The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood–brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the ...intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1–phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1pr1 knockout mice (S1pr1iECKO
) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1pr1iECKO
mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P₁ function led to transient BBB breach. These data suggest that brain endothelial S1P₁ maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P₁ inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.
Innate lymphoid cells (ILCs) are increasingly appreciated as key regulators of tissue immunity. However, their role in human tissue homeostasis and disease remains to be fully elucidated. Here we ...characterize the ILCs in human skin from healthy individuals and from the inflammatory skin disease psoriasis. We show that a substantial proportion of IL-17A and IL-22 producing cells in the skin and blood of normal individuals and psoriasis patients are CD3-negative innate lymphocytes. Deep immunophenotyping of human ILC subsets showed a statistically significant increase in the frequency of circulating NKp44+ ILC3 in the blood of psoriasis patients compared with healthy individuals or atopic dermatitis patients. More than 50% of circulating NKp44+ ILC3 expressed cutaneous lymphocyte–associated antigen, indicating their potential for skin homing. Analysis of skin tissue revealed a significantly increased frequency of total ILCs in the skin compared with blood. Moreover, the frequency of NKp44+ ILC3 was significantly increased in non-lesional psoriatic skin compared with normal skin. A detailed time course of a psoriasis patient treated with anti–tumor necrosis factor showed a close association between therapeutic response, decrease in inflammatory skin lesions, and decrease of circulating NKp44+ ILC3. Overall, data from this initial observational study suggest a potential role for NKp44+ ILC3 in psoriasis pathogenesis.
The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, ...can have an acute systemic (generalized pustular psoriasis GPP) or chronic localized (palmoplantar pustulosis PPP and acrodermatitis continua of Hallopeau ACH) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations.
We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort.
We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases.
Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10−5). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10−15). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10−14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003).
The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.
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Hospital-associated disability (HAD), defined as loss of independence in activities of daily living (ADL) following acute hospitalization, is observed among older adults. The study objective is to ...determine overall prevalence of HAD among older adults hospitalized in acute care, and to assess the impact of study initiation year in moderation of prevalence.
Meta-analysis of data collected from randomized trials, quasi-experimental, and prospective cohort studies. English-language searches to identify included studies were completed February 2018 and updated May 2018 of electronic databases and reference lists of studies and reviews. Included studies were human subjects investigations that measured ADL ≥2 time points before or during and after hospitalization and reported prevalence of ADL decline among older adults.
Acute care hospital units.
Adults aged ≥65 years hospitalized in medical-surgical acute care; total sample size across all included studies was 7375.
Independence in ADL was assessed using the Katz Index of Independence in Activities of Daily Living and Barthel Index of Independence in Activities of Daily Living.
Random effects meta-analysis across included studies identified combined prevalence of HAD as 30% (95% CI 24%, 33%; P < .001). The effect of study initiation year on the prevalence rate was minimal. A large amount of heterogeneity was observed between studies, which may be due in part to nonstandardized measurement of ADL impairment or other methodological differences.
Hospitalization in acute care poses a significant risk to functional independence of older adults, and this risk is unchanged despite shorter lengths of stay. The evidence supports the continued need for hospital-based programs that provide assessment of functional ability and identification of at-risk older adults in order to better treat and prevent HAD.
Although psoriasis has been associated with obesity, there are few prospective studies with objective measures. We prospectively examined the effect of body mass index, waist circumference, waist-hip ...ratio, and 10-year weight change on the risk of developing psoriasis among 33,734 people in the population-based Nord-Trøndelag Health Study (i.e., HUNT), Norway. During follow-up, 369 incident psoriasis cases occurred. Relative risk (RR) of psoriasis was estimated by Cox regression. One standard deviation higher body mass index, waist circumference, and waist-hip ratio gave RRs of 1.22 (95% confidence interval CI = 1.11–1.34), 1.26 (95% CI = 1.15–1.39), and 1.18 (95% CI = 1.07–1.31), respectively. Compared with normal weight participants, obese people had an RR of 1.87 (95% CI = 1.38–2.52), whereas comparing the fourth with the first quartile of waist circumference gave an RR of 1.95 (95% CI = 1.46–2.61). One standard deviation higher weight change gave an RR of 1.20 (95% CI = 1.07–1.35), and people who increased their body weight by 10 kg or more had an RR of 1.72 (95% CI = 1.15–2.58) compared with being weight stable. In conclusion, obesity and high abdominal fat mass doubles the risk of psoriasis, and long-term weight gain substantially increases psoriasis risk. Preventing weight gain and promoting maintenance of a normal body weight could reduce incidence of psoriasis.
