Insulin-like growth factor 1 (IGF1), also known as somatomedin C, is essential for the regulation of animal growth and development. In many species, the IGF1 gene can be alternatively spliced into multiple transcripts, encoding different pre-pro-IGF1 proteins. However, the exact alternative splicing patterns of IGF1 and the sequence information of different splice variants in sheep are still unclear. In this study, four splice variants (class 1-Ea, class 1-Eb, class 2-Ea, and class 2-Eb) were obtained, but no IGF1 Ec, similar to that found in other species, was discovered. Bioinformatics analysis showed that the four splice variants shared the same mature peptide (70 amino acids) and possessed distinct signal peptides and E peptides. Tissue expression analysis indicated that the four splice variants were broadly expressed in all tested tissues and were most abundantly expressed in the liver. In most tissues and stages, the expression of class 1-Ea was highest, and the expression of other splice variants was low. Overall, levels of the four IGF1 splice variants at the fetal and lamb stages were higher than those at the adult stage. Overexpression of the four splice variants significantly increased fibroblast proliferation and inhibited apoptosis (P < 0.05). In contrast, silencing IGF1 Ea or IGF1 Eb with siRNA significantly inhibited proliferation and promoted apoptosis (P < 0.05). Among the four splice variants, class 1-Ea had a more evident effect on cell proliferation and apoptosis. In summary, the four ovine IGF1 splice variants have different structures and expression patterns and might have different biological functions.
Xu-Ting Song, Jia-Nan Zhang, Duo-Wei Zhao, Yu-Fei Zhai, Qi Lu, Mei-Yu Qi, Ming-Hai Lu, Shou-Long Deng, Hong-Bing Han, Xiu-Qin Yang, and Yu-Chang Yao
Yaqian Mao, Lizhen Xu, Ting Xue, Jixing Liang, Wei Lin, Junping Wen, Huibin Huang, Liantao Li, and Gang Chen
To establish a rapid, cost-effective, accurate, and acceptable osteoporosis (OP) screening model for the Chinese male population (age ≥ 40 years) based on data mining technology.
Materials and methods
This was a 3-year retrospective cohort study, which belonged to the sub-cohort of the Chinese Reaction Study. The research period was from March 2011 to December 2014. A total of 1834 subjects who did not have OP at the baseline and completed a 3-year follow-up were included in this study. All subjects underwent quantitative ultrasound examinations for calcaneus at the baseline and follow-ups that lasted for 3 years. We utilized the least absolute shrinkage and selection operator (LASSO) regression model to select feature variables. The characteristic variables selected in the LASSO regression were analyzed by multivariable logistic regression (MLR) to construct the predictive model. This predictive model was displayed through a nomogram. We used the receiver operating characteristic (ROC) curve, C-index, calibration curve, and clinical decision curve analysis (DCA) to evaluate model performance and the bootstrapping validation to internally validate the model.
The predictive factors included in the prediction model were age, neck circumference, waist-to-height ratio, BMI, triglyceride, impaired fasting glucose, dyslipidemia, osteopenia, smoking history, and strenuous exercise. The area under the ROC (AUC) curve of the risk nomogram was 0.882 (95% CI, 0.858–0.907), exhibiting good predictive ability and performance. The C-index for the risk nomogram was 0.882 in the prediction model, which presented good refinement. In addition, the nomogram calibration curve indicated that the prediction model was consistent. The DCA showed that when the threshold probability was between 1 and 100%, the nomogram had a good clinical application value. More importantly, the internally verified C-index of the nomogram was still very high, at 0.870.
This novel nomogram can effectively predict the 3-year incidence risk of OP in the male population. It also helps clinicians to identify groups at high risk of OP early and formulate personalized intervention measures.
Nadia Sabbah, Peter Wolf, Céline Piedvache, Séverine Trabado, Tristan Verdelet, Catherine Cornu, Jean-Claude Souberbielle, and Philippe Chanson
Measurement of IGF-I is important in the management of patients with growth hormone disorders. Here we aim to establish normative data for two new IGF-I assay kits based on a large random sample of the French general adult population.
Subjects and methods
We measured IGF-I in 911 healthy adults (18–90 years) with two immunoassays (ROCHE Elecsys® and IMMULITE-2000 calibrated against the new IS 02/2547). We compared the data with those of the six immunoassays (iSYS, LIAISON XL, IMMULITE-2000 calibrated against the first IS 87/518, IGF-I RIACT, Mediagnost ELISA, and Mediagnost RIA) that we reported previously. The pairwise concordance among the eight assays was assessed with Bland–Altman plots for both the IGF-1 raw data and the standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorizing IGF-I SDS (ClinicalTrials.gov Identifier: NCT01831648).
The normative data included the range of values (2.5–97.5 percentiles) given by the two new IGF-I assays according to age group and sex. A formula for the SDS calculation is provided. As for the previous six assays, the lower limits of the reference intervals of the two new assays were similar, but the upper limits varied markedly. The pairwise concordances were only moderate (kappa 0.57).
