Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. ...We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.
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•Asprosin discovered as a fasting-induced glucogenic protein hormone•Asprosin induces hepatic glucose production by using cAMP as a second messenger•Asprosin is pathologically elevated with human and mouse insulin resistance•Reduction of asprosin protects against metabolic-syndrome-associated hyperinsulinism
Circulating asprosin, a protein hormone, responds to low dietary glucose by triggering the release of liver glucose stores, and the reduction of asprosin protects against the hyperinsulinism associated with metabolic syndrome.
Background
Atopic dermatitis (AD) is associated with a heterogeneous presentation and clinical course. There is a lack of simple and validated severity assessments that are feasible for clinical ...practice and epidemiological research.
Objectives
We sought to validate patient‐reported global AD severity in adults.
Methods
We performed a prospective dermatology practice‐based study using questionnaires and evaluation by a dermatologist (n = 265).
Results
At baseline and follow‐up, patient‐reported global AD severity significantly correlated with oSCORAD (Spearman ρ = 0.56 and 0.49), SCORAD (0.64 and 0.56), EASI (0.56 and 0.50), BSA (0.52 and 0.45), NRS‐itch (0.60 and 0.53), POEM (0.50 and 0.48), and DLQI (0.50 and 0.49) (P < .0001 for all). Patient‐reported moderate and severe AD vs mild AD were associated with significantly higher oSCORAD, SCORAD, EASI, BSA, NRS‐itch, POEM, and DLQI (P < .0001 for all). There was moderate concordance between patient‐reported AD severity (mild, moderate, and severe) and previously developed severity strata for oSCORAD (κ = 0.39), SCORAD (κ = 0.47), EASI (κ = 0.37), NRS‐itch (κ = 0.49), POEM (κ = 0.37), and DLQI (κ = 0.40). Among patients with severe disease at baseline, those who reported mild or moderate disease on follow‐up had significantly greater absolute reductions of oSCORAD (−23.4/−9.7/−1.8), SCORAD (−33.0/−13.2/−2.3), EASI (−17.1/−9.8/−3.2), BSA (−46%/−15%/−4%), NRS‐itch (−5/−2/0), POEM (−5/−2/0), and DLQI (−8/−6/−1) than those who continued to report severe disease (Kruskal‐Wallis, P ≤ .0003 for all).
Conclusions
Patient‐reported AD severity appears to be sufficiently valid for assessing AD severity in the clinical and epidemiological setting.
Summary
Background
Multiple strategies have been used to evaluate the minimal important change (MIC) of the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD). The ...meaningfulness of these MICs is not well established across all severities of atopic dermatitis (AD).
Objectives
To determine the MIC of percentage and absolute improvement of EASI and SCORAD scores in adults and children with AD.
Methods
We performed a prospective dermatology practice‐based study using questionnaires and evaluation by a dermatologist (n = 826). An anchor‐based approach was used to determine thresholds for the percentage and absolute MICs of EASI, SCORAD and objective SCORAD (O‐SCORAD) at follow‐up from baseline.
Results
One‐grade improvements of Physician’s Global Assessment (PGA) and validated Investigator Global Assessment scale for AD (vIGA‐AD) were associated with 50%, 35% and 35% decreases of EASI, SCORAD and O‐SCORAD, respectively. The thresholds for percentage MIC of EASI (Kruskal–Wallis test, P = 0·61), SCORAD (P = 0·07) and O‐SCORAD (P = 0·09) were similar across baseline AD severities. One‐grade improvements of PGA and vIGA‐AD were associated with 14·0‐ and 14·9‐point decreases of EASI, 19·9‐ and 14·9‐point decreases of SCORAD, and 15·5‐ and 17·4‐point decreases of O‐SCORAD. The thresholds for the absolute MIC of EASI (P < 0·001), SCORAD (P < 0·001) and O‐SCORAD (P < 0·001) significantly differed by baseline AD severity. Percentage and absolute MICs for EASI and SCORAD were associated with improvements of AD symptoms and quality of life.
Conclusions
EASI 50, SCORAD 35 and O‐SCORAD 35 were meaningful percentage MICs regardless of baseline AD severity. The absolute MICs for EASI, SCORAD and O‐SCORAD varied by baseline AD severity.
