PARKIN overexpression in human mesenchymal stromal cells from Wharton's jelly suppresses 6-hydroxydopamine-induced apoptosis: Potential therapeutic strategy in Parkinson's disease.

BACKGROUND AIMS: Stem cell transplantation is an excellent option for regenerative or replacement therapy. However, deleterious microenvironmental and endogenous factors (e.g., oxidative stress) compromise ongoing graft survival and longevity. Therefore, (transient or stable) genetically modified cells may be reasonably thought to resist oxidative stress-induced damage. Genetic engineering of mesenchymal stromal cells (MSCs) obtained from Wharton's jelly tissue may offer some therapeutic potential. PARKIN is a multifunctional ubiquitin ligase able to protect dopaminergic cells against stress-related signaling. We, therefore, evaluated the effect of the neurotoxicant 6-hydroxydopamine (6-OHDA) on regulated cell death signaling in MSCs and investigated whether overexpression of PARKIN in MSCs was capable of modulating the effect of 6-OHDA. METHODS: We transiently transfected Wharton's jelly-derived MSCs with an mCherry-PARKIN vector using the Lipofectamine LTX method. Naïve MSCs and MSCs overexpressing PARKIN were exposed to increasing concentrations of 6-OHDA. We used light and fluorescence microscopy, flow cytometry, immunocytochemistry staining, in-cell Western and Western blot analysis. RESULTS: After 12-24 h of 6-OHDA exposure, we detected dichlorofluorescein (DCF)-positive cells (80%) indicative of reactive oxygen species (H2O2) production, reduced cell viability (40-50%), decreased mitochondrial membrane potential (ΔΨm, ~35-45%), DNA fragmentation (18-30%), and G1-arrested cell cycle in the MSCs. 6-OHDA exposure increased the expression of the transcription factor c-JUN, increased the expression of the mitochondria maintenance Phosphatase and tensin homologue-induced putative kinase 1 (PINK1) protein and increased the expression of pro-apoptotic PUMA, caspase-3 and apoptosis-inducing factor (AIF). 6-OHDA exposure also significantly augmented the oxidation of the oxidative stress sensor, DJ-1. Overexpression of PARKIN in MSCs not only significantly reduced the expression of cell death and oxidative stress markers but also significantly reduced DCF-positive cells (~50% reduction). DISCUSSION: 6-OHDA induced apoptosis in MSCs via generation of H2O2, activation of c-JUN and PUMA, mitochondrial depolarization and nuclei fragmentation. Our findings suggest that PARKIN protects MSCs against 6-OHDA toxicity by partly interacting with H2O2, reducing the expression of c-JUN, PUMA, AIF and caspase-3, and maintaining the mitochondrial ΔΨm.

Diagnóstico de síndrome de Brugada tras inyección subaracnoidea de prilocaína / Diagnosis of Brugada's syndrome after subarachnoid injection of prilocaine

El síndrome de Brugada es una enfermedad genética de transmisión autosómica dominante, que afecta a los canales iónicos de sodio, y que se caracteriza por bloqueo de rama derecha del haz de His y elevación del ST en precordiales derechas, en un corazón estructuralmente normal, y que se asocia a muerte súbita. Esta enfermedad puede ser desenmascarada por ciertos fármacos y cambios súbitos en el tono autonómico. Los anestésicos locales pueden aumentar los cambios en el ECG, por ser bloqueantes de canales de sodio, dependiendo, sobre todo, de la dosis y del tipo de anestésico. Se han reportado casos de cambios electrocardiográficos compatibles con síndrome de Brugada, desencadenados tras perfusión epidural o paravertebral de bupivacaína y ropivacaína. Presentamos un caso de un varón de 66 años, programado para hernioplastia inguinal de manera ambulatoria. No tenía historia de síncope ni de arritmias. Tras la anestesia intradural con 40mg de prilocaína presentó elevación del ST>2mm y bloqueo de rama derecha del haz de His en V1-V3 (AU)

Brugada syndrome is an autosomal dominant genetic disease affecting sodium ion channels. It is characterised by right bundle branch block and ST elevation in the right precordial leads, and with no structural cardiac abnormalities. It is associated with sudden death. This disease may be unmasked by certain drugs and sudden changes in autonomic tone. Local anaesthetics may increase ECG changes due to a blockade of the sodium channels, mainly depending on the dose and the type of anaesthetic. Thus, there have been reported electrocardiographic changes consistent with Brugada syndrome, triggered after epidural or paravertebral infusion of bupivacaine and ropivacaine. The case is described of a 66 years old man, scheduled for inguinal herniorrhaphy as an outpatient. He had no history of syncope or arrhythmias. After spinal anaesthesia with 40mg of prilocaine the ECG showed ST elevation>2mm, and right bundle branch block in V1-V3 (AU)

Type 2M von Willebrand disease - more often misidentified than correctly identified.

