The terms idiopathic short stature (ISS) and small for gestational age (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term SGA was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms SGA and ISS as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.
Robert Rapaport, Jan M Wit, and Martin O Savage
Huma Qamar, Nandita Perumal, Eszter Papp, Alison D Gernand, Abdullah Al Mahmud, and Daniel E Roth
Intrauterine growth restriction (IUGR) reflects inadequate growth in-utero and is prevalent in low resource settings. This study aimed to assess the association of maternal delivery parathyroid hormone (PTH), a regulator of bone turnover and calcium homeostasis, with newborn anthropometry, to identify regulators of PTH, and to delineate pathways by which maternal PTH regulates birth size using path analysis. This was a cross-sectional analysis of data from participants (n=537) enrolled in the Maternal Vitamin D for Infant Growth trial in Dhaka, Bangladesh. Primary exposures were maternal delivery intact PTH (iPTH) or whole PTH (wPTH) and outcomes were gestational age- and sex-standardized z-scores for birth length (LAZ), weight (WAZ), and head circumference (HCAZ). Hypothesized regulators of PTH included calcium and protein intake, vitamin D, magnesium, fibroblast-like growth factor-23 (FGF23), and C-reactive protein. Maternal iPTH was not associated with birth size in linear regression analyses; however, in path analysis models, every SD increase in log[iPTH] was associated with 0.08SD (95% CI:0.002,0.162) higher LAZ. In linear regression and path analysis models, wPTH was positively associated with WAZ. Vitamin D suppressed PTH, while FGF23 was positively associated with PTH. In path analysis models, higher magnesium was negatively associated with LAZ; FGF23 was positively associated and protein intake was negatively associated with LAZ, WAZ, and HCAZ. Higher maternal PTH in late pregnancy is unlikely to contribute to IUGR. Future studies should investigate maternal FGF23, magnesium and protein intake as regulators of fetal growth, particularly in settings where food insecurity and IUGR are public health problems.
Kelly Brewer, Isabel Nip, Justin Bellizzi, Jessica Costa-Guda, and Andrew Arnold
Objective: Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation.
Methods: We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBX4, for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis.
Results: We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBX4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7Mb of chromosome 6q25-26. FBX4 was not affected by LOH.
Conclusion: The absence of evidence for specific bi-allelic inactivation in PRKN and FBX4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.
Espen Nordheim, Jørn Petter Lindahl, Rasmus Kirkeskov Carlsen, Anders Åsberg, Kare Inge Birkeland, Rune Horneland, Birgitte Boye, Hanne Scholz, and Trond Geir Jenssen
Objective β-cell replacement therapy (βCRT), including pancreas transplantation alone (PTA) and islet transplantation (ITX), is a treatment option for selected type 1 diabetes patients. All potential candidates for βCRT in Norway are referred to one national transplant centre for evaluation before any pre-transplant work-up is started. This evaluation was performed by a transplant nephrologist alone prior to 2015 and by a multidisciplinary team (MDT) from 2015.
We have reviewed the allocation of patients to treatment modality and the 1-year clinical outcome for the patients after transplantation.
Research design and methods Medical charts of all patients evaluated for βCRT between 2010 and 2020 in Norway were retrospectively analysed and the outcome of patients receiving βCRT were studied.
Results One hundred forty-four patients were assessed for βCRT eligibility between 2010 and 2020. After MDT evaluation was introduced for βCRT eligibility in 2015, the percentage of referred patients accepted for the transplant waiting list fell from 84% to 40% (p<0.005). One year after transplantation, 73% of the PTA and none of the ITX patients were independent of exogenous insulin, 8% of the PTA and 90% of the ITX patients had partial graft function while 19% of the PTA and 10% of the ITX patients suffered from graft loss.
Conclusion The acceptance rate for βCRT was significantly reduced during a 10-year observation period and 81% of the PTA and 90% of the ITX patients had partial or normal graft function one year post-transplant.
Fang Lv, Xiaoling Cai, Chu Lin, Tianpei Hong, Xiaomei Zhang, Zhufeng Wang, Huifang Xing, Guizhi Zong, Juming Lu, Xiaohui Guo, Jing Wu, Leili Gao, Xianghai Zhou, Xueyao Han, and Ji Linong
Aims: To estimate the sex differences in the prevalence of overweight and obesity aged 20-89 in Chinese patients with type 2 diabetes (T2D).
Methods: 811,264 patients with T2D from six hospital-based, cross-sectional studies, and 46,053 subjects from general population were included in our analysis. Prevalence of underweight, overweight, obesity were calculated in each sex.
