Adrenomedullin Levels Research Articles

Utility of Adrenomedullin in Predicting Outcomes in Patients with Acute Febrile Illness in the Tropics: A Prospective Observational Study.

Acute febrile illnesses (AFI) such as dengue, leptospirosis, and scrub typhus start with fever, but some patients can deteriorate rapidly. Identifying these patients at risk is necessary to ensure early referral. The study's objective was to assess the utility of serum adrenomedullin (ADM) as a biomarker in predicting outcomes in adult AFI patients presenting to the emergency department (ED). In this prospective observational study, all consecutive patients admitted with AFI through the ED between June 2023 and February 2024 were assessed for eligibility. Clinical and laboratory findings were noted. The serum samples sent routinely for biochemical tests were used to calculate ADM levels at admission and 48 hours later (whenever possible). Clinically relevant outcome variables were collected for all patients. The utility of ADM in predicting 7-day mortality was evaluated for primary outcome analysis using a stepwise binary logistic regression. A total of 181 patients were recruited, with dengue (n = 91, 50%) being the most common diagnosis. The median sequential organ failure assessment score at admission was 5 (IQR: 3-10). The 7-day mortality was 26 (14%, 95% CI: 9.3-19.5). The median admission ADM levels and difference in ADM levels at 48 hours were significantly higher in those who died by day 7. Adrenomedullin levels at admission were found to be an independent predictor of 7-day mortality (adjusted odds ratio: 1.002, 95% CI: 1.001-1.004, P = 0.005). High ADM levels can be used for early referral in patients with tropical AFI. There is a need to explore the utility of antibodies targeting ADM in clinical studies.

Association of mid-regional pro-adrenomedullin with office and 24-h ambulatory blood pressure in a Swiss general population sample.

Adrenomedullin (ADM) is a potent vasodilator. The association between plasma ADM levels and blood pressure (BP) remains unclear. We assessed the association between mid-regional-pro-ADM (MR-proADM) and BP in a multicenter population- and family-based cohort. We used data from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH). We included participants present at both baseline and 3-year follow-up (N = 843). We examined the association of baseline MR-proADM with baseline office and 24 h ambulatory BP as well as the 3-year change in office BP. In secondary analyses, we studied the association between baseline MR-proADM and 3-year changes in pulse wave velocity (PWV), renal resistive index (RRI) and augmentation index (AI). Mixed-effects linear regression models were used. In cross-sectional analyses, MR-proADM was negatively associated with office, 24-h and daytime diastolic BP (DBP). MR-proADM was positively associated with nighttime systolic BP (SBP). In longitudinal analyses, baseline MR-proADM was associated with an increase in office SBP and pulse pressure (PP) over 3 years [β (95% CI): 8.2 (0.4, 15.9) and β (95% CI): 6.4 (0.3, 12.4), respectively] but not with changes in PWV, RRI and AI. The cross-sectional negative association of MR-proADM with DBP is in line with known vasodilatory properties of ADM. The positive association between MR-proADM and nighttime SBP at baseline may reflect endothelial dysfunction believed to be part of the pathogenesis of nocturnal hypertension. The association of higher baseline MR-proADM levels with increased SBP and PP at 3-year follow-up suggests that ADM levels could be a marker of cardiovascular risk.

The Role of Adrenomedullin as a Predictive Marker of the Risk of Death and Adverse Clinical Events: A Review of the Literature.

Adrenomedullin (ADM) is a vasodilatory peptide that plays a crucial role in maintaining cardiovascular health through its various biological functions. ADM was discovered in the acidic extract of human pheochromocytoma tissue and has been recognized for its significant effects on the vascular system. The main functions of ADM include vasodilation, controlling blood pressure and maintaining vascular integrity, although its role on cardiovascular health is broader. Research has shown that elevated levels of adrenomedullin have been observed in a large number of severe diseases, with high risk of death. In this work, we examined the role of ADM as a predictive molecule of the risk of mortality and adverse clinical outcome through a narrative review of the scientific literature. The results were divided based on the pathologies and anatomical districts examined. This review demonstrates how ADM shows, in many diseases and different systems, a close correlation with the risk of mortality. These results prove the value of ADM as a prognostic marker in various clinical contexts and diseases, with utility in the stratification of the risk of clinical worsening and/or death and in the evaluation of therapeutic efficacy. The results open new perspectives with respect to the concrete possibility that ADM enters clinical practice as an effective diagnostic and prognostic marker of death as well as a molecular target for therapies aimed at patient survival.

