Preferential cholinergic excitation of corticopontine neurons

Abstract

Pyramidal neurons in layer 5 of the neocortex comprise two broad classes of projection neurons: corticofugal neurons, including corticopontine (CPn) neurons, and intratelencephalic neurons, including commissural/callosal (COM) neurons. These non-overlapping neuron subpopulations represent discrete cortical output channels contributing to perception, decision making, and behaviour. CPn and COM neurons have distinct morphological and physiological characteristics, and divergent responses to modulatory transmitters such as serotonin and acetylcholine (ACh). To better understand how ACh regulates cortical output, in slices of mouse prefrontal cortex (PFC) we compared the responsivity of CPn and COM neurons to transient exposure to exogenous or endogenous ACh. In both neuron subtypes, exogenous ACh generated qualitatively similar biphasic responses in which brief hyperpolarization was followed by longer-lasting enhancement of excitability. However, cholinergic inhibition was more pronounced in COM neurons, while excitatory responses were larger and longer lasting in CPn neurons. Similarly, optically triggered release of endogenous ACh from cholinergic terminals preferentially and persistently (for ∼40 s) enhanced the excitability of CPn neurons, but had little impact on COM neurons. Cholinergic excitation of CPn neurons involved at least three distinct ionic mechanisms: suppression of K_V7 channels (the "M-current"), activation of the calcium-dependent nonspecific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable nonspecific cation conductance. Our findings demonstrate projection-specific selectivity in cholinergic signalling in the PFC, and suggest that transient release of ACh during behaviour will preferentially promote corticofugal output.

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Why do African American have a higher risk for cerebral disease?

Abstract

Clinical and epidemiological studies have reported significant racial differences in cardiovascular (CVD) and metabolic disease including hypertension, stroke, atherosclerosis, and type II diabetes which is most prevalent in the African American population.

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Transcriptome Analyses of Mosaic (MSC) Mitochondrial Mutants of Cucumber in a Highly Inbred Nuclear Background

Cucumber (Cucumis sativus L.) has a large, paternally transmitted mitochondrial genome. Cucumber plants regenerated from cell cultures occasionally show paternally transmitted mosaic (MSC) phenotypes, characterized by slower growth, chlorotic patterns on the leaves and fruit, lower fertility, and rearrangements in their mitochondrial DNAs (mtDNAs). MSC lines 3, 12, and 16 originated from different cell cultures all established using the highly-inbred, wild-type line B. These MSC lines possess different rearrangements and under-represented regions in their mtDNAs. We completed RNA-seq on normalized and non-normalized cDNA libraries from MSC3, MSC12, and MSC16 to study their nuclear gene-expression profiles relative to inbred B. Results from both libraries indicated that gene expression in MSC12 and MSC16 were more similar to each other than MSC3. Forty one differentially expressed genes (DEGs) were up- and one down-regulated in the MSC lines relative to B. Gene functional classifications revealed that more than half of these DEGs are associated with stress-response pathways. Consistent with this observation, we detected elevated levels of hydrogen peroxide throughout leaf tissue in all MSC lines compared to wild-type line B. These results demonstrate that independently produced MSC lines with different mitochondrial polymorphisms show unique and shared nuclear responses. This study revealed genes associated with stress response that could become selection targets to develop cucumber cultivars with increased stress tolerance, and further support of cucumber as a model plant to study nuclear-mitochondrial interactions.

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Pediatric Nurse Practitioners' Perspectives on Health Care Transition From Pediatric to Adult Care

This study examined the perspectives of pediatric nurse practitioners (PNPs) regarding the needs of adolescents, parents/caregivers, clinicians, and institutions in the health care transition (HCT) process for adolescents/young adults.

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Upfront Alcian Blue-Periodic Acid Schiff Stain for the Assessment of Upper Gastrointestinal Disorders

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Upfront Alcian Blue-Periodic Acid Schiff Stain for the Assessment of Upper Gastrointestinal Disorders

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The Will-Burt Company celebrates 100th Anniversary

Will-Burt plans events throughout 2018 to honor our heritage and celebrate an exciting future.