Results: In patients with T2D, the standardized prevalence of underweight (BMI<18.5 kg/m2), overweight (24 kg/m2 ≤ BMI<28 kg/m2), and general obesity (BMI ≥28 kg/m2) were 2.2%, 43.2%, and 11.6%, respectively. Similar trend patterns of the prevalence of underweight and overweight were observed in general and T2D population, in males and females with T2D (all p for trend<0.01). In patients with T2D, patients at younger age and older age were more likely to be underweight. The prevalence of overweight increased first, then stabilized or decreased with age. However, different trend patterns of the prevalence of obesity in males and females were found. In males, the prevalence of obesity decreased first, and then stabilized after 60 years of age. In females, the prevalence of obesity decreased first, then increased after 50 years of age. In general population, the prevalence of obesity increased with age in females, while, the trend of prevalence of obesity with age in males was not obvious.
Conclusion: Different trends in the prevalence of obesity with age in different sex were found in Chinese patients with T2D.
Xiao Zong, Qin Fan, Hang Zhang, Qian Yang, Hongyang Xie, Qiujing Chen, Ruiyan Zhang, and Rong Tao
To explore the relationship between soluble ST2 (sST2) and metabolic syndrome (MetS) and determine whether sST2 levels can predict the presence and severity of MetS. We evaluated 550 consecutive subjects (58.91 ± 9.69 years, 50% male) with or without MetS from the Department of Vascular and Cardiology, Shanghai Jiao Tong University-Affiliated Ruijin Hospital. Serum sST2 concentrations were measured. The participants were divided into three groups according to the sST2 tertiles. Univariate and multivariable logistic regression models were used to evaluate the association between serum sST2 concentrations and the presence of MetS. Serum sST2 concentrations were significantly higher in the MetS group than in those in the no MetS group (14.80 ± 7.01 vs. 11.58 ± 6.41 ng/ml, P < 0.01). Subjects with more MetS components showed higher levels of sST2. sST2 was associated with the occurrence of MetS after multivariable adjustment as a continuous log-transformed variable (per 1 SD, odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.13-1.80, P < 0.01). Subgroup analysis showed that individuals with MetS have significantly higher levels of sST2 than those without MetS regardless of sex and age.High serum sST2 levels were significantly and independently associated with the presence and severity of MetS. Thus, sST2 levels may be a novel biomarker and clinical predictor of MetS.
Franka S. Schaebs, Gwen Wirobski, Sarah Marshall-Pescini, Friederike Range, and Tobias Deschner
Within the last decade, oxytocin (OT) has attracted a lot of attention in the context of various human social behaviors. Besides its importance in regulating physiological processes in females related to giving birth and lactation, OT is involved in the establishment and maintenance of social relationships, trust and emotion recognition. However, results are not always consistent across studies, which may partly be due to the incomplete validation of methods used to assess OT levels. Carefully validating a method before its use is of crucial importance to ensure that it can be used to accurately, reliably and repeatedly assess OT levels. With this study we evaluated a commercially available Enzyme Immunoassay to assess OT in human urine samples by conducting a careful analytical validation. Results indicate that, with regard to parallelism and immunoreactivity, human urinary OT can be assessed reliably. However, extraction methods need further improvement to optimize measures of accuracy and extraction efficiency, especially in the lower range of the assay system. Tests on OT stability indicate that OT is affected by degradation when stored at 4°C or room temperature. Storing urine samples over longer periods revealed that OT levels are most stable when stored as ethanol extracts at -20°C compared to being stored as samples at -20°C or -80°C. Although some of the validated parameters did not reach the intended quality criteria, this study highlights the importance of such in depth validation procedures and reporting results to make them available to researchers embarking on projects utilizing such methods.
Satoshi Higuchi, Hideki Ota, Yuta Tezuka, Kazumasa Seiji, Hidenobu Takagi, Jongmin Lee, Yi-Wei Lee, Kei Omata, Yoshikiyo Ono, Ryo Morimoto, Masataka Kudo, Fumitoshi Satoh, and Kei Takase
This study compared cardiac function, morphology, and tissue characteristics between two common subtypes of primary aldosteronism (PA) using a 3T MR scanner.
A retrospective, single-center, observational study.
We retrospectively reviewed 143 consecutive patients with PA, who underwent both adrenal venous sampling and cardiac magnetic resonance. We acquired cine, late gadolinium enhancement, and pre- and postcontrast myocardial T1-mapping images.
