Irreversible atrophy in memory brain regions over 7 years is predicted by glycemic control in type 2 diabetes without mild cognitive impairment.

Memory-related impairments in type 2 diabetes may be mediated by insulin resistance and hyperglycemia. Previous cross-sectional studies have controversially suggested a relationship between metabolic control and a decrease in hippocampal volumes, but only longitudinal studies can test this hypothesis directly. We performed a longitudinal morphometric study to provide a direct test of a possible role of higher levels of glycated hemoglobin with long term brain structural integrity in key regions of the memory system - hippocampus, parahippocampal gyrus and fusiform gyrus. Grey matter volume was measured at two different times - baseline and after ~7 years. We found an association between higher initial levels of HbA1C and grey matter volume loss in all three core memory regions, even in the absence of mild cognitive impairment. Importantly, these neural effects persisted in spite of the fact that patients had significantly improved their glycemic control. This suggests that early high levels of HbA1c might be irreversibly associated with subsequent long-term atrophy in the medial temporal cortex and that early intensive management is critical.

Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes.

Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1.

New Perspectives on Circulating Ferritin: Its Role in Health and Disease.

The diagnosis of iron disturbances usually includes the evaluation of serum parameters. Serum iron is assumed to be entirely bound to transferrin, and transferrin saturation-the ratio between the serum iron concentration and serum transferrin-usually reflects iron availability. Additionally, serum ferritin is commonly used as a surrogate of tissue iron levels. Low serum ferritin values are interpreted as a sign of iron deficiency, and high values are the main indicator of pathological iron overload. However, in situations of inflammation, serum ferritin levels may be very high, independently of tissue iron levels. This presents a particularly puzzling challenge for the clinician evaluating the overall iron status of the patient in the presence of an inflammatory condition. The increase in serum ferritin during inflammation is one of the enigmas regarding iron metabolism. Neither the origin, the mechanism of release, nor the effects of serum ferritin are known. The use of serum ferritin as a biomarker of disease has been rising, and it has become increasingly diverse, but whether or not it contributes to controlling the disease or host pathology, and how it would do it, are important, open questions. These will be discussed here, where we spotlight circulating ferritin and revise the recent clinical and preclinical data regarding its role in health and disease.

The longitudinal impact of type 2 diabetes on brain gyrification.

Type 2 diabetes has an effect on brain structure, including cortical gyrification. The significance of these changes is better understood if assessed over time. However, there is a lack of studies assessing longitudinally the effect of this disease with complex aethology in gyrification. While changes in this feature have been associated mainly with genetic legacy, our study allowed to shed light on the effect of the variation of glycaemic profile over time in gyrification in this metabolic disease. In this longitudinal study, we analysed brain anatomical magnetic resonance images of 15 participants with type 2 diabetes and 13 healthy control participants to investigate the impact of this metabolic disease on the gyrification index over a 7-year period. We observed a significant interaction between time and group in six regions, four of which (left precentral gyrus, left gyrus rectus, left subcentral gyrus and sulci and right inferior temporal gyrus) showed an increase in gyrification in type 2 diabetes and a decrease in the control group and the two others (left pericallosal sulcus and right inferior frontal sulcus) the opposite pattern. The variation of the gyrification was correlated with the variation of the glycaemic profile. Following the interaction, the simple main effect of time in each group separately has shown that in the group with diabetes, there were more regions susceptible to alterations of gyrification. In sum, our results raise credit for the possibility that glycaemic control also might influence gyrification in type 2 diabetes.

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.

The hemodynamic response function as a type 2 diabetes biomarker: a data-driven approach.