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ZOLL first company to receive premarket approval from the FDA on its full portfolio of defibrillators

CHELMSFORD, Mass. — ZOLL® Medical Corporation, a manufacturer of medical devices and related software solutions, today announced that it is the first company to achieve premarket approval (PMA) by the U.S. Food and Drug Administration (FDA) to continue to market and distribute its full line of defibrillators in the U.S. The list of defibrillators that received PMA approval include the R Series® ...

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Impact of valve-less vs. standard insufflation on pneumoperitoneum volume, inflammation, and peritoneal physiology in a laparoscopic sigmoid resection experimental model

Abstract

Background

Standard insufflators compensate for intra-abdominal pressure variations with pressure spikes. Our aim was to evaluate the impact of a stable, low-pressure pneumoperitoneum induced by a valve-less insufflator, on working space, hemodynamics, inflammation, and peritoneal physiology, in a model of laparoscopic sigmoid resection.

Materials and methods

Twelve pigs (47 ± 3.3 kg) were equipped for invasive hemodynamic monitoring and randomly assigned to Standard (n = 6) vs. valve-less (n = 6) insufflation. Animals were positioned in a 30° Trendelenburg on a CT scan bed. A low-pressure pneumoperitoneum (8 mmHg) was started and duration was set for 180 min. Abdominal CT scans were performed, under neuromuscular blockade, before, immediately after, and 1 and 3 h after insufflation. Pneumoperitoneum volumes were calculated on 3D reconstructed CT scans. After creation of a mesenteric window, capillary blood was obtained by puncturing the sigmoid serosa and local lactatemia (mmol/L) was measured using a handheld analyzer. Surgical resection was performed according to the level of lactates, in order to standardize bowel stump perfusion. IL-1 and IL-6 (ng/mL) were measured repeatedly. The peritoneum was sampled close to the surgical site and distantly for the oxygraphic assessment of mitochondrial respiration. A pathologist applied a semi-quantitative score to evaluate the anastomosis.

Results

Mean arterial pressure, pulse, body temperature, oximetry, systemic lactatemia, and local lactates were similar. IL-6 was lower in the valve-less group, reaching a statistically significant difference after 3 h of insufflation (64.85 ± 32.5 vs. 133.95 ± 59.73; p = 0.038) and 48 h (77.53 ± 68.4 vs. 190.74 ± 140.79; p = 0.029). Peritoneal mitochondrial respiration was significantly increased after the survival period, with no difference among the groups. The anastomoses in the valve-less group demonstrated a lower acute (p = 0.04) inflammatory infiltration. The mean anterior posterior thickness was slightly, yet significantly higher in the valve-less group, on all post-insufflation CT scans.

Conclusions

Valve-less insufflation achieved a slightly higher working space and a lower systemic and localized inflammatory response in this experimental setting.

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The mitochondrial genome of red-necked phalarope Phalaropus lobatus (Charadriiformes: Scolopacidae) and phylogeny analysis among Scolopacidae

Abstract

The red-necked phalarope is a wonderful species with specific morphological characters and lifestyles. Mitochondrial genomes, encoding necessary proteins involved in the system of energy metabolism, are important for the evolution and adaption of species. In this study, we determined the complete mitogenome sequence of Phalaropus lobatus (Charadriiformes: Scolopacidae). The circular genome is 16714 bp in size, containing 13 PCGs, two ribosomal RNAs and 22 tRNAs and a high AT-rich control region. The AT skew and GC skew of major strand is positive and negative respectively. Most of PCGs are biased towards A-rich except ND1. A codon usage analysis shows that 3 start codons (ATG, GTG and ATA), 4 stop codons (TAA, TAG, AGG, AGA) and two incomplete terminate codons (T–). Twenty two transfer RNAs have the typical cloverleaf structure, and a total of ten base pairs are mismatched throughout the nine tRNA genes. The phylogenetic tree based on 13 PCGs and 2 rRNA genes indicates that monophyly of the family and genus Phalaropus is close to genus Xenus plus Tringa. The analysis of selective pressure shows 13 protein-coding genes are evolving under the purifying selection and P. lobatus is different from other Scolopacidae species on the selective pressure of gene ND4. This study helps us know the inherent mechanism of mitochondrial structure and natural selection.

