Immunoassay interferences: laboratory pitfall in the diagnosis of adrenocortical carcinoma.

A woman in her late 50s with recent onset of hypertension, diabetes, lumbar pain and unintentional weight loss was diagnosed with a cortisol and androgen-producing adrenal mass. Despite this, serum adrenocorticotropic hormone (ACTH) concentration was inappropriately elevated, which was investigated thoroughly. Investigations included a brain magnetic resonance imaging to exclude concomitant pituitary adenoma, a corticotropin-releasing hormone stimulation test and a gallium-68 DOTATATE and 18F-FDOPA PET scan, both excluding ectopic ACTH production. Considering the disparity between clinical presentation and biochemical results, the ACTH was reanalysed using the Cobas immunoassay (Roche, Switzerland), ultimately unveiling the cause for ACTH elevation. ACTH levels had previously been measured with ACTH Immulite (Siemens, Germany), a two-site immunoassay which is prone to interferences causing falsely elevated ACTH concentrations. Inaccurate laboratory levels can lead to diagnosis delay and unnecessary diagnostic procedures and a close communication between the physicians and laboratorians is of utmost importance.

[Non-Insulin Antidiabetic Agents in the Management of Hyperglycaemia of Non-Critical Hospitalized Patients]. / Antidiabéticos Não Insulínicos na Abordagem da Hiperglicemia nos Doentes Hospitalizados por Doença Aguda Não Crítica.

Hyperglycaemia affects more than 30% of adults hospitalized for non-critical illness and is associated with an increased risk of adverse clinical outcomes. Insulin therapy is widely used for its safety and efficacy. However, given the growing availability of new drugs and new classes of antidiabetic agents with benefits beyond glycaemic control, challenges arise regarding their use in the hospital setting. This article aims to review and summarize the most recently available evidence and recommendations on the role of non-insulin antidiabetic agents in the management of hyperglycaemia in hospitalized patients. Insulin therapy remains the method of choice. Dipeptidyl peptidase 4 inhibitors can be considered in mild to moderate hyperglycaemia. Glucagon-like peptide 1 receptor agonists have recently shown promising results, with high efficacy in glycaemic control and low risk of hypoglycaemia. There are concerns regarding the increased risk of acidosis with metformin use, especially in cases of acute illness, although there is no evidence to support its suspension in selected patients with relative clinical stability. Sodium-glucose cotransporter-2 inhibitors should be discontinued in clinical situations that may predispose to ketoacidosis, including episodes of acute illness. The hospital use of sulfonylureas and thiazolidinediones is not advised.

A hiperglicemia afeta mais de 30% dos adultos hospitalizados por doença não crítica e está associada a um risco aumentado de desfechos clínicos adversos. A insulinoterapia é amplamente utilizada pela sua segurança e eficácia. Contudo, face à disponibilidade crescente de novos fármacos antidiabéticos com benefícios além do controlo glicémico, surgem desafios quanto à sua utilização em contexto hospitalar. Este artigo tem como objetivo rever e sumariar a evidência e as recomendações mais recentemente disponibilizadas sobre o papel dos antidiabéticos não insulínicos na gestão da hiperglicemia a nível hospitalar. A insulinoterapia mantém-se como o método de eleição. Os inibidores da dipeptidil peptidase 4 podem ser considerados em casos de hiperglicemia ligeira a moderada, como alternativa ou de forma complementar à insulinoterapia. Os agonistas dos recetores do glucagon-like peptide 1 têm recentemente revelado resultados promissores, com elevada eficácia no controlo glicémico e risco baixo de hipoglicemia. Existem preocupações relativas ao risco acrescido de acidose com a metformina, sobretudo em casos de doença aguda, apesar de não existir evidência que suporte a sua suspensão em doentes selecionados e com relativa estabilidade clínica. Os inibidores do cotransportador de sódio-glicose-2 devem ser descontinuados em situações clínicas que possam predispor a cetoacidose, incluindo episódios de doença aguda. A utilização hospitalar das sulfonilureias e das tiazolidinedionas é desaconselhada.

From Bariatric Surgery to Conception: The Ideal Timing to Optimize Fetal Weight.