Introduction: There is a need to better understand the neurophysiological changes associated with early brain dysfunction in Type 2 diabetes mellitus (T2DM) before vascular or structural lesions. Our aim was to use a novel unbiased data-driven approach to detect and characterize hemodynamic response function (HRF) alterations in T2DM patients, focusing on their potential as biomarkers. Methods: We meshed task-based event-related (visual speed discrimination) functional magnetic resonance imaging with DL to show, from an unbiased perspective, that T2DM patients' blood-oxygen-level dependent response is altered. Relevance analysis determined which brain regions were more important for discrimination. We combined explainability with deconvolution generalized linear model to provide a more accurate picture of the nature of the neural changes. Results: The proposed approach to discriminate T2DM patients achieved up to 95% accuracy. Higher performance was achieved at higher stimulus (speed) contrast, showing a direct relationship with stimulus properties, and in the hemispherically dominant left visual hemifield, demonstrating biological interpretability. Differences are explained by physiological asymmetries in cortical spatial processing (right hemisphere dominance) and larger neural signal-to-noise ratios related to stimulus contrast. Relevance analysis revealed the most important regions for discrimination, such as extrastriate visual cortex, parietal cortex, and insula. These are disease/task related, providing additional evidence for pathophysiological significance. Our data-driven design allowed us to compute the unbiased HRF without assumptions. Conclusion: We can accurately differentiate T2DM patients using a data-driven classification of the HRF. HRF differences hold promise as biomarkers and could contribute to a deeper understanding of neurophysiological changes associated with T2DM.

Changes in hemodynamic response function components reveal specific changes in neurovascular coupling in type 2 diabetes.

Type 2 Diabetes Mellitus (T2DM) is a metabolic disease that leads to multiple vascular complications with concomitant changes in human neurophysiology, which may lead to long-term cognitive impairment, and dementia. Early impairments of neurovascular coupling can be studied using event-related functional magnetic resonance imaging (fMRI) designs. Here, we aimed to characterize the changes in the hemodynamic response function (HRF) in T2DM to probe components from the initial dip to late undershoot. We investigated whether the HRF morphology is altered throughout the brain in T2DM, by extracting several parameters of the fMRI response profiles in 141 participants (64 patients with T2DM and 77 healthy controls) performing a visual motion discrimination task. Overall, the patients revealed significantly different HRFs, which extended to all brain regions, suggesting that this is a general phenomenon. The HRF in T2DM was found to be more sluggish, with a higher peak latency and lower peak amplitude, relative slope to peak, and area under the curve. It also showed a pronounced initial dip, suggesting that the initial avidity for oxygen is not compensated for, and an absent or less prominent but longer undershoot. Most HRF parameters showed a higher dispersion and variability in T2DM. In sum, we provide a definite demonstration of an impaired hemodynamic response function in the early stages of T2DM, following a previous suggestion of impaired neurovascular coupling. The quantitative demonstration of a significantly altered HRF morphology in separate response phases suggests an alteration of distinct physiological mechanisms related to neurovascular coupling, which should be considered in the future to potentially halt the deterioration of the brain function in T2DM.

A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy.

SUMMARY: Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1-34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability. LEARNING POINTS: Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1. Teriparatide (recombinant human parathyroid hormone 1-34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

A novel morphometric signature of brain alterations in type 2 diabetes: Patterns of changed cortical gyrification.

Type 2 diabetes is a chronic disease that creates atrophic signatures in the brain, including decreases of total and regional volume of grey matter, white matter and cortical thickness. However, there is a lack of studies assessing cortical gyrification in type 2 diabetes. Changes in this emerging feature have been associated mainly with genetic legacy, but environmental factors may also play a role. Here, we investigated alterations of the gyrification index and classical morphometric measures in type 2 diabetes, a late acquired disease with complex aetiology with both underlying genetic and more preponderant environmental factors. In this cross-sectional study, we analysed brain anatomical magnetic resonance images of 86 participants with type 2 diabetes and 40 healthy control participants, to investigate structural alterations in type 2 diabetes, including whole-brain volumetric measures, local alterations of grey matter volume, cortical thickness and the gyrification index. We found concordant significant decrements in total and regional grey matter volume, and cortical thickness. Surprisingly, the cortical gyrification index was found to be mainly increased and mainly located in cortical sensory areas in type 2 diabetes. Moreover, alterations in gyrification correlated with clinical data, suggesting an influence of metabolic profile in alterations of gyrification in type 2 diabetes. Further studies should address causal influences of genetic and/or environmental factors in patterns of cortical gyrification in type 2 diabetes.

Familial neurohypophyseal diabetes insipidus: clinical, genetic and functional studies of novel mutations in the arginine vasopressin gene.