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Differential expression of photosynthesis-related genes in pentaploid interspecific hybrid and its decaploid of Fragaria spp.

Abstract

Polyploidization always induces a series of changes in genome, transcriptome and epigenetics, of which changes in gene expression are the immediate causes of genotype alterations of polyploid plants. In our previous study on strawberry polyploidization, genes related to photosynthesis were found to undergo changes in gene expression and DNA methylation. Therefore, we chose 11 genes that were closely related to plant photosynthesis and analysed their expression during strawberry hybridization and chromosome doubling. Most genes of pentaploids showed expression levels between parents and were more similar to F. × ananassa. Gene expression levels of decaploids were higher than those of pentaploids and F. × ananassa. Different types of photosynthesis-related genes responded differently to hybridization and chromosome doubling. Chloroplast genes and regulatory genes showed complex responses. Structural genes of the photosynthetic system were expressed at a constant level and displayed a clear dosage effect. The methylation levels of one CG site on SIGE, which regulates expression of chloroplast genes, were negatively correlated with gene expression. In pentaploids and decaploids, more transcripts were from F. × ananassa than from F. viridis. The ratio of transcripts from from F. × ananassa to those from F. viridis was close to the ratio (4:1) of the genome of F. × ananassa to that of F. viridis in pentaploids and decaploids, but there were also some exceptions with obvious deviation.

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Changes in tissue and cerebral oxygenation following spinal anesthesia in infants: a prospective study

Abstract

Use of spinal anesthesia (SA) in children may address concerns about potential neurocognitive effects of general anesthesia. We used near-infrared spectroscopy (NIRS) to assess the effects of SA on cerebral and tissue oxygenation in 19 patients aged 7 ± 3 months. Prior to SA placement, NIRS monitors were placed on the forehead (cerebral) and the thigh (tissue). Intraoperative cerebral and tissue saturation were 73 ± 7 and 80 ± 11%, respectively, before SA placement. NIRS measurements were monitored every minute for 30 min after SA placement and modeled using mixed-effects linear regression. Regression estimates showed that cerebral saturation remained stable from 67% [95% confidence interval (CI) 63, 71%] after SA placement to 68% (95% CI 65, 72%) at the conclusion of monitoring. After SA placement, tissue saturation was elevated compared to baseline values; but further change [from 91% (95% CI 89, 93%) to 93% (95% CI 91, 95%) at the end of monitoring] was clinically non-significant. All patients breathed spontaneously on room air without changes in oxygen saturation. Blood pressure and heart rate decreased after SA placement, but no changes in hemodynamic parameters required treatment. These data provide further evidence of the neutral effect of SA on cerebral oxygenation 30 min after block placement.

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Oxidative stress impairs myocyte autophagy, resulting in myocyte hypertrophy

Abstract

Insufficient or excessive myocyte autophagy is associated with left ventricular (LV) hypertrophy. Reactive oxygen species mediate myocyte hypertrophy in vitro and pressure overload-induced LV hypertrophy in vivo. In the present study, we tested the hypothesis that oxidative stress induces autophagy impairment that results in myocyte hypertrophy. H9C2 cardiomyocytes were exposed to 10 and 50 μm hydrogen peroxide (H₂O₂) for 48 h pretreated with autophagy inhibitor 3-methyladenine (3-MA). Male Sprague-Dawley rats underwent abdominal aortic constriction (AAC) or sham operation. The animals were sacrificed at 24, 48 and 72 h after surgery. In a separate group, the AAC and sham-operated rats were randomly received antioxidant N-acetyl-cysteine (NAC) or superoxide dismutase mimic tempol for 72 h. In H9C2 cardiomyocytes, H₂O₂ decreased the LC3 II/I ratio and increased P62 and phosphorylated ERK (p-ERK) proteins and myocyte surface area. 3-MA further increased H₂O₂–induced p-ERK expression. In rats after AAC, the heart to body weight ratio was progressively increased, the LC3 II/I ratio was progressively decreased, p62 and p-ERK expression was increased, and Beclin1, Atg5 and Atg12 expression was decreased. NAC or tempol prevented the decreases in the LC3 II/I ratio and Beclin1 and Atg5 expression and attenuated the increases in LV wall thickness, myocyte diameter and brain natriuretic peptide expression in AAC rats. In conclusion, oxidative stress decreases Beclin1 and Atg5 expression that results in autophagy impairment, leading to myocyte hypertrophy. These findings suggest that antioxidants or restoration of autophagy may be of value in the prevention of early myocardial hypertrophy after pressure overload.