INTRODUCTION: Appropriate diagnosis of von Willebrand disease (VWD), including differential identification of qualitative vs. quantitative von Willebrand factor (VWF) defects has important management implications, but remains problematic. AIM: The aim of the study was to assess whether 2M VWD, defining qualitative defects not associated with loss of high molecular weight (HMW) VWF, is often misidentified, given highly variable reported frequency ranging from 0 to ~60% of all type 2 VWD. METHODS: A comparative evaluation of laboratory ability to appropriately identify 2M VWD (n = 4) vs. HMW VWF reduction (n = 4), as sent to participants of an international external quality assessment programme. RESULTS: Laboratories had considerably greater difficulty identifying type 2M VWD, correctly identifying these on average only 29.4% of occasions, with the 70.6% error rate representing use of insufficient test panels (41.7%), misinterpretation of test results (10.0%) and analytical errors (13.3%). One type 2M case, giving a median of 49 U dL(-1) VWF:Ag, was more often misidentified as type 2A/2B VWD (46.7%) than 2M (34.8%). Another 2M case, giving a median of 189 U dL(-1) VWF:Ag, was instead often misidentified as being normal (non-VWD) (36.4%), with identifications of type 2A/2B VWD (13.6%) also represented. In comparison, errors in identification of HMW VWF reduced samples only averaged 11.5%, primarily driven by use of insufficient test panels (6.3%) or misinterpretation of results (4.2%) and infrequently analytical errors (1.0%). CONCLUSION: Type 2M VWD is more often misidentified (70.6%) than correctly identified as 2M VWD (29.4%), and potentially explaining the relative under-reported incidence of 2M VWD in the literature.

Diagnosis of Brugada's syndrome after subarachnoid injection of prilocaine. / Diagnóstico de síndrome de Brugada tras inyección subaracnoidea de prilocaína.

Brugada syndrome is an autosomal dominant genetic disease affecting sodium ion channels. It is characterised by right bundle branch block and ST elevation in the right precordial leads, and with no structural cardiac abnormalities. It is associated with sudden death. This disease may be unmasked by certain drugs and sudden changes in autonomic tone. Local anaesthetics may increase ECG changes due to a blockade of the sodium channels, mainly depending on the dose and the type of anaesthetic. Thus, there have been reported electrocardiographic changes consistent with Brugada syndrome, triggered after epidural or paravertebral infusion of bupivacaine and ropivacaine. The case is described of a 66 years old man, scheduled for inguinal herniorrhaphy as an outpatient. He had no history of syncope or arrhythmias. After spinal anaesthesia with 40mg of prilocaine the ECG showed ST elevation>2mm, and right bundle branch block in V1-V3.

Academic abilities and glycaemic control in children and young people with Type 1 diabetes mellitus.

AIMS: To determine if children and young people aged < 23 years with Type 1 diabetes differ in academic ability from age-matched control subjects without Type 1 diabetes and whether academic scores are related to glycaemic control. METHODS: Using a cross-sectional study design, we administered cognitive and academic tests (Woodcock-Johnson III Spatial Relations, General Information, Letter-Word Recognition, Calculation and Spelling tests) to young people with Type 1 diabetes (n=61) and control subjects (n=26) aged 9-22 years. The groups did not differ in age or gender. Participants with Type 1 diabetes had a disease duration of 5-17.7 years. History of glycaemic control (HbA1c , diabetic ketoacidosis and severe hypoglycaemic episodes) was obtained via medical records and interviews. RESULTS: The participants with Type 1 diabetes had a lower mean estimated verbal intelligence (IQ) level compared with those in the control group (P=0.04). Greater exposure to hyperglycaemia over time was associated with lower spelling abilities within the group with Type 1 diabetes (P=0.048), even after controlling for age, gender, socio-economic status, blood glucose level at time of testing and verbal IQ (P=0.01). History of severe hypoglycaemia or ketoacidosis was not associated with differences in academic abilities. CONCLUSIONS: In children and young people, Type 1 diabetes was associated with a lower verbal IQ. Moreover, increased exposure to hyperglycaemia was associated with lower spelling performance. These results imply that hyperglycaemia can affect cognitive function and/or learning processes that may affect academic achievement.

