Has the introduction of increased genetic prenatal testing affected rates of termination of pregnancy due to fetal abnormality?

OBJECTIVE: Genetic high-resolution analyses and improved diagnostic imaging have impacted the ability to detect fetal disorders. It is unknown if this resulted in an alteration in the number of terminations of pregnancy due to fetal anomalies (TOPFA). The objective was to describe the incidence and indication of TOPFA. METHODS: A descriptive study based on records from the Regional Abortion Council in the Central Denmark Region from 2008 to 2021 consisting of 1895 TOPFA. RESULTS: A consistent incidence of TOPFA was observed, accounting for 0.96% of the total births during that period. When examining fetal indications, there was a small increase in the occurrence of genetic aberrations, primarily caused by deletions, duplications, and single nucleotide variations, whereas the number of chromosomal aberrations remained stable. Of 35.5% of the cases with malformations, the central nervous system was the most affected organ system, followed by malformations of the heart 29.6%. Overall, the total number of cases remained stable. DISCUSSION AND CONCLUSION: Unexpectedly, despite the development of new diagnostic tools, the incidence of TOPFA from 2008 to 2021 remained stable. However, the number of cases with genetic aberrations increased. This may be attributed to increased genetic testing for fetuses with identified malformations, resulting in more accurate diagnoses.

Rare case of Turner syndrome patient with metastatic dysgerminoma and no Y-chromosomal material with pathogenic variants found in KIT and MTOR.

INTRODUCTION: The presence of Y-chromosomal material in females with Turner syndrome (TS) is a well-established risk factor for developing gonadoblastoma and malignant transformations hereof. However, these events are rarely seen in TS patients with no Y-chromosomal material. Thus, it is the current understanding that parts of the Y-chromosome are essential for malignant transformation of gonadoblastoma in the dysgenetic gonad. METHODS: We report a case of a TS female with an apparent 46,X,idic(Xq) karyotype, who was diagnosed with a metastatic dysgerminoma. Whole exome sequencing of tumor and blood, along with RNA sequencing of the tumor, was performed to comprehensively search for cryptic Y-chromosomal material and pathogenic variants. RESULTS: No Y-chromosomal material was detected in neither tumor nor blood. Whole exome sequencing of DNA and RNA revealed a pathogenic somatic gain-of-function mutation in KIT and a pathogenic missense mutation in MTOR. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy, followed by adjuvant chemotherapy. Unfortunately, she died due to chemotherapy-induced pneumonitis seven months after initial diagnosis. CONCLUSION: Females with TS can develop metastatic dysgerminoma even in the absence of Y-chromosomal material. This questions the current understanding of Y-chromosomal material being essential for the malignant transformation of a gonadoblastoma in the dysgenetic gonad.

Psoriasis and cardiovascular events: updating the evidence.

So far, systematic reviews have suggested an increased risk of cardiovascular diseases (CVD) in psoriatic patients, though some results have been conflicting. The aim of this study was to update the current level of evidence through a systematic search in MEDLINE, EMBASE and Cochrane Central Register databases. In total, 13 high-quality observational studies estimating the incidence of CVD were included. Patients with mild psoriasis had an increased risk of stroke [Hazard ratio (HR) = 1.10, 95% CI: 1.0-1.19] and myocardial infarction (MI) (HR = 1.20, 95% CI: 1.06-1.35), but not cardiovascular death. The risks of both stroke (HR = 1.38, 95% CI: 1.20-1.60), MI (HR = 1.70, 95% CI: 1.18-2.43) and cardiovascular death (HR = 1.37, 95% CI: 1.13-1.67) were increased in patients with severe psoriasis. In conclusion, this updated meta-analysis confirmed that patients with psoriasis have an increased risk of CVD, especially those with severe psoriasis.

Langerhans cell markers CD1a and CD207 are the most rapidly responding genes in lesional psoriatic skin following adalimumab treatment.

