Distinct and Additive Effects of Alcohol and Thiamine Deficiency in the Developing Brain: Relevance to Fetal Alcohol Spectrum Disorder

Background: Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are linked to brain insulin resistance and oxidative stress. However, the role of thiamine deficiency as a distinct or additive factor in the pathogenesis of the neurodevelopmental and metabolic derangements in FASD has not been determined. Methods: Control and ethanol-exposed human PNET2 cerebellar neuronal cells and rat cerebellar slice cultures were treated with vehicle or pyrithiamine (Pyr) to assess independent and additive effects of thiamine deficiency on ethanol-mediated neurotoxicity, mitochondrial dysfunction, insulin resistance, inhibition of neuronal and glial genes, and oxidative stress. Results: Pyr treatments (0 - 200 µM) caused dose-dependent cell loss (Crystal Violet assay) and reduced mitochondrial function (MTT assay) in PNET2 neuronal cultures. Ethanol alone (100 mM) significantly reduced PNET2 neuronal viability, MTT activity, and ATP production. Over the broad dose range of Pyr treatment, ethanol significantly reduced ATP content and cell number and increased mitochondrial mass (MitoTracker Green). Ex vivo cerebellar slice culture studies revealed ethanol-induced developmental architectural disruption that was substantially worsened by Pyr. The adverse effects of ethanol were linked to increased lipid peroxidation and inhibition of asparatyl-asparaginyl-β-hydroxylase (ASPH) expression. The independent and additive effects of Pyr were associated with increased cytotoxicity, lipid peroxidation, Caspase 3 activation, and Tau accumulation. Conclusions: During development, alcohol exposure and thiamine deficiency exert distinct but overlapping molecular pathologies that ultimately impair the structure and function of cerebellar neurons. While both insults drive cell loss and mitochondrial dysfunction with increased lipid peroxidation, ethanol’s additional inhibitory effects on ASPH reflect impairments in insulin and IGF signaling. In contrast, Pyr’s main adverse effects were likely due to neurotoxicity and the activation of apoptosis cascades. The findings suggest that FASD severity may be reduced by thiamine supplementation, but without additional support for insulin/IGF signaling networks, FASD would not be prevented.

Progressive changes in platelet counts and Fib-4 scores precede the diagnosis of advanced fibrosis in NASH patients

BACKGROUND Cirrhosis and its complications develop in a subgroup of patients with nonalcoholic fatty liver disease(NASH).Early detection of liver fibrosis represents an important goal of clinical care.AIM To test the hypothesis that the development of cirrhosis in nonalcoholic fatty liver disease patients is preceded by the long-term trends of platelet counts and Fib-4 scores.METHODS We identified all patients in our healthcare system who had undergone fibrosis staging by liver biopsy or magnetic resonance elastography(MRE)for nonalcoholic fatty liver disease during the past decade(n=310).Platelet counts,serum glutamic-pyruvic transaminase and serum glutamic oxalacetic transaminase values preceding the staging tests were extracted from the electronic medical record system,and Fib-4 scores were calculated.Potential predictors of advanced fibrosis were evaluated using multivariate regression analysis.RESULTS Significant decreases in platelet counts and increases in Fib-4 scores were observed in all fibrosis stages,particularly in patients with cirrhosis.In the liver biopsy group,the presence of cirrhosis was best predicted by the combination of the Fib-4 score at the time closest to staging(P<0.0001),the presence of diabetes(P=0.0001),and the correlation coefficient of the preceding timedependent drop in platelet count(P=0.044).In the MRE group,Fib4 score(P=0.0025)and platelet drop(P=0.0373)were significant predictors.In comparison,the time-dependent rise of the Fib-4 score did not contribute in a statistically significant way.CONCLUSION Time-dependent changes in platelet counts and Fib-4 scores contribute to the prediction of cirrhosis in NASH patients with biopsy-or MRE-staged fibrosis.Their incorporation into predictive algorithms may assist in the earlier identification of high-risk patients.

