Skin expression of IL-23 drives the development of psoriasis and psoriatic arthritis in mice

Psoriasis (PS) is a chronic skin inflammation. Up to 30% of the patients with PS develop psoriatic arthritis (PsA), a condition characterized by inflammatory arthritis that affects joints or entheses. Although there is mounting evidence for a critical role of interleukin-23 (IL-23) signaling in the pathogenesis of both PS and PsA, it remains unclear whether IL-23-induced skin inflammation drives joint disease. Here, we show that mice expressing increased levels of IL-23 in the skin (K23 mice) develop a PS-like disease that is characterized by acanthosis, parakeratosis, hyperkeratosis, and inflammatory infiltrates in the dermis. Skin disease preceded development of PsA, including enthesitis, dactylitis, and bone destruction. The development of enthesitis and dactylitis was not due to high circulating levels of IL-23, as transgenic animals and controls had similar levels of this cytokine in circulation. IL-22, a downstream cytokine of IL-23, was highly increased in the serum of K23 mice. Although IL-22 deficiency did not affect skin disease development, IL-22 deficiency aggravated the PsA-like disease in K23 mice. Our results demonstrate a central role for skin expressed IL-23 in the initiation of PS and on pathogenic processes leading to PsA.Fil: Chen, Lili. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Deshpande, Madhura. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Grisotto, Marcos. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Smaldini, Paola Lorena. Icahn School of Medicine at Mount Sinai; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Garcia, Roberto. Hospital for Special Surgery; Estados UnidosFil: He, Zhengxiang. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Gulko, Percio. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Lira, Sergio A.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Furtado, Glaucia C.. Icahn School of Medicine at Mount Sinai; Estados Unido

A Neural Basis for the Acquired Capability for Suicide

The high rate of fatal suicidal behavior in men is an urgent issue as highlighted in the public eye via news sources and media outlets. In this study, we have attempted to address this issue and understand the neural substrates underlying the gender differences in the rate of fatal suicidal behavior. The Interpersonal-Psychological Theory of Suicide (IPTS) has proposed an explanation for the seemingly paradoxical relationship between gender and suicidal behavior, i.e. greater non-fatal suicide attempts by women but higher number of deaths by suicide in men. This theory states that possessing suicidal desire (due to conditions such as depression) alone is not sufficient for a lethal suicide attempt. It is imperative for an individual to have acquired the capability for suicide (ACS) along with suicidal desire in order to die by suicide. Therefore, higher levels of ACS in men may explain why men are more likely to die by suicide than women, despite being less likely to experience suicidal ideation or depression. In this study, we used activation likelihood estimation meta-analysis to investigate a potential ACS network that involves neural substrates underlying emotional stoicism, sensation seeking, pain tolerance, and fearlessness of death along with a potential depression network that involves neural substrates that underlie clinical depression. Brain regions commonly found in ACS and depression networks for males and females were further used as seeds to obtain regions functionally and structurally connected to them. We found that the male-specific networks were more widespread and diverse than the female-specific ones. Also, while the former involved motor regions such as the premotor cortex and cerebellum, the latter was dominated by limbic regions. This may support the fact that suicidal desire generally leads to fatal/decisive action in males while in females, it manifests as depression, ideation and generally non-fatal actions. The proposed model is a first attempt to characterize the neural networks underlying gender differences in suicidal behavior. Future studies should examine the proposed network to better characterize and refine this network using tasks specifically targeted toward constructs underlying ACS

