bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review
Authors: Sugisawa Chiho , Takamizawa Tetsuya , Abe Kiyomi , Hasegawa Tomonobu , Shiga Kentaro , Sugawara Hidenori , Ohsugi Koji , Muroya Koji , Asakura Yumi , Adachi Masanori , Daitsu Takashi , Numakura Chikahiko , Koike Akemi , Tsubaki Junko , Kitsuda Kazuteru , Matsuura Nobuo , Taniyama Matsuo , Ishii Sumiyasu , Satoh Tetsurou , Yamada Masanobu , Narumi Satoshi 
Published: August 2019

Abstract

Context
Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified.

Objectives
To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations.

Patients and Methods
Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed.

Results
Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap.

Conclusions
The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.
Trimethylamine N-Oxide Metabolites in Early Pregnancy and Risk of Gestational Diabetes: A Nested Case-Control Study
Authors: Huo Xiaoxu , Li Jing , Cao Yun-Feng , Li Sai-Nan , Shao Ping , Leng Junhong , Li Weiqin , Liu Jinnan , Yang Kai , Ma Ronald C W , Hu Gang , Fang Zhong-Ze , Yang Xilin 
Published: August 2019

Abstract

Objectives
This study aimed to investigate the associations between trimethylamine N-oxide (TMAO) and related metabolites in early pregnancy and the risk of gestational diabetes mellitus (GDM).

Design
A prospective cohort of 22,302 pregnant women from 2010 to 2012 in Tianjin, China, was used to perform a nested case-control study. A total of 243 women with GDM and 243 women without GDM matched by maternal age (±1 year) were used as cases and controls, respectively. Conditional logistic regression and restricted cubic spline were used to examine the full-range risk associations between individual TMAOs metabolites at the first antenatal care visit with GDM. Trimethylamine conversion ratio (TMAR) was defined as trimethylamine (TMA)/its precursors, and trimethylamine N-oxide conversion ratio (TMAOR) was defined as TMAO/TMA. An additive interaction between high TMAR and low TMAOR indicates a state of TMA accumulation, and a mathematical interaction between high TMAR and high TMAOR indicates accumulation of TMAO.

Results
TMA was linearly associated with GDM, whereas TMA precursors and TMAO were inversely associated with GDM with clear threshold effects, i.e., 16 nmol/mL for TMAO, 200 nmol/mL for betaine, 112 nmol/mL for l-carnitine, and 110 and 270 nmol/mL for cholinechloride (a U-shaped relationship). Copresence of TMAR >0.35 and TMAOR ≤0.15 was associated with a markedly higher OR (11.16; 95% CI, 5.45 to 22.8), compared with TMAR >0.35 only (OR = 1.71; 95% CI, 0.42 to 6.95) or TMAOR ≤0.15 only (OR = 2.06; 95% CI, 1.09 to 3.90), with a significant additive interaction. However, the mathematical interaction was nonsignificant.

Conclusions
TMAO metabolites in the early pregnancy were associated with the risk of GDM, whereas TMA was more likely to play a causal role in GDM.
Purine Metabolites and Carnitine Biosynthesis Intermediates Are Biomarkers for Incident Type 2 Diabetes
Authors: Ottosson Filip , Smith Einar , Gallo Widet , Fernandez Céline , Melander Olle 
Published: August 2019

