Echocardiographic evaluation of pulmonary hypertension,right ventricular function,and right ventricular-pulmonary arterial coupling in patients with rheumatoid arthritis

Clinical Rheumatology - Rheumatoid arthritis (RA) patients are at increased risk for developing cardiovascular disease, including right heart failure. The evaluation of right ventricle (RV) using...     

Influencia de la neoateroesclerosis en el pronóstico y la respuesta al tratamiento de los pacientes con reestenosis en el stent

Introduction and objectivesNeoatherosclerosis is one of the causes of in-stent restenosis (ISR). Our objective was to evaluate the influence of neoatherosclerosis on prognosis and treatment response in patients with ISR.MethodsThis is a pooled analysis of the optical coherence tomography (OCT)-substudies of 2 multicenter, randomized clinical trials, RIBS IV and V, comparing treatment with paclitaxel-coated balloon vs everolimus-eluting stent in patients with ISR. OCT evaluation was performed at baseline and at 6 to 9 months. Neoatherosclerosis was defined in baseline OCT as neointima with calcified or lipid content. We evaluated the angiographic and OCT results at 6 to 9 months and the occurrence of major adverse cardiovascular events at 3 years of follow-up in patients with and without neoatherosclerosis treated with paclitaxel-coated balloon or everolimus-eluting stents.ResultsSixty-four patients underwent OCT at the time of the index procedure. Neoatherosclerosis was documented in 23 (36%) lesions. Angiographic follow-up at 6 to 9 months showed no differences in restenosis [5 (24%) vs 6 (15%) P = .49], minimum lumen diameter (1.79 ± 0.7 vs 1.94 ± 0.6 mm; P = .41) or late loss (0.33 ± 0.7 vs 0.15 ± 0.5; P = .34) in patients with and without neoatherosclerosis, respectively. Follow-up OCT confirmed the absence of differences in quantitative parameters and the characteristics of tissue coverage between the 2 groups. At 3 years of follow-up, the major adverse cardiovascular events rate was 3 (13%) vs 5 (12%) in the neoatherosclerosis and nonneoatherosclerosis groups (HR, 0.94; 95%CI, 0.22-3.93; P = .93).ConclusionsIn this limited study population, OCT-defined neoatherosclerosis did not seem to influence acute and long-term outcomes in patients randomized to paclitaxel-coated balloon or everolimus-eluting stents for ISR.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Disease severity and treatment requirements in familial inflammatory bowel disease

Purpose

Several studies demonstrate an increased prevalence and concordance of inflammatory bowel disease among the relatives of patients. Other studies suggest that genetic influence is over-estimated. The aims of this study are to evaluate the phenotypic expression and the treatment requirements in familial inflammatory bowel disease, to study the relationship between number of relatives and degree of kinship with disease severity and to quantify the impact of family aggregation compared to other environmental factors.

Methods

Observational analytical study of 1211 patients followed in our unit. We analyzed, according to the existence of familial association, number and degree of consanguinity, the phenotypic expression, complications, extraintestinal manifestations, treatment requirements, and mortality. A multivariable analysis considering smoking habits and non-steroidal-anti-inflammatory drugs was performed.

Results

14.2% of patients had relatives affected. Median age at diagnosis tended to be lower in the familial group, 32 vs 29, p = 0.07. In familial ulcerative colitis, there was a higher proportion of extraintestinal manifestations: peripheral arthropathy (OR = 2.3, p = 0.015) and erythema nodosum (OR = 7.6, p = 0.001). In familial Crohn’s disease, there were higher treatment requirements: immunomodulators (OR = 1.8, p = 0.029); biologics (OR = 1.9, p = 0.011); and surgery (OR = 1.7, p = 0.044). The abdominal abscess increased with the number of relatives affected: 5.1% (sporadic), 7.0% (one), and 14.3% (two or more), p=0.039. These associations were maintained in the multivariate analysis.

Conclusions

Familial aggregation is considered a risk factor for more aggressive disease and higher treatment requirements, a tendency for earlier onset, more abdominal abscess, and extraintestinal manifestations, remaining a risk factor analyzing the influence of some environmental factors.

     

Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: A study in Spanish and Italian populations and meta‐analysis

Objective

The LCE3C_LCE3B‐del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C_LCE3B‐del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta‐analysis including the previous case–control studies.

Methods

We genotyped LCE3C_LCE3B‐del and its tag single‐nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta‐analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed.

Results

We observed a significant association between PsA and the LCE3C_LCE3B‐del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14–1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta‐analysis including data from all previous published studies confirmed an association of PsA with the LCE3C_LCE3B‐del tag SNP.

Conclusion

LCE3C_LCE3B‐del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders.

