Impact of intravitreal ranibizumab, aflibercept and bevacizumab on retinal ganglion cell and nerve fibre layer thickness in Neovascular age-related macular degeneration

Purpose: To compare the effects of monotherapy with intravitreal ranibizumab, aflibercept and bevacizumab on retinal ganglion cell layer (RGCL) and retinal nerve fibre layer (RNFL) in patients with naïve neovascular age-related macular degeneration (nAMD). Methods: This is a retrospective cohort study with three-groups comparison. 83 patients and 97 eyes on continuous monotherapy with an intravitreal anti-vascular endothelial growth factor (anti-VEGF) were followed for 24months and divided into three groups according to anti-VEGF (aflibercept: 25 eyes, ranibizumab: 34 eyes, bevacizumab: 38 eyes). Main outcome measures included: RGCL and RNFL thickness, best corrected visual acuity (BCVA), central macular thickness (CMT), macular volume (MV) and the presence of intraretinal fluids (IRF), subretinal fluids (SRF) and retinal pigment epithelial atrophy (RPE-atrophy). All outcome measures were recorded at the time of the first injection, 1 and 2years after treatment and compared longitudinally and between groups. Results: The mean age was 79±7years. The RGCL thickness, MV, CMT and the presence of IRF and SRF decreased significantly within all three medication groups (p<0.05 for all) with no significant difference between groups over the 2-year follow-up period (p>0.10 for all). The decrease in RNFL thickness was not significant within or between the groups after a 2-year follow-up (p>0.055 for all). RPE-atrophy increased significantly after 2 years in all three groups (p<0.028 for all) with no significant difference between groups at all three time points (p>0.307 for all). BCVA was comparable between the three groups over the 2-year follow-up period (p>0.22 for all). Conclusions: Monotherapy with intravitreal aflibercept, bevacizumab and ranibizumab was associated with comparable significant decreases in RGCL thickness, CMT, MV, IRF and SRF in naïve nAMD patients during the first 2 years of treatment. Furthermore, no significant differences either in BCVA or RNFL thickness were observed between the three intravitreal anti-VEFGs during the first 2 years of treatment

Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment

Producción CientíficaParkinson's disease (PD), the second most common neurodegenerative disorder, is etiologically heterogeneous, with most cases thought to arise from a combination of environmental factors and genetic predisposition; about 10% of cases are caused by single gene mutations. While neurotoxin models replicate many of the key behavioral and neurological features, they often have limited relevance to human exposures. Genetic models replicate known disease-causing mutations, but are mostly unsuccessful in reproducing major features of PD. In this study, we created a BAC (bacterial artificial chromosome) transgenic rat model of PD expressing the E46K mutation of α-synuclein, which is pathogenic in humans. The mutant protein was expressed at levels ~2-3-fold above endogenous α-synuclein levels. At 12 months of age, there was no overt damage to the nigrostriatal dopamine system; however, (i) alterations in striatal neurotransmitter metabolism, (ii) accumulation and aggregation of α-synuclein in nigral dopamine neurons, and (iii) evidence of oxidative stress suggest this model replicates several preclinical features of PD. Further, when these animals were exposed to rotenone, a mitochondrial toxin linked to PD, they showed heightened sensitivity, indicating that α-synuclein expression modulates the vulnerability to mitochondrial impairment. We conclude that these animals are well-suited to examination of gene-environment interactions that are relevant to PD

Renewal of Collaborative Research: Economically Viable Forest Harvesting Practices That Increase Carbon Sequestration

Forests provide wildlife habitat, water and air purification, climate moderation, and timber and nontimber products. Concern about climate change has put forests in the limelight as sinks of atmospheric carbon. The C stored in the global vegetation, mostly in forests, is nearly equivalent to the amount present in atmospheric CO{sub 2}. Both voluntary and government-mandated carbon trading markets are being developed and debated, some of which include C sequestration resulting from forest management as a possible tradeable commodity. However, uncertainties regarding sources of variation in sequestration rates, validation, and leakage remain significant challenges for devising strategies to include forest management in C markets. Hence, the need for scientifically-based information on C sequestration by forest management has never been greater. The consequences of forest management on the US carbon budget are large, because about two-thirds of the {approx}300 million hectare US forest resource is classified as 'commercial forest.' In most C accounting budgets, forest harvesting is usually considered to cause a net release of C from the terrestrial biosphere to the atmosphere. However, forest management practices could be designed to meet the multiple goals of providing wood and paper products, creating economic returns from natural resources, while sequestering C from the atmosphere. The shelterwood harvest strategy, which removes about 30% of the basal area of the overstory trees in each of three successive harvests spread out over thirty years as part of a stand rotation of 60-100 years, may improve net C sequestration compared to clear-cutting because: (1) the average C stored on the land surface over a rotation increases, (2) harvesting only overstory trees means that a larger fraction of the harvested logs can be used for long-lived sawtimber products, compared to more pulp resulting from clearcutting, (3) the shelterwood cut encourages growth of subcanopy trees by opening up the forest canopy to increasing light penetration. Decomposition of onsite harvest slash and of wastes created during timber processing releases CO{sub 2} to the atmosphere, thus offsetting some of the C sequestered in vegetation. Decomposition of soil C and dead roots may also be temporarily stimulated by increased light penetration and warming of the forest floor. Quantification of these processes and their net effect is needed. We began studying C sequestration in a planned shelterwood harvest at the Howland Forest in central Maine in 2000. The harvest took place in 2002 by the International Paper Corporation, who assisted us to track the fates of harvest products (Scott et al., 2004, Environmental Management 33: S9-S22). Here we present the results of intensive on-site studies of the decay of harvest slash, soil respiration, growth of the remaining trees, and net ecosystem exchange (NEE) of CO{sub 2} during the first six years following the harvest. These results are combined with calculations of C in persisting off-site harvest products to estimate the net C consequences to date of this commercial shelterwood harvest operation. Tower-based eddy covariance is an ideal method for this study, as it integrates all C fluxes in and out of the forest over a large 'footprint' area and can reveal how the net C flux, as well as gross primary productivity and respiration, change following harvest. Because the size of this experiment precludes large-scale replication, we are use a paired-airshed approach, similar to classic large-scale paired watershed experiments. Measurements of biomass and C fluxes in control and treatment stands were compared during a pre-treatment calibration period, and then divergence from pre-treatment relationships between the two sites measured after the harvest treatment. Forests store carbon (C) as they accumulate biomass. Many forests are also commercial sources of timber and wood fiber. In most C accounting budgets, forest harvesting is usually considered to cause a net release of C from the terrestrial biosphere to the atmosphere. However, it might also be possible for commercial use of forests to contribute to terrestrial sequestration of C. The objective of the our research project is to determine whether shelterwood cutting regimes now being adopted in the commercial forests of Maine and other areas of the country can achieve these multiple goals

