bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pitfalls in RET Fusion Detection Using Break-Apart FISH Probes in Papillary Thyroid Carcinoma
Authors: Liu Yuanyuan , Wu Shafei , Zhou Liangrui , Guo Yong , Zeng Xuan 
Published: December 2020

Abstract

Objective
A standardized procedure of fused REarranged during Transfection (RET) gene detection using fluorescence in situ hybridization (FISH) remains to be established in papillary thyroid carcinoma (PTC). Our purpose was to investigate false-negative and false-positive events and their FISH signal characteristics.

Methods
A total of 111 PTC cases were analyzed using break-apart FISH probes for RET status evaluation. All FISH results were validated using fusion-induced asymmetric transcription assay (FIATA)-based reverse transcription droplet digital PCR (RT-ddPCR). Then, suspected RET-positive cases were tested using quantitative reverse transcription-PCR (RT-qPCR), followed by next-generation sequencing (NGS) for recognizing fusion variants.

Results
Thirty RET+ cases were revealed, including 20 CCDC6 (exon 1)-RET (exon 12), 6 NCOA4 (exon 8)-RET (exon 12), 1 NCOA4 (exon 7)-RET (exon 12), 1 CCDC186 (exon 7)-RET (exon 12), 1 ERC1 (exon 12)-RET (exon 12) and 1 SPECC1L (exon 9)-RET (exon 12) tumors. All RET fusion cases occurred in the BRAF- population, with a prevalence of 41.7% (30/72). Four cases of 8% to 13% (cutoff was 7.6%) dominant isolated 3′ green (IG) FISH signals were RET-. One FISH- case with isolated 5′ red (IR) signals with 94% abnormal tumor cells was demonstrated to be positive, harboring the NCOA4 (exon 7)-RET (exon 12) variant. Compared with RET fusions characterized by dominant break-apart signals with 29% to 100% aberrant cells, RET + with dominant IG-signal patterns all showed more frequent FISH+ cells (84%-92%). RET+ PTC with a break-apart signal pattern was more frequently found in unifocal lesions than in multifocal/bilateral tumors (P = 0.049).

Conclusions
A false-positive or false-negative event may exist for RET status detection in PTCs using the traditional FISH scoring method with break-apart probes.
Early Decline of Androgen Levels in Healthy Adult Men: An Effect of Aging Per Se? A Prospective Cohort Study
Authors: Banica Thiberiu , Verroken Charlotte , Reyns Tim , Mahmoud Ahmed , T’Sjoen Guy , Fiers Tom , Kaufman Jean-Marc , Lapauw Bruno 
Published: December 2020

Abstract

Context
Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) body mass index (BMI), lifestyle factors, and intercurrent disease.

Objective
Investigating longitudinal changes in serum androgen levels in healthy men in relation to body composition, lifestyle factors, and intercurrent disease.

Design, Setting, and Participants
Longitudinal, population-based sibling pair study at a university research center. 999 healthy men aged 24 to 46 years of whom 691 were reevaluated after a mean period of 12 years.

Main outcome measures
Serum SHBG, LH, and FSH levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), and androstenedione (Adione) measured using liquid chromatography-tandem mass spectometry, free T calculated (cFT).

Results
Baseline age was 34 ± 6 years. Mean BMI increased by 1.19 kg/m2, T levels decreased by 14.2% (20.8 nmol/L vs. 17.8 nmol/L), cFT by 19.1% (392 pmol/L vs. 317 pmol/L), DHT by 15.6% (1.5 nmol/L vs.1.3 nmol/L), and Adione by 10.7% (3.7 nmol/L vs. 3.3 nmol/L; all P &lt; 0.001). E2 did not change over time. SHBG increased by 3.0% (39.8 nmol/L vs. 41.0 nmol/L), LH by 5.8% (4.6 U/L vs. 4.9 U/L) and FSH by 14.7% (4.3 U/L vs. 5.1 U/L) (all P &lt; 0.001). For T, cFT, DHT, Adione, and SHBG, these longitudinal changes persisted after adjustment for confounders (all P &lt; 0.001).