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections.

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department.

Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool. In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission. Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin). One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1. None. The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively. Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.

Adrenomedullin has a pivotal role in trophoblast differentiation: A promising nanotechnology-based therapeutic target for early-onset preeclampsia.

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.

Impact of adrenomedullin on mitochondrial respiratory capacity in human adipocyte

Mitochondrial function in adipocyte is an important aspect in maintaining metabolic homeostasis. Our previous observation showed that circulating levels of adrenomedullin (ADM) and mRNA and protein for ADM in omental adipose tissue were higher in patients with gestational diabetes mellitus (GDM), and these alterations are accompanied by glucose and lipid metabolic dysregulation, but the impact of ADM on mitochondrial biogenesis and respiration in human adipocyte remain elusive. The present study demonstrated that: (1) Increasing doses of glucose and ADM inhibit human adipocyte mRNA expressions of mitochondrial DNA (mtDNA)-encoded subunits of electron transport chain, including nicotinamide adenine dinucleotide dehydrogenase (ND) 1 and 2, cytochrome (CYT) b, as well as ATPase 6; (2) ADM significantly increases human adipocyte mitochondrial reactive oxygen species generation and this increase is reversed by ADM antagonist, ADM22-52, but treatment with ADM does not significantly affect mitochondrial contents in the adipocytes; (3) Adipocyte basal and maximal oxygen consumption rate are dose-dependently suppressed by ADM, thus results in impaired mitochondrial respiratory capacity. We conclude that elevated ADM observed in diabetic pregnancy may be involved in glucose and lipid dysregulation through compromising adipocyte mitochondrial function, and blockade of ADM action may improve GDM-related glucose and adipose tissue dysfunction.

Effect of magnesium sulfate treatment on mediators of endothelial dysfunction and electrolytes in mild and severe preeclampsia: A case-control study.

Magnesium sulfate (MgSO4) treatment is widely used for the prevention of eclamptic seizures. However, its effect on mediators of endothelial dysfunction (ED) and electrolytes remains unclear. We evaluated the effects of MgSO4 treatment on mediators of ED and electrolytes. We recruited 100 women comprising 50 severe, 50 mild preeclampsia (PE) as cases and 50 normotensive pregnant women as controls from the Sampa Government Hospital, Ghana. We estimated for adrenomedullin (AM),calcitonin gene-related peptide (CGRP),soluble forms of intercellular adhesion molecule-1 (sICAM-1), Na+, K+, and Mg2+ before MgSO4 treatment, 24 h after MgSO4 treatment, and 48 h after delivery. p < 0.05 were considered significant for statistical analyses. Levels of AM, sICAM-1, and Na+ decreased significantly at 24 h after MgSO4 treatment and 48 h after delivery among PEwomen compared to the AM levels before treatment (p < 0.0001). The levels of CGRP and Mg2+ increased significantly after 24 h of MgSO4 treatment and 48 h after delivery among PE compared to the AM levels before treatment (p < 0.0001). The changes in AM, sICAM-1, CGRP, and Mg2+ at 24 h after treatment and 48 h after delivery were significantly higher in severe compared to mild PE (p < 0.0001). AM levels reduced significantly by 14.7% in mild and 42.7% in severe PE after MgSO₄ treatment (p < 0.05). sICAM-1 levels reduced significantly by 20.9% in mild and 25% in severe PE after MgSO₄ treatment. After MgSO₄ treatment, there was significant increase of 42.1% and >100% in CGRP levels in mild and severe PE, respectively (p < 0.05). After MgSO₄ treatment, Mg²⁺ levels increased significantly by 67.0% and 63.8% in mild and severe PE, respectively (p < 0.05). MgSO₄ treatment reduces AM, sICAM-1, and sodium levels but improves magnesium and CGRP in severe than mild PE thus have more beneficial role in severe PE.

Calcitonin Gene-Related Peptide and Adrenomedullin Levels During Ictal and Interictal Periods in Patients With Migraine.