Coeliac disease presenting as severe hypoglycaemia in youth with type 1 diabetes.

BACKGROUND: Coeliac disease is an autoimmune disorder classically characterized by gastrointestinal symptoms and poor growth. The disease can be difficult to recognize in patients with Type 1 diabetes mellitus. Some clinicians find treatment of the disease in asymptomatic individuals controversial. CASE REPORTS: Two adolescent female patients with Type 1 diabetes experienced recurrent hypoglycaemic seizures. Neither patient reported gastrointestinal symptoms or poor growth. After diagnosis and treatment of coeliac disease, hypoglycaemia resolved. CONCLUSION: These cases illustrate how frequent unexplained severe hypoglycaemia can be an atypical presentation of coeliac disease in youth with Type 1 diabetes. Furthermore, they emphasize the importance of screening and treatment of coeliac disease in asymptomatic patients with Type 1 diabetes. Although controversial, management of coeliac disease in these asymptomatic patients can prevent the vicious cycle of recurrent hypoglycaemia and decrease risk for morbidity and death.

Hypoglycaemia-induced changes in regional brain volume and memory function.

BACKGROUND: Hypoglycaemic events can be a serious complication of insulin therapy in Type 1 diabetes mellitus. Severe hypoglycaemic exposure can lead to episodic memory impairments, including anterograde amnesia. However, relatively little is known regarding the long-term impact of severe hypoglycaemia on brain structure in Type 1 diabetes mellitus. The goals of the present study were to gain a greater understanding of the long-term effects of severe hypoglycaemia exposure on brain structure and the neural correlates of memory impairments in Type 1 diabetes mellitus. CASE REPORT: Regional grey and white matter volume and total white matter lesion volume were quantified in an individual with long-standing hypoglycaemia-induced anterograde amnesia and compared with age- and gender-matched healthy controls. Our patient has significant reductions in grey matter volume in the hippocampus, thalamus and pallidum, and significant reductions in white matter volume in the splenium, isthmus of the cingulate and cerebellum. He also has a significantly larger total white matter lesion volume than controls. CONCLUSION: This case study highlights the potential of hypoglycaemia for permanent deleterious effects on brain structure and memory function. Our results suggest that subcortical grey matter, periventricular white matter and posterior white matter may be most susceptible to injury from hypoglycaemia exposure, and that structural damage to the hippocampus and isthmus of the cingulate may play a central role in hypoglycaemia-induced memory impairments.

C-reactive protein, waist circumference, and family history of heart attack are independent predictors of body iron stores in apparently healthy premenopausal women.

Ferritin levels have been associated with metabolic syndrome and insulin resistance. The aim of the present study was to evaluate the prediction of ferritin levels by variables related to cardiometabolic disease risk in a multivariate analysis. For this aim, 123 healthy women (72 premenopausal and 51 posmenopausal) were recruited. Data were collected through procedures of anthropometric measurements, questionnaires for personal/familial antecedents, and dietary intake (24-h recall), and biochemical determinations (ferritin, C reactive protein (CRP), glucose, insulin, and lipid profile) in blood serum samples obtained. Multiple linear regression analysis was used and variables with no normal distribution were log-transformed for this analysis. In premenopausal women, a model to explain log-ferritin levels was found with log-CRP levels, heart attack familial history, and waist circumference as independent predictors. Ferritin behaves as other cardiovascular markers in terms of prediction of its levels by documented predictors of cardiometabolic disease and related disorders. This is the first report of a relationship between heart attack familial history and ferritin levels. Further research is required to evaluate the mechanism to explain the relationship of central body fat and heart attack familial history with body iron stores values.

A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Demencia semántica: descripción de un caso / Semantic dementia: a case report

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MRI in a patient with the Worster-Drought syndrome.

We describe a patient with the Worster-Drought syndrome (congenital suprabulbar paresis), thought to be a failure of development of the corticobulbar tracts. MRI showed bilateral perisylvian cortical dysplasia.

Diffusion-weighted MR imaging offers no advantage over routine noncontrast MR imaging in the detection of vertebral metastases.