A Neural Basis for the Acquired Capability for Suicide

The high rate of fatal suicidal behavior (SB) in men is an urgent issue as highlighted in the public eye via news sources and media outlets. In this study, we have attempted to address this issue and understand the neural substrates underlying the gender differences in the rate of fatal SB. The Interpersonal–Psychological Theory of Suicide has proposed an explanation for the seemingly paradoxical relationship between gender and SB, i.e., greater non-fatal suicide attempts by women but higher number of deaths by suicide in men. This theory states that possessing suicidal desire (due to conditions such as depression) alone is not sufficient for a lethal suicide attempt. It is imperative for an individual to have the acquired capability for suicide (ACS) along with suicidal desire in order to die by suicide. Therefore, higher levels of ACS in men may explain why men are more likely to die by suicide than women, despite being less likely to experience suicidal ideation or depression. In this study, we used activation likelihood estimation meta-analysis to investigate a potential ACS network that involves neural substrates underlying emotional stoicism, sensation-seeking, pain tolerance, and fearlessness of death, along with a potential depression network that involves neural substrates that underlie clinical depression. Brain regions commonly found in ACS and depression networks for males and females were further used as seeds to obtain regions functionally and structurally connected to them. We found that the male-specific networks were more widespread and diverse than the female-specific ones. Also, while the former involved motor regions, such as the premotor cortex and cerebellum, the latter was dominated by limbic regions. This may support the fact that suicidal desire generally leads to fatal/decisive action in males, while, in females, it manifests as depression, ideation, and generally non-fatal actions. The proposed model is a first attempt to characterize the neural networks underlying gender differences in SB. Future studies should examine the proposed network to better characterize and refine this network using tasks specifically targeted toward constructs underlying ACS

Monsoon-extratropical circulation interactions in Himalayan extreme rainfall

Extreme precipitation and flood episodes in the Himalayas are oftentimes traced to synoptic situations involving connections between equatorward advancing upper level extratropical circulations and moisture-laden tropical monsoon circulation. While previous studies have documented precipitation characteristics in the Himalayan region during severe storm cases, a comprehensive understanding of circulation dynamics of extreme precipitation mechanisms is still warranted. In this study, a detailed analysis is performed using rainfall observations and reanalysis circulation products to understand the evolution of monsoon-extratropical circulation features and their interactions based on 34 extreme precipitation events which occurred in the Western Himalayas (WEH) during the period 1979–2013. Our results provide evidence for a common large-scale circulation pattern connecting the extratropics and the South Asian monsoon region, which is favorable for extreme precipitation occurrences in the WEH region. This background upper level large-scale circulation pattern consists of a deep southward penetrating midlatitude westerly trough, a blocking high over western Eurasia and an intensifying Tibetan anticyclone. It is further seen from our analysis that the key elements of monsoon-midlatitude interactions, responsible for extreme precipitation events over the WEH region, are: (1) midlatitude Rossby wave breaking, (2) west-northwest propagation of monsoon low-pressure system from the Bay of Bengal across the Indian subcontinent, (3) eddy shedding of the Tibetan anticyclone, (4) ageostrophic motions and transverse circulation across the Himalayas, and (5) strong moist convection over the Himalayan foothills. Furthermore, high-resolution numerical simulations indicate that diabatic heating and mesoscale ageostrophic effects can additionally amplify the convective motions and precipitation in the WEH region

Relationship between Serum Ferritin and Outcomes in β-Thalassemia: A Systematic Literature Review

Among the difficulties of living with β-thalassemia, patients frequently require blood transfusions and experience iron overload. As serum ferritin (SF) provides an indication of potential iron overload, we conducted a systematic literature review (SLR) to assess whether SF levels are associated with clinical and economic burden and patient-reported outcomes (PROs). The SLR was conducted on 23 April 2020 and followed by analysis of the literature. Dual-screening was performed at the title, abstract, and full-text levels using predefined inclusion and exclusion criteria. Ten studies identified by the SLR were eligible for inclusion in the analysis. Seven studies were conducted in Europe, and most were prospective or retrospective in design. The patient populations had a median age of 20.7–42.6 years, with a percentage of men of 38–80%. Sparse data were found on the correlation between SF levels and mortality, and hepatic, skeletal, and cardiac complications; however, in general, higher SF levels were associated with worsened outcomes. The bulk of the evidence reported on the significant association between higher SF levels and endocrine dysfunction in its many presentations, including a 14-fold increase in the risk of diabetes for patients with persistently elevated SF levels. No studies reporting data on PROs or economic burden were identified by the SLR. SF levels provide another option for prognostic assessment to predict a range of clinical outcomes in patients with β-thalassemia

