Adrenal Research Articles

Disseminated pleomorphic rhabdomyosarcoma in a horse

An 8-y-old National Show Horse mare was presented for evaluation of pneumonia and laminitis. Harsh bronchovesicular sounds were auscultated throughout both lung fields, and the mare had signs of moderately painful laminitis. Thoracic ultrasonography revealed lung consolidation throughout the dorsal aspect of both lungs, and radiography revealed an extensive diffuse-to-patchy bronchointerstitial lung pattern. The mare’s clinical condition rapidly deteriorated, and euthanasia was elected. On postmortem examination, the lungs, omentum, spleen, liver, adrenal glands, kidneys, and femur contained 0.5–2.5-cm, firm, tan nodules. Histologically, the lungs, spleen, liver, kidneys, adrenal glands, omentum, left eye, and femur were infiltrated by bundles and nests of pleomorphic polygonal-to-spindloid cells intermixed with frequent multinucleate cells. Lymphatic vessels in the affected tissues were frequently distended with tumor emboli. Neoplastic cells were diffusely positive for vimentin, desmin, sarcomeric actin, myoblastic differentiation protein 1, and myogenin, supportive of the diagnosis of rhabdomyosarcoma (RMS), which is a rare neoplasm in horses. Cross-striations were not evident with H&E or phosphotungstic acid–hematoxylin stains. Markedly pleomorphic neoplastic cells, multinucleate cells, and lack of cross-striations suggested the subclassification of pleomorphic RMS.

Remodeling of the structural components of the capsule and glomerular zone of the adrenal glands cortex of white rats under the influence of a complex of food additives at the late terms of the experimental study

With food additives, we can add flavour to food, extend its shelf life, and make it look good. However, even small amounts of these additives can lead to diseases of various organs and systems. The aim of our work is to establish metrics and morphological changes in the structure of the capsule and the glomerular zone of the cortex of the adrenal glands of rats at the later stages of the experimental study under the conditions of consumption of a complex of food additives: monosodium glutamate, sodium nitrite and Ponceau 4R. The control group of rats consumed oral drinking water and saline. The rats of the experimental groups were orally administered once a day with a 10 % solution of sodium nitrite (E250), sodium glutamate (E621) or Ponceau 4R. The dosages of food additives were two times lower than the permissible norm in food. The rats were withdrawn from the experiment after 8, 12 and 16 weeks. The adrenal glands were removed for the study. Paraffin sections were stained with hematoxylin and eosin, and semi-thin sections with toluidine blue, and examined using a light microscope Biorex with a digital microphoto attachment DSM 900. Ultrathin sections were examined in a TEM-125 K electron microscope. For morphometric analysis, the structure of the capsule and the glomerular zone of the cortex of the adrenal glands of rats at the later stages of the experimental study was studied. The study results were analysed using the software package “InStat”. At the late stages of the experimental study, the adrenal capsule underwent irreversible changes. The average thickness of the adrenal connective tissue capsule decreased by the end of the 16th week of the experimental research. Similarly, the average thickness of the cortex decreased with each subsequent week relative to the control values, indicating significant structural and functional disorders. The average thickness of the glomerular zone of the adrenal cortex periodically changed as a compensatory reaction in response to the administration of a complex of food additives to rats. The phenomena of nucleus pyknosis and sludge syndrome were detected, which indicated compensatory and adaptive processes at the microscopic level. The analysis of electron micrographs revealed destroyed granular endoplasmic reticulum cisternae and mitochondrial remnants. Thus, it has been established that using a complex of food additives (monosodium glutamate, sodium nitrite and Ponceau 4R) directly affects the adrenal glands of rats. This effect causes structural changes in the cortex and medulla, causing alteration and hypertrophy of cells in these areas. Additionally, hyperhydration of the connective tissue stroma and compensatory-restorative reactions aimed at transcription factors and internal mechanisms of nitric oxide formation were recorded.

