Forest performance is challenged by climate change but higher atmospheric CO2 (ca) could help trees mitigate the negative effect of enhanced water stress. Forest projections using data assimilation ...with mechanistic models are a valuable tool to assess forest performance. Firstly, we used dendrochronological data from 12 Mediterranean tree species (six conifers and six broadleaves) to calibrate a process‐based vegetation model at 77 sites. Secondly, we conducted simulations of gross primary production (GPP) and radial growth using an ensemble of climate projections for the period 2010–2100 for the high‐emission RCP8.5 and low‐emission RCP2.6 scenarios. GPP and growth projections were simulated using climatic data from the two RCPs combined with (i) expected ca; (ii) constant ca = 390 ppm, to test a purely climate‐driven performance excluding compensation from carbon fertilization. The model accurately mimicked the growth trends since the 1950s when, despite increasing ca, enhanced evaporative demands precluded a global net positive effect on growth. Modeled annual growth and GPP showed similar long‐term trends. Under RCP2.6 (i.e., temperatures below +2 °C with respect to preindustrial values), the forests showed resistance to future climate (as expressed by non‐negative trends in growth and GPP) except for some coniferous sites. Using exponentially growing ca and climate as from RCP8.5, carbon fertilization overrode the negative effect of the highly constraining climatic conditions under that scenario. This effect was particularly evident above 500 ppm (which is already over +2 °C), which seems unrealistic and likely reflects model miss‐performance at high ca above the calibration range. Thus, forest projections under RCP8.5 preventing carbon fertilization displayed very negative forest performance at the regional scale. This suggests that most of western Mediterranean forests would successfully acclimate to the coldest climate change scenario but be vulnerable to a climate warmer than +2 °C unless the trees developed an exaggerated fertilization response to CO2.
We analyzed dynamics of forest growth and GPP in relation to climate change and CO2 across the western Mediterranean. Tree growth was not enhanced in the recent past despite raising CO2. Models suggest that forests would mostly resist an increase in temperature below +2 °C. Further warming over that threshold would result in very negative Mediterranean forest performance. A strong fertilization effect in response to exponentially raising CO2 could counteract the negative effect of a warmer climate, but this effect seems unrealistic.
Fingolimod approval was based mainly on two clinical trials, FREEDOMS and TRANSFORMS, which demonstrated the efficacy and safety of fingolimod in patients with multiple sclerosis (MS). We present an ...observational study that validates these trials findings in a real-world setting, whereby the effectiveness and safety of fingolimod was assessed in Seville's' (Spain) clinical practice. This retrospective study in MS patients assessed effectiveness (relapses, EDSS, gadolinium-enhancing T1 and new/enlarged T2-weighted lesions): total cohort (n = 249) and stratified according to prior treatment (glatiramer acetate/interferon beta-1 immunomodulator, natalizumab, naïve), gender, basal EDSS score, basal Gd+ lesions, ARR prior to treatment, age at treatment initiation and number of prior treatments. A multivariante model was used to assess the ARR with baseline characteristics. The safety profile (adverse events AEs) was also described. Fingolimod reduced the annualized relapse rate (ARR) by 75%, 67% and 85% in the total cohort, patients previously treated with immunomodulatory and naïve patients (p<0.0001 all cases). However, patients previously treated with natalizumab kept a constant ARR. The ARR results and the consequent increase in the proportion of relapse-free patients were independent of the age at treatment initiation, number of prior treatments, gender and basal Gd+ lesions. Although fingolimod was effective regardless the basal EDSS score and ARR prior to fingolimod treatment, better outcomes were observed in patients with basal EDSS score <3 (0.2 vs. 0.4; p = 0.0244) and ARR ≥ 2 prior to fingolimod treatment (p = 0.0338). Only the basal EDSS score was association with ARR in the first 24 months of fingolimod treatment in the multivariante model (p = 0.0439). The cumulative probability of disability progression was 20% (month-24) in the total cohort, and was independent from prior treatment, age at treatment initiation, number of prior treatments, gender, basal EDSS score, basal Gd+ lesions and ARR prior to treatment. The real-world fingolimod benefits observed in this study seem to be similar than those observed in previous clinical trials.
Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing-remitting disease (RRMS) and is followed by a progressive phase (SPMS). The progressive phase ...causes the greatest disability and has no effective therapy, but the processes that drive SPMS are mostly unknown. Here we found higher serum concentrations of 15alpha-hydroxicholestene (15-HC) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis (EAE) but not in patients with RRMS. In mice, 15-HC activated microglia, macrophages and astrocytes through a pathway involving Toll-like receptor 2 (TLR2) and poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 activity was higher in monocytes of patients with SPMS, and PARP-1 inhibition suppressed the progression of EAE. Thus, the TLR2-PARP-1 pathway is a potential new therapeutic target in SPMS.
Purpose To compare the outcomes of 2 groups of patients undergoing anterior cruciate ligament (ACL) reconstruction: the first with a quadrupled semitendinosus gracilis (ST-G) autograft larger than ...8 mm diameter and the second with a 5-strand ST-G autograft larger than 8 mm due to an insufficient diameter graft harvesting. Methods This was a retrospective study with 70 patients divided into 2 groups. Inclusion criteria included ACL ruptures of less than 3 months, ST-G ACL reconstructions, and final (4-strand or 5-strand) graft size larger than 8 mm. Exclusion criteria included multiligament knee injuries, meniscal or chondral pathology, ACL re-ruptures, inflammatory joint disease, or other procedures in the knee. Results Group A comprised 33 patients with a quadruple ST-G graft, and group B comprised 37 patients with an insufficient graft diameter (<8 mm) in which a 5-strand graft was used. Mean age in group A was 29.7 (range 17-52) years and in group B was 30.6 (range 13-53) years ( P = .78). Average follow-up in group A was 32.2 (range 24-48) months and in group B was 30.35 (range 24-48) months ( P = .75). Average graft diameter in group A was 8.5 mm (range 8-10) and in group B when the graft was measured as quadruple was 7.2 mm (range 6.5-7.5) and 9.2 mm (range 8-10) when it was converted to 5-strand ( P = .00596). Group A had 3 (9%) re-ruptures, and group B had 2 (5.4%) ( P = .55). The average postoperative Lysholm score in group A was 93.3 (range 71-100) and in group B was 97.1 (range 80-100) ( P = .79). Mean postoperative International Knee Documentation Committee in group A was 91 (range 75.9-100) and in group B was 96.8 (range 82-100) ( P = .18). Conclusions In our study, the 5-strand hamstring autograft in ACL reconstruction was clinically comparable with the quadruple autograft larger than 8 mm. The differences in re-rupture and clinical outcomes were not statistically significant between the 2 groups, suggesting that it is a valid option when we have a graft of insufficient diameter. Level of Evidence Level III, retrospective comparative study.
Objective
In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no ...studies have directly compared the outcomes of switching to either of these agents.
Methods
Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing–remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi‐randomization with propensity score–based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise‐censored analyses.
Results
Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on‐study follow‐up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability–time curve) differed between natalizumab and fingolimod (−0.12 vs 0.04 per year, respectively, p < 0.001).
Interpretation
This study suggests that in active multiple sclerosis during treatment with injectable disease‐modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short‐term disability burden. Ann Neurol 2015;77:425–435
Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and ...disease progression to determine if male MS patients have a worse clinical outcome than females.
Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS.
In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change.
Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar.
Severe droughts have the potential to reduce forest productivity and trigger tree mortality. Most trees face several drought events during their life and therefore resilience to dry conditions may be ...crucial to long-term survival. We assessed how growth resilience to severe droughts, including its components resistance and recovery, is related to the ability to survive future droughts by using a tree-ring database of surviving and now-dead trees from 118 sites (22 species, >3,500 trees). We found that, across the variety of regions and species sampled, trees that died during water shortages were less resilient to previous non-lethal droughts, relative to coexisting surviving trees of the same species. In angiosperms, drought-related mortality risk is associated with lower resistance (low capacity to reduce impact of the initial drought), while it is related to reduced recovery (low capacity to attain pre-drought growth rates) in gymnosperms. The different resilience strategies in these two taxonomic groups open new avenues to improve our understanding and prediction of drought-induced mortality.
In this case report, we describe the effectiveness of fine-needle aspiration of Virchow’s node for the diagnosis of metastatic prostate cancer in a 62-year-old male without any medical history, ...negative urinary tract symptoms, and a normal digital rectal examination. The patient presented with respiratory distress, diffuse lymphadenopathy, and high levels of prostate-specific antigen. Multiple studies were done with inconclusive results until positive findings of the NKX3.1 gene were found in the immunostain smear of the Virchow’s node, which led to the identification of metastatic prostate cancer.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial ...aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.
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