PURPOSE: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder characterized by childhood-onset progressive polyuria and polydipsia due to mutations in the arginine vasopressin (AVP) gene. The aim of the study was to describe the clinical and molecular characteristics of families with neurohypophyseal diabetes insipidus. METHODS: Five Portuguese families with autosomal dominant FNDI underwent sequencing of the AVP gene and the identified mutations were functionally characterized by in vitro studies. RESULTS: Three novel and two recurrent heterozygous mutations were identified in the AVP gene. These consisted of one initiation codon mutation in the signal peptide coding region (c.2T > C, p.Met1?), three missense mutations in the neurophysin II (NPII) coding region (c.154T > C, p.Cys52Arg; c.289C > G, p.Arg97Gly; and c.293G > C, p.Cys98Ser), and one nonsense mutation in the NPII coding region (c.343G > T, p.Glu115Ter). In vitro transfection of neuronal cells with expression vectors containing each mutation showed that the mutations resulted in intracellular retention of the vasopressin prohormone. Patients showed progressive symptoms of polyuria and polydipsia, but with wide variability in severity and age at onset. No clear genotype-phenotype correlation was observed. CONCLUSION: The intracellular accumulation of mutant vasopressin precursors supports the role of cellular toxicity of the mutant proteins in the etiology of the disorder and explains the progressive onset of the disorder. These findings further expand the AVP mutational spectrum in FNDI and contribute to the understanding of the molecular pathogenic mechanisms involved in FNDI.

DesHospitaliza: plano de gestão para alta responsável de pacientes idosos com doenças crônicas / Dishospitalizes: management plan for senior care of elderly patients with chronic diseases

Introdução: O Brasil está passando pelo envelhecimento demográfico mais rápido do mundo. No Brasil o segmento populacional que mais aumenta é o de idosos, com taxas de crescimento acima de 4% ao ano no período de 2012 a 2022. As consequências desse crescimento são o aumento das demandas assistenciais, previdenciárias, econômica, familiares e de saúde para atender esse segmento. Além disso, os sistemas de atenção à saúde são fragmentados, atuam de forma isolada, sem uma comunicação entre os pontos de cuidado, ou seja, a atenção primária à saúde não se comunica fluidamente com a atenção secundária à saúde e esses dois também não se comunicam com a atenção terciária, nem com os sistemas de apoio. Nesse contexto, e pensando na contribuição para a melhoria da assistência prestada ao paciente idoso portador de doença crônica, emerge a questão norteadora: na elaboração de um plano de gestão para alta responsável, que categorias deverão ser contempladas para atender o idoso de forma integral e integrada durante a internação e alta hospitalar, com vistas a continuidade do cuidado pela Atenção Primária à Saúde (APS)? Objetivos: O principal foi elaborar o plano de gestão para alta responsável de pacientes idosos com doenças crônicas como estratégia para a transição segura do cuidado e sua continuidade na APS. Os objetivos específicos foram: Identificar as categorias fundamentais que devem compor o plano de gestão para alta responsável e validar as categorias e orientações a serem apresentados no Deshospitaliza- Plano de Gestão para Alta Responsável. Método: Trata-se de um estudo descritivo exploratório com abordagem qualitativa e quantitativo, com uso da técnica de grupo focal (segunda etapa do estudo) e método Delphi (etapa de validação do plano de alta). Resultados: A partir dos resultados obtidos com o grupo focal foram identificadas as seguintes categorias: acolhimento e porta de entrada; planejamento para alta responsável; atenção centrada na pessoa e educação em saúde e, posteriormente, obteve a validação da mesmas (IVC=0,97 e coeficiente de kappa=0,87), bem como das orientações presentes no plano de gestão para alta responsável de pacientes idoso com doenças crônicas. Conclusão: A produção técnica desta pesquisa caracteriza-se como uma tecnologia leve dura que se propõem a operar no processo de trabalho em saúde, pensando num cuidado integral, considerando o conjunto de necessidades e riscos do usuário, com articulação pactuada entre profissionais de diferentes setores do hospital ou pontos de atenção à saúde. Tem alto impacto social por ser um documento norteador para os hospitais federais no Rio de Janeiro, podendo ser referência para demais unidades hospitalares estaduais e nacionais

