A Genomic Point Mutation in the Extracellular Domain of the Thyrotropin Receptor in Patients with Graves’ Ophthalmopathy

Orbital and pretibial fibroblasts are targets of autoimmune attack in Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD). The fibroblast autoantigen involved in these peripheral manifestations of Graves' disease and the reason for the association of GO and PTD with hyperthyroidism are unknown. RNA encoding the full-length extracellular domain of the TSH receptor has been demonstrated in orbital and dermal fibroblasts from patients with GO and normal subjects, suggesting a possible antigenic link between fibroblasts and thyrocytes. RNA was isolated from cultured orbital, pretibial, and abdominal fibroblasts obtained from patients with severe GO (n = 22) and normal subjects (n = 5). RNA was reverse transcribed, and the resulting cDNA was amplified by the polymerase chain reaction, using primers spanning overlapping regions of the entire extracellular domain of the TSH receptor. Nucleotide sequence analysis showed an A for C substitution in the first position of codon 52 in 2 of the patients, both of whom had GO, PTD, and acropachy. Genomic DNA isolated from the 2 affected patients, and not from an additional 12 normal subjects, revealed the codon 52 mutation by direct sequencing and AciI restriction enzyme digestions. In conclusion, we have demonstrated the presence of a genomic point mutation, leading to a threonine for proline amino acid shift in the predicted peptide, in the extracellular domain of the TSH receptor in two patients with severe GO, PTD, acropachy, and high thyroid-stimulating immunoglobulin levels. RNA encoding this mutant product was demonstrated in the fibroblasts of these patients. We suggest that the TSH receptor may be an important fibroblast autoantigen in GO and PTD, and that this mutant form of the receptor may have unique immunogenic properties

A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves' ophthalmopathy

Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital tissues associated with elevated serum levels of TSH receptor (TSHR) autoantibodies. Because previous studies have demonstrated evidence of adipogenesis within the GO orbit, we sought to determine whether M22, a human monoclonal antibody directed against TSHR, enhances adipogenesis in orbital fibroblasts from patients with GO and, if so, to identify signaling mechanisms involved. GO orbital fibroblast cultures (n=10) were treated for 10 days with bovine TSH (1 or 10·0 U/l) or M22 (1 or 10 ng/ml) in serum-free adipocyte differentiation medium. Some cultures also received a phosphoinositide 3-kinase (PI3K) inhibitor or an inhibitor of cAMP production. In other experiments, confluent cultures (n=8) were treated for between 1 and 30 min with TSH (0·1–10·0 U/l) or M22 (0·1–100 ng/ml) with measurement of cAMP production or levels of phosphorylated AKT (pAKT). We found levels of adiponectin, leptin, and TSHR mRNA to be increased in GO cultures treated for 10 days with either M22 (2·6 mean fold ±0·7; P=0·03) or TSH (13·2±5·8-fold, P=0·048). In other studies, M22 and TSH stimulated cAMP production and pAKT levels in GO cells. Inhibition of PI3K activity during 10 days in culture decreased the levels of M22-stimulated mRNA encoding adiponectin (67±12%; P=0·021), as well as adiponectin and CCAAT/enhancer-binding protein α protein levels. In conclusion, M22 is a pro-adipogenic factor in GO orbital preadipocytes. This antibody appears to act via the PI3K signaling cascade, suggesting that inhibition of PI3K signaling may represent a potential novel therapeutic approach in GO

A Risk Prediction Index for Amiodarone-Induced Thyrotoxicosis in Adults with Congenital Heart Disease

Amiodarone therapy in adults with congenital heart disease (CHD) is associated with a significant risk of amiodarone-induced thyrotoxicosis (AIT). We developed a risk index to identify those patients being considered for amiodarone treatment who are at high risk for AIT. We reviewed the health records of adults with CHD and assessed the association between potential clinical predictors and AIT. Significant predictors were included in multivariate analyses. The parameter estimates from multivariate analysis were subsequently used to develop a risk index. 169 adults met eligibility criteria and 23 developed AIT. The final model included age, cyanotic heart disease and BMI. The risk index developed identified 3 categories of risk. Their AIT likelihood ratios were: 0.37 for low risk (95% CI 0.15–0.92); 1.12 for medium risk (95% CI 0.65–1.91); and 3.47 for high risk (95% CI 1.7–7.11). The AIT predicted risk in our population was 5% for the low risk group, 15% for the medium risk group and 47% for the high risk group. Conclusions. We derived the first model to quantify the risk for developing AIT among adults with CHD. Before using it clinically to help selecting among alternative antiarrhythmic options, it needs validation in an independent population

Reallabor Asylsuchende in der Rhein-Neckar-Region: Vielfalt an Problemen - Vielfalt an Lösungen

Deutschland steht vor der Aufgabe, viele Geflüchtete unterzubringen und ihnen neue Lebensperspektiven zu eröffnen. Die Menschen, die in den vergangenen Jahren gekommen sind, um Schutz zu suchen, sind keine homogene Gruppe. Sie unterscheiden sich nach Geschlecht, Alter, Herkunft, kulturellem Hintergrund, Bildung, Arbeitserfahrung, Sprachkompetenz, Migrations- und Fluchterfahrung, Zukunftsentwürfen und vielerlei mehr. Standardmaßnahmen für alle laufen so oftmals ins Leere, Ressourcen werden schlecht genutzt und Chancen verschenkt

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Contraception Methods and Cervical Cancer Prevention: Opportunities or Unintended Consequences?

Background: Patients may seek sexual and reproductive health care for a range of clinical services, including cervical cancer prevention through human papillomavirus (HPV) vaccination or screening with Pap and/or HPV testing, or pregnancy prevention through initiation or continuation of contraceptive methods. Recommendations for frequency of cervical cancer screening are clearly defined, but clinical surveillance for contraception varies significantly between methods. Despite the opportunities presented to complete preventive health care during clinical encounters for contraception, there are no existing analyses that explicitly consider the associations between contraceptive services and cervical cancer prevention and screening.Methods: A secondary data analysis of the 2015-2019 National Survey of Family Growth (NSFG) was completed to investigate the association between past and current contraception use and (a) awareness of cervical cancer screening recommendations, (b) history of HPV vaccination, (c) maintenance of current cervical cancer screening, and (d) Pap testing interval. Special populations, including sexual minority women and rural residents, were also considered. Univariate and bivariate statistics were calculated and logistic regression was used to estimate odds ratios (OR) using STATA 17.0, guided by a theory-based model. Results: Use of provider-surveilled contraception methods was associated with higher rates of HPV vaccination, increased odds of Pap testing prior to age 21, higher odds of current Pap testing, and lower odds of a \u3e12 month Pap testing interval. There were no significant differences among contraception users in awareness of screening recommendations, nor were there differences in maintenance of current screening according to sexual orientation or place of residence. Significance: While provider-surveilled contraception use was associated with protective behaviors, individuals may undergo excessive cervical cancer screening that could increase risk for physical, emotional, or financial consequences, while not providing additional protection against cervical cancer. Clinical interactions should emphasize evidence-based cervical cancer prevention counseling and screening, while public health campaigns and health policy enhance awareness of these measures and reimbursement for services, respectively. Further research is necessary to understand the consequences of excessive screening while developing interventions to reach those at risk for delayed screening