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between T2DM and cancer.

Mechanisms underlying pituitary corticotroph adenoma ACTH production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes.

We characterized the 5' ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production.

We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent pituitary corticotroph adenomas (SCA) that immunostain for but do not secrete ACTH.

We identified a novel regulatory region located near the intron2/exon3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCA, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the USP8 mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing's disease.

We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.Factors associated with the severity with which different challenge models (CMs) compromise growth performance in pigs were investigated using hierarchical clustering on principal components (HCPC) analysis. One hundred seventy-eight studies reporting growth performance variables (average daily gain [ADG], average daily feed intake [ADFI], gainfeed [GF], and final body weight [FBW]) of a Control (Ct) vs. a Challenged (Ch) group of pigs using different CMs (enteric [ENT], environmental [ENV], lipopolysaccharide [LPS], respiratory [RES], or sanitary condition [SAN] challenges) were included. Studies were grouped by similarity in performance in three clusters (C1, C2, and C3) by HCPC. The effects of CM, cluster, and sex (males [M], females [F], mixed [Mi]) were investigated. Linear (LRP) and quadratic (QRP) response plateau models were fitted to assess the interrelationships between the change in ADG (∆ADG) and ADFI (∆ADFI) and the duration of challenge. All variables increased from C1 through C3, except for GF, which decreased (P 0.10). The ∆ADG independent of duration post-Ch (irreparable portion of growth) was significant in C1 and C2 pigs, whereas the ∆ADFI independent of duration post-Ch (irreparable portion of feed intake) was significant in C1 pigs only (P less then 0.05). Moreover, the time for recovery of ADG and ADFI after Ch was significant in pigs belonging to C1 and C2 (P less then 0.05). Control F showed reduced ADG compared with Ct-M, and Ch-F showed reduced ADFI compared with Ch-M (P less then 0.05). Moreover, the irreparable portion of ΔADG was 4.8 higher in F (-187.7; P less then 0.05) compared with M (-39.1; P less then 0.05). There are significant differences in growth performance response to CM based on cluster and sex. Furthermore, bacterial lipopolysaccharide appears to be an appropriate noninfectious model for immune stimulation and growth impairment in pigs.

Vision impairment (VI) is associated with incident cognitive decline and dementia. However, it is not known whether VI is associated only with the transition to cognitive impairment, or whether it is also associated with later transitions to dementia.

We used data from the population-based Aging, Demographics and Memory Study (ADAMS) to investigate the association of visual acuity impairment (VI; defined as binocular presenting visual acuity <20/40) with transitions from cognitively normal (CN) to cognitive impairment no dementia (CIND) and from CIND to dementia. Multivariable Cox proportional hazards models and logistic regression were used to model the association of VI with cognitive transitions, adjusted for covariates.

There were 351 participants included in this study (weighted percentages 45% male, 64% age 70-79 years) with a mean follow-up time of 4.1 years. In a multivariable model, the hazard of dementia was elevated among those with VI (HR=1.63, 95%CI=1.04-2.58). Participants with VI had a greater hazard of transitioning from CN to CIND (HR=1.86, 95%CI=1.09-3.18). However, among those with CIND and VI a similar percentage transitioned to dementia (48%) and remained CIND (52%); there was no significant association between VI and transitioning from CIND to dementia (HR=0.94, 95%CI=0.56-1.55). Using logistic regression models, the same associations between VI and cognitive transitions were identified.

Poor vision is associated with the development of CIND. The association of VI and dementia appears to be due to the higher risk of dementia among individuals with CIND. Findings may inform the design of future interventional studies.

Poor vision is associated with the development of CIND. The association of VI and dementia appears to be due to the higher risk of dementia among individuals with CIND. Findings may inform the design of future interventional studies.

There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state.

To study the association of thyroid function with renovascular parameters in a well phenotyped cohort of euthyroid normotensive and hypertensive individuals.

Cross sectional study, the HyperPATH Consortium.

Multi-center study in five US and European academic institutions.

789 individuals aged 18-65 years with serum TSH 0.4-5.5 mIU/L. Subjects with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded.

Hemodynamic parameters including renal plasma flow, thyroid function testing and the Thr92Ala deiodinase 2 polymorphism were assessed in the setting of liberal and restricted salt diet.

We searched for associations between thyroid function and renovasculvestigation.

Serum TSH levels, but not fTI nor the Thr92Ala deiodinase 2 polymorphism, were independently inversely associated with renal plasma flow in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection of TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.

The neuronal ELAV-like proteins (nElavls; Elavl2, Elavl3, Elavl4) have been known to regulate neuronal differentiation, maintenance, and axonogenesis in the brain. However, the specific role of nElavls in retina remains unclear. Here, we attempted to identify the expression pattern of Elavl2 during retinogenesis and aimed to decipher the function of Elavl2 in the retina.

We have used the Cre-loxP system to conditionally inactivate Elavl2 in order to examine its role in developing retina. Eyes were collected for histology, immunohistochemistry, and TUNEL analysis to identify the structure of retina, and examined by RNA sequencing to analyze the function and pathway enrichment of differentially expressed genes in transgenic mice. Moreover, the mechanism by which Elavl2 regulates the differentiation of amacrine cells (ACs) was explored by RNA immunoprecipitation assays. Finally, eyes were functionally assessed by whole-cell patch-clamp, electroretinography (ERG) and optomotor response.

Elavl2 was expressed in retinal progenitor cells and retinal ganglion cells (RGCs), ACs, and horizontal cells. Retina-specific ablation of Elavl2 led to the loss of ACs and the transcription factors involved in ACs differentiation were also downregulated. In addition, the spontaneous activities of RGCs were obviously increased in Elavl2-deficient mice. Meanwhile, the loss of ACs that induced by Elavl2 deficiency lead to a decrease in ERG responses and visual acuity.

Elavl2 is an intrinsic factor that involved in the differentiation of ACs subtype during retinogenesis, and essential for maintaining the normal retinal function.

Elavl2 is an intrinsic factor that involved in the differentiation of ACs subtype during retinogenesis, and essential for maintaining the normal retinal function.

To investigate the progression of angle closure from primary angle closure suspect (PACS) and associated risk factors over five years in rural Chinese adults.

In this population-based cohort study, subjects aged ≥30 years old with unilateral or bilateral PACS at baseline of the Handan Eye Study who participated in the follow-up and had undergone baseline and follow-up gonioscopic examinations were included. learn more The progression of angle closure was defined as the presence of primary angle closure (PAC)/primary angle-closure glaucoma (PACG) during the follow-up in subjects with PACS at baseline. Ocular data from the right eye were used for cases with bilateral PACS and unilateral PACS in the right eye at baseline. For those with unilateral PACS in the left eye at baseline, ocular data from the left eye were used. Demographic information, ocular conditions, personal history, and systemic comorbidities were compared between the progression and nonprogression groups. Univariate and multivariate logistic regression was performed to identify the baseline risk factors for progression of angle closure.

In total, 526 subjects (111 male, 415 female) with baseline PACS were finally enrolled. The overall progression of PACS to angle closure was 32 cases (31 PAC, 1 PACG). Logistic regression analysis identified narrower mean angle width (P < 0.001) to be associated with the progression.

We report the progression from baseline PACS to PAC/PACG after five years. And baseline mean angle width was determined to be independent predictive risk factor for the progression of angle closure.

We report the progression from baseline PACS to PAC/PACG after five years. And baseline mean angle width was determined to be independent predictive risk factor for the progression of angle closure.