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.

Emerging drugs for Cushing's disease.

INTRODUCTION: Considering the effects of uncontrolled hypercortisolism on morbidity and mortality, there is a clear need for effective medical therapy for patients with Cushing's disease (CD). Therefore, the search for new medical effective tools remains active, and already promising results have been obtained. AREAS COVERED: The importance of the design and conduct of trials to validate old drugs or to test new compounds is discussed. The results of the ongoing clinical trials, targeting the specific properties of drugs, such as ketoconazole, LCI699, mifepristone, etomidate and pasireotide, are also reported. The authors also emphasise the advantages and drawbacks of each particular drug, and the potential combined use of agents with complementary mechanisms of action. EXPERT OPINION: CD is an excellent example of a situation where effective therapy is essential, but where the balance of risk and benefit must be carefully judged. Metyrapone is the drug of choice when rapid control of the hypercortisolaemia is required, ketoconazole represents a good second-line drug, although in the future LCI699 may be a better alternative. Mifepristone can also be used in the rare situation when previous drugs are inappropriate. Etomidate is useful where immediate parenteral action is required. For drugs working directly on the pituitary, cabergoline is occasionally effective and pasireotide can be attempted in patients with mild CD.

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.

Adrenocortical carcinoma: Retrospective analysis of the last 22 years.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The clinical experience acquired, even from a small number of cases, has improved understanding of this condition. The purpose of this study is to characterize patients with ACC followed up at a Portuguese reference center over the past 22 years. METHODS: Retrospective analysis of clinical records of patients with histopathological diagnosis of ACC followed up from 1992 to 2014. RESULTS: The study sample consisted of 22 patients, 20 of them female. Eleven patients were in stage II, four in stage III, and five in stage IV; 13 patients had functioning lesions. Adrenalectomy was performed in 20 patients, with complete tumor resection in 90% of the cases. During follow-up, eight patients experienced recurrence of local disease, and 12 distant metastases. Fourteen patients received mitotane, 35.7% (n=5) as adjuvant therapy and 64.3% (n=9) after recurrence; therapeutic plasma mitotane levels were achieved in 70% of patients. Stage III patients who received adjuvant therapy had longer survival time (13.5 vs. 2.5 months). Two patients were given chemotherapy associated to mitotane. Median survival was 11 months (0-257 months); it was slightly longer in younger patients or patients with non-functioning tumors. Six patients are still alive, four of them with no evidence of disease. CONCLUSION: Despite the overall poor prognosis, some patients with ACC may have a long survival time. Although complete tumor removal remains the only potentially curative treatment, diagnosis at a younger age, presence of non-functioning tumors, and mitotane treatment also seemed to be associated to longer survival in our patients.

Long-term survival in a patient with brain metastases of papillary thyroid carcinoma.

We present the case of a 43-year-old woman who underwent total thyroidectomy with bilateral lymphadenectomy for a papillary thyroid carcinoma (PTC), solid variant (T4bN1bMx), with V600E BRAF mutation. After ablative therapy, she presented undetectable thyroglobulin (Tg) but progressively increasing anti-Tg antibodies (TgAbs). During follow-up, nodal, lung and brain metastases were identified. She was submitted to surgical excision of lung lesions, radiosurgery of brain metastases and five radioiodine treatments. The latest brain MRI showed no lesions, pulmonary CT showed stable micronodules and there was progressive reduction in TgAbs. This is a peculiar case of a PTC with lung and brain metastatic lesions detected through TgAbs. Initial histological and molecular study suggested a more aggressive clinical behaviour, which was eventually confirmed. Although PTC brain metastases are extremely rare and present poor prognosis, our patient presented a good response to treatment and longer survival than usually reported for similar cases.

Relations between Cardiac and Visual Phenotypes in Diabetes: A Multivariate Approach.

Cardiovascular disease and diabetes represent a major public health concern. The former is the most frequent cause of death and disability in patients with type 2 diabetes, where left ventricular dysfunction is highly prevalent. Moreover, diabetic retinopathy is becoming a dominant cause of visual impairment and blindness. The complex relation between cardiovascular disease and diabetic retinopathy as a function of ageing, obesity and hypertension remains to be clarified. Here, we investigated such relations in patients with diabetes type 2, in subjects with neither overt heart disease nor advanced proliferative diabetic retinopathy. We studied 47 patients and 50 controls, aged between 45 and 65 years, equally distributed according to gender. From the 36 measures regarding visual structure and function, and the 11 measures concerning left ventricle function, we performed data reduction to obtain eight new derived variables, seven of which related to the eye, adjusted for age, gender, body mass index and high blood pressure using both discriminant analysis (DA) and logistic regression (LR). We found moderate to strong correlation between left ventricle function and the eye constructs: minimum correlation was found for psychophysical motion thresholds (DA: 0.734; LR: 0.666), while the maximum correlation was achieved with structural volume density in the neural retina (DA: 0.786; LR: 0.788). Controlling the effect of pairwise correlated visual constructs, the parameters that were most correlated to left ventricle function were volume density in retina and thickness of the retinal nerve fiber layers (adjusted multiple R2 is 0.819 and 0.730 for DA and LR), with additional contribution of psychophysical loss in achromatic contrast discrimination. We conclude that visual structural and functional changes in type 2 diabetes are related to heart dysfunction, when the effects of clinical, demographic and associated risk factors are taken into account, revealing a genuine relation between cardiac and retinal diabetic phenotypes.

