Viral infections, such as HIV, have been linked to obesity, but mechanistic evidence that they cause adipose dysfunction in vivo is lacking. We investigated a pathogenic role for the HIV-1 accessory ...protein viral protein R (Vpr), which can coactivate the glucocorticoid receptor (GR) and co-repress peroxisome proliferator-activated receptor γ (PPARγ) in vitro, in HIV-associated adipose dysfunction. Vpr circulated in the blood of most HIV-infected patients tested, including those on antiretroviral therapy (ART) with undetectable viral load. Vpr-mediated mechanisms were dissected in vivo using mouse models expressing the Vpr transgene in adipose tissues and liver (Vpr-Tg) or infused with synthetic Vpr. Both models demonstrated accelerated whole-body lipolysis, hyperglycemia and hypertriglyceridemia, and tissue-specific findings. Fat depots in these mice had diminished mass, macrophage infiltration, and blunted PPARγ target gene expression but increased GR target gene expression. In liver, we observed blunted PPARα target gene expression, steatosis with decreased adenosine monophosphate-activated protein kinase activity, and insulin resistance. Similar to human HIV-infected patients, Vpr circulated in the serum of Vpr-Tg mice. Vpr blocked differentiation in preadipocytes through cell cycle arrest, whereas in mature adipocytes, it increased lipolysis with reciprocally altered association of PPARγ and GR with their target promoters. These results delineate a distinct pathogenic sequence: Vpr, released from HIV-1 in tissue reservoirs after ART, can disrupt PPAR/GR co-regulation and cell cycle control to produce adipose dysfunction and hepatosteatosis. Confirmation of these mechanisms in HIV patients could lead to targeted treatment of the metabolic complications with Vpr inhibitors, GR antagonists, or PPARγ/PPARα agonists.
Core Ideas
Acknowledge the role of experiential knowledge in informing soil use and management.
Investigate knowledge needs and discourse in a deeper and all‐encompassing way.
Train work‐ready ...graduates who can succeed as existing staff retire.
Form knowledge partnerships with genuine commitment, trust and social cohesion.
Broaden the way the discipline communicates and engages with social networks.
Provide a dynamic learning environment which balances the digital and real world.
Evaluate impact of activities and appraise their worth through reflection.
Our aim was to examine the challenges and opportunities to soil knowledge sharing in the 21st Century. Soil can only be effectively managed if we are better connected to it by being well‐informed and with appropriate support. A central observation has been the diminishing human capital and capacity in the sectors of higher education, training and outreach, and the ramifications for knowledge sharing between the various groups: educators, policymakers, researchers, outreach agents and practitioners (including the public). We encourage a movement away from a linear learning model to a socially constructivist learning approach to address the consequences of declining resources, including: a loss of legacy soil information, moribund social networks, loss of experienced outreach staff, and finally a loss of expertise in soil science to prepare graduates for the workplace with improved soil knowledge and practical experiences. Blurring the lines between knowledge generator and user will encourage solutions for the sustainable use of soil from outside traditional knowledge‐holders. We suggest the solution, to a shrinking on‐the‐ground presence, is to invest in relationships and social networks to foster understanding of soil‐building practices and achieve wider adoption of technologies. We need to balance placing information in a digital environment with providing opportunities for sharing information via interpersonal interactions, over a sustained period. This opinion piece reflects on how soil education, training and outreach can form a genuine partnership between those with experience and those with expertise to create a dynamic learning environment with a high probability of ensuring a more sustainably managed landscape.
Most patients with childhood-onset growth hormone deficiency (CO-GHD) receive treatment with exogenous growth hormone (GH) to facilitate the attainment of their full potential adult height. Recent ...evidence suggests that continuing GH administration during the transition period between the end of linear growth and full adult maturity is necessary for proper body composition and bone and muscle health, and may also have beneficial effects on metabolic parameters, bone mineral density, and quality of life. The timing of this transition period coincides with the transfer of care from a pediatric to an adult endocrinologist, creating the potential for a care gap as a consequence of losing the patient to follow-up.
An advisory board comprising both pediatric and adult endocrinologists was assembled to address current clinical unmet needs and to collaborate on a structured transitional plan for optimal management of patients with CO-GHD.
The advisors suggest collaborative, multidisciplinary approaches to ensure continuity of care; ongoing testing and monitoring of GHD status into adulthood; and a clearly structured protocol that includes practical guidance for clinicians to establish best practices for transitioning older adolescents with persistent CO-GHD to adult care.
•Effective transition of care from pediatric to adult services is challenging.•Patients transitioning from childhood to adulthood often experience a care gap.•Endocrinologists met and discussed unmet needs and optimal management of patients.•Collaborative, multidisciplinary approaches to ensure continuity of care are needed.•A consensus document providing practical guidance on transition care is needed.