PURPOSE: Bariatric surgery (BS) increases the risk of small for gestational age (SGA) neonates. Guidelines recommend postponing pregnancy for 12-24 months, but optimal surgery-to-conception interval (BSCI) remains uncertain. We aimed to evaluate the impact of BSCI on birth weight and SGA. MATERIALS AND METHODS: Retrospective cohort study of 42 pregnancies following BS, including Roux-en-Y gastric bypass, gastric sleeve, adjustable gastric banding and biliopancreatic diversion. Neonates were classified as SGA if birth weight < 10th percentile. Optimal BSCI was obtained from the analysis of ROC curves, and pregnancies were compared by that cut-off. RESULTS: There was a linear association between BSCI and birth weight and an inverse association with SGA, with each additional month of BSCI translating into additional 4.5 g (95%CI: 2.0-7.0) on birth weight and -6% risk of SGA (95%CI: 0.90-0.99). We established a cut-off of 24.5 months of BSCI for lower risk of SGA. Pregnancies conceived in the first 24 months had a more than tenfold increased risk of SGA (OR 12.6, 95%CI: 2.4-66.0), even when adjusted for maternal age, gestational diabetes and inadequate gestational weight gain. CONCLUSION: BSCI was associated with birth weight and SGA. Our results are in line with the recommendations of BSCI of at least 24 months to reduce the risk of SGA.

Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes.

Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus∆NLS/+ mice. Yet, the mechanisms linking FUS mislocalization to hippocampal function and memory formation are still not characterized. Herein, we show that in these mice, the hippocampus paradoxically displays nuclear FUS accumulation. Multi-omic analyses showed that FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus∆NLS/+ mice. Furthermore, these mice lacked precision in a hippocampal-dependent spatial memory task and displayed decreased dendritic spine density. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. These data call for further investigation in the neurological phenotype of FUS-related diseases and open therapeutic strategies towards epigenetic drugs.

Association Between Follicle-Stimulating Hormone Receptor (FSHR) rs6166 and Estrogen Receptor 1 (ESR1) rs2234693 Polymorphisms and Polycystic Ovary Syndrome Risk, Phenotype, and Reproductive Outcomes in an Infertile Portuguese Population.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrine disorder often leading to anovulatory infertility. PCOS pathophysiology is still unclear and several potential genetic susceptibility factors have been proposed. The effect of polymorphisms in two genesrelated to follicular recruitment and development, the follicle-stimulating hormone receptor (FSHR) and the estrogen receptor 1 (ESR1), have been studied in different populations with contradictory results. AIMS: To evaluate the influence of FSHR rs6166 (c.2039A>G) and of ESR1 rs2234693 (Pvull c.453-397 T > C) polymorphisms on PCOS risk, phenotype, and response to controlled ovarian stimulation (COS). MATERIALS AND METHODS: Genotyping of the FSHR rs6166 and the ESR1 rs2234693 polymorphisms was performed in PCOS women and a control group undergoing in vitro fertilization (IVF). Demographic, clinical, and biochemical data, genotype frequency, and IVF outcomes were compared between groups. RESULTS: We evaluated 88 PCOS women and 80 controls. There was no significant difference in the genotype distribution of FSHR rs6166 polymorphism between PCOS women and controls (AA 31.8%/AS 48.9%/SS 19.3% in PCOS women vs AA 37.5%/AS 40.0%/SS 22.5% in controls; p = 0.522). The same was true for the ESR1 rs2234693 (CC 24.1%/CT 46.0%/TT 29.9% in PCOS women vs CC 18.8%/CT 48.8%/TT 32.5% in controls; p = 0.697). In PCOS women, we found higher follicle-stimulating hormone (FSH) levels on the third day of the menstrual cycle associated with the SS variant of the FSHR polymorphism (9.2 vs 6.2 ± 1.6 and 5.6 ± 1.6 mUI/mL; p = 0.011). We did not find other associations between the baseline hormonal parameters, antral follicle count, and response measures to COS with FSHR or ESR1 genotypes. We found, however, a need for higher cumulative doses of FSH for COS in patients with the SS variant of the FSHR rs6166 polymorphism (1860.5 ± 627.8 IU for SSvs 1498.1 ± 359.3 for AA and 1425.4 ± 474.8 for SA; p = 0.046 and p = 0.046). CONCLUSION: Our data suggest that in the population, FSHR rs6166and ESR1 rs2234693 polymorphisms do not influence the risk of developing PCOS nor do they influence the patient's phenotype and IVF success. However, the SS variant of the FSHR rs6166 polymorphism may be associated with FSH resistance requiring higher FSH doses for COS.