Background Peptides related to calcitonin gene-related peptide (CGRP) have been suggested to have a role in migraine. Adrenomedullin (AM) might be a candidate molecule because it is related to pain pathways in the peripheral and central nervous systems and uses the same receptors as CGRP. Methodology In this study, we examined the serum CGRP and AM levels during unprovoked ictal and interictal periods of 30 migraine patients as well as 25 healthy controls. Another focus of this study was on the association of CGRP and AM levels with clinical features. Results Mean serum AM levels were 15.80 pg/mL (11.91-21.43 pg/mL) in the ictal and 15.85pg/mL (12.25-19.29 pg/mL) in the interictal periods in the migraine group and 13.36pg/mL (10.84-17.18 pg/mL) in the control group. Mean serum CGRP levels were 2.93pg/mL (2.45-3.90 pg/mL) in the ictal and 3.25pg/mL (2.85-4.67 pg/mL) in the interictal periods in the migraine group and 3.03pg/mL (2.48-3.80 pg/mL) in the control group. There were no statistical differences between ictal and/or interictal AM and CGRP levels (p = 0.558 and p = 0.054, respectively) which were also comparable with the results of the control group (p = 0.230, p = 0.295, p = 0.987, p = 0.139, respectively). Ictal serum CGRP and/or AM levels did not correlate with any of the reported clinical features. Conclusions Serum AM and CGRP levels are similar in interictal and unprovoked ictal periods in migraine patients and as well in controls. These results do not indicate that these molecules do not have a role in migraine pathophysiology. Considering the broad mechanisms of action of peptides in the CGRP family, further studies are needed in larger cohorts.

Procalcitonin and Adrenomedullin in Infectious Diseases

Calcitonin (CT) and adrenomedullin (ADM) are members of the CT family. Procalcitonin (PCT) is a prohormone of CT. Elevations in serum PCT and ADM levels are associated with severe sepsis and coronavirus disease 2019 (COVID-19). PCT enhances sepsis mortality and it binds to the CGRP receptor, which is a heterodimer of CT receptor-like receptor and receptor activity-modifying protein 1. The N-terminal truncated form of PCT, PCT3-116, is produced by the cleavage of PCT by dipeptidyl peptidase 4 (DPP-4) and is the main form of PCT in serum during sepsis, inducing microvascular permeability. Mid-regional pro-adrenomedullin (MR-proADM) is used instead of ADM as a biological indicator because ADM is rapidly degraded, and MR-proADM is released at the same rate as ADM. ADM reduces endothelial permeability and promotes endothelial stability. Endothelial dysfunction is responsible for multiple organ failure in sepsis and COVID-19 patients. Therefore, ADM may be an important molecule for improving the severity associated with sepsis and COVID-19. This review focuses on the current knowledge of PCT and ADM in sepsis and COVID-19.

Effects of enrichment strategies on outcome of adrecizumab treatment in septic shock: Post-hoc analyses of the phase II adrenomedullin and outcome in septic shock 2 trial.

Adrecizumab, a non-neutralizing antibody of adrenomedullin (ADM) was recently investigated regarding its potential to restore endothelial barrier function in septic shock patients with high plasma ADM levels. Circulating dipeptidyl peptidase 3 (cDPP3), a protease involved in the degradation of several cardiovascular mediators, represents another biological pathway strongly associated with outcome in septic shock, although unrelated to ADM. Therefore, the prognosis of patients with elevated cDPP3 may not be influenced by Adrecizumab. Also, time until initiation of treatment may influence efficacy. To evaluate effects of cDPP3-based enrichment on treatment efficacy of Adrecizumab. Post-hoc analysis of AdrenOSS-2, a phase-II, double-blind, randomized, placebo-controlled biomarker-guided trial of Adrecizumab. Compared to the total study cohort [HR for 28-day mortality of 0.84 (95% CI 0.53;1.31), p = 0.439], therapeutic benefit of Adrecizumab tended to be more pronounced in the subgroup of 249 patients with low cDPP3 (<50 ng/mL); [HR of 0.61 (95% CI 0.34;1.08), p = 0.085]. Median duration to study drug infusion was 8.5 h. In the subgroup of 129 patients with cDPP3 <50 ng/mL and an early start of treatment (<8.5 h after septic shock diagnosis) HR for 28-day mortality vs. placebo was 0.49 (95% CI 0.21-1.18), p = 0.105. In multivariate interaction analyses corrected for baseline disease severity, both cDPP3, as well as the cDPP3 * treatment interaction term were associated with a reduced HR for 28-day mortality in the Adrecizumab treated group; p = 0.015 for cDPP3 in univariate analysis, p = 0.025 for the interaction term between cDPP3 and treatment group. In contrast, treatment timing was not significantly associated with 28-day mortality in multivariate interaction analyses. In septic shock patients with high ADM levels, a further post-hoc enrichment strategy based on cDPP3 may indicate (with all the caveats to be considered for post-hoc subgroup analyses) that therapeutic efficacy is most pronounced in patients with lower cDPP3 levels.