Introduction: Brazil is experiencing the fastest demographic aging in the world. In Brazil, the population segment that most increases is the elderly, with growth rates above 4% per year in the period from 2012 to 2022. The consequences of this growth are the increase in assistance, social security, economic, family and health demands to serve this segment . In addition, health care systems are fragmented, acting in isolation, without communication between the points of care, that is, primary health care does not communicate fluently with secondary health care and these two do not communicate either. communicate with tertiary care or support systems. In this context, and considering the contribution to the improvement of the care provided to elderly patients with chronic illness, the guiding question emerges: in the elaboration of a management plan for senior managers, which categories should be considered to fully assist the elderly and integrated during hospitalization and hospital discharge, with a view to the continuity of care through Primary Health Care (PHC)? Objectives: main The was and laboring the management plan for the igh responsible of elderly patients with chronic diseases like and stratégia for safe transition of care and continuity in the APS. The objectives specific were: Identify the key categories that should be included in the management plan for the igh responsible e v Alidar categories and guidelines to be presented at Deshospitaliza- Management Plan for the igh responsible. Method: This is a descriptive exploratory study with a qualitative and quantitative approach, using the focus group technique (second stage of the study) and the Delphi method (stage of validation of the discharge plan). Results: Based on the results obtained with the focus group, the following categories were identified: reception and entrance door; planning for senior management; person-centered attention and health education and subsequently obtained their validation (CVI = 0.97 and kappa coefficient = 0.87), as well as the guidelines in the management plan for responsible discharge of elderly patients with diseases chronic. Conclusion: This is a tough lightweight technology that purport to operate r n health work process, thinking n integral care, considering the set of user needs and risks, with the agreed coordination between professionals from different sectors hospital or health care points. It has a high social impact as it is a guiding document for federal hospitals in Rio de Janeiro, and can be a reference for other state and national hospital units.

The neurometabolic profiles of GABA and Glutamate as revealed by proton magnetic resonance spectroscopy in type 1 and type 2 diabetes.

Glucose metabolism is pivotal for energy and neurotransmitter synthesis and homeostasis, particularly in Glutamate and GABA systems. In turn, the stringent control of inhibitory/excitatory tonus is known to be relevant in neuropsychiatric conditions. Glutamatergic neurotransmission dominates excitatory synaptic functions and is involved in plasticity and excitotoxicity. GABAergic neurochemistry underlies inhibition and predicts impaired psychophysical function in diabetes. It has also been associated with cognitive decline in people with diabetes. Still, the relation between metabolic homeostasis and neurotransmission remains elusive. Two 3T proton MR spectroscopy studies were independently conducted in the occipital cortex to provide insight into inhibitory/excitatory homeostasis (GABA/Glutamate) and to evaluate the impact of chronic metabolic control on the levels and regulation (as assessed by regression slopes) of the two main neurotransmitters of the CNS in type 2 diabetes (T2DM) and type 1 diabetes (T1DM). Compared to controls, participants with T2DM showed significantly lower Glutamate, and also GABA. Nevertheless, higher levels of GABA/Glx (Glutamate+Glutamine), and lower levels of Glutamate were associated with poor metabolic control in participants with T2DM. Importantly, the relationship between GABA/Glx and HbA1c found in T2DM supports a relationship between inhibitory/excitatory balance and metabolic control. Interestingly, this neurometabolic profile was undetected in T1DM. In this condition we found strong evidence for alterations in MRS surrogate measures of neuroinflammation (myo-Inositol), positively related to chronic metabolic control. Our results suggest a role for Glutamate as a global marker of T2DM and a sensitive marker of glycemic status. GABA/Glx may provide a signature of cortical metabolic state in poorly controlled patients as assessed by HbA1c levels, which indicate long-term blood Glucose control. These findings are consistent with an interplay between abnormal neurotransmission and metabolic control in particular in type 2 diabetes thereby revealing dissimilar contributions to the pathophysiology of neural dysfunction in both types of diabetes.

Corticotroph adenoma and pituitary fungal infection: a rare association.