Psoriasis is a common inflammatory skin disease caused by the interplay between multiple genetic and environmental risk factors. This review summarises recent progress in elucidating the genetic ...basis of psoriasis, particularly through large genome-wide association studies. We illustrate the power of genetic analyses for disease stratification. Psoriasis can be stratified by phenotype (common plaque versus rare pustular variants), or by outcome (prognosis, comorbidities, response to treatment); recent progress has been made in delineating the genetic contribution in each of these areas. We also highlight how genetic data can directly inform the development of effective psoriasis treatments.
The relationship between psoriasis and increased risk of cardiovascular disease (CVD) is controversial. We critically evaluate 14 cohorts and meta-analyze the magnitude of CVD risk for the primary ...outcomes of CVD mortality, stroke, and myocardial infarction (MI), and establish subgroup risk for different psoriasis severities and age groups. Increased CVD risk was identified only in individuals with severe psoriasis (defined as requiring systemic therapy or hospital admission): the risk ratio relative to the general population was 1.37 (95% confidence interval (CI) 1.17–1.60) for CVD mortality, 3.04 (95% CI 0.65–14.35) for MI, and 1.59 (95% CI 1.34–1.89) for stroke. The relative risks of CVD were highest in the younger, severe psoriasis population (e.g., 3.10 (95% CI 1.98–4.86) for MI at 30 years), and absolute risks were greatest in older individuals with severe psoriasis (e.g., 23.2 excess MIs per 10,000 person-years at 60 years). Uncertainty remains about whether CVD risk is directly attributable to psoriasis, as the majority of studies failed to adequately adjust for key traditional risk factors.
Why are there more species in the tropics than in temperate regions? In recent years, this long‐standing question has been addressed primarily by seeking environmental correlates of diversity. But to ...understand the ultimate causes of diversity patterns, we must also examine the evolutionary and biogeographic processes that directly change species numbers (i.e., speciation, extinction, and dispersal). With this perspective, we dissect the latitudinal diversity gradient in hylid frogs. We reconstruct a phylogeny for 124 hylid species, estimate divergence times and diversification rates for major clades, reconstruct biogeographic changes, and use ecological niche modeling to identify climatic variables that potentially limit dispersal. We find that hylids originated in tropical South America and spread to temperate regions only recently (leaving limited time for speciation). There is a strong relationship between the species richness of each region and when that region was colonized but not between the latitudinal positions of clades and their rates of diversification. Temperature seasonality seemingly limits dispersal of many tropical clades into temperate regions and shows significant phylogenetic conservatism. Overall, our study illustrates how two general principles (niche conservatism and the time‐for‐speciation effect) may help explain the latitudinal diversity gradient as well as many other diversity patterns across taxa and regions.
The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair
. Depletion ...of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides
. Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers.
Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and ...psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk.
We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma eczema, psoriatic arthritis psoriasis, Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index BMI, smoking status, and, in eczema only, sleep quality insomnia diagnoses, specific sleep problem medications and high-dose oral glucocorticoids).
We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR 95% CI: eczema 1.14 1.13-1.16, psoriasis 1.17 1.15-1.19) and depression (adjusted HR 95% CI: eczema 1.11 1.1-1.12, psoriasis 1.21 1.19-1.22). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry.
Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management.
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