Screening and treatment of endocrine hypertension focusing on adrenal gland disorders: a narrative review.

Most cases of high blood pressure have no identifiable cause, termed essential hypertension; however, in approximately 15% of cases, hypertension occurs due to secondary causes. Primary aldosteronism (PA) and pheochromocytoma and paraganglioma (PPGL) are representative endocrine hypertensive diseases. The differentiation of endocrine hypertension provides an opportunity to cure and prevent target organ damage. PA is the most common cause of secondary hypertension, which significantly increases the risk of cardiovascular disease compared to essential hypertension; thus, patients with clinical manifestations suggestive of secondary hypertension should be screened for PA. PPGL are rare but can be fatal when misdiagnosed. PPGL are the most common hereditary endocrine tumors; therefore, genetic testing using next-generation sequencing panels is recommended. Herein, we aimed to summarize the characteristic clinical symptoms of PA and PPGL and when and how diagnostic tests and treatment strategies should be performed.

A single-center retrospective review of metastatic prostate cancer on PSMA position emission tomography/computed tomography: Beyond lymph nodes and bones.

Prostate-specific membrane antigen (PSMA) Positron emission tomography/computed tomography (PET/CT) has become a crucial imaging modality for the staging of patients with prostate cancer. The purpose of this study is to retrospectively determine the frequency, anatomical distribution, and clinical-pathologic correlates of extra-nodal and extra-osseous metastatic prostate cancer detected on PSMA PET/CT. All available 650 PSMA PET/CT performed in patients with biopsy-proved prostate cancer in our institution between September 2021 and December 2023 were reviewed for the presence of extra-nodal and extra-osseous metastatic disease (M1C disease). Thirty-four patients with M1C disease were identified. The most frequent sites of visceral/soft tissue metastases were the lungs (58.8%), liver (23.5%) and adrenal glands (20.6%). 75% of patients with lung metastases detected on PSMA PET/CT had concurrent intrathoracic lymph node involvement. A higher frequency of patients with M1C disease (55.9%) had a high Gleason score. The median prostate-specific antigen (PSA) level at the time of the PSMA scan was 20.16 ng/mL. There was a statistically significant association between PSA level and osseous disease (p = 0.004), as well as PSA level and nodal disease (p = 0.008). While a large number of patients had concurrent osseous and nodal disease (82.4% and 79.4%, respectively), no visceral/soft tissue sites demonstrated a significant association with the presence of osseous or nodal involvement. Given the increasing utilization of PSMA PET/CT, increased knowledge of the location and pattern of distribution of visceral/soft tissue metastatic sites is crucial not only for staging but also to better understand patterns of therapeutic response. We identified the lungs, liver and adrenal glands as the most common visceral/soft tissue metastatic sites from prostate cancer. We found that higher PSA levels at the time of PSMA PET/CT imaging were positively associated with concurrent osseous and nodal involvement.

Neurobiological Implications of Chronic Stress and Metabolic Dysregulation in Inflammatory Bowel Diseases.

Chronic stress is a significant factor affecting modern society, with profound implications for both physical and mental health. Central to the stress response is cortisol, a glucocorticoid hormone produced by the adrenal glands. While cortisol release is adaptive in acute stress, prolonged exposure to elevated levels can result in adverse effects. This manuscript explores the neurobiological implications of chronic stress and its impact on metabolic dysregulation, particularly in the context of inflammatory bowel diseases (IBDs). The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production, which influences metabolism, immune response, and neurobiology. Elevated cortisol levels are associated with the development and exacerbation of metabolic disorders like IBD and contribute to neurodegenerative processes, including cognitive impairments and increased susceptibility to psychiatric conditions. The interaction between cortisol and its receptors, particularly glucocorticoid receptors, underscores the complexity of these effects. This review aims to elucidate the mechanisms through which chronic stress and cortisol dysregulation impact metabolic health and neurobiological function, providing insights into potential therapeutic strategies for mitigating these effects.