PA was diagnosed as unilateral aldosterone-producing adenoma (APA) in 70 patients and bilateral hyperaldosteronism (BHA) in 73. The APA group showed significantly higher plasma aldosterone concentration (PAC) and aldosterone to renin rate (ARR) than the BHA group. After controlling for age, sex, antihypertensive drugs, systolic and diastolic blood pressure, and disease duration, the parameters independently associated with APA were: left ventricular end-diastolic volume index (EDVI: adjusted odds ratio (aOR) = 1.06 (95% CI: 1.030–1.096), P < 0.01), end-systolic volume index (ESVI: 1.06 (1.017–1.113), P < 0.01), stroke index (SI: 1.07 (1.020–1.121), P < 0.01), cardiac index (CI: 1.001 (1.000–1.001), P < 0.01), and native T1 (1.01 (1.000–1.019), P = 0.038). Weak positive correlations were found between PAC and EDVI (R = 0.28, P < 0.01), ESVI (0.26, P < 0.01), and SI (0.18, P = 0.03); and between ARR and EDVI (0.25, P < 0.01), ESVI (0.24, P < 0.01), and native T1 (0.17, P = 0.047).
APA is associated with greater LV volumetric parameters and higher native T1 values, suggesting a higher risk of volume overload and myocardial damage.
Shih-Rong Lin, Shih-Fen Chen, Yu-Cih Yang, Chung-Y Hsu, and Yu-Chih Shen
Hyperthyroidism contributes to many other disease conditions, including neurodegenerative diseases. Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. The purpose of this study was to investigate the risk of PD in patients with hyperthyroidism. A total of 8788 patients with hyperthyroidism and 8788 controls (without hyperthyroidism) matched by age, gender, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were then followed until the end of 2013 using Taiwan’s National Health Insurance Research Database, at which time participants who developed PD were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% CI of PD incidence rate between patients with hyperthyroidism and unaffected controls. Patients with hyperthyroidism had a significantly increased risk of PD compared with unaffected controls (1.21 vs 0.45 per 1000 person-years, HR: 2.69, 95% CI: 1.08–6.66) after adjusting for age, gender, CCI score, comorbidities, and antithyroid therapy. Hyperthyroidism and PD may share common manifestations. After excluding the first year of observation, a similar result is obtained (HR: 2.57, 95% CI: 1.61–4.01). Also, this study found that older age (HR: 3.74–8.53), more comorbidities (HR: 1.58–1.63), and specific comorbidities (brain injury (HR: 1.57) and cerebrovascular disease (HR: 3.44)) were associated with an increased risk of developing PD. Patients with hyperthyroidism have an increased risk of developing PD. Additional prospective clinical studies are warranted to examine the relationship between hyperthyroidism and PD and determine if there is an intervention that could reduce PD risk.
Xingrong Tan, Wenjing Hu, Shan Yang, Han Dai, Shangcheng Xu, Gangyi Yang, Ling Li, Shiguo Tang, and Yi Wang
The purpose of this study was to investigate the relationship between circulating zinc α 2-glycoprotein (ZAG), irisin, betatrophin and adiponectin concentrations and metabolic syndrome (MetS) components and to analyze the effects of blood glucose and insulin on these cytokine concentrations in vivo.
A total of 196 young women, including 78 healthy women and 118 women with MetS components, were recruited for this cross-sectional study. An oral glucose tolerance test and euglycemic-hyperinsulinemic clamp (EHC) were performed in healthy subjects and women with MetS components. An ELISA kit was used to measure serum ZAG, irisin, betatrophin, and adiponectin levels, and their relationship with the MetS components was analyzed.
In women with MetS components, circulating irisin and betatrophin levels were significantly higher than those in the healthy women ((207 (150–248) vs 178 (147–228); P < 0.05) for irisin; (0.51 (0.38–0.63) vs 0.38 (0.23–0.52); P < 0.001) for betatrophin), but circulating ZAG and adiponectin levels were significantly lower (39.8 (26.4–50.4) vs (46.7 (40.6–63.0); P < 0.001) for ZAG; (36.5 (22.0–47.6) vs 41.2 (35.7–54.7); P < 0.01) for adiponectin). FBG, WC, and triglyceride were significantly correlated with the circulating levels of these four cytokines (P < 0.001 or <0.05). All four cytokines were associated with MetS and its components. In response to increasing insulin levels, circulating ZAG concentrations were markedly increased in both healthy subjects and women with MetS components during the EHC. However, serum irisin, betatrophin, and adiponectin levels in both healthy subjects and women with MetS components were significantly reduced compared with baseline.
Serum ZAG, irisin, betatrophin and adiponectin were associated with MetS and might be biomarkers for screening MetS components.