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations

partially_open16Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.partially_openembargoed_20230131Pollyea, Daniel A; DiNardo, Courtney D; Arellano, Martha L; Pigneux, Arnaud; Fiedler, Walter; Konopleva, Marina; Rizzieri, David A; Smith, B Douglas; Shinagawa, Atsushi; Lemoli, Roberto M; Dail, Monique; Duan, Yinghui; Chyla, Brenda; Potluri, Jalaja; Miller, Catherine L; Kantarjian, Hagop MPollyea, Daniel A; Dinardo, Courtney D; Arellano, Martha L; Pigneux, Arnaud; Fiedler, Walter; Konopleva, Marina; Rizzieri, David A; Smith, B Douglas; Shinagawa, Atsushi; Lemoli, Roberto M; Dail, Monique; Duan, Yinghui; Chyla, Brenda; Potluri, Jalaja; Miller, Catherine L; Kantarjian, Hagop

An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice

Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI

Climate control of terrestrial carbon exchange across biomes and continents

Understanding the relationships between climate and carbon exchange by terrestrial ecosystems is critical to predict future levels of atmospheric carbon dioxide because of the potential accelerating effects of positive climate-carbon cycle feedbacks. However, directly observed relationships between climate and terrestrial CO2exchange with the atmosphere across biomes and continents are lacking. Here we present data describing the relationships between net ecosystem exchange of carbon (NEE) and climate factors as measured using the eddy covariance method at 125 unique sites in various ecosystems over six continents with a total of 559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of mean annual temperature at mid- and high-latitudes, (2) a strong function of dryness at mid- and low-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt (45°N). The sensitivity of NEE to mean annual temperature breaks down at ∼16 ®C (a threshold value of mean annual temperature), above which no further increase of CO,.2uptake with temperature was observed and dryness influence overrules temperature influence. © 2010 lOP Publishing Ltd

Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease

BACKGROUND: One typical feature in chronic obstructive pulmonary disease (COPD) is the disturbance of the oxidant/antioxidant balance. Glutaredoxins (Grx) are thiol disulfide oxido-reductases with antioxidant capacity and catalytic functions closely associated with glutathione, the major small molecular weight antioxidant of human lung. However, the role of Grxs in smoking related diseases is unclear. METHODS: Immunohistochemical and Western blot analyses were conducted with lung specimens (n = 45 and n = 32, respectively) and induced sputum (n = 50) of healthy non-smokers and smokers without COPD and at different stages of COPD. RESULTS: Grx1 was expressed mainly in alveolar macrophages. The percentage of Grx1 positive macrophages was significantly lower in GOLD stage IV COPD than in healthy smokers (p = 0.021) and the level of Grx1 in total lung homogenate decreased both in stage I–II (p = 0.045) and stage IV COPD (p = 0.022). The percentage of Grx1 positive macrophages correlated with the lung function parameters (FEV1, r = 0.45, p = 0.008; FEV1%, r = 0.46, p = 0.007, FEV/FVC%, r = 0.55, p = 0.001). Grx1 could also be detected in sputum supernatants, the levels being increased in the supernatants from acute exacerbations of COPD compared to non-smokers (p = 0.013) and smokers (p = 0.051). CONCLUSION: The present cross-sectional study showed that Grx1 was expressed mainly in alveolar macrophages, the levels being decreased in COPD patients. In addition, the results also demonstrated the presence of Grx1 in extracellular fluids including sputum supernatants. Overall, the present study suggests that Grx1 is a potential redox modulatory protein regulating the intracellular as well as extracellular homeostasis of glutathionylated proteins and GSH in human lung

Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1

Niemann‐Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post‐mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C‐X‐C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL‐3, IL‐10 and IL‐13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147148/1/jimd0083.pd