Regular physical activity moderates the adverse impact of type 2 diabetes on brain atrophy independently from HbA1c.

Objective: Brain atrophy has been consistently associated with type 2 diabetes, beginning in early stages of dysglycemia, independently from micro and macrovascular complications. On the contrary, physical activity relates with larger brain volumes. Our aim is to assess the influence of regular physical activity on brain volumes in people with type 2 diabetes. Methods: A cross-sectional multimodal evaluation with 3T MRI was performed on 170 individuals: 85 individuals with type 2 diabetes and 85 controls. They underwent clinical examination, blood sampling and 3T MRI. Brain volumes (mm3) were estimated using FreeSurfer 7. Physical activity duration was self-reported by the participants as the number of hours of physical activity per week for at least the previous 6 months. Statistical analysis was performed with IBM SPSS 27. Results: People with type 2 diabetes had significantly lower cortical and subcortical volumes, adjusted for age and individual intracranial volume, comparing to controls. Regression analysis showed that within type 2 diabetes group, lower gray matter volumes were associated with lesser physical activity duration (hours/week), independently from HbA1c. Moreover, there were significant moderate positive correlations between regular physical activity duration and gray matter volumes of cortical and subcortical subregions, specifically in the diabetes group. Conclusions: This study reveals a putative beneficial effect of regular physical activity independently of glycemic control, as assessed by HbA1c, which might contribute to reduce the negative impact of type 2 diabetes in the brain.

miR-101a-3p Impairs Synaptic Plasticity and Contributes to Synucleinopathy.

BACKGROUND: Synucleinopathies are disorders characterized by the abnormal accumulation of α-synuclein (aSyn). Synaptic compromise is observed in synucleinopathies parallel to aSyn aggregation and is accompanied by transcript deregulation. OBJECTIVE: We sought to identify microRNAs associated with synaptic processes that may contribute to synaptic dysfunction and degeneration in synucleinopathies. METHODS: We performed small RNA-sequencing of midbrain from 6-month-old transgenic mice expressing A30P mutant aSyn, followed by comparative expression analysis. We then used real-time quantitative polymerase chain reaction (qPCR) for validation. Functional analysis was performed in primary neurons by biochemical assays and imaging. RESULTS: We found several deregulated biological processes linked to the synapse. miR-101a-3p was validated as a synaptic miRNA upregulated in aSyn Tg mice and in the cortex of dementia with Lewy bodies patients. Mice and primary cultured neurons overexpressing miR-101a-3p showed downregulation of postsynaptic proteins GABA Ab2 and SAPAP3 and altered dendritic morphology resembling synaptic plasticity impairments and/or synaptic damage. Interestingly, primary cultured neuron exposure to recombinant wild-type aSyn species efficiently increased miR-101a-3p levels. Finally, a dynamic role of miR-101a-3p in synapse plasticity was shown by identifying downregulation of miR-101a-3p in a condition of enhanced synaptic plasticity modelled in Wt animals housed in enriched environment. CONCLUSION: To conclude, we correlated pathologic aSyn with high levels of miR-101a-3p and a novel dynamic role of the miRNA in synaptic plasticity.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear feature: clinical, pathological, and molecular update 5 years after the nomenclature revision.

The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed in 2016 and incorporated as a new entity in the World Health Organization (WHO) classification of tumours of endocrine organs in 2017. Since then, there has been debate regarding the histological criteria for the diagnosis, the need for molecular studies or the risk of lymph node metastasis or recurrence associated with this entity. Over the years, the concept of NIFTP evolved, now including both small (<1 cm) and large (>4 cm) tumours and oncocytic lesions. On the other hand, recent data on NIFTP in the setting of thyroid follicular nodular disease or frequent coexistence of malignant tumours raised concerns regarding the follow-up of these patients. Today, both pathologists and clinicians still face several challenges in the diagnosis, treatment, and follow-up of patients with NIFTP.