TNFα-, IL-23- and IL-17-targeting drugs are highly effective in the treatment of psoriasis. However, the precise molecular mechanism remains unknown. In psoriatic skin, the presence of Langerhans cells (LCs) is reduced, but the role of LC is poorly understood. The purpose of this study was to investigate the impact of TNFα and IL-23/IL-17 on the presence of LC in the skin during treatment. Therefore, psoriatic skin was investigated before and after 4 days of adalimumab or ustekinumab treatment. Furthermore, TNFα and IL-17A stimulation was investigated in an ex vivo model of epidermis and dermis from healthy normal skin kept in cultures at an air-liquid interphase for 4 days. In a gene array analysis, we found that the two LC markers, CD1a and CD207, were among the most up- or downregulated genes in psoriatic skin after anti-TNFα therapy. Validation showed that both mRNA expression and protein level followed the same pattern and became significantly upregulated after 4 days of treatment. No changes were seen after ustekinumab treatment. In the ex vivo skin model, a decrease in the CD1a level was seen after TNFα stimulation and it was caused by LC migration from epidermis. No response in LC migration was seen after IL-17A stimulation. Taken together, we demonstrated that changes in the LC level in epidermis precede the histological and clinical changes during adalimumab treatment in psoriatic skin. Furthermore, TNFα plays a prominent role in orchestrating LC migration in the skin. This seems not to be the true for the IL-23/IL-17A pathway.

Methotrexate Use and Monitoring in Patients with Psoriasis: A Consensus Report Based on a Danish Expert Meeting.

Methotrexate (MTX) has been used in the treatment of psoriasis and other dermatological diseases for more than 50 years. However, there is limited evidence regarding its effect, dose and monitoring, and a lack of consensus regarding how the drug should be used in daily practice. Although the use of MTX is governed by guidelines, such as the European S3-Guidelines and the National Institute for Health and Care Excellence (NICE) guideline, it is important to discuss and adjust these guidelines to national standards. An expert meeting was held in Denmark at the end of 2014, in order to reach consensus regarding the use of MTX in dermatological practice in Denmark. Participants included dermatologists, hepatologists, paediatricians, clinical biochemists and a rheumatologist. Topics discussed were: liver disease monitoring, teratogenic effects of MTX, risk of cancer, and use of MTX in children. We report here the conclusions of this expert meeting regarding use of MTX in dermatological practice.

TRIM21 is important in the early phase of inflammation in the imiquimod-induced psoriasis-like skin inflammation mouse model.

Tripartite motif-containing protein 21 (TRIM21) regulates pro-inflammatory cytokines and type I interferons and acts as an autoantigen in certain autoimmune diseases, but TRIM21 has not been investigated in psoriasis. It has been suggested that TRIM21 may have a dual function; in the early phase of inflammation, it may function as a stimulator; but upon immune stimulation, its ubiquitinating mode of action may shift from stabilization to degradation of IRF3 causing inhibition of the immune responses. The imiquimod (IMQ)-induced psoriasis-like mouse model displays features similar to those of human psoriasis. However, chronicity is lacking in this model. We investigated whether the role of TRIM21 in psoriasis was pro-inflammatory or anti-inflammatory. We hypothesized that a shift of the TRIM21-ubiquitinating mode of action may explain the lack of chronicity in the IMQ-induced psoriasis-like mouse model. We showed that TRIM21 expression is increased in lesional psoriatic skin and in the early phase of IMQ-induced inflammation both in vitro and in vivo. Surprisingly, inflammation was significantly less pronounced in TRIM21 knockout mice than in wild-type mice as shown by ear thickness measured at days 8, 9 and 10 after treatment start, by spleen weight as a marker of systemic effect of IMQ at 10 days after treatment start and by expression of IL-12p40 at days 3 and 10 after treatment start and IL-17A at day 3 after treatment start. Therefore, induction of TRIM21 expression cannot explain the lack of chronicity in the IMQ-induced psoriasis-like skin inflammation mouse model.

Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α.

Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.

Increased Prevalence of Coronary Artery Disease in Severe Psoriasis and Severe Atopic Dermatitis.