Neurotrophins differentially stimulate the growth of cochlear neurites on collagen surfaces and in gels

The electrodes of a cochlear implant are located far from the surviving neurons of the spiral ganglion, which results in decreased precision of neural activation compared to the normal ear. If the neurons could be induced to extend neurites toward the implant, it might be possible to stimulate more discrete subpopulations of neurons, and to increase the resolution of the device. However, a major barrier to neurite growth toward a cochlear implant is the fluid filling the scala tympani, which separates the neurons from the electrodes. The goal of this study was to evaluate the growth of cochlear neurites in three-dimensional extracellular matrix molecule gels, and to increase biocompatibility by using fibroblasts stably transfected to produce neurotrophin-3 and brain-derived neurotrophic factor. Spiral ganglion explants from neonatal rats were evaluated in cultures. They were exposed to soluble neurotrophins, cells transfected to secrete neurotrophins, and/or collagen gels. We found that cochlear neurites grew readily on collagen surfaces and in three-dimensional collagen gels. Co-culture with cells producing neurotrophin-3 resulted in increased numbers of neurites, and neurites that were longer than when explants were cultured with control fibroblasts stably transfected with green fluorescent protein. Brain-derived neurotrophic factor-producing cells resulted in a more dramatic increase in the number of neurites, but there was no significant effect on neurite length. It is suggested that extracellular matrix molecule gels and cells transfected to produce neurotrophins offer an opportunity to attract spiral ganglion neurites toward a cochlear implant.

Presenting clinical features of patients with vitreoretinal lymphoma

AIM: To assess the presenting clinical features, time from presentation to diagnosis and association with central nervous system(CNS) lymphoma in patients with vitreoretinal lymphoma.METHODS: Retrospective case series of patients diagnosed with vitreoretinal lymphoma between 2009 and 2011 at a single center.RESULTS: Fifteen eyes in 9 patients were included. Common presenting ocular symptoms included blurred vision(78%) and worsening floaters(44%) with an average symptom duration prior to presentation of 88.4 d(range 7-365 d). Common ophthalmic exam findings were vitreous haze(89%) and subretinal lesions(56%). The average time from presentation to diagnosis was 56.3 d(range 16-180 d). All patients were diagnosedwith large B-cell lymphoma according to pathology results. Lymphoma was restricted to the eye in 33%, while 67% of patients had CNS involvement. Of the patients with secondary vitreoretinal lymphoma, 67% initially presented with CNS lymphoma while 33% initially presented with vitreoretinal lymphoma. Of the patients with CNS involvement, memory loss(67%) was the most common presenting symptom.CONCLUSION: Vitreoretinal lymphoma most commonly presents with symptoms of blurred vision and/or worsening floaters and vitreous haze on exam. The average time from presentation to diagnosis may be decreasing with increased awareness among clinicians.

节律控制房颤随访调查(AFFIRM)研究中心脏复律后房颤复发的预测因素

Background: The early recurrence of atrial fibrillation(AF)after cardioversion and the need for frequent cardioversions to maintain sinus rhythm are important clinical features of AF management. Methods: We evaluated patients in the AFFIRM study whose qualifying episode of AF lasted >48 hours and was terminated by cardioversion. Clinical, electrocardiographic, and echocardiographic risk factors associated with AF recurrence within 2 months of cardioversion and ≥ 2 cardioversions during the first year were identified using multivariate analysis in 1293 eligible patients. Results: The risk factors for the recurrence of AF within 2 months of cardioversion were no coronary artery disease and an electrocardiographic lead II P- wave duration of >135 milliseconds. In the subset of patients not taking antiarrhythmic drug therapy, the multivariate risk factors were no coronary artery disease, second or greater episode of AF, left ventricular ejection fraction< 0.50, and mitral valve thickening. Significant risk factors for the need for>2 cardioversions in the first year in patients taking antiarrhythmic medication were left atrial diameter >4.5 cm and mitral valve thickening. The overall sensitivity and specificity of these parameters for recurrence and repeated cardioversion are low. Conclusion: There are several risk factors for difficulty maintaining sinus rhythm after cardioversion of persistent AF. The clinical predictive value of these factors is low, and they probably should not be used to justify withholding rhythm control efforts in patients who might benefit from sinus rhythm.

Effects of noise on fishes: What we can learn from humans and birds

In this paper we describe the masking of pure tones in humans and birds by manmade noises and show that similar ideas can be applied when considering the potential effects of noise on fishes,as well as other aquatic vertebrates.Results from many studies on humans and birds,both in the field and in the laboratory,show that published critical ratios can be used to predict the masked thresholds for pure tones when maskers consist of complex manmade and natural noises.We argue from these data that a single,simple measure,the species critical ratio,can be used to estimate the effect of manmade environmental noises on the perception of communication and other biologically relevant sounds.We also reason that if this principle holds for species as diverse as humans and birds,it probably also applies for all other vertebrates,including fishes.