The complex nature and heterogeneity involving pituitary surgery results have increased interest in machine learning (ML) applications for prediction of outcomes over the last decade. This study aims ...to systematically review the characteristics of ML models involving pituitary surgery outcome prediction and assess their reporting quality.
We searched the PubMed, Scopus, and Web of Knowledge databases for publications on the use of ML to predict pituitary surgery outcomes. We used the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) to assess report quality. Our search strategy was based on the terms "artificial intelligence", "machine learning", and "pituitary".
20 studies were included in this review. The principal models reported in each article were post-surgical endocrine outcomes (
= 10), tumor management (
= 3), and intra- and postoperative complications (
= 7). Overall, the included studies adhered to a median of 65% (IQR = 60-72%) of TRIPOD criteria, ranging from 43% to 83%. The median reported AUC was 0.84 (IQR = 0.80-0.91). The most popular algorithms were support vector machine (
= 5) and random forest (
= 5). Only two studies reported external validation and adherence to any reporting guideline. Calibration methods were not reported in 15 studies. No model achieved the phase of actual clinical applicability.
Applications of ML in the prediction of pituitary outcomes are still nascent, as evidenced by the lack of any model validated for clinical practice. Although studies have demonstrated promising results, greater transparency in model development and reporting is needed to enable their use in clinical practice. Further adherence to reporting guidelines can help increase AI's real-world utility and improve clinical practice.
Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin ...secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global
mice (in vivo) and
-ablated pancreatic islets (ex vivo). GSIS was attenuated in both
mice and
-ablated islets, while the islet morphology was similar between WT and
mice. To elucidate the mechanism underpinning
-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (
) and the glucose-metabolic intermediate-glucose-6-phosphate (G6P) were reduced in
-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and
mice, but the ATP/ADP ratio in
islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in
islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of
mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.
PIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary ...neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs.
We conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction.
As for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8–17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients.
Patients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.
•4% of PIT1-positive pituitary adenomas tested negative for GH, PRL, and TSH.•Half of these presented with functioning pituitary adenomas.•These patients need close endocrine follow-up despite negative hormone stains.
Glis3 is a member of the Krüppel-like family of transcription factors and is highly expressed in islet β cells. Mutations in GLIS3 cause the syndrome of neonatal diabetes and congenital ...hypothyroidism (NDH). Our aim was to examine the role of Glis3 in β cells, specifically with regard to regulation of insulin gene transcription. We demonstrate that insulin 2 (Ins2) mRNA expression in rat insulinoma 832/13 cells is markedly increased by wild-type Glis3 overexpression, but not by the NDH1 mutant. Furthermore, expression of both Ins1 and Ins2 mRNA is downregulated when Glis3 is knocked down by siRNA. Glis3 binds to the Ins2 promoter in the cell, detected by chromatin immunoprecipitation. Deletion analysis of Ins2 promoter identifies a sequence (5′-GTCCCCTGCTGTGAA-3′) from −255 to −241 as the Glis3 response element and binding occur specifically via the Glis3 zinc finger region as revealed by mobility shift assays. Moreover, Glis3 physically and functionally interacts with Pdx1, MafA and NeuroD1 to modulate Ins2 promoter activity. Glis3 also may indirectly affect insulin promoter activity through upregulation of MafA and downregulation of Nkx6-1. This study uncovers a role of Glis3 for regulation of insulin gene expression and expands our understanding of its role in the β cell.
Invasive prolactinomas often require multimodal management including medical and surgical interventions. Here, we present the case of a 34-year-old man with a history of progressive visual ...disturbances. MRI unveiled a sella lesion with suprasellar and retrosellar extensions. Elevated prolactin levels (6125 ng/mL) confirmed the diagnosis of prolactinoma, leading to initiation of medical treatment, with gradual escalation to maximum dosing. The patient achieved only partial hormonal response and incomplete improvement of symptoms, and therefore, surgical intervention was pursued with objective of maximum safe resection. The patient consented to the procedure. An endonasal endoscopic approach was selected. Surgical procedures encompassed transsellar, transtuberculum, and transplanum approaches, extended laterally to expose the right parasellar carotid and the anterior wall of the cavernous sinus. Subsequent steps involved opening the sellar and suprasellar dura mater, anterior wall of the cavernous sinus, and transcavernous hemipituitary transposition for access to the retrosellar region.1-5 Debulking of the lesion was performed, followed by dissection of the retrosellar space and resection of tumor component within the interpeduncular cistern. Reconstruction employed dura substitute and vascularized nasoseptal flap. Histopathology confirmed diagnosis of prolactinoma. Postoperative MRI findings and significantly improved prolactin levels (50 ng/mL) were compatible with near total resection. The patient's postoperative course was uneventful, resulting in discharge on the second postoperative day. The patient was additionally started on cabergoline 0.5 mg 2x/week to achieve hormonal control. This case demonstrates the application of surgical anatomy and its translation in modern surgical techniques that allow improved resection of such complex tumors while ensuring optimal clinical outcomes.
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