AbstractContextMetabolomics has the potential to generate biomarkers that can facilitate understanding relevant pathways in the pathophysiology of type 2 diabetes (T2DM).MethodsNontargeted metabolomics was performed, via liquid chromatography–mass spectrometry, in a discovery case-cohort study from the Malmö Preventive Project (MPP), which consisted of 698 metabolically healthy participants, of whom 202 developed T2DM within a follow-up time of 6.3 years. Metabolites that were significantly associated with T2DM were replicated in the population-based Malmö Diet and Cancer–Cardiovascular Cohort (MDC-CC) (N = 3423), of whom 402 participants developed T2DM within a follow-up time of 18.2 years.ResultsUsing nontargeted metabolomics, we observed alterations in nine metabolite classes to be related to incident T2DM, including 11 identified metabolites. N2,N2-dimethylguanosine (DMGU) (OR = 1.94; P = 4.9e-10; 95% CI, 1.57 to 2.39) was the metabolite most strongly associated with an increased risk, and beta-carotene (OR = 0.60; P = 1.8e-4; 95% CI, 0.45 to 0.78) was the metabolite most strongly associated with a decreased risk. Identified T2DM-associated metabolites were replicated in MDC-CC. Four metabolites were significantly associated with incident T2DM in both the MPP and the replication cohort MDC-CC, after adjustments for traditional diabetes risk factors. These included associations between three metabolites, DMGU, 7-methylguanine (7MG), and 3-hydroxytrimethyllysine (HTML), and incident T2DM.ConclusionsWe used nontargeted metabolomics in two Swedish prospective cohorts comprising >4000 study participants and identified independent, replicable associations between three metabolites, DMGU, 7MG, and HTML, and future risk of T2DM. These findings warrant additional studies to investigate a potential functional connection between these metabolites and the onset of T2DM.
Low-Normal Thyroid Function Predicts Incident Anemia in the General Population With Euthyroid Status
Authors: Gu Yeqing , Chi Vu Thi Quynh , Zhang Qing , Liu Li , Meng Ge , Wu Hongmei , Bao Xue , Zhang Shunming , Sun Shaomei , Wang Xing , Zhou Ming , Jia Qiyu , Song Kun , Niu Kaijun 
Published: August 2019

Abstract

Context
Thyroid hormones (THs) have direct and indirect effects on hematopoiesis. However, few studies have directly evaluated the effect of THs on incident anemia among euthyroid subjects. This cohort study aimed to explore whether THs under physiological conditions can affect the development of anemia in the general population.

Design
A total of 12,310 participants were enrolled in the cohort study (∼5-year follow-up period; mean, 3.1 years). A chemiluminescence immunoassay was used to measure free T3 (FT3), free T4 (FT4), and TSH, and anemia was defined according to the World Health Organization recommendation. THs, TSH, and Hb were assessed yearly during follow-up. Multivariable Cox proportional hazards regression models were used to assess the association between THs, TSH, and incident anemia.

Results
The fully adjusted hazards ratios (95% CI) of anemia per 1-unit change in FT3, FT4, and TSH concentrations were 0.70 (0.56, 0.87), 0.93 (0.88, 0.98), and 1.19 (0.94, 1.50) (P < 0.01, P < 0.01, and P = 0.14, respectively). Moreover, a significant and positive association between FT3, FT4, and annual changes in Hb (standard regression coefficients of 0.056 and 0.028, respectively; both P < 0.01) was observed. Similar associations were observed when the participants who had thyroid dysfunction upon follow-up were excluded.

Conclusions
The current study demonstrated that THs significantly predict future anemia and annual changes in Hb, even in the euthyroid population.
Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy
Authors: Püttgen Sonja , Bönhof Gidon J , Strom Alexander , Müssig Karsten , Szendroedi Julia , Roden Michael , Ziegler Dan 
Published: August 2019

AbstractContextThe factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.ObjectiveWe hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.Design and MethodsIn this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.ResultsAfter adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.ConclusionDespite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.
The Medical Therapy of Craniopharyngiomas: The Way Ahead
Authors: Alexandraki Krystallenia I , Kaltsas Gregory A , Karavitaki Niki , Grossman Ashley B 
Published: August 2019

AbstractContextCraniopharyngiomas, which are categorized as adamantinomatous (ACPs) or papillary (PCPs), have traditionally been treated with surgery and/or radiotherapy, although when the tumors progress or recur, therapeutic possibilities are very limited. Following recent advances in their molecular pathogenesis, new medical therapeutic options have emerged.Evidence AcquisitionThe search strategy that we selected to identify the appropriate evidence involved the following medical subject headings (MeSH) terms: (“Craniopharyngioma” [MeSH] AND “Craniopharyngioma/drug therapy” [MeSH]) NOT (“review” [Publication Type] OR “review literature as topic” [MeSH Terms] OR “review” [All Fields]) AND (“2009/05/01” [PDat]: “2019/04/28” [PDat]).Evidence SynthesisMutations of β-catenin causing Wnt activation with alterations of the MEK/ERK pathway are encountered in the great majority of patients with ACPs; specific alterations also stratify patients to a more aggressive behavior. In most PCPs there is primary activation of the Ras/Raf/MEK/ERK pathway secondary to BRAF-V600E mutations. BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCPs producing clinically useful and, in some cases, sustained responses. In contrast to PCPs, drugs targeting β-catenin and its downstream MAPK pathway in ACPs have so far only been used in in vitro studies, but there appear to be promising new targets clinically.ConclusionsThe identification of specific genetic alterations in patients with craniopharyngiomas has expanded the therapeutic options, providing evidence for a customized approach using newer molecular agents. More studies including a larger number of carefully selected patients are required to evaluate the response to currently available and evolving agents alone and in combination.
Dysglycemia, Not Altered Sex Steroid Hormones, Affects Cognitive Function in Polycystic Ovary Syndrome
Authors: Jarrett Brittany Y , Vantman Natalie , Mergler Reid J , Brooks Eric D , Pierson Roger A , Chizen Donna R , Lujan Marla E 
Published: August 2019

