic\ud location choices to psychically distant developed markets, strategic asset seeking orientation,\ud pace of internationalisation and entry mode decisions

Evaluating alternate models to estimate genetic parameters of calving traits in United Kingdom Holstein-Friesian dairy cattle

<p>Abstract</p> <p>Background</p> <p>The focus in dairy cattle breeding is gradually shifting from production to functional traits and genetic parameters of calving traits are estimated more frequently. However, across countries, various statistical models are used to estimate these parameters. This study evaluates different models for calving ease and stillbirth in United Kingdom Holstein-Friesian cattle.</p> <p>Methods</p> <p>Data from first and later parity records were used. Genetic parameters for calving ease, stillbirth and gestation length were estimated using the restricted maximum likelihood method, considering different models i.e. sire (−maternal grandsire), animal, univariate and bivariate models. Gestation length was fitted as a correlated indicator trait and, for all three traits, genetic correlations between first and later parities were estimated. Potential bias in estimates was avoided by acknowledging a possible environmental direct-maternal covariance. The total heritable variance was estimated for each trait to discuss its theoretical importance and practical value. Prediction error variances and accuracies were calculated to compare the models.</p> <p>Results and discussion</p> <p>On average, direct and maternal heritabilities for calving traits were low, except for direct gestation length. Calving ease in first parity had a significant and negative direct-maternal genetic correlation. Gestation length was maternally correlated to stillbirth in first parity and directly correlated to calving ease in later parities. Multi-trait models had a slightly greater predictive ability than univariate models, especially for the lowly heritable traits. The computation time needed for sire (−maternal grandsire) models was much smaller than for animal models with only small differences in accuracy. The sire (−maternal grandsire) model was robust when additional genetic components were estimated, while the equivalent animal model had difficulties reaching convergence.</p> <p>Conclusions</p> <p>For the evaluation of calving traits, multi-trait models show a slight advantage over univariate models. Extended sire models (−maternal grandsire) are more practical and robust than animal models. Estimated genetic parameters for calving traits of UK Holstein cattle are consistent with literature. Calculating an aggregate estimated breeding value including direct and maternal values should encourage breeders to consider both direct and maternal effects in selection decisions.</p

The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid

<p>Abstract</p> <p>Background</p> <p>Cerebrospinal fluid (CSF) contacts many brain regions and may mediate humoral signaling distinct from synaptic neurotransmission. However, synthesis and transport mechanisms for such signaling are not defined. The purpose of this study was to investigate whether human CSF contains discrete structures that may enable the regulation of humoral transmission.</p> <p>Methods</p> <p>Lumbar CSF was collected prospectively from 17 participants: with no neurological or psychiatric disease, with Alzheimer's disease, multiple sclerosis, or migraine; and ventricular CSF from two cognitively healthy participants with long-standing shunts for congenital hydrocephalus. Cell-free CSF was subjected to ultracentrifugation to yield supernatants and pellets that were examined by transmission electron microscopy, shotgun protein sequencing, electrophoresis, western blotting, lipid analysis, enzymatic activity assay, and immuno-electron microscopy.</p> <p>Results</p> <p>Over 3,600 CSF proteins were identified from repeated shotgun sequencing of cell-free CSF from two individuals with Alzheimer's disease: 25% of these proteins are normally present in membranes. Abundant nanometer-scaled structures were observed in ultracentrifuged pellets of CSF from all 16 participants examined. The most common structures included synaptic vesicle and exosome components in 30-200 nm spheres and irregular blobs. Much less abundant nanostructures were present that derived from cellular debris. Nanostructure fractions had a unique composition compared to CSF supernatant, richer in omega-3 and phosphoinositide lipids, active prostanoid enzymes, and fibronectin.</p> <p>Conclusion</p> <p>Unique morphology and biochemistry features of abundant and discrete membrane-bound CSF nanostructures are described. Prostaglandin H synthase activity, essential for prostanoid production and previously unknown in CSF, is localized to nanospheres. Considering CSF bulk flow and its circulatory dynamics, we propose that these nanostructures provide signaling mechanisms <it>via </it>volume transmission within the nervous system that are for slower, more diffuse, and of longer duration than synaptic transmission.</p

Nutrição mineral de hortaliças: XXIX. absorção de macronutrientes por quatro cultivares de morangueiro (Fragaria spp.)