Data obtained for these two new IGF-I immunoassays confirm that despite being obtained in the same large healthy population, the reference intervals of the eight commercial IGF-1 assay kits showed noteworthy differences. The agreement among the various methods was moderate to good.
Milena Kloter, Claudia Gregoriano, Ellen Haag, Alexander Kutz, Beat Mueller, and Philipp Schuetz
Systemic infections and sepsis lead to strong activation of the vasopressin system, which is pivotal for stimulation of the endocrine stress response and, in addition, has vasoconstrictive and immunomodulatory effects. Our aim was to assess the significance of the vasopressor system through measurement of C-terminal proAVP (copeptin) regarding mortality prediction in a large prospective cohort of patients with systemic infection.
Design and methods
This secondary analysis of the observational cohort TRIAGE study included consecutive, adult, medical patients with an initial diagnosis of infection seeking emergency department care. We used multivariable regression analysis to assess associations of copeptin levels in addition to the Sequential Organ Failure Assessment (SOFA) score with 30-day mortality. Discrimination was assessed by calculation of the area under the curve (AUC).
Overall, 45 of 609 (7.4%) patients with infection died within 30 days. Non-survivors had a marked upregulation of the vasopressin system with a more than four-fold increase in admission copeptin levels compared to non-survivors (199.9 ± 204.7 vs 46.6 ± 77.2 pmol/L). In a statistical model, copeptin was significantly associated with mortality (adjusted odds ratio of 1.04, 95% CI 1.01 to 1.07, P = 0.002). Regarding discrimination, copeptin alone showed an AUC of 0.82, while adding copeptin to the SOFA score significantly improved its prognostic ability (AUC 0.83 vs 0.86, P = 0.027).
Activation of the vasopressin system mirrored by an increase in copeptin levels provided significant information regarding mortality risk and improved the SOFA score for prediction of sepsis mortality.
Kim K B Clemmensen, Jonas S Quist, Dorte Vistisen, Daniel R Witte, Anna Jonsson, Oluf Pedersen, Torben Hansen, Jens J Holst, Torsten Lauritzen, Marit E Jørgensen, Signe Torekov, and Kristine Færch
Mei Li, Yanfei Chen, Binrong Liao, Jing Tang, Jingzi Zhong, and Dan Lan
To evaluate the characteristics and significance of serum kisspeptin and makorin ring finger protein 3 (MKRN3) levels for the diagnosis of central precocious puberty (CPP) in girls.
Thirty four individuals with CPP, 17 individuals with premature thelarche (PT), and 28 age-matched prepubertal girls as normal control (NC) were recruited in this case–control study. Physical measurements included BMI and tests for breast, bone, and sexual characteristics. Biochemical measurements included serum LH, FSH, estradiol, insulin-like growth factor-1, MKRN3, and kisspeptin. Blood samples were taken from individuals with CPP and PT before the gonadotrophin-releasing hormone stimulation test and at 30, 60, 90, and 120 min after injection with triptorelin.
Serum kisspeptin levels were higher in the CPP group when compared to the NC group (P = 0.020), while serum MKRN3 levels were lower in the two groups (P = 0.028). There were no significant differences between the CPP and PT groups as well as the PT and NC groups (all, P > 0.05). The cut-off value of serum kisspeptin differentiating patients with CPP from those without CPP was 0.40 nmol/L, with 82.4% sensitivity and 57.1% specificity, while the cut-off value of serum MKRN3 was 0.33 pmol/L, with 79.4% sensitivity and 53.6% specificity. The area under the curves (AUCs) of both kisspeptin and MKRN3 for differentiating those girls with CPP from PT were less than 0.5.
Serum levels of kisspeptin and MKRN3 may play an auxiliary role in predicting CPP. However, the two measurements were not able to differentiate girls with CPP from PT and prepubertal control. This study emphasizes the need to search for markers to simplify the accurate diagnosis of CPP in girls.
Rossella Cannarella, Andrea Crafa, Sandro La Vignera, Rosita A Condorelli, and Aldo E Calogero
Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus–pituitary–testicular axis, especially in childhood, but the evidence in humans is scanty. Laron syndrome, a human model of IGF1 deficiency, may help to solve this issue.
This systematic review aims to analyze puberty onset and progression, testicular volume, gonadotropin, and total testosterone serum levels, sperm parameters and fertility, and penile length in patients with Laron syndrome.
Specific keywords were used. All data on male patients with Laron syndrome were included.
Seventeen articles matched the inclusion criteria and were entered in the analysis, for a total of 125 male patients. Puberty was absent in 8.9% and delayed in 35.6% of untreated patients of pubertal age. After onset, the duration of the pubertal process was prolonged in 76.9% of untreated patients. The growth spurt was absent in 52.6% and delayed in 31.6% of untreated patients. The testicular volume was small in the two patients who did not receive any treatment. Treatment with IGF1 increased gonadotropin and testosterone serum levels in five out of five patients of pubertal age. No effect was found in four out of four patients younger than 5 years. No study reported data on sperm parameters and fertility. Micropenis occurred in 67.2% of patients.