     

Ontogeny of adenohypophyseal cells in the pituitary of the American shad (Alosa sapidissima)

The distribution and ontogeny of adenohypophyseal cells have been studied in the pituitary gland of embryos, larvae, and juveniles of the clupeid American shad (Alosa sapidissima) using immunocytochemical techniques. In juvenile specimens, adenohypophysis was composed of rostral pars distalis (RPD), formed by cavities lined by prolactin (PRL), adrenocorticotropic hormone (ACTH), and gonadotropic hormone (GTH) cells; proximal pars distalis (PPD), containing growth hormone (GH), GTH, and putative thyroid stimulating hormone (TSH) cells; and pars intermedia (PI) with somatolactin (SL) and melanophore stimulating hormone (MSH) cells. At 3 days post-fertilization (3 days pre-hatching) the pituitary of embryos consisted of an oval mass of cells, close to the ventral margin of the diencephalon, divided in rostral and caudal regions. At this time PRL and ACTH cells appeared in the rostral region of the adenohypophysis, while SL cells were observed in the caudal region where MSH cells showed reactivity 1 day before hatching. At variance, GH cells showed a weak immunoreactivity in the rostral portion at hatching that increased 2 days latter. GTH cells also showed weak immunoreactivity in the rostral region of the adenohypophysis at hatching time. Two days later GTH cells were located in the rostral and central regions of the adenohypophysis. At hatching, the neurohypophysis was very small and no nerve processes were seen to penetrate the adenohypophysis tissue. After hatching, the pituitary gland elongated and in 7 days old larvae, the RPD showed a small lumen surrounded by a palisade of PRL, ACTH, and GHT cells; the PPD showed GH and GTH cells while the PI contained SL and MSH cells. The adenohypophysis and neural lobe increased in size with development and, in 42 days old larvae, they were similar to those of juvenile specimens.     

Induction of tumor NK-cell immunity by anti-CD69 antibody therapy

The leukocyte activation marker CD69 is a novel regulator of the immune response, modulating the production of cytokines including transforming growth factor-beta (TGF-beta). We have generated an antimurine CD69 monoclonal antibody (mAb), CD69.2.2, which down-regulates CD69 expression in vivo but does not deplete CD69-expressing cells. Therapeutic administration of CD69.2.2 to wild-type mice induces significant natural killer (NK) cell-dependent antitumor responses to major histocompatibility complex (MHC) class I low RMA-S lymphomas and to RM-1 prostatic carcinoma lung metastases. These in vivo antitumor responses are comparable to those seen in CD69(-/-) mice. Enhanced host NK cytotoxic activity correlates with a reduction in NK-cell TGF-beta production and is independent of tumor priming. In vitro studies demonstrate the novel ability of anti-CD69 mAbs to activate resting NK cells in an Fc receptor-independent manner, resulting in a substantial increase in both NK-cell cytolytic activity and interferon gamma (IFNgamma) production. Modulation of the innate immune system with monoclonal antibodies to host CD69 thus provides a novel means to antagonize tumor growth and metastasis.     

Functional rarity and evenness are key facets of biodiversity to boost multifunctionality

The functional traits of organisms within multispecies assemblages regulate biodiversity effects on ecosystem functioning. Yet how traits should assemble to boost multiple ecosystem functions simultaneously (multifunctionality) remains poorly explored. In a multibiome litter experiment covering most of the global variation in leaf trait spectra, we showed that three dimensions of functional diversity (dispersion, rarity, and evenness) explained up to 66% of variations in multifunctionality, although the dominant species and their traits remained an important predictor. While high dispersion impeded multifunctionality, increasing the evenness among functionally dissimilar species was a key dimension to promote higher multifunctionality and to reduce the abundance of plant pathogens. Because too-dissimilar species could have negative effects on ecosystems, our results highlight the need for not only diverse but also functionally even assemblages to promote multifunctionality. The effect of functionally rare species strongly shifted from positive to negative depending on their trait differences with the dominant species. Simultaneously managing the dispersion, evenness, and rarity in multispecies assemblages could be used to design assemblages aimed at maximizing multifunctionality independently of the biome, the identity of dominant species, or the range of trait values considered. Functional evenness and rarity offer promise to improve the management of terrestrial ecosystems and to limit plant disease risks.