BACKGROUND: Psoriasis and atopic dermatitis (AD) are immuno-inflammatory diseases that can result in lifelong systemic inflammation. Unlike AD, psoriasis has been associated with cardiovascular disease. The aim of this study was to examine the prevalence, severity, and subtype of coronary artery disease (CAD) in psoriasis and AD patients without known cardiovascular disease. METHODS: Consecutively enrolled patients (psoriasis n = 58, AD n = 31) and retrospectively matched controls (n = 33) were examined using cardiac computed tomography angiography (CCTA) and assessed using an 18-segment model of the coronary tree. RESULTS: The prevalence of a coronary artery calcium score >0 was 29.8% in psoriasis and 45.2% in AD, vs 15.2% in controls (P = .09 and P = .01, respectively). More patients with psoriasis had a coronary artery calcium score ≥100 (psoriasis 19.3%, controls 2.9%; P = .02). CCTA showed the presence of plaques in 38.2% of psoriasis patients and 48.1% of AD patients, vs 21.2% of controls (P = .08 and P = .03, respectively). Psoriasis was associated with an increased prevalence of significant coronary stenosis (stenosis >70%) (psoriasis 14.6%, controls 0%; P = .02) and 3-vessel coronary affection or left main artery disease (psoriasis 20%, controls 3%; P = .02), whereas AD was associated with mild (AD 40.7%, controls 9.1%; P = .005) single-vessel affection. CONCLUSIONS: These findings suggest that psoriasis and AD are associated with an increased prevalence of CAD. Patients with psoriasis have an increased prevalence of severe CAD.

TNFα- and IL-17A-mediated S100A8 expression is regulated by p38 MAPK.

The antimicrobial peptide S100A8 is known to be upregulated in lesional psoriatic skin compared with non-lesional psoriatic skin and is believed to play a role in the pathogenesis of psoriasis. However, little is known about the signalling pathways involved in the regulation of S100A8 expression. Using quantitative real-time RT-PCR analysis, we demonstrated that stimulation with TNFα and IL-17A in combination resulted in a significant and synergistic induction of S100A8 mRNA in human keratinocytes. TNFα and IL-17A also induced the S100A8 promoter activity synergistically. This was demonstrated by a gene reporter assay in cells transfected with a luciferase plasmid construct, consisting of 3502 base pairs of the human S100A8 promoter. The TNFα- and IL-17A-mediated induction of S100A8 mRNA and protein was mediated by a p38 MAPK-dependent mechanism, as demonstrated by the use of a p38 MAPK inhibitor. Finally, adalimumab treatment for patients with psoriasis significantly decreased S100A8 mRNA at day fourteen after start of treatment, but not at day four. Taken together, this study demonstrates that the p38 MAPK signalling pathway plays a key role in the TNFα- and IL-17A-induced expression of S100A8 in cultured human keratinocytes.

A Characterization of the expression of 14-3-3 isoforms in psoriasis, basal cell carcinoma, atopic dermatitis and contact dermatitis.

14-3-3 is a highly conserved protein involved in a number of cellular processes including cell signalling, cell cycle regulation and gene transcription. Seven isoforms of the protein have been identified; ß, γ, ε, ζ η σ and τ. The expression profile of the various isoforms in skin diseases is unknown. To investigate the expression of the seven 14-3-3 isoforms in involved and uninvolved skin from psoriasis, basal cell carcinoma (BCC), atopic dermatitis and nickel induced allergic contact dermatitis. Punch biopsies from involved and uninvolved skin were analyzed with quantitative reverse transcription-polymerase chain reaction to determine the mRNA expression of the 14-3-3 isoforms. The protein level of 14-3-3 isoforms was measured by Western blot technique in keratome biopsies from patients with psoriasis. Evaluation of dermal and epidermal protein expression was performed by immunofluorescence staining. Increased 14-3-3τ mRNA levels were detected in involved skin from patients with psoriasis, contact dermatitis and BCC. 14-3-3σ mRNA expression was increased in psoriasis and contact dermatitis, but not in BCC. In atopic dermatitis no significant difference between involved and uninvolved skin was found. The expression of the 14-3-3 isoforms was also studied at the protein level in psoriasis. Only 14-3-3τ expression was significantly increased in involved psoriatic skin compared with uninvolved skin. Immunofluorescence staining with 14-3-3τ- and 14-3-3σ-specific antibodies showed localization of both isoforms to the cytoplasm of the keratinocytes in the various skin sections. These results demonstrate a disease specific expression profile of the 14-3-3τ and 14-3-3σ iso-forms.

Inter-observer variation of the Bandim TB-score.

We assessed the inter-observer variation for a clinical staging score for tuberculosis (TB). 87 TB patients were examined by 2 independent observers within 2 h, and kappa was calculated. The kappa value of the total Bandim TBscore being at or above 8 points was 0.637, representing a good inter-observer agreement. No systematic bias was found.