Usefulness of the Primary Tumor Standardized Uptake Value of Iodine-123 Metaiodobenzylguanidine for Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma.

To examine the usefulness of semi-quantitative analysis using the standardized uptake value (SUV) of iodine-123 metaiodobenzylguanidine ([123I]-MIBG) for predicting metastatic potential in patients with pheochromocytoma (PHEO) and paraganglioma (PGL). This study included 18 PHEO and 2 PGL patients. [123I]-MIBG visibility and SUV-related parameters (SUVmax, SUVmean, tumor volume of [123I]-MIBG uptake [TV_MIBG], and total lesion [123I]-MIBG uptake) were compared with the pathological grading obtained using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP), which are used to predict metastatic potential. The PASS scores were categorized as < 4 and ≥ 4. Based on the GAPP scores, PHEOs/PGLs were categorized as follows: well, moderately, and poorly differentiated tumors. The Mann-Whitney U test or Spearman's rank correlation was used to assess differences or associations between two quantitative variables. All PHEOs/PGLs were visualized on [123I]-MIBG scintigraphy. There were 16 PASS < 4 and 4 PASS ≥ 4 tumors. Moreover, 11 and 9 tumors were well and moderately differentiated, respectively. The uptake scores and SUV-related parameters significantly differed between tumors with a PASS score of < 4 and those with a PASS score of ≥ 4 (each, p > 0.05). Moderately differentiated tumors had significantly higher uptake scores and SUV-related parameters except TV_MIBG than well-differentiated tumors (each, p < 0.05). The GAPP score was positively correlated with the uptake scores and SUV-related parameters (each, p < 0.05) except TV_MIBG. The primary tumor [123I]-MIBG uptake assessed using SUV-related parameters can be an imaging tool for predicting metastatic potential in patients with PHEO/PGL.

Intra-Individual Reproducibility of Automated Abdominal Organ Segmentation-Performance of TotalSegmentator Compared to Human Readers and an Independent nnU-Net Model.

The purpose of this study is to assess segmentation reproducibility of artificial intelligence-based algorithm, TotalSegmentator, across 34 anatomical structures using multiphasic abdominal CT scans comparing unenhanced, arterial, and portal venous phases in the same patients. A total of 1252 multiphasic abdominal CT scans acquired at our institution between January 1, 2012, and December 31, 2022, were retrospectively included. TotalSegmentator was used to derive volumetric measurements of 34 abdominal organs and structures from the total of 3756 CT series. Reproducibility was evaluated across three contrast phases per CT and compared to two human readers and an independent nnU-Net trained on the BTCV dataset. Relative deviation in segmented volumes and absolute volume deviations (AVD) were reported. Volume deviation within 5% was considered reproducible. Thus, non-inferiority testing was conducted using a 5% margin. Twenty-nine out of 34 structures had volume deviations within 5% and were considered reproducible. Volume deviations for the adrenal glands, gallbladder, spleen, and duodenum were above 5%. Highest reproducibility was observed for bones (- 0.58% [95% CI: - 0.58, - 0.57]) and muscles (- 0.33% [- 0.35, - 0.32]). Among abdominal organs, volume deviation was 1.67% (1.60, 1.74). TotalSegmentator outperformed the reproducibility of the nnU-Net trained on the BTCV dataset with an AVD of 6.50% (6.41, 6.59) vs. 10.03% (9.86, 10.20; p < 0.0001), most notably in cases with pathologic findings. Similarly, TotalSegmentator's AVD between different contrast phases was superior compared to the interreader AVD for the same contrast phase (p = 0.036). TotalSegmentator demonstrated high intra-individual reproducibility for most abdominal structures in multiphasic abdominal CT scans. Although reproducibility was lower in pathologic cases, it outperforms both human readers and a nnU-Net trained on the BTCV dataset.

A natural language processing-informed adrenal gland incidentaloma clinic improves guideline-based care.