What is already known about this topic?
Most existing clinician‐reported outcomes for atopic dermatitis severity are not feasible or valid for use in clinical practice.
What does this study add?
This study demonstrated that 50% decrease in Eczema Area and Severity Index (EASI 50), 35% decrease in Scoring Atopic Dermatitis (SCORAD 35) and 35% decrease in in objective SCORAD (O‐SCORAD) appear to be the most meaningful endpoints for EASI, SCORAD and O‐SCORAD in clinical practice.
The minimal important change for absolute improvement of EASI, SCORAD and O‐SCORAD varied by baseline atopic dermatitis severity and may need to be selected based on the target population.
What are the clinical implications of this work?
EASI 50, SCORAD 35 and O‐SCORAD 35 should be evaluated in future studies of atopic dermatitis that use EASI and SCORAD.
Linked Comment: Vazquez et al. Br J Dermatol 2021; 184:794–795.
Summary
Background
Scoring systems for assessing the signs of atopic dermatitis (AD) are complex and difficult to interpret. Severity strata are helpful to interpret these assessments properly.
...Objectives
To confirm previously reported strata for the Eczema Area and Severity Index (EASI), Scoring Atopic Dermatitis (SCORAD) and the objective component of SCORAD (oSCORAD), and to develop strata for the modified EASI (mEASI), Atopic Dermatitis Severity Index (ADSI) and body surface area (BSA) for use in adults with AD.
Methods
Skin examination was performed in 673 adolescents and adults (age ≥ 13 years) with diagnosed AD, in a dermatology practice setting. Strata were selected using an anchoring approach based on a four‐point Investigator's Global Assessment of severity (clear of active skin lesions, mild, moderate or severe disease).
Results
We determined potential severity strata for EASI (0 clear, 0·1–5·9 mild, 6·0–22·9 moderate, 23·0–72 severe; κ = 0·69), mEASI (0–0·9 clear, 1–8·9 mild, 9·0–29·9 moderate, 30·0–90 severe; κ = 0·71), oSCORAD (0–7·9 clear, 8·0–23·9 mild, 24·0–37·9 moderate, 38·0–83 severe; κ = 0·70), SCORAD (0–9·9 clear, 10·0–28·9 mild, 29·0–48·9 moderate, 49·0–103 severe; κ = 0·68), ADSI (0–1·9 clear, 2–5·9 mild, 6·0–8·9 moderate, 9·0–15 severe; κ = 0·55) and BSA (0 clear, 0·1–15·9 mild, 16·0–39·9 moderate, 40·0–100 severe; κ = 0·66). oSCORAD values > 0 were found in clear skin due to the presence of xerosis, which is scored in oSCORAD. Similarly, SCORAD values > 0 were found in clear skin due to the scoring of xerosis, pruritus and sleeplessness. Similarly, mEASI and ADSI scores > 0 occurred in patients with clear skin due to scoring of pruritus.
Conclusions
We recommend using these strata for interpretation of their respective measures in clinical trials of AD. There are important differences between the five assessments, which profoundly impact the interpretation of their scores.
What's already known about this topic?
Multiple assessments have been used for the signs of atopic dermatitis. However, scores from these instruments can be difficult to interpret.
What does this study add?
The present study developed novel severity strata for the Eczema Area and Severity Index (EASI), modified EASI (mEASI), Scoring Atopic Dermatitis (SCORAD), the objective component of SCORAD, Atopic Dermatitis Severity Index and body surface area in a cohort of adults with atopic dermatitis.
What are the clinical implications of this work?
The strata presented for these measures can be used to improve interpretation of clinical and research data, and have important ramifications for future clinical trials of atopic dermatitis.
Linked Comment: Drucker. Br J Dermatol 2017; 177:1158–1159.
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Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as ...the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly ...activates orexigenic AgRP
neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and ...Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1mg/kg, but did not induce significant emetic reflexes at doses <30mg/kg. Overall, the pharmacological effects of apremilast are consistent with those of a targeted PDE4 inhibitor, with selective effects on innate immune responses and a wide therapeutic index compared to its gastrointestinal side effects.
