Glucose and lipopolysaccharide regulate proatherogenic cytokine release from mononuclear cells in polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) have chronic low-grade inflammation, which can increase the risk of atherogenesis. We examined the effect of glucose ingestion and lipopolysaccharide (LPS) on markers of proatherogenic inflammation in the mononuclear cells (MNC) and plasma of women with PCOS. Sixteen women with PCOS (8 lean, 8 obese) and 15 weight-matched controls (8 lean, 7 obese) underwent a 3-h oral glucose tolerance test (OGTT). Interleukin-6 (IL-6) and interleukin-1β (IL-1β) release from MNC cultured in the presence of LPS and plasma IL-6, C-reactive protein (CRP), and soluble vascular adhesion molecule-1 (sVCAM-1) were measured from blood samples drawn while fasting and 2 h after glucose ingestion. Truncal fat was measured by dual-energy absorptiometry (DEXA). Lean women with PCOS and obese controls failed to suppress LPS-stimulated IL-6 and IL-1β release from MNC after glucose ingestion. In contrast, obese women with PCOS suppressed these MNC-derived cytokines under the same conditions. In response to glucose ingestion, plasma IL-6 and sVCAM-1 increased and CRP suppression was attenuated in both PCOS groups and obese controls compared with lean controls. Fasting plasma IL-6 and CRP correlated positively with percentage of truncal fat. The absolute change in plasma IL-6 correlated positively with testosterone. We conclude that glucose ingestion promotes proatherogenic inflammation in PCOS with a systemic response that is independent of obesity. Based on the suppressed MNC-derived cytokine responses suggestive of LPS tolerance, chronic low-grade inflammation may be more profound in obese women with PCOS. Excess abdominal adiposity and hyperandrogenism may contribute to atherogenesis in PCOS

Molecular biomarkers of neuronal injury in epilepsy shared with neurodegenerative diseases

In neurodegenerative diseases, changes in neuronal proteins in the cerebrospinal fluid and blood are viewed as potential biomarkers of the primary pathology in the central nervous system (CNS). Recent reports suggest, however, that level of neuronal proteins in fluids also alters in several types of epilepsy in various age groups, including children. With increasing evidence supporting clinical and sub-clinical seizures in Alzheimer's disease, Lewy body dementia, Parkinson's disease, and in other less common neurodegenerative conditions, these findings call into question the specificity of neuronal protein response to neurodegenerative process and urge analysis of the effects of concomitant epilepsy and other comorbidities. In this article, we revisit the evidence for alterations in neuronal proteins in the blood and cerebrospinal fluid associated with epilepsy with and without neurodegenerative diseases. We discuss shared and distinctive characteristics of changes in neuronal markers, review their neurobiological mechanisms, and consider the emerging opportunities and challenges for their future research and diagnostic use

Improved Lentiviral Transduction of ALS Motoneurons <i>in Vivo</i> via Dual Targeting

Treatment of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, is hampered by its complex etiology and lack of efficient means for targeted transfer of therapeutics into motoneurons. The objective of this research was engineering of a versatile motoneuron targeting adaptera full-length atoxic tetanus toxin fused to core-streptavidin (CS-TeTIM)for retro-axonal transduction of viral vectors; validation of the targeting efficiency of CS-TeTIM <i>in vivo</i>, by expression of green fluorescence protein (GFP) reporter in motoneurons of presymptomatic and symptomatic ALS-like SOD1^G93A mice, and comparison with age-matched controls; and appraisal of lentiviral transduction with CS-TeTIM relative to (1) a H_C binding fragment of tetanus toxin CS-TeTx­(H_C), (2) rabies glycoprotein (RG), and (3) a CS-TeTIM-RG dual targeting approach. CS-TeTIM and CS-TeTx­(H_C) were engineered using recombinant technology and site-directed mutagenesis. Biotinylated vectors, pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G) or RG, were linked to these adaptors and injected intraperitoneally (ip) into presymptomatic (12 weeks old), symptomatic SOD1^G93A (22 weeks old) or wild type control mice, followed by monitoring of GFP expression in the spinal cord and supraspinal motor structures with quantitative PCR and immuno-histochemistry. Transcripts were detected in the spinal cord and supraspinal motor structures of all mice 2 weeks after receiving a single ip injection, although in symptomatic SOD1^G93A animals reporter RNA levels were lower compared to presymptomatic and wild-type controls irrespective of the targeting approach. GFP transduction with CS-TeTIM proved more efficient than CS-TeTx­(H_C) across all groups while CS-TeTIM-RG dual-targeted vectors yielded the highest transcript numbers. Importantly, in both wild-type and presymptomatic SOD1^G93A mice strong colabeling of choline-acetyltransferase (ChAT) and GFP was visualized in neurons of the brain stem and spinal cord. CS-TeTIM, a versatile adaptor protein for targeted lentiviral transduction of motoneurons, has been engineered and its competence assessed relative to CS-TeTx­(H_C) and RG. Evidence has been provided that highlights the potential usefulness of this novel recombinant tool for basic research with implications for improved transfer of therapeutic candidates into motoneurons for the amelioration of ALS and related diseases