Adrenal gland incidentalomas (AGIs) are found in up to 5% of cross-sectional images. However, rates of guideline-based workup for AGIs are notoriously low. We sought to determine if a natural language processing (NLP)-informed AGI clinic could improve the rates of indicated biochemical evaluation and adrenal-specific imaging. An NLP algorithm was created to detect clinically significant adrenal nodules from radiology reports of cross-sectional images at an academic institution. The NLP algorithm was applied to scans occurring between June 2020 and July 2021 to form a baseline cohort. The NLP algorithm was re-applied to scans from August 2021 to February 2023 and identified patients were invited to join an outpatient clinic dedicated to AGIs. Patients evaluated in the clinic from March 2022 to February 2023 were included in the intervention cohort. Statistical analysis utilized chi-square, t-test, and a multivariable logistic regression. The baseline and intervention cohorts included 1784 and 322 unique patients, respectively. Patients in the intervention cohort were more likely to be female (59% vs. 51%, p=0.01), be younger (60±13.1 vs. 64±13.2years, p<0.001), have smaller nodules (1.7cm, IQR 1.4-2.1 vs. 1.8cm, IQR 1.4-2.5cm, p=0.017), have had biochemical workup (99% vs. 13%, p<0.001), and have had adrenal-specific imaging (40% vs. 11%, p<0.001). In a multivariable analysis, intervention cohort patients were significantly more likely to have had biochemical workup (odds ratio ,OR 1209, confidence interval ,CI 434-5117, p<0.001) and adrenal-specific imaging (OR 8.89, CI 6.42-12.4, p<0.001). The implementation of an NLP-informed AGI clinic was associated with a seven-fold increase in biochemical workup and a three-fold increase in adrenal-specific imaging in participating patients.

Amino polycarboxylic acids-modified abiraterone derivatives as potential injectable anti-prostate cancer agents

Abiraterone (Abi), an effective cytochrome oxidase P450 C17 (CYP17) inhibitor, inhibits androgen synthesis in testes, adrenal glands, and prostate tumors. However, their low bioavailability and dissolution rate due to their poor solubility and toxic side effects have hindered their clinical applications. In this study, water-soluble and injectable Abi derivatives were developed by introducing amino polycarboxylic acids into Abi, and their antiproliferation effects in vitro, mechanism of action, antitumor activities in vivo, pharmacokinetics, and toxicity were investigated. Compared to Abi, the water-soluble derivative Abi-DTPA exhibited excellent antitumor activity in vitro and in vivo. It decreased cell migration, invasion, and mitochondrial membrane potential. A mechanistic study revealed that it still targeted the CYP17 enzyme and increased the expression levels of apoptosis-related proteins, including cleaved caspase 9, cleaved PARP, and cleaved caspase 3. Abi-DTPA was the main form in the plasma and exhibited lower toxicity after intravenous administration. These findings suggest that Abi-DTPA can be used as a novel injectable anti-prostate cancer agent.

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer.

Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality 1-3 . The exact cause of this phenomenon - whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVN CRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVN CRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVN CRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVN CRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVN CRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

Comparative Assessment of the Influence of Embolizing Agents on the Adrenal Parenchyma.

A comparative analysis of morphological and functional changes in the adrenal glands after embolization of supplying arteries with Lifepearl microspheres (100±25 μm; Terumo) and with a solution of polidocanol (Aethoxysklerol, Kreussler Pharma) was performed in male Vietnamese Lop-Bellied pigs (n=20). The introduction of the microspheres into the arterial bed did not affect the adrenal parenchyma. However, the injection of the liquid sclerosing agent caused foci of productive inflammation leading to the formation of sclerotic tissue and reduction of the volume of glandular tissue. Administration of the sclerosant was accompanied by arterial hypotension, an indirect indication of a decrease in vasoactive hormone production by the adrenal cortex. These findings suggest that polidocanol can be used as an embolization agent for hyperplastic diseases of the adrenal cortex.