Circadian functioning of Locus Cœruleus of the nocturnal rat and diurnal rodent Arvicanthis.

The noradrenergic Locus Cœruleus is one of the major arousal structures involved in inducing wakefulness. While brain noradrenaline (NA) amounts display 24-h variations, the origin of NA rhythm is currently unknown. In this study, we tested the hypothesis that NA rhythm could result from its rhythmic synthesis. Therefore, we investigated the 24-h expression profile of NA rate-limiting enzyme, tyrosine hydroxylase (th), in the Locus Cœruleus (LC) of the nocturnal rat and the diurnal rodent Arvicanthis, under 12 h:12 h light/dark (LD) and constant darkness (DD) conditions. In both species, th mRNA levels vary significantly over 24-h. In nocturnal rats, th mRNA profiles show a unimodal rhythm, with peak values in late day in LD, and in the middle of the subjective day in DD. In contrast, th mRNA rhythm in Arvicanthis is characterized by a bimodal profile, with higher levels at the beginning of the day and of the night in LD, and in the middle of the subjective day and night in DD. The rhythmic pattern of th expression may be dependent on a LC clock machinery. Therefore, we investigated the expression of three clock genes, namely bmal1, per1, and per2, and found that their mRNAs display significant variations between day and nighttime points in both species, but in opposite directions. These data show that NA rhythm may be related to circadian expression of th gene in both species, but differs between nocturnal and diurnal rodents. Furthermore, the phase opposition of clock gene expression in the rat compared to Arvicanthis suggests that the clock machinery might be one of the mechanisms involved in th rhythmic expression.

An Uncommon Presentation of Pheochromocytoma in Neurofibromatosis Type 1 and the Importance of Long-Term Follow-Up.

Neurofibromatosis type 1 (NFT1) is a disease caused by mutations in the tumor suppressor gene NF1. It is associated with a higher incidence of chromaffin cell tumors which are usually adrenal, unilateral and benign. The presence of these tumors during pregnancy is extremely rare and frequently associated with fatal outcomes. We report the case of a female patient with NFT1, who presented with paroxysmal spells of headache, palpitations, dizziness and pre-cordial discomfort, starting immediately after the delivery of her third child. Diagnostic work-up came to reveal a bilateral pheochromocytoma and the patient underwent bilateral adrenalectomy. Over 12 years after the initial surgery, metastatic disease was diagnosed, and a reintervention was performed. This is a rare presentation of bilateral malignant pheochromocytoma in a patient with NFT1, with postpartum occurrence of the first symptoms. This text focuses the important details and challenges found at each stage of diagnosis and follow-up.

A neurofibromatose tipo 1 (NFT1) é uma doença causada por mutações no gene supressor de tumor NF1. Está associada a uma maior incidência de tumores de células cromafins que geralmente são adrenais, unilaterais e benignos. A presença destes tumores durante a gravidez é extremamente rara e com frequência associada a resultados fatais. Relatamos o caso de uma doente com NFT1, que apresentou crises paroxísticas de cefaleias, palpitações, tonturas e desconforto pré-cordial, com início imediatamente após o parto de seu terceiro filho. A investigação diagnóstica revelou feocromocitoma bilateral e a doente foi submetida a adrenalectomia bilateral. Mais de 12 anos após a cirurgia inicial, foi diagnosticada doença metastática e efetuada reintervenção. Esta é uma apresentação rara de feocromocitoma maligno bilateral numa doente com NFT1, com ocorrência pós-parto dos primeiros sintomas. Este texto foca detalhes e desafios importantes encontrados em cada fase do diagnóstico e acompanhamento.

An Orthodenticle Homeobox 2 (OTX2) Mutation in a Patient With Combined Pituitary Hormone Deficiency, Pituitary Malformation, and Retinitis Pigmentosa.

Heterozygous mutations of orthodenticle homeobox 2 (OTX2)can result in ocular malformations, pituitary abnormalities, or hypopituitarism spanning from isolated growth hormone (GH) deficiency to combined pituitary hormone deficiency. We present a patient exhibiting growth and pubertal disturbances, developmental delay, and pigmentary retinopathy. Further examination revealed deficiencies in GH following clonidine stimulation, hypogonadism, and, subsequently, central hypothyroidism. Brain magnetic resonance imaging uncovered hypoplasia of the pituitary and an ectopic pituitary tissue. Sequence analysis of OTX2 identified a novel heterozygous mutation c.555_556dup, p.(Ser186Ilefs*21), indicative of a frameshift mutation. Replacement therapy with recombinant human GH, testosterone enanthate, and levothyroxine was started. Notably, GH therapy resulted in significant catch-up growth. This case report contributes to our comprehension of the molecular and clinical findings, particularly highlighting endocrine manifestations and a rare ophthalmologic manifestation associated with mutations in the OTX2 gene.

GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

A serious and unusual presentation of congenital isolated ACTH deficiency due to TBX19 mutation, beyond the neonatal period.

Summary: Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency due to T-box transcription factor-19 (TBX19 mutation) (MIM 201400; ORPHA 199296) usually presents in the neonatal period with severe hypoglycemia, seizures, and sometimes prolonged cholestatic jaundice. We report a case with an unusual presentation that delayed the diagnosis. A 9-month-old female patient with no relevant personal history was admitted to the emergency department due to a hypoglycemic seizure in the context of acute gastroenteritis. There was rapid recovery after glucose administration. At age 4, she presented with tonic-clonic seizures, fever, and gastrointestinal symptoms and came to need support in an intensive care unit. Low serum cortisol was documented and hydrocortisone was initiated. After normalization of inflammatory parameters, the patient was discharged with hydrocortisone. The genetic investigation was requested and compound heterozygous mutations in TBX19 were detected. This is a rare case of presentation of TBX19 mutation outside the neonatal period and in the setting of acute disease, which presented a diagnostic challenge. Learning points: Congenital isolated adrenocorticotrophic hormone deficiency due to TBX19 mutation usually presents with neonatal hypoglycemia and prolonged cholestatic jaundice. An uneventful neonatal period, however, does not exclude the diagnosis as the disease may be asymptomatic at this stage. In the context of idiopathic hypoglycemia, even in the context of acute disease, hypocortisolism must always be excluded. Genetic evaluation should be performed in cases of congenital central hypocortisolism to allow proper counselling.

Turner syndrome and neurofibromatosis type 1: the unusual combination of two common genetic disorders.

Summary: The coexistence of neurofibromatosis type 1 (NFT1) and Turner syndrome (TS) has only been reported in a few patients and may represent a diagnostic challenge. We describe the case of a 16-year-old girl, with a prior clinical diagnosis of NFT1, who was referred to Endocrinology appointments for the etiological study of primary amenorrhea. Evaluation of the anterior pituitary function was requested and hypergonadotropic hypogonadism was detected. During the etiological study, a 45X karyotype was found and TS was diagnosed. The fact that NFT1 can also be associated with short stature, short broad neck and hypertelorism was likely responsible for TS being diagnosed in late adolescence. As both TS and NFT1 are relatively common genetic disorders, it is important to be alert to the possibility that the presence of one disease does not invalidate the other. Learning points: The concomitant presence of two syndromes in the same patient is unlikely and represents a diagnostic challenge. Some phenotypic characteristics and clinical manifestations may be shared by several syndromes. Some syndromes, such as neurofibromatosis type 1 may have very heterogeneous presentations. It is important to be alert to the characteristics that are not explained by the initial diagnosis. If such features are present, diagnostic work-up must be performed regardless of the initial syndromic diagnosis.

The Mysterious Universe of the TSH Receptor.