SUMMARY: Pituitary infections, particularly with fungus, are rare disorders that usually occur in immunocompromised patients. Cushing's syndrome predisposes patients to infectious diseases due to their immunosuppression status. We report the case of a 55-year-old woman, working as a poultry farmer, who developed intense headache, palpebral ptosis, anisocoria, prostration and psychomotor agitation 9 months after initial diabetes mellitus diagnosis. Cranioencephalic CT scan showed a pituitary lesion with bleeding, suggesting pituitary apoplexy. Patient underwent transsphenoidal surgery and the neuropathologic study indicated a corticotroph adenoma with apoplexy and fungal infection. Patient had no preoperative Cushing's syndrome diagnosis. She was evaluated by a multidisciplinary team who decided not to administer anti-fungal treatment. The reported case shows a rare association between a corticotroph adenoma and a pituitary fungal infection. The possible contributing factors were hypercortisolism, uncontrolled diabetes and professional activity. Transsphenoidal surgery is advocated in these infections; however, anti-fungal therapy is still controversial. LEARNING POINTS: Pituitary infections are rare disorders caused by bacterial, viral, fungal and parasitic infections. Pituitary fungal infections usually occur in immunocompromised patients. Cushing's syndrome, as immunosuppression factor, predisposes patients to infectious diseases, including fungal infections. Diagnosis of pituitary fungal infection is often achieved during histopathological investigation. Treatment with systemic anti-fungal drugs is controversial. Endocrine evaluation is recommended at the time of initial presentation of pituitary manifestations.

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations.

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

Challenging diagnosis of resistance to thyroid hormone in a patient with pituitary adenoma.

The elevation of thyroid hormone with a normal or elevated thyroid-stimulation hormone (TSH) occurs uncommonly. This set a diagnosis challenge between TSH-secreting pituitary adenoma and resistance to thyroid hormone (RTH). We report a case of a young female patient with palpitations, with elevated thyroid hormone and non-suppressed TSH. TSH receptor antibody was undetectable. Thyroid ultrasound revealed mild heterogeneous goitre, and MRI revealed a microadenoma with 7.5 mm length in pituitary's left lobe. Pituitary hormones were within normal ranges. The thyrotropin-releasing hormone stimulation test showed normal TSH elevation, consistent with RTH. The genetic test revealed a mutation in heterozygosity in THRB gene (G344R) confirming RTH-beta. No pituitary surgery or thyroidectomy was performed nor were prescribed any antithyroid drugs. Inappropriate secretion of TSH requires a high level of clinical suspicion and the proper laboratory, genetic and radiological studies to conduct a correct diagnosis and prevent unnecessary and potential harmful therapies.

Interleukin-6 Producing Pheochromocytoma: A Rare Cause of Systemic Inflammatory Response Syndrome.

Systemic inflammatory response syndrome (SIRS) can be a rare manifestation of pheochromocytoma, since this adrenal tumor may produce cytokines and other hormones or neuropeptides besides catecholamines. We report the case of a 53-year-old female patient with a pheochromocytoma that presented with fever and weight loss of 5% in one month along with normocytic anemia, thrombocytosis, leukocytosis, and elevated C-reactive protein. In this setting, interleukin-6 (IL-6) was requested and was elevated [26.7ng/L (<7.0)]. She also presented biochemical evidence of ACTH-independent cortisol production without overt Cushing syndrome. After adrenalectomy, the inflammatory syndrome resolved and all biochemical parameters normalized, including IL-6 and ACTH. To our knowledge, this is the first case report of IL6-producing pheochromocytoma along with autonomous cortisol production.

Bifocal germinoma in a patient with 16p11.2 microdeletion syndrome.

Intracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background. Learning points: Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism. The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation. Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology. 16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders. Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion. Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.

[The Impact of Prolonged Use of Continuous Subcutaneous Insulin Infusion in the Control of Type-1 Diabetes]. / Impacto do Uso Prolongado da Terapêutica Subcutânea Contínua com Insulina no Controlo da Diabetes Mellitus Tipo 1.