Advantage of Adrenomedullin as remedial contrivance for left ventricular remodeling after acute myocardial infarction

Adrenomedullin is a potent vasoactive and natriuretic peptide normally found in human plasma and secreted by adipocytes that interfere with lipolysis through nitroxide-mediated oxidation. The level of adrenomedullin becomes high in patients with acute myocardial infarction. It has also been reported to inhibit the growth of cardiac myocytes as well as fibroblasts. In recent studies, it has been reported that the long-term administration of adrenomedullin has a significant effect on left ventricular remodeling and hormonal homeostasis, as well as on hemodynamics in the experimental subject. On the basis of recent studies, it is known that activation of protein kinase attenuates ischemia-reperfusion injury of myocardial origin. However, adrenomedullin is also known as a powerful activator of protein kinase Akt imparting cardioprotective effects. The long-term continuous administration of adrenomedullin has a significant effect on left ventricular remodeling and hemodynamics. Based on this effect, it would be worthwhile to utilize this peptide as useful therapeutic for the management of acute myocardial infarction. Moreover, the adrenomedullin is also known for its vasodilatory and stabilization properties referring to endothelial barriers.

Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure.

Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous injection of mercury chloride (RD-Ag) and the other by completely blocking bilateral renal blood flow (RD-Bl). Sixty minutes after starting intravenous AM infusion, AM levels in RD-Ag, RD-Bl, and rats with normal renal function (NF) were still increased slightly; however, plasma AM levels in RD-Ag rats were approximately three times as high as in RD-Bl and NF rats. Plasma AM disappearance after the end of treatment was similar among the three groups. Pharmacokinetic analysis revealed that elevated plasma AM in RD-Ag rats may be caused by a reduced volume of distribution. The adrenomedullin functional receptor is composed of heterodimers, including GPCR, CLR (calcitonin receptor-like receptor, CALCRL), and the single transmembrane proteins, RAMP2 or RAMP3 (receptor activity modifying protein). Calcrl expression was downregulated in the lungs and kidneys of RD-Ag rats. Furthermore, the plasma concentration of exogenous AM was elevated in mice deficient in vascular endothelium-specific Ramp2. These results suggest that decreased plasma AM clearance in RD-Ag is not due to impaired renal excretion but to a decreased volume of distribution caused by a reduction in adrenomedullin receptors.

Adrenomedullin is a biological marker of heart failure: review of modern literature&#x0D; Amina M. Alieva*1, Natalia

It has been proven that in patients with heart failure (HF), there is an increased level of adrenomedullin (ADM) in plasma. Biomarker indices correlate with the severity of hemodynamic dysfunction, as well as with neurohumoral indices, which are activated depending on the severity of congestive circulatory failure. In addition, the expression of the ADM gene in the heart and kidneys is increased in experimental and clinical HF. A small number of studies have examined the effect of ADM infusion. These studies have generally shown that hormone infusion has beneficial hemodynamic effects and promotes the maintenance/improvement of renal function, but most of the studies have been short-lived. The available results suggest that increasing ADM levels reduce the negative effects of vasoconstriction and sodium retention. A better understanding of the role of a biological marker in congestive circulatory failure may lead to the development of drugs that target ADM receptors.

Adrenomedullin Expression Is Associated With the Severity and Poor Prognosis of Interstitial Lung Disease in Dermatomyositis Patients.