Spatial and Spectral Mapping and Decomposition of Neural Dynamics and Organization of the Mouse Brain with Multispectral Optoacoustic Tomography

Summary: In traditional optical imaging, limited light penetration constrains high-resolution interrogation to tissue surfaces. Optoacoustic imaging combines the superb contrast of optical imaging with deep penetration of ultrasound, enabling a range of new applications. We used multispectral optoacoustic tomography (MSOT) for functional and structural neuroimaging in mice at resolution, depth, and specificity unattainable by other neuroimaging modalities. Based on multispectral readouts, we computed hemoglobin gradient and oxygen saturation changes related to processing of somatosensory signals in different structures along the entire subcortical-cortical axis. Using temporal correlation analysis and seed-based maps, we reveal the connectivity between cortical, thalamic, and sub-thalamic formations. With the same modality, high-resolution structural tomography of intact mouse brain was achieved based on endogenous contrasts, demonstrating near-perfect matches with anatomical features revealed by histology. These results extend the limits of noninvasive observations beyond the reach of standard high-resolution neuroimaging, verifying the suitability of MSOT for small-animal studies. : Olefir et al. apply multispectral optoacoustic (photoacoustic) tomography (MSOT) for noninvasive spatial and spectral mapping and decomposition of neural dynamics and organization of the intact mouse brain in vivo. The results extend the boundaries of noninvasive high-resolution observations beyond the reach of intravital optical neuroimaging in small-animal studies. Keywords: photoacoustic imaging, hemodynamic response, whole-brain tomography, near-infrared neuroimaging, label-free interrogation, temporal coherenc

A Defined Heteromeric KV1 Channel Stabilizes the Intrinsic Pacemaking and Regulates the Efferent Code of Deep Cerebellar Nuclear Neurons to Thalamic Targets

The output of the cerebellum to the motor axis of the central nervous system is orchestrated mainly by synaptic inputs and intrinsic pacemaker activity of deep cerebellar nuclear (DCN) projection neurons. Herein, we demonstrate that the soma of these cells is enriched with KV1 channels produced by mandatory multi-merization of KV1.1, 1.2 α and KV β2 subunits. Being constitutively active, the K+ current (IKV1) mediated by these channels stabilizes the rate and regulates the temporal precision of self-sustained firing of these neurons. Placed strategically, IKV1 provides a powerful counter-balance to prolonged depolarizing inputs, attenuates the rebound excitation, and dampens the membrane potential bi-stability. Somatic location with low activation threshold render IKV1 instrumental in voltage-dependent de-coupling of the axon initial segment from the cell body of projection neurons, impeding invasion of backpropagating initial segment action potentials into the somato-dendr itic compartment. The latter also promotes the dominance of clock like somatic pace-making in driving the regenerative firing activity of these neurons, to encode time variant inputs with high fidelity. Through the use of multi-compartmental modeling and retro-axonal labeling, the physiological significance of the described functions for processing and communication of information from the lateral DCN to thalamic relay nuclei is establishedPeer reviewedFinal Accepted Versio

A Polymorphism, R653Q, in the Trifunctional Enzyme Methylenetetrahydrofolate Dehydrogenase/Methenyltetrahydrofolate Cyclohydrolase/Formyltetrahydrofolate Synthetase Is a Maternal Genetic Risk Factor for Neural Tube Defects: Report of the Birth Defects Research Group

Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C→T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate–dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 “Q” allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16–1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival