Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus.

In the era of precision medicine, the tremendous progress in next-generation sequencing technologies has allowed the identification of an ever-increasing number of genes associated with known Mendelian disorders. Neonatal diabetes mellitus is a rare, genetically heterogeneous endocrine disorder diagnosed before 6 months of age. It may occur alone or in the context of genetic syndromes. Neonatal diabetes mellitus has been linked with genetic defects in at least 26 genes to date. Novel mutations in these disease-causing genes are being reported, giving us a better knowledge of the molecular events that occur upon insulin biosynthesis and secretion from the pancreatic ß-cell. Of great importance, some of the identified genes encode proteins that can be therapeutically targeted by drugs per os, leading to transitioning from insulin to sulfonylureas. In this review, we provide an overview of pancreatic ß-cell physiology, present the clinical manifestations and the genetic causes of the different forms of neonatal diabetes, and discuss the application of next-generation sequencing methods in the diagnosis and therapeutic management of neonatal diabetes and on research in this area.

The clinical impact of growth differentiation factor-15 in heart disease: A 2019 update.

Growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1) or non-steroidal anti-inflammatory drug-activated gene (NAG-1) has been identified as a biomarker of response to treatment and prognosis in cardiovascular diseases. GDF-15 is a member of the transforming growth factor-ß superfamily and is involved in several pathological conditions such as inflammation, cancer, cardiovascular, pulmonary and renal diseases. Cardiac myocytes produce and secrete GDF-15 in response to oxidative stress, stimulation with angiotensin II or proinflammatory cytokines, ischemia, and mechanical stretch. Other cellular sources of GDF-15 production are macrophages, vascular smooth muscle cells, endothelial cells, and adipocytes, which secrete GDF-15 in response to oxidative or metabolic stress or stimulation of proinflammatory cytokines. GDF-15 is induced in hypertrophic and dilated cardiomyopathy after volume overload, ischemia, and heart failure. GDF-15 can be used as a marker of prognosis in patients with cardiovascular disorders, in combination with conventional prognostic factors, such as N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT).

Biomarkers of diabetic nephropathy: A 2017 update.

Diabetic nephropathy (DN), also named diabetic kidney disease (DKD), is a devastating complication in patients with both type 1 and 2 diabetes mellitus (T1D and T2D) and its diagnosis has been traditionally based on the presence of micro-albuminuria (MA). The aim of this article is to update, through review of the relevant medical literature, the most promising biomarkers for early DKD detection. MA has historically been employed as an early marker of microvascular complications, indicating risk for advanced CKD. However, due to the inability of MA to adequately predict DKD, especially in young patients or in non-albuminuric DKD, additional biomarkers of glomerular and/or tubular injury have been proposed to uncover early renal dysfunction and structural lesions, even before MA occurs. Defining new predictive biomarkers to use alongside urinary albumin excretion (UAE) during the initial stages of DKD would provide a window of opportunity for preventive and/or therapeutic interventions to prevent or delay the onset of irreversible long-term complications and to improve outcomes by minimizing the rates of severe cardio-renal morbidity and mortality in DKD patients.

Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis.

Diabetic nephropathy constitutes a devastating complication in patients with type 1 diabetes mellitus, and its diagnosis is traditionally based on microalbuminuria. The aim of this review is to update through the medical literature the suggested early natural course of diabetic nephropathy, the theories behind the pathways of its pathogenesis, and its diagnosis. Poor glycemic control, dyslipidemia, smoking, advanced glycation end products, and environmental and genetic clues play an important role in the development of diabetic nephropathy. Microalbuminuria has been traditionally considered as a primary early marker of microvascular complication unraveling the risk for progress to the advanced stages of chronic kidney disease, but because of our inability to make an early diagnosis of diabetic nephropathy in young patients as well as nonalbuminuric diabetic nephropathy, recently, other additional markers of renal injury like serum and urinary neutrophil gelatinase-associated lipocalin, chitinase-3-like protein 1, cystatin C, and plasma growth differentiation factor 15 have been proposed to unmask early renal dysfunction, even before microalbuminuria supervenes. Copyright © 2016 John Wiley & Sons, Ltd.

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.

The role of chemokines in type 1 diabetes-associated neuropathy.

INTRODUCTION: To investigate whether circulating chemokines contribute to the development of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes (T1D). METHODS: Fifty-two patients with childhood-onset T1D (mean age 28 ± 4 yrs.; diabetes duration 19.5 ± 5.5 yrs.) and 19 control subjects (mean age 26.5 ± 4.5 yrs.) were included in a cross-sectional analysis of this long-term longitudinal cohort study. A subgroup of 24 patients was followed prospectively for a further 10 yrs. Plasma levels of Th1- (CXCL9, CXCL10 and CXCL11), Th2- (CCL17 and CCL22) and Th17-associated (CXCL8 and CCL20) chemokines were assessed in all subjects. Additionally, the TID patients underwent clinical examination and electroneurography. RESULTS: The frequency of neuropathy was 21% (11/52). Higher levels of CXCL9 levels were found in patients with DPN compared with control subjects (p = .019); by contrast, no difference between patients without DPN and control subjects was seen after adjustment for multiple comparisons. In patients with DPN, CXCL10 correlated negatively with suralis MCV and suralis SNAP (rho -0.966, p < .001 and rho -0.738, p < .001, respectively) and was positively correlated with the vibration perception threshold (rho 0.639, p = .034), while CXCL8 correlated negatively with the cold perception threshold (rho -0.645, p = .032). The frequency of neuropathy increased to 54% (13/24) in the subgroup of 23 TID patients, followed by an additional 10 yrs. CONCLUSIONS: Changes in Th1- and Th17-associated chemokines were associated with impaired peripheral sensory nerve function and nerve conduction after long disease duration in childhood-onset T1D.

Photoplethysmography (PPG)-determined heart rate variability (HRV) and extracellular water (ECW) in the evaluation of chronic stress and inflammation.

BACKGROUND: Heart rate variability (HRV) is the physiological variation in the time interval between consecutive heartbeats. Extracellular water (ECW) is the aqueous compartment surrounding cells and has been used as an inflammation index. Medically unexplained symptoms (MUS) refer to persistent psychosomatic bodily complaints, and their presence may be employed as a clinical index of chronic stress and inflammation, useful in distinguishing suffering patients from healthy subjects. AIM: To evaluate the clinical performance of SDNN (standard deviation of intracardiac beat time interval of normal sinus beats) and RMSSD (square root of the mean squared differences of successive NN intervals) as indices of HRV, and their correlation with ECW and MUS. PATIENTS AND METHODS: A large multicenter retrospective study was conducted in 37 Italian medical practices in Caucasian men and women aged 20 to 70 years. SDNN and RMSSD were measured with the PPG Stress Flow® device (BioTekna, Italy), while ECW was determined with the BIA-ACC® device (BioTekna, Italy). All subjects filled in a MUS® questionnaire with 19 "nonspecific" symptom questions. The study sample was stratified by decade of age into five groups. RESULTS: Data from 9246 subjects comprising 3127 males and 6119 females, with a median age of 47 years, were analyzed. HRV index SDNN and RMSSD distributions in the entire sample and in each of the five age groups were significantly greater in subjects with a limited number of MUS (0-5) than in subjects with six or more symptoms, while both distributions correlated negatively with ECW. CONCLUSION: SDNN and RMSSD and ECW were predictors of MUS and were successfully used to objectively evaluate chronic stress and inflammation.

Plasma levels of tissue inhibitor of metalloproteinase-1 in patients with type 1 diabetes mellitus associate with early diabetic neuropathy and nephropathy.

BACKGROUND: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been suggested as a marker for abnormal regulation of tissue remodelling in type 1 diabetes. Metalloproteinase-9 (MMP-9) has been associated with matrix turnover, and Neutrophil gelatinase associated lipocalin (NGAL) is a marker of tubular injury in diabetic nephropathy. The aim was to analyse these biomarkers to unmask early diabetic complications. METHODS: Thirty-three type 1 diabetes patients, aged 20-35 years, and disease duration 20 ± 5.3 years were included. Along with clinical examination, neurophysiological measurements, routine biochemistry, plasma concentrations of TIMP-1, MMP-9 and NGAL were determined with immunoenzymatic techniques. RESULTS: TIMP-1 correlated with abnormal unilateral and bilateral vibratory sense foot perception (r = -0.49 and r = -0.51, respectively), foot neuropathy impairment assessment score (NIA; r = -0.55), neuropathy symptom assessment score (r = 0.42), microalbuminuria (r = 0.50) and eGFR (r = -0.45). MMP-9 correlated with impaired foot NIA (r = 0.51). Multiple regression analysis showed an association for TIMP-1 (p = 0.004) with impaired neurophysiological examinations and renal dysfunction along with NGAL (p = 0.016 and p = 0.015 respectively). CONCLUSIONS: This study suggests that plasma levels of TIMP-1, MMP-9 and NGAL may serve as useful biomarkers in unravelling subclinical neuropathy and nephropathy in type 1 diabetes.

Endocrine paraneoplastic syndromes in patients with neuroendocrine neoplasms.

OBJECTIVE: Our aim was to assess the prevalence of endocrine paraneoplastic syndromes (EPNS) in neuroendocrine neoplasms (NENs) and estimate its impact on patient outcomes. DESIGN: This is a retrospective analysis of 834 patients with NENs (611 gastrointestinal, 166 thoracic, 57 of unknown and various other primary origin). We included 719 consecutive NEN patients treated at EKPA-Laiko Hospital, Athens, Greece and 115 patients with lung carcinoid (LC) treated at Uppsala University Hospital, Uppsala, Sweden. EPNS diagnosis was based on standard criteria. METHODS: Twenty-one patients with EPNS were detected: 16 with ectopic Cushing's syndrome (ECS), one with hypercalcaemia due to parathyroid hormone-related protein (PTHrP) secretion, three with hypercalcitonaemia and one patient with dual secretion of calcitonin and beta-human chorionic gonadotropin (ß-HCG). All tumours were well-differentiated; 10 patients had Stage IV disease at diagnosis. RESULTS: The prevalence of EPNS in the Greek cohort was 1.9%, whereas that of ECS among LC patients in both centres was 6.7%. Median overall survival (OS) for patients with EPNS was 160.7 months (95%CI, 86-235.4) and median event-free survival (EFS) was 25.9 months (95%CI, 0-57.2). Patients presenting with EPNS prior to NEN diagnosis had longer EFS compared to patients with synchronous or metachronous EPNS (log-rank P = 0.013). Patients with ECS of extra-thoracic origin demonstrated shorter OS and EFS compared to patients with ECS of lung or thymic origin (log-rank P = 0.001 and P < 0.001, respectively). LC patients with and without ECS were comparable in 5-year and 10-year OS rates (66.7% and 33.3% versus 89.8% and 60.2%, respectively; 95%CI [189.6-300.4 months], log-rank P = 0.94) and in median EFS, 67 versus 183 months, 95%CI [50.5-207.5], log-rank P = 0.12). CONCLUSION: EPNS are relatively rare in patients with NENs and mainly concern well-differentiated tumours of the foregut. Among patients with EPNS, LC-related ECS may not adversely affect patient outcomes when diagnosed prior to NEN and effectively been treated.

On type 1 diabetes mellitus pathogenesis.

Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of ß cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the ß cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy ß cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of ß cells that need to be destroyed before overt diabetes become evident.

Diabetic nephropathy in type 1 diabetes.

Diabetic nephropathy (DN) also named diabetic kidney disease (DN) is one of the leading causes of mortality in people with diabetes. The aim of this review is to update the medical literature, the theories behind its early natural history, the pathways of its pathogenesis, its diagnosis and treatment. Poor glycemic control, hyperlipidemia, smoking, oxidative stress, accumulation of advanced glycated end products, environmental, genetic and epigenetic factors play an important role in the pathophysiological development of DN. Microalbuminuria has been traditionally used as the primary early diagnostic marker of microvascular complication unraveling the risk for progress to severe cardiorenal outcomes, but its prognostic role has been recently debated. The disease often leads to end-stage renal disease and it is often associated with major cardiovascular outcomes. Its early diagnosis is crucial for the patients in order to have a chance for proper treatment.

NGAL as an Early Predictive Marker of Diabetic Nephropathy in Children and Young Adults with Type 1 Diabetes Mellitus.

AIMS: Type 1 diabetes (T1D) is often associated with early microvascular complications. Previous studies demonstrated that increased systolic (SAP) and diastolic arterial blood pressures (DAP) are linked to microvascular morbidity in T1D. The aim of the study was to investigate the predictive role of neutrophil gelatinase-associated lipocalin (NGAL) in unravelling early cardio-renal dysfunction in T1D. METHODS: Two T1D patient groups participating in two-centre prospective cohorts were studied. Group A consisted of 57 participants aged 13.9 years (SD: 3.1) and group B consisted of 59 patients aged 28.0 years (SD: 4.4). Forty-nine healthy children [age: 10.5 years (SD: 6.6)] and 18 healthy adults [age 27.7 years (SD: 4.2)] served as controls. Serum concentrations of NGAL (ELISA) were determined, and SAP and DAP were examined (SAP and DAP also expressed as z-scores in the younger group). RESULTS: NGAL correlated positively with SAP in both patient groups (P = 0.020 and P = 0.031, resp.) and SAP z-score (P = 0.009) (group A) and negatively with eGFR in both groups (P < 0.001 and P < 0.001, resp.). CONCLUSIONS: NGAL may be proposed as a biomarker of early renal dysfunction even in nonalbuminuric T1D patients, since it was strongly associated with renal function decline and increasing systolic arterial pressure even at prehypertensive range in people with T1D, in a broad age range.