INTRODUCTION: The use of continuous subcutaneous insulin infusion therapy in type 1 diabetes mellitus has increased due to its benefits on glycemic control and on the lifestyle flexibility. The aim of this study was to assess the impact of continuous subcutaneous insulin infusion therapy on glycemic control, body mass index, total daily dose of insulin and complications associated with this therapy, during 20 years of experience in Centro Hospitalar e Universitário de Coimbra. MATERIAL AND METHODS: This retrospective study included patients with type 1 diabetes mellitus who started continuous subcutaneous insulin infusion therapy up until 2005, followed at Centro Hospitalar e Universitário de Coimbra. Glycated hemoglobin A1c, body mass index, total daily dose of insulin and acute complications associated with continuous subcutaneous insulin infusion therapy were evaluated immediately prior to initiation of continuous subcutaneous insulin infusion therapy with follow-up at six months, one year, five, 10, 15 and 20 years. The frequency of acute complications associated with this type of therapy was also evaluated. RESULTS: This study included 20 patients (seven males, 13 females) with mean disease duration up to the start of continuous subcutaneous insulin infusion therapy of 16.1 ± 7.9 years, mean age of onset of continuous subcutaneous insulin infusion therapy of 31.1 ± 8.4 years and follow-up during 13.2 ± 2.3 years. The reasons for initiating pump therapy were: inadequate metabolic control in 15 patients, history of asymptomatic or severe hypoglycemia in four patients, and pregnancy/pregnancy planning in one patient. The previous median of glycated hemoglobin A1c was 9.3% (6.5 - 16.0) and, at six months, decreased to the minimum value of 7.2% (5.3 - 9.8); p < 0.0125. The reduction of glycated hemoglobin A1c remained statistically significant in the first 10 years of follow-up. There was a statistically significant difference in the body mass index variation at 10 years with continuous subcutaneous insulin infusion therapy compared to previous body mass index; 24.7 kg/m2 (18.9 - 31.8) vs 25,5 kg/m2 (18.9 - 38.9), p <0.0125. Daily insulin requirements were reduced from 56.5 U (32.0 - 94.0) to 43.8 U (33.0 - 64.0) (p < 0.0125) at six months and no statistical differences were found in the remaining follow-up. There were two severe episodes of hypoglycemia (incidence 0.0095/patient/year), five episodes of diabetic ketoacidosis (0.0238/patient/year) and no infections at the site of catheter insertion. DISCUSSION: This study shows that continuous subcutaneous insulin infusion therapy improved glycemic control, especially during the first 10 years of follow-up and allowed a significant decrease in total daily dose of insulin in the first six months. The rate of acute complications was low. CONCLUSION: Treatment with continuous subcutaneous insulin infusion therapy seems effective in achieving metabolic control in selected patients with type 1 diabetes mellitus.

Introdução: O uso da terapêutica com perfusão subcutânea contínua de insulina na diabetes mellitus tipo 1 é cada vez mais frequente devido aos seus efeitos benéficos no controlo glicémico e na flexibilidade do estilo de vida. Constituiu objetivo deste estudo avaliar o impacto da terapêutica com perfusão subcutânea contínua de insulina no controlo glicémico, índice de massa corporal, dose diária total de insulina e complicações desta modalidade terapêutica durante vinte anos de experiência no Centro Hospitalar e Universitário de Coimbra. Material e Métodos: Estudo retrospetivo que inclui doentes com diabetes mellitus tipo 1 seguidos no Centro Hospitalar e Universitário de Coimbra, que iniciaram terapêutica com perfusão subcutânea contínua de insulina até 2005 e com pelo menos 10 anos de tratamento com terapêutica com perfusão subcutânea contínua de insulina. Avaliou-se a hemoglobina glicada A1c, o índice de massa corporal e a dose diária total de insulina imediatamente antes e seis meses, um ano, cinco, 10, 15 e 20 anos após terapêutica com perfusão subcutânea contínua de insulina a partir dos registos médicos. Avaliou-se ainda a frequência de complicações agudas associadas a este tipo de terapêutica. Resultados: Obtiveram-se dados de 20 doentes (sete homens; 13 mulheres) com duração média de doença até início da terapêutica com perfusão subcutânea contínua de insulina de 16,1 ± 7,9 anos, idade média de início de terapêutica com perfusão subcutânea contínua de insulina de 31,1 ± 8,4 anos e seguimento durante 13,2 ± 2,3 anos. As indicações para colocação de bomba foram: inadequado controlo metabólico em 15 doentes, história de hipoglicemias assintomáticas ou severas em quatro doentes, e gravidez/planeamento de gravidez em um doente. A mediana de hemoglobina glicada A1c prévia foi 9,3% (6,5 - 16,0) tendo diminuído aos seis meses para o valor mínimo de 7,2% (5,3 - 9,8); p < 0,0125. A redução da hemoglobina glicada A1c manteve-se estatisticamente significativa nos primeiros 10 anos de seguimento. Verificou-se uma diferença estatisticamente significativa na variação do índice de massa corporal após 10 anos de seguimento comparativamente com o valor prévio à terapêutica com perfusão subcutânea contínua de insulina; 24,7kg/m2 (18,9 - 31,8) vs 25,5 kg/m2 (18,9 - 38,9), p < 0,0125. As necessidades diárias de insulina foram reduzidas de 56,5 U (32,0 - 94,0) para 43,8 U (33,0 - 64,0) (p < 0,0125) nos primeiros seis meses e não se encontraram diferenças estatísticas no restante seguimento relativamente às necessidades prévias à terapêutica com perfusão subcutânea contínua de insulina. Verificaram-se duas hipoglicemias severas (incidência 0,0095/doente/ano), cinco cetoacidoses diabéticas (0,0238/doente/ano) e nenhuma infeção no local de inserção do cateter. Discussão: Este estudo demonstrou a eficácia da terapêutica com perfusão subcutânea contínua de insulina, que está associada a uma diminuição significativa da hemoglobina glicada A1c sustentada durante 10 anos e a uma redução da dose diária total de insulina, significativa nos primeiros seis meses. A taxa de complicações agudas foi baixa. Conclusão: A evidência sugere que a terapêutica com perfusão subcutânea contínua de insulina é efetivamente vantajosa no controlo metabólico em doentes com diabetes mellitus tipo 1 selecionados.