[Relation between metformin treatment and the development of hyperlactacidemia at the emergency room]. / Relação entre o Tratamento com Metformina e o Desenvolvimento de Hiperlactacidemia no Serviço de Urgência.

INTRODUCTION: In type 2 diabetic patients treated with metformin the development of hyperlactacidemia or even lactic acidosis seems to result from an acute precipitating event. This study aims to assess the prevalence and relative risk of hyperlactacidemia in diabetic patients admitted in the Emergency Room, the predictive factors for high lactate concentration and the influence of hyperlactacidemia in patients' prognosis. MATERIAL AND METHODS: Transversal observational study including patients observed between June and October 2012: 138 type 2 diabetics, 66 treated with metformin, and 83 non-diabetic patients. Studies' variables: age, sex, cause of admition, blood pressure, drugs, personal history, analytical study (biochemistry and arterial blood gas analyses with lactate) and destination. Statistical analysis was performed using SPSS 21.0(®). RESULTS: Mean lactate concentration and hyperlactacidemia prevalence were significantly higher in diabetic patients (2.1 ± 0.1 mmol/L vs 1.1 ± 0.1 mmol/L, p < 0.001 and 39.1% vs 3.6%, p < 0.001, respectively) and in those under metformin compared to other diabetics (2.7 ± 0.2 mmol/L vs 1.6 ± 0.1 mmol/L, p < 0.001 and 56.9% vs 23.3%, p < 0.001, respectively). Diabetics on metformin presented a 25-fold increased risk of hyperlactacidemia (OR = 25.10, p < 0.05). Creatinine was the only independent predictive factor for lactate concentrations (B = 1.33, p < 0.05). Patients with hyperlactacidemia had 4.4 times higher odds of being hospitalized or dying (OR = 4.37, p < 0.05). When hospitalized, they had longer hospitalization periods (21.66 ± 5.86 days vs 13.68 ± 5.33 days, p < 0.001) and higher rate of deaths (12.5% (n = 4) vs 4.3% (n = 2), p < 0.05). CONCLUSION: There was an increased risk of hyperlactacidemia in patients with type 2 diabetes, particularly for those under metformin. Serum creatinine represented the only independent associated factor of lactate concentration. The presence of hyperlactacidemia was associated with worse prognosis.

Introdução: Em diabéticos tipo 2 sob metformina o desenvolvimento de hiperlactacidemia ou mesmo acidose láctica parece decorrer de um evento precipitante agudo. Este estudo objetiva avaliar a prevalência e risco relativo de hiperlactacidemia em diabéticos observados no Serviço de Urgência, os fatores preditores da concentração de lactatos e a influência da lactacidémia no prognóstico.Material e Métodos: Estudo observacional transversal incluindo 138 diabéticos tipo 2, dos quais 66 sob metformina, e 83 doentes não diabéticos atendidos entre junho e outubro de 2012. Variáveis estudadas: idade, sexo, motivo de urgência, pressão arterial, hábitos farmacológicos, antecedentes, estudo analítico (bioquímica e gasometria arterial com doseamento de lactatos) e destino após observação. Análise estatística realizada com SPSS 21.0®.Resultados: A concentração de lactatos e proporção de hiperlactacidemia foram significativamente superiores nos diabéticos (2,1 ± 0,1 mmol/L vs. 1,1 ± 0,1mmol/L, p < 0,001 e 39,1% vs. 3,6%, p < 0,001, respetivamente); particularmente naqueles sob metformina comparativamente aos restantes diabéticos (2,7 ± 0,2 mmol/L vs. 1,6 ± 0,1 mmol/L, p < 0,001 e 56,9 % vs. 23,3 %, p < 0,001, respetivamente). Os diabéticos sob metformina contabilizaram uma probabilidade de hiperlactacidemia 25x superior (OR = 25,10, p < 0,05). A creatinina representou o único fator preditor independente da lactacidemia (B = 1,33; p < 0,05). Os doentes com hiperlactacidemia apresentaram probabilidade 4,4x superior de serem internados ou falecerem (OR = 4,37, p < 0,05). E, quando internados, contabilizaram tempo de internamento (21,66 ± 5,86 dias vs 13,68 ± 5,33dias, p < 0,001) e número de óbitos superiores (12,5% (n = 4) vs 4,3% (n = 2), p < 0,05).Conclusões: Demonstrou-se um risco acrescido de hiperlactacidemia em diabéticos tipo 2, particularmente naqueles sob metformina. A creatinina sérica representou o único fator preditor independente da concentração de lactatos. A presença de hiperlactacidemia condicionou um pior prognóstico.