ObjectiveTo evaluate adrenomedullin mRNA levels in the peripheral blood mononuclear cells (PBMCs) of patients with dermatomyositis (DM) as well as their correlation with the severity of interstitial lung disease (ILD).MethodsA total of 41 DM patients and seven immune-mediated necrotizing myopathy (IMNM) patients were recruited, in addition to 21 healthy controls (HCs). The adrenomedullin mRNA levels in PBMCs were measured via quantitative reverse-transcription real-time polymerase chain reaction (qRT-PCR). The associations between adrenomedullin expression levels and major clinical, laboratory, pulmonary function parameters and the prognosis of patients with DM-related ILD (DM-ILD) were analyzed. Immunohistochemical analysis was performed on lung tissues of DM-ILD patients to determine adrenomedullin expression.ResultsAdrenomedullin mRNA levels in PBMCs were significantly higher in DM patients than in IMNM patients and HCs (p = 0.022 and p<0.001, respectively). Among DM patients, the levels were significantly higher in those with rapidly progressive ILD (RP-ILD) than in those with chronic ILD (p = 0.002) or without ILD (p < 0.001). The adrenomedullin mRNA levels in DM-ILD were positively correlated with serum ferritin (r =0.507, p =0.002), lactate dehydrogenase (LDH) (r =0.350, p =0.045), and lung visual analog scale (VAS) (r=0.392, p=0.021) and were negatively correlated with pulmonary function test parameters, including predicted forced vital capacity (FVC)% (r = −0.523, p = 0.025), forced expiratory volume in 1 s (FEV1)% (r = -0.539, p = 0.020), and diffusing capacity of carbon monoxide (DLco)% (r = -0.495, p = 0.036). Immunohistochemical analysis of adrenomedullin confirmed higher expression in the alveolar epithelial cells and macrophages of DM patients with RP-ILD. Among the DM patients with ILD, the six decedents exhibited higher adrenomedullin levels than the 28 survivors (p = 0.042). The cumulative survival rate was significantly lower (62.5% vs. 100%, P = 0.005) in patients with an adrenomedullin level > 0.053 than in those with a level <0.053.ConclusionsAdrenomedullin levels are upregulated in DM patients with RP-ILD and are associated with ILD severity and poor prognosis. Adrenomedullin may be a potential prognostic biomarker in DM patients with ILD, although need further investigation.

Associations of Plasma Bioactive Adrenomedullin Levels with Cardiovascular Risk Factors in BRCA1/2 Mutation Carriers

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors. Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors. Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 – 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p < 0.001). Elevated ADM levels were associated with lower cardiorespiratory fitness (OR = 0.88, p < 0.001) and several parameters of obesity (p < 0.001). ADM levels were higher in women who have ever smoked (OR = 1.72, p = 0.02). ADM levels were not associated with a previous diagnosis of breast cancer (p = 0.28). Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined.

Altered Arginine/Nitric Oxide Pathway in Children Diagnosed Attention Deficit Hyperactivity Disorder, and the Effect of 10 Weeks Methylphenidate Treatment.

ObjectiveIn this study, we investigated the levels of arginine, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and adrenomedullin that are presumed to play a role in attention deficit hyperactivity disorder (ADHD) etiology, and to compare the findings with healthy controls.MethodsThirty ADHD patients and thirty healthy control subjects aged 6−12 years were included in the study. Sociodemographic data form, Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version; Conners’ Parent/Teacher Rating Scale-Revised Long Form; Children’s Depression Inventory; and The State-Trait Anxiety Inventory for Children were applied to all cases. All participants included in the study were evaluated in terms of their serum arginine, NO, ADMA, and adrenomedullin levels. Subsequently, methylphenidate treatment was started in ADHD patients and blood parameters were tested again in the tenth week of treatment.ResultsAt the start of the study, arginine and ADMA levels were significantly higher and NO and adrenomedullin levels were significantly lower in the ADHD group compared to the control group. Post-treatment arginine and ADMA levels were found to be significantly lower than in the pre-treatment period. There were no significant differences in NO and adrenomedullin levels before and after treatment. There was no correlation between scale scores and blood parameters.ConclusionThese variations in the blood parameters of the ADHD group seem to be worth further investigation. Studies to be conducted with larger sample groups after longer-term treatment may provide new information about the alterations in neurobiological processes related to ADHD etiology and treatment.