Early visual cortical structural changes in diabetic patients without diabetic retinopathy.

BACKGROUND: It is known that diabetic patients have changes in cortical morphometry as compared to controls, but it remains to be clarified whether the visual cortex is a disease target, even when diabetes complications such as retinopathy are absent. Therefore, we compared type 2 diabetes patients without diabetic retinopathy with control subjects using magnetic resonance imaging to assess visual cortical changes when retinal damage is not yet present. METHODS: We performed T1-weighted imaging in 24 type 2 diabetes patients without diabetic retinopathy and 27 age- and gender-matched controls to compare gray matter changes in the occipital cortex between groups using voxel based morphometry. RESULTS: Patients without diabetic retinopathy showed reduced gray matter volume in the occipital lobe when compared with controls. CONCLUSIONS: Reduced gray matter volume in the occipital cortex was found in diabetic patients without retinal damage. We conclude that cortical early visual processing regions may be affected in diabetic patients even before retinal damage occurs.

Diabetic brain or retina? Visual psychophysical performance in diabetic patients in relation to GABA levels in occipital cortex.

Visual impairment is one of the most feared complications of Type 2 Diabetes Mellitus. Here, we aimed to investigate the role of occipital cortex γ-aminobutyric acid (GABA) as a predictor of visual performance in type 2 diabetes. 18 type 2 diabetes patients were included in a longitudinal prospective one-year study, as well as 22 healthy age-matched controls. We collected demographic data, HbA1C and used a novel set of visual psychophysical tests addressing color, achromatic luminance and speed discrimination in both groups. Psychophysical tests underwent dimension reduction with principle component analysis into three synthetic variables: speed, achromatic luminance and color discrimination. A MEGA-PRESS magnetic resonance brain spectroscopy sequence was used to measure occipital GABA levels in the type 2 diabetes group. Retinopathy grading and retinal microaneurysms counting were performed in the type 2 diabetes group for single-armed correlations. Speed discrimination thresholds were significantly higher in the type 2 diabetes group in both visits; mean difference (95% confidence interval), [0.86 (0.32-1.40) in the first visit, 0.74 (0.04-1.44) in the second visit]. GABA from the occipital cortex predicted speed and achromatic luminance discrimination thresholds within the same visit (r = 0.54 and 0.52; p = 0.02 and 0.03, respectively) in type 2 diabetes group. GABA from the occipital cortex also predicted speed discrimination thresholds one year later (r = 0.52; p = 0.03) in the type 2 diabetes group. Our results suggest that speed discrimination is impaired in type 2 diabetes and that occipital cortical GABA is a novel predictor of visual psychophysical performance independently from retinopathy grade, metabolic control or disease duration in the early stages of the disease.