Conclusion
Serum androgen levels start declining early during adult life and independently from changes in BMI and other lifestyle factors, suggesting that aging per se leads to an altered sex steroid status. Given the concurrent rise in gonadotropin levels, the decline in androgen status most likely arises from primary decrease in testicular function.
Congenital Glucagon-like Peptide-1 Deficiency in the Pathogenesis of Protracted Diarrhea in Mitchell–Riley Syndrome
Authors: Nóbrega Sara , Monteiro Mariana P , Pereira-da-Silva Luís , Pereira Sofia S , Hartmann Bolette , Holst Jens J , Barbosa Silva Raul , Cordeiro-Ferreira Gonçalo 
Published: December 2020

Abstract

Context
Mitchell–Riley syndrome due to RFX6 gene mutations is characterized by neonatal diabetes and protracted diarrhea. The RFX6 gene encodes a transcription factor involved in enteroendocrine cell differentiation required for beta-cell maturation. In contrast to the pathway by which RFX6 mutations leads to diabetes, the mechanisms underlying protracted diarrhea are unknown.

Objective
To assess whether glucagon-like peptide-1 (GLP-1) was involved in the pathogenesis of Mitchell–Riley syndrome protracted diarrhea.

Methods
Two case report descriptions. in a tertiary pediatric hospital. “Off-label” treatment with liraglutide. We describe 2 children diagnosed with Mitchell–Riley syndrome, presenting neonatal diabetes and protracted diarrhea. Both patients had nearly undetectable GLP-1 plasma levels and absence of GLP-1 immunostaining in distal intestine and rectum. The main outcome was to evaluate whether GLP-1 analogue therapy could improve Mitchell–Riley syndrome protracted diarrhea.

Results
“Off-label” liraglutide treatment, licensed for type 2 diabetes treatment in children, was started as rescue therapy for protracted intractable diarrhea resulting in rapid improvement during the course of 12 months.

Conclusion
Congenital GLP-1 deficiency was identified in patients with Mitchell–Riley syndrome. The favorable response to liraglutide further supports GLP-1 involvement in the pathogenesis of protracted diarrhea and its potential therapeutic use.
S-glutathionylation of the Na+-K+ Pump: A Novel Redox Mechanism in Preeclampsia
Authors: Liu Chia-Chi , Zhang YunJia , Makris Angela , Rasmussen Helge H , Hennessy Annemarie 
Published: December 2020

AbstractContextReduced Na+-K+ pump activity is widely reported in preeclampsia and may be caused by a reversible oxidative modification that is a novel pathological feature of preeclampsia.ObjectiveThis work aims to determine whether β 1 subunit (GSS-β 1) protein glutathionylation of the Na+-K + pump occurs in preeclampsia.MethodsThe GSS-β1 of the Na+-K+ pump and its subunit expression in human placentas were compared between women with healthy pregnancies and women with preeclampsia.Human placental samples of pregnant women with preeclampsia (n = 11, mean gestational age 36.5 weeks) were used to examine the GSS-β 1 of the Na+-K+ pump, compared to healthy pregnancies (n = 11, mean gestational age 39 weeks).The potential pathogenetic role of GSS-β 1-mediated Na+-K+ pump dysfunction in preeclampsia was investigated.ResultsProtein expression of the β 1 subunit was unchanged in placentas from women with preeclampsia vs those with normotensive pregnancies. Preeclamptic placentas had a significantly increased GSS-β 1 of the Na+-K+ pump compared to those from healthy pregnancies, and this was linked to a decrease in α 1/β 1 subunit coimmunoprecipitation. The cytosolic p47phox nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase subunit and its coimmunoprecipitation with the α 1 Na+-K+ pump subunit was increased in preeclamptic placentas, thus implicating NADPH oxidase–dependent pump inhibition.ConclusionsThe high level of β 1 pump subunit glutathionylation provides new insights into the mechanism of Na+-K+ pump dysfunction in preeclampsia.
Insulin-Stimulated Muscle Glucose Uptake and Insulin Signaling in Lean and Obese Humans
Authors: Ramos Paola A , Lytle Kelli A , Delivanis Danae , Nielsen Søren , LeBrasseur Nathan K , Jensen Michael D 
Published: December 2020

Abstract

Purpose
Skeletal muscle is the primary site for insulin-stimulated glucose disposal, and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin-resistant obese humans is controversial.

Methods
We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 nonobese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 nonobese and 25 obese male and female volunteers matched for fitness using a 1-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2).

Results
Insulin-stimulated glucose disposal (Si) was reduced by &gt; 60% (P &lt; 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between nonobese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the nonobese (r = 0.53, P = 0.03) and the obese (r = 0.55, P = 0.01) groups. Total muscle GLUT4 protein was 17% less (P &lt; 0.05) in obese subjects.