•The current analyses studied the pharmacodynamic properties of apremilast.•Apremilast activates the CREB/ATF-1 pathway and does not bind to human cereblon.•Apremilast does not affect B/T-cell expansion or immunoglobulin production.•Effects of apremilast on innate immunity are greater than on adaptive immunity.•Apremilast is a selective inhibitor of PDE4 that regulates inflammatory mediators.
Summary
Background
Standardized quality‐of‐life (QoL) assessments can provide important and clinically relevant information. There is currently a lack of standardization in QoL assessments used in ...atopic dermatitis (AD).
Objectives
To determine the content validity, construct validity, internal consistency, differential reporting, responsiveness, floor or ceiling effects and feasibility of the Dermatology Life Quality Index (DLQI), Itchy Quality of Life (ItchyQoL) and 5‐dimensions (5‐D) itch scales for assessing burden of AD in adults and to compare their performance.
Methods
Self‐administered questionnaires and skin examination were performed in 340 adults with AD in a dermatology practice setting.
Results
DLQI, ItchyQoL and 5‐D all had good content validity. DLQI, mean ItchyQoL and 5‐D itch all had strong correlations with frequency of AD symptoms (Patient‐Oriented Eczema Measure) and intensity of itch (numerical rating scale for itch), and moderate correlations with AD severity (Eczema Area and Severity Index and Scoring Atopic Dermatitis) (Spearman correlations, P < 0·001 for all). DLQI and 5‐D itch showed good internal consistency (Cronbach's alpha = 0·89 and 0·84), although ItchyQoL appeared to have several redundant items (alpha = 0·96). Uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity was found for multiple items in DLQI, ItchyQoL and 5‐D itch. DLQI, ItchyQoL and 5‐D itch scores all demonstrated responsiveness, although ItchyQoL demonstrated the greatest responsiveness. There were no floor or ceiling effects for total scores. The median times for completion of DLQI, ItchyQoL and 5‐D itch were 2 min.
Conclusions
The DLQI, ItchyQoL and 5‐D itch scales all showed good content and construct validity, and responsiveness in the assessment of AD in adults, and were feasible for use in clinical trials and practice.
What's already known about this topic?
Dermatology Life Quality Index (DLQI), 5‐dimensions (5‐D) itch and ItchyQoL are quality‐of‐life assessments that have been used to assess the burden of inflammatory and/or pruritic skin disorders.
Conflicting and/or limited results have been demonstrated about their validity, reliability and feasibility, particularly in atopic dermatitis.
What does this study add?
This study demonstrates that DLQI, ItchyQoL and 5‐D itch had good construct validity and responsiveness, and similar amounts of time for completion in the assessment of adult atopic dermatitis, with no observed floor or ceiling effects.
What are the clinical implications of this work?
DLQI, ItchyQoL and 5‐D itch all appear to have sufficient validity and feasibility to be used as assessments of burden in adults with atopic dermatitis in clinical practice.
Linked Comment: Apfelbacher and Ofenloch. Br J Dermatol 2019; 180:979–980.
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Abstract
STUDY QUESTION
How reliable are cleavage stage and trophectoderm (TE) biopsies compared to inner cell mass (ICM) biopsies?
SUMMARY ANSWER
The reliability of TE biopsy compared to ICM biopsy ...is almost perfect, but only substantial between cleavage stage biopsy and ICM biopsy.
WHAT IS KNOWN ALREADY
One of the prevailing reasons for implantation failure is presumed to be chromosomal aneuploidy in human preimplantation embryos. Preimplantation genetic testing for aneuploidies (PGT-A) has been introduced into assisted reproduction in an effort to increase pregnancy rates. Increasing evidence indicates that genetic results obtained following blastomere or TEbiopsy may not accurately reflect the true genetic status of the embryo due to the presence of embryonic mosaicism, and therefore the reliability of PGT is highly controversial.