A Systematic Literature Review of the Relationship between Serum Ferritin and Outcomes in Myelodysplastic Syndromes

Anemia is the most common form of cytopenia in patients with myelodysplastic syndromes (MDS), who require chronic red blood cell transfusions and may present high serum ferritin (SF) levels as a result of iron overload. To better understand the potential effects of high SF levels, we conducted a systematic literature review (SLR) to identify evidence on the relationship between SF levels and clinical, economic, or humanistic outcomes in adult patients with MDS. Of 267 references identified, 21 were included. No studies assessing SF levels and their relationship with humanistic or economic outcomes were identified. Increased SF levels were an indicator of worse overall survival and other worsened outcomes; however, the association was not consistently significant. SF levels were a significant prognostic factor for relapse incidence of MDS and showed a significant positive correlation with number of blood units transfused but were not associated with progression to acute myeloid leukemia or the time to transformation. Higher SF levels were also an indicator of a lower likelihood of leukemia-free survival, relapse-free survival, and event-free survival. The SLR suggests that SF levels are associated with clinical outcomes in MDS, with higher levels correlated with number of blood units transfused, frequently indicating worse outcomes

Characterization of Structural Connectivity of the Default Mode Network in Dogs using Diffusion Tensor Imaging

Diffusion tensor imaging (DTI) provides us an insight into the micro-architecture of white-matter tracts in the brain. This method has proved promising in understanding and investigating the neuronal tracts and structural connectivity between the brain regions in primates as well as rodents. The close evolutionary relationship between canines and humans may have spawned a unique bond in regard to social cognition rendering them useful as an animal model in translational research. In this study, we acquired diffusion data from anaesthetized dogs and created a DTI-based atlas for a canine model which could be used to investigate various white matter diseases. We illustrate the application of this atlas by calculating DTI tractography based structural connectivity between the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) regions of the default mode network (DMN) in dogs. White matter connectivity was investigated to provide structural basis for the functional dissociation observed between the anterior and posterior parts of DMN. A comparison of the integrity of long range structural connections (such as in the DMN) between dogs and humans is likely to provide us with new perspectives on the neural basis of the evolution of cognitive functions

Monsoon-extratropical circulation interactions in Himalayan extreme rainfall

Extreme precipitation and flood episodes in the Himalayas are oftentimes traced to synoptic situations involving connections between equatorward advancing upper level extratropical circulations and moisture-laden tropical monsoon circulation. While previous studies have documented precipitation characteristics in the Himalayan region during severe storm cases, a comprehensive understanding of circulation dynamics of extreme precipitation mechanisms is still warranted. In this study, a detailed analysis is performed using rainfall observations and reanalysis circulation products to understand the evolution of monsoon-extratropical circulation features and their interactions based on 34 extreme precipitation events which occurred in the Western Himalayas (WEH) during the period 1979–2013. Our results provide evidence for a common large-scale circulation pattern connecting the extratropics and the South Asian monsoon region, which is favorable for extreme precipitation occurrences in the WEH region. This background upper level large-scale circulation pattern consists of a deep southward penetrating midlatitude westerly trough, a blocking high over western Eurasia and an intensifying Tibetan anticyclone. It is further seen from our analysis that the key elements of monsoon-midlatitude interactions, responsible for extreme precipitation events over the WEH region, are: (1) midlatitude Rossby wave breaking, (2) west-northwest propagation of monsoon low-pressure system from the Bay of Bengal across the Indian subcontinent, (3) eddy shedding of the Tibetan anticyclone, (4) ageostrophic motions and transverse circulation across the Himalayas, and (5) strong moist convection over the Himalayan foothills. Furthermore, high-resolution numerical simulations indicate that diabatic heating and mesoscale ageostrophic effects can additionally amplify the convective motions and precipitation in the WEH region