Adrenal Insufficiency following Stereotactic Ablative Radiotherapy (SAbR) of Adrenal Gland Metastases.

Adrenal metastases are often treated with stereotactic ablative radiation (SAbR). We aimed to assess the incidence, timing, and factors associated with the development of primary adrenal insufficiency (PAI) following SAbR. A retrospective cohort study comprised 66 consecutive patients (73% men, median age 61 years) who underwent SAbR for adrenal metastasis. The series encompassed metastases from renal cell carcinoma (41%), lung tumors (38%), colorectal adenocarcinoma (9%), melanoma (5%), and others (7%). Median follow-up was 17 months from SAbR. Nine (14%) patients developed PAI at a median of 4.3 months (range, 0.7-20.2). The incidence of PAI was 44% in patients with prior adrenalectomy receiving unilateral SAbR, 44% with bilateral SAbR, 2% with unaffected contralateral gland, and 0% with bilateral metastases treated with unilateral SAbR. PAI was associated with prior adrenalectomy (odds ratio [OR] 32) and bilateral SAbR (OR 8.2), but not age, sex, metastasis size, or biological effective dose. Post-SAbR 6-month and 1-year local control rates were 82% and 75%, respectively. Patients undergoing SAbR for adrenal metastasis are at high risk of developing PAI. PAI is associated with bilateral SAbR and contralateral adrenalectomy. PAI is unlikely with a remaining unaffected adrenal gland or in the setting of bilateral adrenal metastases with unilateral SAbR.

Ablation and laparoscopic adrenalectomy: Balancing efficacy and safety in the treatment of benign adrenal gland tumors: A systematic review and meta-analysis

BackgroundAldosterone-producing adenomas cause hypertension in 5–10 % of cases. Laparoscopic adrenalectomy is the gold standard treatment for early-stage adrenal gland tumors, but minimally invasive procedures, such as ablative techniques can also be applied. Therefore, we aimed to compare laparoscopic adrenalectomy and ablation techniques in terms of efficacy and safety in the treatment of benign adrenal gland tumors. Materials and methodsWe conducted a systematic search in five databases and included studies comparing the efficacy and safety of ablation techniques and laparoscopic adrenalectomy. We calculated odds ratios (ORs) for eligible studies with binary outcomes, and mean differences (MD) with 95 % confidence intervals (CI) for continuous outcomes. ResultsFive studies focusing on aldosterone-producing adenomas were included in our review. A total of 119 patients at 14 centers underwent ablation, and 161 patients had laparoscopic adrenalectomy. The complication rates (OR: 0.98, CI: 0.35–2.69) were similar in both groups, but among complications, hypertensive crisis (OR: 8.13; CI: 1.14–58.11) was more frequent in the ablative group, and even the success rate of interventions - the resolution of hypertension (OR: 0.30, CI: 0.16–0.56) - was lower in this group. On the other hand, the advantage of ablation was shorter intervention time (MD: 75.64 min; CI: 6.33–144.95), shorter hospital stay (MD: 1.6 days; CI: 0.88–2.31), and less perioperative blood loss (MD: 43.55 ml; CI: 12.07–75.04) compared to laparoscopy. ConclusionLaparoscopic adrenalectomy is still the best therapeutic approach, but ablation can be an appropriate alternative option for the treatment of aldosterone-producing adrenal gland tumors.

Influence of Anticholinesterase Drugs on Activity and Properties of Na+,K+-ATPase in Rat Erythrocytes under Stress Caused by Intense Physical Exercise.