BACKGROUND AND PURPOSE: Diffusion-weighted MR imaging of the spine has been used to differentiate benign from pathologic vertebral body compression fractures. We sought to determine the utility of diffusion-weighted MR imaging in the detection of vertebral metastases and to compare it with conventional noncontrast T1- and T2-weighted MR imaging. METHODS: Fifteen patients with metastases to the spine were studied using conventional MR imaging and diffusion-weighted imaging. Blinded review of all images was undertaken, and patients were categorized according to whether they had focal or multiple lesions. The signal intensity of the lesions was compared on T1-, T2- (fast spin-echo), and diffusion-weighted images. RESULTS: In five patients with focal disease, metastases were hypointense on T1-weighted images; hypointense (n = 2), isointense (n = 1), or hyperintense (n = 2) on T2-weighted images; and hypointense (n = 3) or hyperintense (n = 2) on diffusion-weighted images with respect to presumed normal bone marrow. In 10 patients with disease in multiple sites, all lesions were hypointense on T1-weighted images; hypointense (n = 2), isointense (n = 4), hyperintense (n = 2), or mixed (n = 2) on T2-weighted images; and hypointense (n = 5), hyperintense (n = 3), or mixed (n = 2) on diffusion-weighted images with respect to presumed normal bone marrow. CONCLUSION: As used in this study, diffusion-weighted MR imaging of the spine showed no advantage in the detection and characterization of vertebral metastases as compared with noncontrast T1-weighted imaging, but was considered superior to T2-weighted imaging.

Diffusion-weighted MR imaging of global cerebral anoxia.

BACKGROUND AND PURPOSE: Diffuse cerebral anoxia is a devastating event, and its acute findings, as revealed by conventional MR imaging and CT scanning, may be subtle. We analyzed diffusion-weighted and conventional MR images of patients with diffuse cerebral anoxia to determine their usefulness in establishing the diagnosis during the acute period and in determining the age of insult. METHODS: We reviewed 11 MR imaging studies of 10 patients who had experienced prolonged cardiac arrest. All of the patients underwent echo-planar diffusion-weighted imaging with low- and high-strength B values and multiplanar unenhanced MR imaging. We considered bright areas on the high-strength diffusion-weighted images to be abnormal when compared with low-strength images. Special attention was given to the cortex, basal ganglia, thalami, hippocampi, cerebellum, and white matter. Conventional MR studies also were reviewed, and abnormalities noted. The medical records of all of the patients were reviewed. RESULTS: Four patients who underwent imaging during the acute period (<24 hours) had bright basal ganglia (n = 2), bright cerebellum (n = 3), and bright cortex (n = 1) shown on their diffusion-weighted images. For these patients, conventional MR images showed questionable increased T2-weighted signal intensity in the basal ganglia (n = 1), and the results of two studies were judged to be normal. During the early subacute period (24 hours-13 days), four patients were studied, and were determined to have an abnormal cortex (n = 3) and basal ganglia (n = 2). For two of these patients, conventional MR images showed similar abnormalities, and the results of one study were normal. For two patients who underwent imaging during the late subacute period (14-20 days), diffusion-weighted images showed abnormalities mostly confined to white matter. Two patients who underwent imaging during the chronic phase (>21 days) had normal results of their diffusion-weighted imaging and one had evidence of laminar necrosis revealed by conventional MR imaging. CONCLUSION: During the acute period, high-strength diffusion-weighted images showed the abnormal basal ganglia, cerebellum, and cortex to a better extent than did conventional MR images. During the early subacute period, gray matter abnormalities were seen on diffusion-weighted images. During the late subacute period, diffusion-weighted images showed mostly white matter abnormalities. During the chronic stage, the results of diffusion-weighted imaging were normal. Our findings suggest that diffusion-weighted images are helpful for evaluating and dating diffuse cerebral anoxia, and therefore aid in the determination of prognosis and management of these patients.

Imaging features of intraventricular melanoma.

We present the MR imaging findings in a patient with symptoms of increased intracranial pressure and a mass in the left lateral ventricle. The mass showed increased signal intensity on T1-weighted images and low signal intensity on T2-weighted images. The histologic diagnosis was that of melanoma, and detailed physical and funduscopic examinations disclosed no evidence of a primary lesion. We believe that the mass was a primary intraventricular melanoma, possibly arising from the choroid plexus, and we discuss the mechanisms that may be responsible for its occurrence in this location.

Acute retroviruses and oncogenesis.

This review addresses the role of acute retroviruses in oncogenesis and the molecular mechanisms of viral carcinogenesis.