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Shank3-deficient thalamocortical neurons show HCN channelopathy and alterations in intrinsic electrical properties

Abstract

Shank3 is a scaffolding protein that is highly enriched in excitatory synapses. Mutations in Shank3 gene have been linked to neuropsychiatric disorders especially the Autism Spectrum Disorders (ASD). Shank3 deficiency is known to cause impairments in synaptic transmission, but its effects on basic neuronal electrical properties that are more localized to the soma and proximal dendrites remain unclear. Here we confirmed that in heterologous expression systems two different Shank3 isoforms, Shank3A and Shank3C, significant increase the surface expression of the hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channel. In Shank3^Δ13-16 knockout mice, which lack exons 13 to 16 in the Shank3 gene (both Shank3A and Shank3C are removed) and display severe behavioural phenotype, the expression of HCN2 is reduced to an undetectable level. The thalamocortical (TC) neurons from the ventrobasal (VB) complex of Shank3^Δ13-16 mice demonstrate reduced I_h current amplitude and correspondingly increased input resistance, negatively shifted resting membrane potential, and abnormal spike firing in both tonic and burst modes. Impressively, these changes closely resemble those of HCN2-/- TC neurons but not of the TC neurons from the Shank ^Δ4-9 mice, which lack exons 4 to 9 in the Shank3 gene (Shank3C still exists) and demonstrate moderate behavioural phenotypes. Additionally, Shank3 deficiency increases the ratio of excitatory/inhibitory balance in VB neurons but has a limited impact on the electrical properties of connected thalamic reticular (RTN) neurons. These results provide new understanding about the role of HCN channelopathy in mediating detrimental effects downstream from Shank3 deficiency.

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Gastroenterology Fellowship Match: An Inside Look

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Revenge of the NERDs: Cadherin Fragments Differentiate Functional Heartburn from Non-erosive Reflux Disease

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Analysis of Plasma Tenascin-C in Post-HCV Cirrhosis: A Prospective Study

Abstract

Background and aim

Hepatitis C virus (HCV)-related cirrhosis, one of the most common etiologies of liver cirrhosis in the Western world, is a risk factor for hepatocellular carcinoma. To confirm and improve current effectiveness of screening and prognosis of patients with established cirrhosis, a credible, simple plasma biomarker is needed. Hepatic stellate cell activation, a pivotal event in cirrhosis development, results in increased secretion of extracellular matrix proteins, including tenascin-C (TnC). Herein, we tested TnC as a simple biomarker to identify cirrhotic patients with active HCV infection from those with HCV eradication.

Methods

A prospective study of subjects with HCV-related cirrhosis, stratified into two groups, HCV or virologic cure, was conducted. Plasma TnC expression was measured by ELISA and Western blots. TnC values were correlated with markers of liver injury and ROC analyses performed between groups.

Results

The HCV cirrhotic cohort, consisting mostly of men (56%), Caucasians (76%), and genotype 1a or 1b (84%), was compared to healthy controls (HCs). Plasma TnC was significantly higher in HCV cirrhotic patients with active infection compared to HCs (P < 0.0001) and virologic cure (P < 0.0001). TnC concentrations in virologic cure subjects were not statistically different from HCs. TnC levels correlated with AST, platelets, MELD, APRI, FIB-4, and Child–Pugh score. TnC and AST together were significantly better indicators of cirrhosis in patients with active HCV infection than other markers tested.

Conclusions

TnC and AST provided the best model for discriminating HCV cirrhotics with active infection from HC and virologic cure cohorts over current liver injury markers, suggesting TnC as a potential indicator of ongoing hepatic injury and inflammation.

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Expanding the phenotype of SLC25A42-associated mitochondrial encephalomyopathy

ABSTRACT

SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Co-enzyme A (CoA) into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.

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