Abstract

Context
Polycystic ovary syndrome (PCOS) is a complex endocrine condition characterized by multiple reproductive and metabolic abnormalities. Because individual reproductive and metabolic abnormalities modulate working memory in the general population, there is growing interest in whether cognitive function is dually and negatively affected in PCOS.

Objective
To examine the association of reproductive and metabolic features with cognitive function in women with and without PCOS.

Design
An observational, cross-sectional study was conducted at an academic clinical research center in North America between 2006 and 2009. Common tests of working memory (i.e., manual dexterity, perceptual speed, and visuospatial ability) were performed by women with PCOS (n = 40) and control subjects (n = 40). Markers of sex steroid hormones, ovulatory function, and cardiometabolic health were also assessed.

Results
Reduced visuospatial ability was observed in women with PCOS compared with control subjects (P < 0.01). Reduced visuospatial ability was linked to higher levels of hemoglobin A1c in the entire study cohort, independent of body mass index or PCOS status. No associations were observed between visuospatial ability and reproductive features, after controlling for confounding variables.

Conclusion
Our findings support a role for glycemic control, and not PCOS per se, in cognitive dysfunction in women of reproductive age. Additional studies are needed to understand the short- and long-term effects of dysglycemia on brain health in women with PCOS, given their increased propensity for metabolic comorbidities, compared with control subjects.
Glucocorticoid and Mineralocorticoid Receptors in the Brain: A Transcriptional Perspective
Authors: Koning Anne-Sophie C A M , Buurstede Jacobus C , van Weert Lisa T C M , Meijer Onno C 
Published: August 2019

AbstractAdrenal glucocorticoid hormones are crucial for maintenance of homeostasis and adaptation to stress. They act via the mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs)—members of the family of nuclear receptors. MRs and GRs can mediate distinct, sometimes opposite, effects of glucocorticoids. Both receptor types can mediate nongenomic steroid effects, but they are best understood as ligand-activated transcription factors. MR and GR protein structure is similar; the receptors can form heterodimers on the DNA at glucocorticoid response elements (GREs), and they share a number of target genes. The transcriptional basis for opposite effects on cellular physiology remains largely unknown, in particular with respect to MR-selective gene transcription. In this review, we discuss proven and potential mechanisms of transcriptional specificity for MRs and GRs. These include unique GR binding to “negative GREs,” direct binding to other transcription factors, and binding to specific DNA sequences in conjunction with other transcription factors, as is the case for MRs and NeuroD proteins in the brain. MR- and GR-specific effects may also depend on specific interactions with transcriptional coregulators, downstream mediators of transcriptional receptor activity. Current data suggest that the relative importance of these mechanisms depends on the tissue and physiological context. Insight into these processes may not only allow a better understanding of homeostatic regulation but also the development of drugs that target specific aspects of disease.
Practice Variation in the Care of Subclinical Hypothyroidism During Pregnancy: A National Survey of Physicians in the United States
Authors: Toloza Freddy J K , Singh Ospina Naykky M , Rodriguez-Gutierrez Rene , O’Keeffe Derek T , Brito Juan P , Montori Victor M , Maraka Spyridoula 
Published: August 2019