We studied the effect of intramuscular injection of physostigmine and neostigmine on Na+,K+-ATPase activity in erythrocytes of rats subjected to intense physical exercise. Both anticholinesterase drugs had a significant effect on the development of the stress response, which was expressed in a decrease in the manifestation of its individual components such as the concentration of ascorbic acid in the adrenal glands, stress-related erythrocyte polycythemia, and LPO indicators. Anticholinesterase drugs reverse the stress-induced decrease in Na+,K+-ATPase activity, as well as changes in its magnesium-dependent properties. There were no changes in the activity of the studied enzyme in the erythrocyte ghosts. We associate the observed differences with the correction of the functions of the cholinergic components of the hypothalamic-pituitary-adrenal axis leading to the development of a hypoergic type stress reaction.

Optical Based Surface Plasmon Resonance Sensor for the Detection of the Various Kind of Cancerous Cell.

This research explores a novel biosensor design that exhibits much higher sensitivity compared to conventional biosensors. The biosensor's uniqueness originated from its innovative structure, which incorporates N-FK51A/Ag/AlON/BlueP materials, as well as its cutting-edge fabrication method. The refractive index component was considered when designing the SPR biosensor, which was developed from the angular analysis of the attenuated total reflection (ATR) approach for cancer detection. For instance, the resonance angle shifts by 15.57 deg when the refractive index changes from 1.360 to 1.401, demonstrating the sensor's responsiveness to variation in the refractive index. The sensitivities for skin (basal), cervical (HeLa), blood (Jurkat), adrenal gland (PC12), and breast (MDA-MB-231 and MCF-7) cancer cells were 197.65, 243.66, 255.36, 302.71, 372.57, and 416.85 deg/RIU, respectively. Also, the detection accuracy (DA), the figure of merit (FoM), and the quality factor were 0.37/deg, 155.94 (deg/RIU), and 26.71 RIU-1. We also examine the effects of substituting the noble, dielectric, 2D material layer with conventional biosensor materials for six cancers. Each time, the Ag/AION/BlueP layered structure performed best in distinguishing cancer cells from healthy cells. We also study the prism effects. The proposed biosensor, with a RI of 1.29-1.40, has a linear regression coefficient of R2 of 0.96094.

Experience of using lenvatinib in the treatment of hepatocellular cancer at the Republican Oncology Center of the Republic of North Ossetia-Alania in 2018–2022. Balance of efficiency and accessibility in regional practice

The overall incidence of liver cancer in the Republic of North Ossetia-Alania has remained stable over the past five years. Moreover, the initial diagnostic of HCC occurs at widespread stage, which limits the possibilities of cured therapy. The Republican Oncology Clinic has accumulated experience in using the drug lenvatinib for advanced and metastatic hepatocellular cancer. In the realities of a small regional dispensary, and has to find a balance between efficiency and availability of therapeutic options to provide effective therapy for all patients. The authors conducted a single-center retrospective analysis of the effectiveness and safety of lenvatinib in real clinical practice in patients with hepatocellular cancer at the Republican Oncology Center of the Republic of North Ossetia Alania. The analysis included 18 patients with HCC who received lenvatinib monotherapy. 11(61%) patients had concomitant viral hepatitis B or C, 15 (83%) had distant metastases to the lymph nodes, lungs, adrenal glands or other organs. A feature of this patient population is the long period of time from the prescription of drug therapy for HCC to its actual start – on average 46 days, with a range from 5 to 100 days. We believe that a delay in initiating therapy may affect the results obtained. Median PFS in 1st line of lenvatinib therapy was 10.1 months (2.3 months to 13.1 months). Median PFS2 (defined as the time from 1st line treatment on lenvatinib to progression on first subsequent therapy) was 19.1 months. 6 (33%) patients received lenvatinib in the second line after progression on another drug therapy. The median second-line PFS in this case was 5.9 months (3.8 months‑7.7 months). Lenvatinib had a manageable and predictable tolerability profile. No new safety signals were identified.Conclusion: The use of lenvatinib as monotherapy in adult patients with advanced or unresectable hepatocellular carcinoma has proven to be an effective strategy that balances clinical benefit and availability of the drug.