The thyroid-stimulating hormone receptor (TSH-R) is predominantly expressed in the basolateral membrane of thyrocytes, where it stimulates almost every aspect of their metabolism. Several extrathyroidal locations of the receptor have been found including: the pituitary, the hypothalamus, and other areas of the central nervous system; the periorbital tissue; the skin; the kidney; the adrenal; the liver; the immune system cells; blood cells and vascular tissues; the adipose tissue; the cardiac and skeletal muscles, and the bone. Although the functionality of the receptor has been demonstrated in most of these tissues, its physiological importance is still a matter of debate. A contribution to several pathological processes is evident in some cases, as is the case of Grave's disease in its multiple presentations. Conversely, in the context of other thyroid abnormalities, the contribution of the TSH-R and its ligand is still a matter of debate. This article reviews the several different sites of expression of the TSH-R and its potential role in both physiological and pathological processes.

Complexation of 5-Fluorouracil with ß-Cyclodextrin and Sodium Dodecyl Sulfate: A Useful Tool for Encapsulating and Removing This Polluting Drug.

The formation of complexes of the drug 5-fluorouracil (5-FU) with ß-cyclodextrin (ß-CD) and sodium dodecyl sulphate (SDS) was studied through experimental measurements of the ternary mutual diffusion coefficients (D11, D22, D12, and D21) for the systems {5-FU (component 1) + ß-CD (component 2) + water} and {5-FU (component 1) + SDS (component 2) + water} at 298.15 K and at concentrations up to 0.05 mol dm-3 by using the Taylor dispersion method, with the objective of removing this polluting drug from the residual systems in which it was present. The results found showed that a coupled diffusion of 5-FU occurred with both ß-CD and SDS, as indicated by the nonzero values of the cross-diffusion coefficients, D12 and D21, as a consequence of the complex formation between 5-FU and the ß-CD or SDS species. That is, 5-FU was solubilized (encapsulated) by both carriers, although to a greater extent with SDS (K = 20.0 (±0.5) mol-1 dm3) than with ß-CD (K = 10.0 (±0.5) mol-1 dm3). Values of 0.107 and 0.190 were determined for the maximum fraction of 5-FU solubilized with ß-CD and SDS (at concentrations above its CMC), respectively. This meant that SDS was more efficient at encapsulating and thus removing the 5-FU drug.

Hypoglycemia unawareness in type 1 diabetes patients using intermittent continuous glucose monitoring: Identification of risk factors and glycemic patterns.

BACKGROUND: Hypoglycemia unawareness designates failure to detect eminent hypoglycemia. Clarke's questionnaire is one of the most used systems to evaluate this problem. AIMS: To relate Clarke's questionnaire (QQ) results with continuous glucose monitoring data. METHODS: Application of the questionnaire in a sample of type 1 diabetes mellitus (T1DM) patients using intermittent continuous glucose monitoring (iCGM). RESULTS: 111 T1DM patients were evaluated, 56.8% female, mean age 35.0 ± 12.4 years and mean disease duration 18.8 ± 10.5 years. According to CQ, 13.5% had unawareness, 76.6% awareness and 9.9% indeterminate awareness to hypoglycemia. Those with unawareness had longer disease duration (25.1 ± 10.4 vs 18.2 ± 10.3 for awareness and 14.9 ± 9.9 for indeterminate awareness, p = 0.047), more time below range (10.3 ± 4.9% vs 6.3 ± 5.1 and 6.3 ± 4.8; p = 0.009) and higher mean duration of hypoglycemia (131.7 ± 38.6 vs 116.6 ± 49.6 and 131.7 ± 38.6; p = 0.008). In multivariate analysis, mean duration of hypoglycemia was an independent predictor of CQ results. In a receiver operating curve (AUC 0.746; p = 0.004) a mean duration of hypoglycemia ≥106.5 min showed 84.6% sensitivity/64.4% specificity for unawareness. CONCLUSIONS: Our sample had a significative prevalence of hypoglycemia unawareness which increased with longer diabetes duration. iCGM data can be indicative of this problem, with a mean hypoglycemia duration ≥106.5 min being suggestive, albeit unspecific.

Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription.

Caffeine is the most widely consumed psychoactive substance in the world. Strikingly, the molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus at the epigenomic, proteomic, and metabolomic levels. Caffeine lowered metabolism-related processes (e.g., at the level of metabolomics and gene expression) in bulk tissue, while it induced neuron-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through fine-tuning of metabolic genes, while boosting the salience of information processing during learning in neuronal circuits.