Abstract
Evidence regarding the effects of subclinical hypothyroidism (SCH) on adverse pregnancy outcomes and the ability of levothyroxine (LT4) treatment to prevent them is unclear. Available recommendations for the management of SCH during pregnancy are inconsistent. We conducted a nationwide survey among physicians assessing their knowledge of and current practices in the care of SCH in pregnancy and compared these with the most recent American Thyroid Association (ATA) recommendations. In this cross-sectional study, an online survey was sent to active US members of the Endocrine Society. This survey included questions about current practices and clinical scenarios aimed at assessing diagnostic evaluation, initiation of therapy, and follow-up in pregnant women with SCH. In total, 162 physicians completed the survey. ATA guidelines were reviewed by 76%, of whom 53% indicated that these guidelines actually changed their practice. Universal screening was the preferred screening approach (54%), followed by targeted screening (30%). For SCH diagnosis, most respondents (52%) endorsed a TSH level >2.5 mIU/L as a cutoff, whereas 5% endorsed a population-based cutoff as recommended by the ATA. The decision to initiate treatment varied depending on the specific clinical scenario; however, when LT4 was initiated, respondents expected a small/very small reduction in maternofetal complications. In conclusion, despite recently updated guidelines, there is still wide variation in clinical practices regarding the care of women with SCH in pregnancy. Highly reliable randomized trials are required to evaluate the effectiveness of the most uncertain treatment practices on the care of pregnant women with SCH.
ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers
Authors: Kyo Chika , Usui Takeshi , Kosugi Rieko , Torii Mizuki , Yonemoto Takako , Ogawa Tatsuo , Kotani Masato , Tamura Naohisa , Yamamoto Yutaro , Katabami Takuyuki , Kurihara Isao , Saito Kohei , Kanamoto Naotetsu , Fukuoka Hidenori , Wada Norio , Murabe Hiroyuki , Inoue Tatsuhide 
Published: August 2019

Abstract

Context
Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH.

Objectives
This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients.

Patients and Methods
Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied.

Results
Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant–positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant–positive group.

Conclusions
ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant–positive mutant group showed a higher basal cortisol level than the negative group.
The Egalitarian binding partners Dynein light chain and Bicaudal-D act sequentially to link mRNA to the Dynein motor
Authors: Goldman Chandler H. , Neiswender Hannah , Veeranan-Karmegam Rajalakshmi , Gonsalvez Graydon B. 
Published: August 2019

ABSTRACT
A conserved mechanism of polarity establishment is the localization of mRNA to specific cellular regions. Although it is clear that many mRNAs are transported along microtubules, much less is known about the mechanism by which these mRNAs are linked to microtubule motors. The RNA binding protein Egalitarian (Egl) is necessary for localization of several mRNAs in Drosophila oocytes and embryos. Egl also interacts with Dynein light chain (Dlc) and Bicaudal-D (BicD). The role of Dlc and BicD in mRNA localization has remained elusive. Both proteins are required for oocyte specification, as is Egl. Null alleles in these genes result in an oogenesis block. In this report, we used an shRNA-depletion strategy to overcome the oogenesis block. Our findings reveal that the primary function of Dlc is to promote Egl dimerization. Loss of dimerization compromises the ability of Egl to bind RNA. Consequently, Egl is not bound to cargo, and is not able to efficiently associate with BicD and the Dynein motor. Our results therefore identify the key molecular steps required for assembling a localization-competent mRNP.
Ahi1 promotes Arl13b ciliary recruitment, regulates Arl13b stability and is required for normal cell migration
Authors: Muñoz-Estrada Jesús , Ferland Russell J. 
Published: August 2019

ABSTRACT
Mutations in the Abelson-helper integration site 1 (AHI1) gene are associated with neurological/neuropsychiatric disorders, and cause the neurodevelopmental ciliopathy Joubert syndrome (JBTS). Here, we show that deletion of the transition zone (TZ) protein Ahi1 in mouse embryonic fibroblasts (MEFs) has a small effect on cilia formation. However, Ahi1 loss in these cells results in: (1) reduced localization of the JBTS-associated protein Arl13b to the ciliary membrane, (2) decreased sonic hedgehog signaling, (3) and an abnormally elongated ciliary axoneme accompanied by an increase in ciliary IFT88 concentrations. While no changes in Arl13b levels are detected in crude cell membrane extracts, loss of Ahi1 significantly reduced the level of non-membrane-associated Arl13b and its stability via the proteasome pathway. Exogenous expression of Ahi1–GFP in Ahi1−/− MEFs restored ciliary length, increased ciliary recruitment of Arl13b and augmented Arl13b stability. Finally, Ahi1−/− MEFs displayed defects in cell motility and Pdgfr-α-dependent migration. Overall, our findings support molecular mechanisms underlying JBTS etiology that involve: (1) disruptions at the TZ resulting in defects of membrane- and non-membrane-associated proteins to localize to primary cilia, and (2) defective cell migration.
This article has an associated First Person interview with the first author of the paper.