Conclusion and future perspectives
Delayed puberty is common in patients with Laron syndrome. The growth hormone–IGF1 axis may influence the time of puberty onset. Serum levels of IGF1 should be investigated in children with delayed puberty, scarce progression of testicular growth, and/or micropenis. IGF1 levels might be measured in children with delayed puberty, poor testicular growth, and/or micropenis.
C Chiapponi, H Alakus, M Faust, A M Schultheis, J Rosenbrock, and M Schmidt
Five percent of patients with differentiated thyroid cancer are diagnosed with radioiodine refractory relapse in the course of the disease. For isolated or oligometastatic cervical recurrence, resection or another local treatment is recommended. In this study, the impact of surgical treatment of cervical radioiodine refractory 18F-FDG-PET positive relapse of papillary thyroid cancer (PTC) was evaluated.
Patients receiving radioiodine therapy between 2005 and 2015 at the University Hospital of Cologne, Germany, for PTC were screened. The subgroup of patients undergoing surgery during the course of disease after recommendation by a multidisciplinary endocrine team for cervical radioiodine refractory 18F-FDG-PET positive recurrence was identified. Demographics, clinic-pathologic characteristics, oncologic treatment, and outcome were analyzed.
Thirty (3%) of 969 patients with PTC treated with radioiodine therapy at our institution underwent surgery for radioiodine refractory 18F-FDG-PET positive cervical recurrence during the course of the disease. In eight (26.6%) patients, more than one operation was performed. Sixteen (53%) patients received external beam radiation therapy (EBRT) after surgery. Follow-up was on average, 79.2 ± 61.6 months after the last surgical treatment. Biochemical and radiological cure was seen in 12 (40%) patients. Remission was significantly more frequent in younger patients (P = 0.0001) with lymph node rather than soft tissue tumor recurrence (P = 0.004).
Surgical treatment of radioiodine refractory 18F-FDG-PET positive cervical recurrence led to biochemical and radiological cure in about 40% of patients in this study. Further data are needed concerning risk stratification of potential subgroups benefitting of surgical approach and the possible role of EBRT after repetitive surgery.
Chun-feng Lu, Wang-shu Liu, Xiao-qin Ge, and Feng Xu
The aim of the present study was to evaluate the association between adenosine deaminase (ADA) levels and diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D). In this study, patients with T2D who had been screened for DKD were recruited. Patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or a urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g for 3 months were identified as having DKD. The prevalence of DKD was 13.3%, and the range of serum ADA levels was 4–37 U/L. Serum ADA levels were positively associated with cystatin C levels and UACR (r = 0.295 and r = 0.302, respectively, both P < 0.05) and negatively associated with eGFR (r = −0.342, P < 0.05). The proportion of participants with DKD increased significantly from 3.8% in the first tertile (T1) to 13.6% in the second tertile (T2) and 25.9% in the third tertile (T3) of ADA (P for trend < 0.001). After adjusting for clinical risk factors for DKD via multiple logistic regression, the corresponding odds ratios (ORs) of DKD for the participants in T2 and T3 vs those in T1 of ADA were 5.123 (1.282–20.474) and 10.098 (1.660–61.431), respectively. Receiver operating characteristic (ROC) analysis revealed that the optimal cutoff value of ADA to indicate DKD was 10 U/L. Its corresponding sensitivity and specificity were 75.5 and 56.4%, respectively. Our results demonstrated that serum ADA levels were closely associated with DKD and partly reflect the risk of DKD in patients with T2D.
Dorte Glintborg, Katrine Hass Rubin, Simon Bang Mohr Kristensen, Øjvind Lidegaard, Guy T’Sjoen, Aisa Burgwal, Malene Hilden, and Marianne Skovsager Andersen
Gender dysphoria could be associated with low socioeconomic status (SES). SES could be modified by age, ethnic background, and medical morbidity.
To determine SES in a national study population including transgender persons in Denmark.
National register-based cohort study in Danish transgender persons and age-matched controls. The transgender study cohort included persons with ICD-10 diagnosis code of 'gender identity disorder' and/or persons with legal sex change and persons who fulfiled the inclusion criteria during 2000–2018. The main outcome measure was SES including personal income, occupational status, and education.
The cohort included 2770 transgender persons and 27,700 controls. In the transgender study cohort, 1437 were assigned male at birth (AMAB), median age (interquartile range, IQR) 26.0 (17.3) years, and 1333 were assigned female at birth (AFAB), median age 22.5 (10.3) years. Adjusting for age and sex, the relative risk ratio (RRR) of low vs high personal income was 5.6 (95% CI: 4.9; 6.3) in transgender persons compared to controls. The RRR of low vs high income was 6.9 (5.8; 8.3) in persons AMAB compared to control males and 4.7 (3.9; 5.6) in persons AFAB compared to control females. The RRR of low vs high income was 3.7 (3.2; 4.3) in transgender persons of Danish origin compared to controls. The Charlson comorbidity index was comparable in transgender persons vs controls.
Being transgender was negatively associated with SES. In transgender persons, the risk of low vs high income could be more pronounced in transgender persons of foreign origin.