Sjögren’s and non-Sjögren’s sicca share a similar symptom burden but with a distinct symptom-associated proteomic signature

ObjectivesGiven the similarity in symptoms between primary Sjogren’s syndrome (SjS) and non-SjS sicca syndrome (sicca), we sought to characterise clinical and proteomic predictors of symptoms in both groups in order...

Adrenomedullin and its receptors are expressed in mouse pancreatic β-cells and suppresses insulin synthesis and secretion.

Gestational diabetes mellitus (GDM) is associated with defective pancreatic β-cell adaptation in pregnancy, but the underlying mechanism remains obscure. Our previous studies demonstrated that GDM women display increased plasma adrenomedullin (ADM) levels, and non-obese GDM mice show decreased serum concentrations of insulin and the number of β-cells in pancreas islets. The aims of this study is to examine if ADM and its receptors are expressed in female mouse pancreas, and if so, whether insulin secretion is regulated by ADM in mouse β-cell line, NIT-1 cells and isolated mouse pancreatic islets. Present study shows that ADM and its receptor components CRLR, RAMPs are present in mouse pancreatic islets and co-localized with insulin. The expressions of ADM, CRLR and RAMP2 in islets from pregnant mice are reduced compared to that of non-pregnant mice. NIT-1-β cells express ADM and its receptor mRNA, and glucose dose-dependently stimulates expressions. Furthermore, ADM inhibits NIT-1-β cell growth, and this inhibition is reversed by ADM antagonist, ADM22-52. The glucose-induced insulin secretion was suppressed by ADM in NIT-1-β cells and isolated pancreatic islets from pregnant mice. These inhibitory effects are accompanied by upregulation of endoplasmic reticulum (ER) stress biomarker genes in NIT-1-β cells. This study unveils that reduced ADM and its receptors may play a role in β-cell adaptation during pregnancy, while increased plasma ADM in GDM may contribute to the β-cells dysfunction, and blockade of ADM may reverse β-cell insulin production.

Endoglin and Activin Receptor-like Kinase 1 (Alk1) Modify Adrenomedullin Expression in an Organ-Specific Manner in Mice.

Simple SummaryHereditary hemorrhagic telangiectasia (HHT) is called a rare disease because it affects relatively few people. It is characterized by malformations in some blood vessels and usually results in profuse nose bleedings. In a recent article, we found that these patients have higher levels of adrenomedullin (AM), a molecule with cardiovascular activities, than healthy people. Thus we wanted to know whether the mutations that cause the HHT disease are directly responsible for these higher levels of AM. To investigate this issue, we used mutant mice, which express lower levels of the genes involved in the disease (called Eng and Acvrl1), and measured how much AM was found in different tissues. Although we expected a higher amount of AM in all organs, that was not the case. Some organs showed no variation, some had lower levels of AM than normal mice (fat, skin, and adrenals), and others had a higher expression (cerebellum and colon). Interestingly, our results suggest that these genes and the related molecule BMP-9 may have novel functions, which have not been yet investigated, which may shed more light on the physiopathology of HHT.Hereditary hemorrhagic telangiectasia (HHT) is a rare disease characterized by vascular malformations and profuse bleeding. The disease is caused by mutations in the components of the BMP-9 receptor: endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes. Recently, we reported that HHT patients expressed higher serum levels of adrenomedullin (AM) than healthy volunteers; thus, we studied the expression of AM (by enzyme immunoassay, qRT-PCR, immunohistochemistry, and Western blotting) in mice deficient in either one of the receptor components to investigate whether these defects may be the cause of that elevated AM in patients. We found that AM expression is not affected by these mutations in a consistent pattern. On the contrary, in some organs (blood, lungs, stomach, pancreas, heart, kidneys, ovaries, brain cortex, hippocampus, foot skin, and microvessels), there were no significant changes, whereas in others we found either a reduced expression (fat, skin, and adrenals) or an enhanced production of AM (cerebellum and colon). These results contradict our initial hypothesis that the increased AM expression found in HHT patients may be due directly to the mutations, but open intriguing questions about the potential phenotypic manifestations of Eng and Acvrl1 mutants that have not yet been studied and that may offer, in the future, a new focus for research on HHT.