The aim of this work was to estimate the differences in growth (dry weight basis), nutrients uptake, fruits yield, total uptake and exportation of nutrients among several strawberry cultivars: Campinas (IAC-2712), Camanducaia (IAC-3530), Monte Alegre (IAC-3113) and SH-2. The experimental was carried out in the Escola Superior de Agricultura "Luiz de Queiroz", in field conditions, in 1975/76. The soil belongs to Terra Roxa Estruturada type, and "Luiz de Queiroz" serie. This soil has been cultivated for more than 25 years. The experimental design was that randomized blocks with four replications and analysed together following the design of split-plot. The soil of the plots were revolved to a deep of 12 cm following application of 10 kg organic matter/m². The fertilizers were applied in the groove and in the same amount for all cultivars: Ammonium sulfate (20% N), 10 g/m; triple superphosphate (20% P(2)0(5)) 10 g/m; Potassium cloride (60% K(2)0), 10 g/m. Therty days after planting, 10 g/plant of ammonium sulfate was applied. After 76 days from planting, the firsa sample was taken. Other samples were taken in equal intervals of 20 days, up to 216 days. When a decrease in fruitproduction was noted. The sample (plants) were divided in stems, leaves and fruits and chemical analysis were made for N, R, K, Ca, Mg e S. The variation on production (dry matter) nutrient uptake' and fruits yield, were obtained from data calculated by adjusted regression equation analysis. The maxima point from these equations were taken to show the total nutrient uptake. From the data obtained, the following conclusions could be drawn. Growth - The dry matter of stems, leaves and fruits were different among the cultivars. The production of dry matter by the stems and fruits were linnear for all cultivars up to 196 and 216 days. The highest productions on dry matter varied between 15 to 25 g and 12 to 20 g/plant. The maximum production of dry matter in the leaves among the cultivars varied between 20 to 30 g at 196 and 173 days respectivelly. The cultivars Campinas (IAC-2712) and Camanducaia (IAC-3530) produced more dry matter than SH-2 cultivar. Nutrient uptake -< The were differences on nutrient content in stems and leaves among cultivars (R, K, Ca, S, B) and in the fruits for N, R, K, Mg, S. The highest absorption of nutrients (days after planting) is shown in Table I. Yield - No significant difference in fruit production was observed among the cultivars. The highest yield among the cultivars showed a variation between 103 to 151 g per plant at the 207 and 207 days,Efetuou-se um estudo para avaliar a absorção e a extração dos macronutrientes nos seguintes cultivares de morangueiro: Campinas (IAC-2712); Camanducaia (IAC-3530) ; Monte Alegre (IAC-3113) e SH-2 em condições de campo. A instalação deu-se em um solo pertencente ao grande grupo Terra Roxa Estruturada, e à série "Luiz de Queiroz" cultivado intensivamente com hortaliças há mais de 25 anos, em Piracicaba-SP. A adubação aplicada foi uniforme para todos os cultivares. São apresentadas as concentrações dos macronutrientes em porcentagem nos seguintes órgãos: caules, folhas e frutos dos cultivares em função da idade (X) em dias. Constatou-se que os cultivares diferem quanto à absorção dos macronutrientes (R, K, Ca e S em relação a caules e folhas, e, N, R, K, Mg e S em relação aos frutos). Constatou-se também que os cultivares extraem totais diferentes de R, K, Ca, Mg e S sendo as extrações de R pelos cultivares menores do que as extrações de Ca e Mg, e no global as de Mg são equivalentes às de S. As quantidades máximas extraídas pelos cultivares para uma população de 150.000 plantas/ha foram : N - 192 kg; R - 24-50 kg; K - 133-244 kg; Ca - 76-116 kg; Mg - 30-34 kg; S - 13-27 kg. - A maior produção de matéria seca tanto nos órgãos como na planta inteira, ocorreu nos cultivares Campinas (IAC-2712) e Camanducaia (IAC-3530) e a menor produção verificou-se no cultivar SH-2. - Os cultivares diferem na absorção dos nutrientes: R, K, Ca, S para caules e folhas. E para frutos, N, R, K, Mg e S. - Os cultivares atingem o máximo da absorção de nutrientes nos órgãos nas seguintes épocas, em dias: - Os cultivares extraem e exportam totais diferentes de R, K, Ca e Mg. - Tanto os macronutrientes são extraídos em quantidades mais elevadas através das folhas e em menor proporção por caules e frutos. - As extrações de N, K e Ca são mais altas que aquelas dos demais macronutrientes. - As extrações de R pelos cultivares são menores que as de Ca e Mg, sendo ainda as extrações de Ca superiores às de Mg, enquanto no global as de Mg são equivalentes às de S. - A extração de macronutrientes verifica-se na ordem decrescente: K, N, Ca, Mg, S e P

Early Gnathostome Phylogeny Revisited: Multiple Method Consensus

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.A series of recent studies recovered consistent phylogenetic scenarios of jawed vertebrates, such as the paraphyly of placoderms with respect to crown gnathostomes, and antiarchs as the sister group of all other jawed vertebrates. However, some of the hylogenetic relationships within the group have remained controversial, such as the positions of Entelognathus, ptyctodontids, and the Guiyu-lineage that comprises Guiyu, Psarolepis and Achoania. The revision of the dataset in a recent study reveals a modified phylogenetic hypothesis, which shows that some of these phylogenetic conflicts were sourced from a few inadvertent miscodings. The interrelationships of early gnathostomes are addressed based on a combined new dataset with 103 taxa and 335 characters, which is the most comprehensive morphological dataset constructed to date. This dataset is investigated in a phylogenetic context using maximum parsimony (MP), Bayesian inference (BI) and maximum likelihood (ML) approaches in an attempt to explore the consensus and incongruence between the hypotheses of early gnathostome interrelationships recovered from different methods. Our findings consistently corroborate the paraphyly of placoderms, all `acanthodians' as a paraphyletic stem group of chondrichthyans, Entelognathus as a stem gnathostome, and the Guiyu-lineage as stem sarcopterygians. The incongruence using different methods is less significant than the consensus, and mainly relates to the positions of the placoderm Wuttagoonaspis, the stem chondrichthyan Ramirosuarezia, and the stem osteichthyan LophosteusÐthe taxa that are either poorly known or highly specialized in character complement. Given that the different performances of each phylogenetic approach, our study provides an empirical case that the multiple phylogenetic analyses of morphological data are mutually complementary rather than redundant