Biodiversity is of pivotal importance for maintaining ecosystem functions, such as primary productivity, litter decomposition, or soil nutrient cycling, and for preventing disease risks (1–4). Despite the important advances in our understanding of the role of biodiversity in natural and managed ecosystems, we still ignore how the physiological, morphological, and biochemical characteristics of species—their functional traits—should assemble to boost multiple functions simultaneously [multifunctionality (5)]. Uncovering the trait assemblages that promote high multifunctionality is critical to identify baselines that track the consequences of biodiversity loss on ecosystems, to undertake effective restoration actions, or to engineer the species assemblages of managed ecosystems that promote biodiversity and high multifunctionality in a changing world.The relationship between functional traits and multifunctionality has been shown to vary from positive to negative depending on the ecosystem, species pool, and biogeographical context considered (6–8). Such a high context dependency may largely depend on how functional traits are assembled within communities (9). While the traits of dominant species (hereafter referred to as functional dominance) can strongly determine individual ecosystem functions (10), their role becomes less clear when considering multifunctionality (7, 11). This is so because in an ecosystem, species that are functionally different from the dominant ones—functional diversity—may contribute more to certain key functions than their lower abundance would suggest (7, 11, 12). High functional diversity—through the dispersion of trait values (hereafter referred to as functional dispersion) or the presence of species with infrequent trait values (hereafter referred to as functional rarity)—for instance, in the case of keystone species—may enhance multifunctionality (9) if functionally dissimilar species exploit or release contrasting resources or the same resources but at different spatial or temporal scales (1). However, if species become too dissimilar, this could lead to strong negative effects on ecosystems (e.g., in the case of invasive species adding a new set of trait values) (6, 7, 13). In the later case, higher evenness among functionally dissimilar species (hereafter referred to as functional evenness) could promote synergistic interactions and counteract such negative biodiversity effects on multifunctionality (6, 7). However, functional dominance, dispersion, rarity, and evenness often covary in real-world ecosystems (14), hindering the evaluation of their individual effect on multifunctionality (6, 14, 15). A manipulative study revealing which trait assemblages could boost positive biodiversity effects on multifunctionality across multiple ecosystems is yet lacking.The distribution of trait values (hereafter referred to as trait distribution) within complex, multispecies assemblages often deviates from the symmetric normal distribution, classically assumed in ecological studies (14, 15). While the mean and the variance allow for characterization of the functional dominance and dispersion of a normal distribution, the skewness and kurtosis offer insights on the shape of the complex trait distributions encountered in naturally assembled communities (6, 14, 15). The skewness represents the asymmetry of the distributions. High negative or positive values of skewness occur when trait distributions are strongly left or right tailed as a result of rare species with infrequent trait values compared with the bulk of the distribution: a definition of functional rarity. Kurtosis represents the relative peakiness of trait distribution, where a low kurtosis value reflects functionally even distributions. Investigating complex trait distributions thus offers a unique opportunity to decipher the interplay of functional dominance, dispersion, rarity, and evenness in determining multifunctionality and represents a fundamental step toward the design and management of species assemblages that could maximize biodiversity effects on ecosystems.Here, we present results from a multibiome experiment examining how the functional dominance, dispersion, evenness, and rarity of plant litter assemblages influence multifunctionality and soil microbial communities. We manipulated complex trait distributions to disentangle the influence of the four biodiversity attributes, while species richness (n = 15 species each) and total litter biomass (1 g) were kept constant among litter assemblages. We assembled 570 experimental leaf litter mixtures and monocultures using 90 species from six biomes covering a wide range of the global variability of two key plant functional traits (Specific Leaf Area [SLA] and lignin content) (16, 17) and tracked changes in multifunctionality and soil microbial communities as litter decomposed (Fig. 1; see also Methods and SI Appendix, Tables S1 and S2 and Figs. S1 and S2). We used a single decomposition environment (i.e., one soil type and controlled climatic condition) to avoid variations due to differences in decomposer communities, soil parameters, and climate. Leaf litter assemblages were set up using a set of 120,000 simulated functional trait distributions (see Methods and SI Appendix, Figs. S3 and S4). Then, we selected a subset of 570 assemblages that covered the entire range of values that functional dominance and diversity could take while minimizing their correlations within and across biomes (SI Appendix, Table S3 and Fig. S4). We calculated multifunctionality using nine litter and soil functions related to carbon (C), nitrogen (N), and phosphorus (P) cycling (see Methods and SI Appendix, Fig. S5). We also addressed the relative abundance (fungal trophic modes) and diversity of soil bacteria and fungi. Monitoring changes in litter decomposition, soil processes, and microbial communities thus allowed us to consider a part—albeit a functionally important part—of whole ecosystem functioning. We tested the core hypothesis that functionally dispersed and highly even trait distributions are the litter trait assemblages to maximize multifunctionality.Open in a separate windowFig. 1.The experimental and analytical framework to test the effects of dominant species and their traits (dominance) and of functional diversity (dispersion, rarity, and evenness) on multifunctionality. (A) The SLA and leaf litter lignin content of 90 species from six biomes covering a wide array of the global variation in the traits observed (see also SI Appendix, Table S2). (B) Disentangling functional dominance, dispersion, rarity, and evenness by manipulating the mean, variance, skewness, and kurtosis of trait-abundance distributions. (C) The microcosms containing the leaf litter communities (photographs by J.H.C.C, L.D., N.G., N.S., and R.M.).