Conclusions
We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significant gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity do not replicate the pathophysiology of obesity.
Improving Science by Overcoming Laboratory Pitfalls With Hormone Measurements
Authors: Hillebrand Jacquelien J , Wickenhagen Wjera V , Heijboer Annemieke C 
Published: December 2020

Abstract
Despite all the effort taken, there is often surprisingly little attention paid to the hormone analyses involved in research studies. Thinking carefully about the quality of the hormone measurements in these studies is, however, of major importance, as this attention to methods may prevent false conclusions and inappropriate follow-up studies. We discuss issues regarding hormone measurements that one should consider, ideally prior to starting, or otherwise, as they arise during a scientific study: quality of the technique, expertise, matrices, timing and storage conditions, freeze-thaw cycles, lot-to-lot and day-to-day variation, analyses per batch or sample-wise, singlicate or duplicate measurements, combining methods, and standardization. This article and the examples mentioned herein aim to clarify the need to pay attention to the hormone analyses, and to help in making decisions. In addition, these examples help editors and reviewers of scientific journals to pay attention to the methods section in the submitted manuscripts and ask the right critical questions when needed.
Procoagulant Imbalance in Klinefelter Syndrome Assessed by Thrombin Generation Assay and Whole-Blood Thromboelastometry
Authors: Indirli Rita , Ferrante Emanuele , Scalambrino Erica , Profka Eriselda , Clerici Marigrazia , Lettera Tommaso , Serban Andreea Liliana , Vena Walter , Pizzocaro Alessandro , Bonomi Marco , Cangiano Biagio , Carosi Giulia , Mazziotti Gherardo , Persani Luca , Lania Andrea , Arosio Maura , Peyvandi Flora , Mantovani Giovanna , Tripodi Armando 
Published: December 2020

Abstract

Context
Klinefelter syndrome (KS) is a condition at increased risk of thrombosis compared to 46,XY men.

Objective
This work aimed to investigate the coagulation balance of KS patients by thrombin generation assay (TGA) and thromboelastometry.

Methods
An observational, cross-sectional study was conducted at 3 tertiary endocrinological centers in Milan, Italy. Fifty-eight KS patients and 58 age-matched healthy controls were included. Anticoagulant or antiplatelet therapy and known coagulation disorders were exclusion criteria. TGA was performed in platelet-poor plasma (PPP) and platelet-rich plasma (PRP). Whole-blood thromboelastometry and activities of coagulation factors were assessed. Endogenous thrombin potential (ETP), the area under the thrombin generation curve, assessed with and without thrombomodulin (ETP-TM+ and ETP-TM–), and their ratio (ETP ratio), were considered as indexes of procoagulant imbalance.

Results
Patients with KS displayed higher PPP-ETP-TM+ (mean 1528 vs 0.1315 nM × min; P &lt; .001), PPP-ETP ratio (0.78 vs 0.0.70; P &lt; .001), factor (F)VIII (135% vs 0.107%; P = .001), fibrinogen (283 vs 0.241 mg/dL; P &lt; .001), and FVIII/protein C ratio (1.21 vs 0.1.06; P &lt; .05) compared to controls. Protein C was comparable in the 2 groups. Similar results were observed in PRP. The ETP ratio was positively associated with FVIII (ρ = 0.538, P &lt; .001) in KS. Thromboelastometry parameters confirmed evidence of hypercoagulability in KS.

Conclusion
Patients with KS display a procoagulant imbalance expressed by increased thrombin generation both in PPP and PRP, which is at least in part explained by increased FVIII levels. The procoagulant imbalance, which was confirmed by thromboelastometry, may be responsible for the thrombotic events observed in these patients. Further investigation on the benefit/risk ratio of antithrombotic prophylaxis is warranted.
Limited Genetic Overlap Between Overt Hashimoto’s Thyroiditis and Graves’ Disease in Twins: A Population-based Study
Authors: Skov Jakob , Calissendorff Jan , Eriksson Daniel , Magnusson Patrik , Kämpe Olle , Bensing Sophie , Kuja-Halkola Ralf 
Published: December 2020

Abstract

Context
Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are known to coaggregate in families, but the magnitude and nature of a shared etiology is unknown.

Objectives
To estimate the shared genetic influence on overt HT and GD and to examine if the heritability differs between men and women.