STUDY DESIGN, SIZE, DURATION
This was an observational descriptive study, performed in a private infertility centre from August 2016 to January 2017.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The mean female age was 33.9 years, ranging from 24 to 46 years, and the mean number of biopsied embryos per couple was 2.2 (range 1–7 embryos). Blastomere biopsies had been performed at cleavage stage on Day 3 (D3) due to the turnover time of genetic testing and the inability to cryopreserve embryos in accordance with the local law governing ART. To confirm the genetic results in embryos not chosen for transfer, additional biopsies of the TE at blastocyst stage (BLASTO–TE) as well as of the ICM (BLASTO–ICM) were performed on D5. Only surplus blastocysts, which had not been selected for transfer and were not cryopreserved in accordance with the law governing ART, had been included.
MAIN RESULTS AND THE ROLE OF CHANCE
Comparison of all biopsies (D3/BLASTO–ICM/BLASTO–TE) per embryo demonstrated that 50 (59.5%) out of 84 embryos showed concordance in all three results (= full concordance). Thirty-four (40.4%) embryos had at least two discordant results between the three biopsies, regardless of whether the embryo diagnosis (aneuploid/euploid) was discordant or not, or in aneuploid embryos, whether the chromosomal patterns were inconsistent. Nine (= 10.7%) embryos had complete discordance between all three biopsies. False positive results between D3/BLASTO–TE, D3/BLASTO–ICM and BLASTO–TE/BLASTO–ICM were 26.4%/30.2% and 7.5%, respectively, while the Kappa agreement between the different approaches was 0.647, 0.553 and 0.857, respectively. Therefore the reliability of D3/BLASTO–TE, D3/BLASTO–ICM and BLASTO–TE/BLASTO–ICM can be interpreted as substantial, as moderate and as almost perfect.
LIMITATIONS, REASONS FOR CAUTION
The limitation of this study is the possible bias in the concordance/discordance rate because embryos that had been selected for transfer did not undergo biopsy on D5.
WIDER IMPLICATIONS OF THE FINDINGS
The obvious discordance between the three different approaches for PGT-A underlines the limitations of genetic testing and highlights the importance of ongoing research in order to improve the accuracy of PGT-A results. Until then reproductive specialists will continue to make challenging decisions on whether to transfer or discard an embryo in light of current evidence questioning the reliability of genetic results.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by Igenomix. The funder provided support in the form of salary for R.C. The co-author R.C. is an employee of Igenomix. She participated in the blinded analysis of the samples; however the final data collection and statistical analysis of the results, as well as the decision to publish, was taken by B.L, I.E. and H.F. The authors B.L., I.E., A.L., A.B., A.A., N.D. and H.F. have no competing interests. The funder did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The commercial affiliation of R.C. did not play any role in the study.
TRIAL REGISTRATION NUMBER
This study was approved by the Ethics Committee of IVIRMA Middle East Fertility Clinic, Abu Dhabi, UAE (Research Ethics Committee IVI-MEREFA009a/2017).
The unreliability of commercial recombinant asprosin preparations and variability between asprosin detection assays have proven to be a bottleneck in experimental interpretation. This protocol ...describes the use of viral vectors and expression plasmid for overexpression and secretion of human asprosin to achieve sustained elevation of asprosin protein in mice and HEK293T cells without using recombinant proteins. This protocol also includes a sandwich ELISA using anti-asprosin monoclonal antibodies for detection of asprosin in media from cultured cells and in plasma of mice.
For complete details on the use and execution of this protocol, please refer to Duerrschmid et al. (2017), Mishra et al. (2021), and Mishra et al. (2022).
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•Protocol for overexpression and secretion of asprosin in mice and HEK293T cell culture•Injection of mice with adenoviral and AAV vector for in vivo asprosin overexpression•HEK293T cell transfection with expression plasmid for in vitro asprosin overexpression•ELISA protocol using anti-asprosin monoclonal antibodies for detection of asprosin
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
The unreliability of commercial recombinant asprosin preparations and variability between asprosin detection assays have proven to be a bottleneck in experimental interpretation. This protocol describes the use of viral vectors and expression plasmid for overexpression and secretion of human asprosin to achieve sustained elevation of asprosin protein in mice and HEK293T cells without using recombinant proteins. This protocol also includes a sandwich ELISA using anti-asprosin monoclonal antibodies for detection of asprosin in media from cultured cells and in plasma of mice.
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