Glucocorticoid treatment increases cholesterol availability during critical illness: effect on adrenal and muscle function

BackgroundHypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function.MethodsIn a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water.ResultsIn human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five (P < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated (P < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis (P < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice (P < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo (P < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo (P < 0.05).ConclusionsGlucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass.Graphical abstract

Characterization of Ucp1-iCre knockin mice reveals the recombination activity in male germ cells.

Ucp1 promoter-driven Cre transgenic mice are useful in the manipulation of gene expression specifically in thermogenic adipose tissues. However, the wildly used Ucp1-Cre line was generated by random insertion into the genome and showed ectopic activity in some tissues beyond adipose tissues. Here, we characterized a knockin mouse line Ucp1-iCre generated by targeting IRES-Cre cassette immediately downstream the stop codon of the Ucp1 gene. The Cre insertion had little to no effect on uncoupling protein 1 (UCP1) levels in brown adipose tissue. Ucp1-iCre mice of both genders exhibited normal thermogenesis and cold tolerance. When crossed with Rosa-tdTomato reporter mice, Ucp1-iCre mice showed robust Cre activity in thermogenic adipose tissues. In addition, limited Cre activity was sparsely present in the ventromedial hypothalamus (VMH), choroid plexus, kidney, adrenal glands, ovary, and testis in Ucp1-iCre mice, albeit to a much lesser extent and with reduced intensity compared with the conventional Ucp1-Cre line. Single-cell transcriptome analysis revealed Ucp1 mRNA expression in male spermatocytes. Moreover, male Ucp1-iCre mice displayed a high frequency of Cre-mediated recombination in the germline, whereas no such effect was observed in female Ucp1-iCre mice. These findings suggest that Ucp1-iCre mice offer promising utility in the context of conditional gene manipulation in thermogenic adipose tissues, while also highlighting the need for caution in mouse mating and genotyping procedures.NEW & NOTEWORTHY Ucp1 promoter-driven Cre transgenic mice are useful in the manipulation of gene expression specifically in thermogenic adipose tissues. The widely used Ucp1-Cre mouse line (Ucp1-CreEvdr), which was generated using the bacterial artificial chromosome (BAC) strategy, exhibits major brown and white fat transcriptomic dysregulation and ectopic activity beyond adipose tissues. Here, we comprehensively validate Ucp1-iCre knockin mice, which serve as another optional model besides Ucp1-CreEvdr mice for specific genetic manipulation in thermogenic tissue.

Epinephrine, Pregabalin, and Crizotinib as Three Medicines with Polish Implications over Three Last Centuries and in View of Three Different Drug Discovery Approaches.

The discovery of epinephrine (adrenaline) and its subsequent implications in medicine owes significant contributions to Cybulski across different centuries, who, in 1894, was pivotal in identifying the adrenal medulla's role in blood pressure regulation and naming the active substance "nadnerczyna", known today as adrenaline. His work demonstrated the adrenal glands' critical function in the body's regulatory mechanisms beyond the nervous system. Cybulski's groundbreaking research laid foundational knowledge for future endocrinological studies and pharmaceutical advancements. In the late 20th century, Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin, the active ingredient in Lyrica. Their innovative synthesis of gamma-aminobutyric acid derivatives led to a significant advancement in treating epilepsy, neuropathic pain, and fibromyalgia. Andruszkiewicz's expertise in organic chemistry and enzymology was crucial in this collaborative effort, resulting in the successful development and commercialization of Lyrica. Additionally, Mroczkowski's leadership at Pfizer contributed to the development of crizotinib, a notable anaplastic lymphoma kinase and proto-oncogene 1 tyrosine-protein kinase inhibitor used to treat specific types of non-small cell lung cancer. Her work exemplifies the continuing influence of Polish researchers in pioneering drug discovery and advancing therapeutic treatments over the past three centuries. These contributions highlight Poland's significant role in global pharmaceutical innovations and medical research.

Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via β2 Adrenergic Receptor Signaling.

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune-mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)-KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL-KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)-dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep-deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.