Design, setting, and patients
We used national health registries to identify cases of HT and GD in a cohort of 110 814 Swedish twins. By comparing intra-class and cross-twin cross-trait correlations in dizygotic and monozygotic twins, we calculated heritability and the proportions thereof shared between the diseases. Univariate estimates of heritability were calculated by sex.

Results
The heritability for HT and GD was 65% (95% CI, 61-70) and 63% (95% CI, 55-72), respectively. The genetic correlation was 0.35 (95% CI, 0.20-0.50) and shared genetic effects accounted for 8% of the variance for both HT and GD. Univariate heritability was significantly higher in men than in women for HT (90% vs 60%, P &lt; 0.001) but not for GD (79% vs 63%, P = 0.085).

Conclusions
From a genetic perspective, HT and GD appear to be only modestly related diseases. Hence, the term “autoimmune thyroid disease,” used to cluster these disorders, may have limited validity in a genetic context. Moreover, the mechanisms contributing to HT are partly different for the sexes, with genetic components more important in men.
Mouse Models of Human Proprotein Convertase Insufficiency
Authors: Shakya Manita , Lindberg Iris 
Published: December 2020

AbstractThe kexin-like proprotein convertases perform the initial proteolytic cleavages that ultimately generate a variety of different mature peptide and proteins, ranging from brain neuropeptides to endocrine peptide hormones, to structural proteins, among others. In this review, we present a general introduction to proprotein convertase structure and biochemistry, followed by a comprehensive discussion of each member of the kexin-like subfamily of proprotein convertases. We summarize current knowledge of human proprotein convertase insufficiency syndromes, including genome-wide analyses of convertase polymorphisms, and compare these to convertase null and mutant mouse models. These mouse models have illuminated our understanding of the roles specific convertases play in human disease and have led to the identification of convertase-specific substrates; for example, the identification of procorin as a specific PACE4 substrate in the heart. We also discuss the limitations of mouse null models in interpreting human disease, such as differential precursor cleavage due to species-specific sequence differences, and the challenges presented by functional redundancy among convertases in attempting to assign specific cleavages and/or physiological roles. However, in most cases, knockout mouse models have added substantively both to our knowledge of diseases caused by human proprotein convertase insufficiency and to our appreciation of their normal physiological roles, as clearly seen in the case of the furin, proprotein convertase 1/3, and proprotein convertase 5/6 mouse models. The creation of more sophisticated mouse models with tissue- or temporally-restricted expression of specific convertases will improve our understanding of human proprotein convertase insufficiency and potentially provide support for the emerging concept of therapeutic inhibition of convertases.
TENDÊNCIA DE COBERTURA E USO DO SOLO PARA A BACIA DE SEPETIBA: NOVOS ELEMENTOS PARA O PLANEJAMENTO AMBIENTAL E A GESTÃO DO TERRITÓRIO
Authors: Deus Leandro Andrei Beser de , Oscar Júnior Antonio Carlos 
Published: December 2020

O tempo é uma das categorias fundamentais para a Geografia, afinal é a partir dele que se compreendem os processos de organização do território, bem como dos problemas ambientais, portanto, elemento peremptório para a gestão do território e o planejamento ambiental. O presente artigo tem como objetivo avaliar as mudanças de cobertura e uso do solo na bacia da Baía de Sepetiba, no município de Rio de Janeiro, oferecendo, a partir de uma metodologia baseada em um Sistema de Informação Geográfica Temporal (SIGT), uma perspectiva de análise que combina o tempo passado (2004), presente (2013) e futuro (tendencial). Através da metodologia aplicada foi possível constatar o intenso padrão de conversão de cobertura e uso do solo para a bacia, explicado, sobretudo, pelo desenvolvimento industrial, orientado pelo Programa de Aceleração do Crescimento (PAC), bem como, a ocupação residencial de classe baixa e média, sobretudo, em áreas suscetíveis a enchentes, inundações e deslizamentos, transparecendo os impactos de um ordenamento territorial orientado não pelo poder público, mas pelos agentes produtivos e dinâmica dos megaeventos.
B2 or not B2? That is the question: a review of periprosthetic fractures around cemented taper-slip femoral components
Authors: Maggs Joanna L. , Swanton Eric , Whitehouse Sarah L. , Howell Jonathan R. , Timperley A. John , Hubble Matthew J. W. , Wilson Matt J. 
Published: December 2020

