Nitrite (NO2−) is a substrate for both oxidative and reductive microbial metabolism. NO2− accumulates at the base of the euphotic zone in oxygenated, stratified open-ocean water columns, forming a ...feature known as the primary nitrite maximum (PNM). Potential pathways of NO2− production include the oxidation of ammonia (NH3) by ammonia-oxidizing bacteria and archaea as well as assimilatory nitrate (NO3−) reduction by phytoplankton and heterotrophic bacteria. Measurements of NH3 oxidation and NO3− reduction to NO2− were conducted at two stations in the central California Current in the eastern North Pacific to determine the relative contributions of these processes to NO2− production in the PNM. Sensitive (< 10 nmol L−1), precise measurements of NH4+ and NO2− indicated a persistent NH4+ maximum overlying the PNM at every station, with concentrations as high as 1.5 μmol L−1. Within and just below the PNM, NH3 oxidation was the dominant NO2− producing process, with rates of NH3 oxidation to NO2− of up to 31 nmol L−1 d−1, coinciding with high abundances of ammonia-oxidizing archaea. Though little NO2− production from NO3− was detected, potentially nitrate-reducing phytoplankton (photosynthetic picoeukaryotes, Synechococcus, and Prochlorococcus) were present at the depth of the PNM. Rates of NO2− production from NO3− were highest within the upper mixed layer (4.6 nmol L−1 d−1) but were either below detection limits or 10 times lower than NH3 oxidation rates around the PNM. One-dimensional modeling of water column NO2− production agreed with production determined from 15N bottle incubations within the PNM, but a modeled net biological sink for NO2− just below the PNM was not captured in the incubations. Residence time estimates of NO2− within the PNM ranged from 18 to 470 days at the mesotrophic station and was 40 days at the oligotrophic station. Our results suggest the PNM is a dynamic, rather than relict, feature with a source term dominated by ammonia oxidation.
Twenty-six patients with advanced Hodgkin's disease received a related HLA haploidentical unmanipulated BMT, following a non-myeloablative conditioning with low-dose TBI, proposed by the Baltimore ...group; GvHD prophylaxis consisted of high-dose post-transplantation CY (PT-CY), mycophenolate and a calcineurin inhibitor. All patients had received a previous autograft, and 65% had active disease at the time of BMT. Sustained engraftment of donor cells occurred in 25 patients (96%), with a median time to neutrophil recovery (>0.5 × 10(9)/L) and platelet recovery (>20 × 10(9)/L) of +18 and +23 days from BMT. The incidence of grade II-IV acute GVHD and of chronic GVHD was 24% and 8%, respectively. With a median follow-up of 24 months (range 18-44) 21 patients are alive, 20 disease free. The cumulative incidence of TRM and relapse was 4% and 31%, respectively. The actuarial 3-year survival is 77%, the actuarial 3-year PFS is 63%. In conclusion, we confirm that high-dose PT-CY is effective as prophylaxis of GVHD after HLA haploidentical BMT, can prevent rejection and does not appear to eliminate the allogeneic graft versus lymphoma effect.
The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain ...disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders.
In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.
Introduction
According to the World Health Organization (WHO, 2017) depressive disorder continues to be the most widespread and growing mental illness in the world, also assumes that in 2020 ...depression will have a prevalence equal to one in six individuals. Studies of neuroanatomy have highlighted structural alterations in the hippocampus, striatal nuclei and prefrontal cortex in patients with mood disorders. This alteration in depressed patients is closely related to the secretion of neurotrophic factors, in particular there is a reduction in BDNF (Brain Derived Neurotrophic Factor).
Objectives
The objective of this study is to demonstrate which treatments are effective in reducing depressive symptoms that allow the increase of BDNF and consequently the structural homostaticity of the brain.
Methods
We have selected data from the literature of the last decade, collected on major search engines such as: Google Scholar, Research Gate, PubMed, Ebsco. Articles collected by selecting the following Keyword: depression, BDNF (Brain Derived Neurotrophic Factor), neuroimaging cognitive behavior therapy.
Results
The results show that in patients treated with a single drug treatment or vagus nerve stimulation, repetitive transcranial magnetic stimulation (Lang et al., 2008) or electroconvulsive therapy had improvements in BDNF levels, although compared to drug treatment there are problems of no responders, no compliance and lack of effectiveness in reducing vulnerability to relapse. In addition, the study has shown that patients treated with cognitive behavioral therapy have reported greater changes in the frontal and temporal cortex reducing both depressive symptoms and the risk of relapse.
Conclusions
Underlines the importance of an integrated approach
The research and development leading to the discovery and distribution of safe and effective COVID-19 vaccines demonstrated the indispensable nature of the pharmaceutical industry. While governments ...played an important role in financing these efforts by prepaying for dosages, it was private industry that delivered the scientific and technical miracles. At the same time, because of vaccine nationalism and hoarding, citizens of the global south have inadequate access to vaccines. This is a moral and human rights tragedy for which governments, not the pharmaceutical industry, are primarily responsible. This article argues that, as illustrated by humanitarian disaster of inadequate vaccine access in the global south, the failure of the UNGPs to adequately address the paramount role of government in human rights violations, even when there is shared responsibility with business, is a systemic failure that makes the United Nations an inappropriate forum for addressing business and human rights issues.
The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). ...The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT.
Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor.
A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms.
Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care.
Background: MET amplification has been detected in ∼20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to ...tyrosine kinase inhibitor (TKI) therapy. Patients and methods: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. Results: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. Conclusions: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.
When soil nitrate levels are low, plants suffer nitrogen (N) deficiency but when the levels are excessive, soil nitrates can pollute surface and subsurface waters. Strategies to reduce the nitrate ...pollution are necessary to reach a sustainable use of resources such as soil, water and plant. Buffer strips and cover crops can contribute to the management of soil nitrates, but little is known of their effectiveness in semiarid vineyards plantations. The research was carried out in the south coast of Sicily (Italy) to evaluate nitrate trends in a vineyard managed both conventionally and using two different cover crops (Triticum durum and Vicia sativa cover crop). A 10 m-wide buffer strip was seeded with Lolium perenne at the bottom of the vineyard. Soil nitrate was measured monthly and nitrate movement was monitored by application of a 15N tracer to a narrow strip between the bottom of vineyard and the buffer and non-buffer strips. Lolium perenne biomass yield in the buffer strips and its isotopic nitrogen content were monitored. Vicia sativa cover crop management contributed with an excess of nitrogen, and the soil management determined the nitrogen content at the buffer areas. A 6 m buffer strip reduced the nitrate by 42% with and by 46% with a 9 m buffer strip. Thanks to catch crops, farmers can manage the N content and its distribution into the soil over the year, can reduced fertilizer wastage and reduce N pollution of surface and groundwater.
We report on an extensive characterization of the cracking noise produced by charcoal samples when dampened with ethanol. We argue that the evaporation of ethanol causes transient and irregularly ...distributed internal stresses that promote the fragmentation of the samples and mimic some situations found in mining processes. The results show that, in general, the most fundamental seismic laws ruling earthquakes (the Gutenberg-Richter law, the unified scaling law for the recurrence times, Omori's law, the productivity law, and Båth's law) hold under the conditions of the experiment. Some discrepancies were also identified (a smaller exponent in the Gutenberg-Richter law, a stationary behavior in the aftershock rates for long times, and a double power-law relationship in the productivity law) and are related to the different loading conditions. Our results thus corroborate and elucidate the parallel between the seismic laws and fracture experiments caused by a more complex loading condition that also occurs in natural and induced seismicity (such as long-term fluid injection and gas-rock outbursts in mining processes).
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