AimsPeriprosthetic fractures (PPFs) around cemented taper-slip femoral prostheses often result in a femoral component that is loose at the prosthesis-cement interface, but where the cement-bone interface remains well-fixed and bone stock is good. We aim to understand how best to classify and manage these fractures by using a modification of the Vancouver classification.MethodsWe reviewed 87 PPFs. Each was a first episode of fracture around a cemented femoral component, where surgical management consisted of revision surgery. Data regarding initial injury, intraoperative findings, and management were prospectively collected. Patient records and serial radiographs were reviewed to determine fracture classification, whether the bone cement was well fixed (B2W) or loose (B2L), and time to fracture union following treatment.ResultsIn total, 47 B2W fractures (54.0%) and one B3 fracture (1.1%) had cement that remained well-fixed at the cement-bone interface. These cases were treated with cement-in-cement (CinC) revision arthroplasty. Overall, 43 fractures with follow-up united, and two patients sustained further fractures secondary to nonunion and required further revision surgery. A total of 19 B2L fractures (21.8%) and 19 B3 fractures (21.8%) had cement that was loose at the cement-bone interface. These cases were managed by revision arthroplasty with either cemented or uncemented femoral components, or proximal femoral arthroplasty. One case could not be classified.ConclusionWe endorse a modification of the original Vancouver system to include a subclassification of B2 fractures around cemented femoral prostheses to include B2W (where cement is well-fixed to bone) and B2L (where the cement is loose). Fractures around taper-slip design stems are more likely to fracture in a B2W pattern compared to fractures around composite beam design stems which are more likely to fracture in a B2L pattern. B2W fractures can reliably be managed with CinC revision. Cite this article: Bone Joint J 2021;103-B(1):71–78.
A prospective randomized controlled trial comparing the systemic inflammatory response in conventional jig-based total knee arthroplasty versus robotic-arm assisted total knee arthroplasty
Authors: Kayani Babar , Tahmassebi Jenni , Ayuob Atif , Konan Sujith , Oussedik Sam , Haddad Fares S. 
Published: December 2020

AimsThe primary aim of this study was to compare the postoperative systemic inflammatory response in conventional jig-based total knee arthroplasty (conventional TKA) versus robotic-arm assisted total knee arthroplasty (robotic TKA). Secondary aims were to compare the macroscopic soft tissue injury, femoral and tibial bone trauma, localized thermal response, and the accuracy of component positioning between the two treatment groups.MethodsThis prospective randomized controlled trial included 30 patients with osteoarthritis of the knee undergoing conventional TKA versus robotic TKA. Predefined serum markers of inflammation and localized knee temperature were collected preoperatively and postoperatively at six hours, day 1, day 2, day 7, and day 28 following TKA. Blinded observers used the Macroscopic Soft Tissue Injury (MASTI) classification system to grade intraoperative periarticular soft tissue injury and bone trauma. Plain radiographs were used to assess the accuracy of achieving the planned postioning of the components in both groups.ResultsPatients undergoing conventional TKA and robotic TKA had comparable changes in the postoperative systemic inflammatory and localized thermal response at six hours, day 1, day 2, and day 28 after surgery. Robotic TKA had significantly reduced levels of interleukin-6 (p < 0.001), tumour necrosis factor-α (p = 0.021), ESR (p = 0.001), CRP (p = 0.004), lactate dehydrogenase (p = 0.007), and creatine kinase (p = 0.004) at day 7 after surgery compared with conventional TKA. Robotic TKA was associated with significantly improved preservation of the periarticular soft tissue envelope (p < 0.001), and reduced femoral (p = 0.012) and tibial (p = 0.023) bone trauma compared with conventional TKA. Robotic TKA significantly improved the accuracy of achieving the planned limb alignment (p < 0.001), femoral component positioning (p < 0.001), and tibial component positioning (p < 0.001) compared with conventional TKA.ConclusionRobotic TKA was associated with a transient reduction in the early (day 7) postoperative inflammatory response but there was no difference in the immediate (< 48 hours) or late (day 28) postoperative systemic inflammatory response compared with conventional TKA. Robotic TKA was associated with decreased iatrogenic periarticular soft tissue injury, reduced femoral and tibial bone trauma, and improved accuracy of component positioning compared with conventional TKA. Cite this article: Bone Joint J 2021;103-B(1):113–122.