Τρίτη, 5 Φεβρουαρίου 2019

Testes Proteases Expression and Hybrid Male Sterility Between Subspecies of Drosophila pseudoobscura

Hybrid male sterility (HMS) is a form of postmating postzygotic isolation among closely related species that can act as an effective barrier to gene flow. The Dobzhansky-Muller model provides a framework to explain how gene interactions can cause HMS between species. Genomics highlights the preponderance of non-coding DNA targets that could be involved in gene interactions resulting in gene expression changes and the establishment of isolating barriers. However, we have limited knowledge of changes in gene expression associated with HMS, gene interacting partners linked to HMS, and whether substitutions in DNA regulatory regions (cis) causes misexpression (i.e. expression of genes beyond levels found in parental species) of HMS genes in sterile hybrids. A previous transcriptome survey in a pair of D. pseudoobscura species found male reproductive tract (MRT) proteases as the largest class of genes misregulated in sterile hybrids. Here we assay gene expression in backcross (BC) and introgression (IG) progeny, along with site of expression within the MRT, to identify misexpression of proteases that might directly contribute to HMS. We find limited evidence of an accumulation of cis-regulatory changes upstream of such candidate HMS genes. The expression of four genes was differentially modulated by alleles of the previously characterized HMS gene Ovd.



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Evidence for an Integrated Gene Repression Mechanism Based on mRNA Isoform Toggling in Human Cells

We recently described an unconventional mode of gene regulation in budding yeast by which transcriptional and translational interference collaborate to down-regulate protein expression. Developmentally timed transcriptional interference inhibited production of a well translated mRNA isoform and resulted in the production of an mRNA isoform containing inhibitory upstream open reading frames (uORFs) that prevented translation of the main ORF. Transcriptional interference and uORF-based translational repression are established mechanisms outside of yeast, but whether this type of integrated regulation was conserved was unknown. Here we find that, indeed, a similar type of regulation occurs at the locus for the human oncogene MDM2. We observe evidence of transcriptional interference between the two MDM2 promoters, which produce a poorly translated distal promoter-derived uORF-containing mRNA isoform and a well-translated proximal promoter-derived transcript. Down-regulation of distal promoter activity markedly up-regulates proximal promoter-driven expression and results in local reduction of histone H3K36 trimethylation. Moreover, we observe that this transcript toggling between the two MDM2 isoforms naturally occurs during human embryonic stem cell differentiation programs.



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Tibiofemoral Joint Forces in Female Recreational Runners Vary with Step Frequency

Purpose Elevated tibiofemoral joint (TFJ) contact forces have been linked to the development and progression of knee osteoarthritis. The primary objective of this study was to determine the association between peak TFJ shear and compression forces during running at different self-selected step frequencies (SF) in female recreational runners. Methods Fifty-five healthy female recreational runners ran at 2.98 m/s on an instrumented treadmill. Peak TFJ anterior shear force, peak axial TFJ compression force and peak medial compartment TFJ compression force were estimated using a musculoskeletal model with inputs from 3D joint kinematics and inverse dynamics calculations. Three SF groups were generated using tertiles and differences between the groups were compared using one-way analyses of variance (α=0.05). Results Runners with a SF of ≥178 steps per minute demonstrated the lowest peak TFJ anterior shear (p=0.049), peak axial TFJ compression force (p=0.001) and peak TFJ medial compartment compression forces (p=0.001) compared with runners using lower SF. Conclusion Female recreational runners with low SF of ≤166 steps per minute experience greater TFJ contact forces. This study provides evidence of an association between SF and both shear and axial peak TFJ contact forces during running. Corresponding author: Bhushan Thakkar, 1200 East Broad Street, Basement, Box 980224, Richmond, VA 23298. E-mail: thakkarbs2@vcu.edu. Phone: (804) 300-5578. Fax: (804) 828-8111 There was no funding received for this project. Conflict of Interest The authors have no conflicts of interests to disclose. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for publication: 2 January 2019. © 2019 American College of Sports Medicine

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Combined Exercise Training Positively Affects Muscle Wasting in Tumor-bearing Mice

Introduction Cancer cachexia is characterized by loss of muscle mass and function. Increased protein catabolism, inflammation, impaired anabolism and mitochondrial function markedly contribute to the pathogenesis of this syndrome. Physical activity has been suggested as a useful tool to prevent or at least delay the onset and progression of cancer-induced muscle wasting. Two main types of exercise can be adopted, namely resistance and endurance training. The present study is aimed to investigate the effectiveness of a combined (resistance + endurance) exercise protocol in preventing/reverting cancer-induced muscle wasting. Methods Mice bearing the C26 colon carcinoma have been used as a model of cancer cachexia. They have been exposed to combined exercise training during 6 weeks (4 before tumor implantation, 2 during tumor growth). Climbing a 1-m ladder inclined at 85° has been used for resistance training, while aerobic (endurance) exercise has been carried out on the same day using a motorized wheel. Results In C26-bearing mice, both muscle mass and strength are improved by combined training, while just the latter increased in exercised healthy animals. Such a pattern is associated with modulations of two markers of autophagy, namely LC3B I/II ratio, increased in sedentary tumor hosts and reduced in exercised C26-bearing mice, and p62, steadily increased in both sedentary and trained tumor-bearing animals. Finally, combined training is not able to modify PGC-1α protein levels, while it improves succinate dehydrogenase activity, both reduced in the muscle of the C26 hosts. Conclusion The data reported in the present study show that combined training improves muscle mass and function in the C26 hosts, likely modulating autophagy and improving mitochondrial function; these observations suggest that combined exercise might become part of a multimodal approach to treat cancer cachexia. Corresponding author: Paola Costelli, Department of Clinical and Biological Sciences, University of Turin. Corso Raffaello, 30. 10125 Turin, Italy. E-mail: paola.costelli@unito.it These authors equally contributed to the work (Kia Ranjbar and Riccardo Ballarò) Work supported by University of Turin. K. Ranjbar was recipient of a scholarship funded by the Ministry of Science, Research and Technology, Islamic Republic of Iran. Conflict of interest: The authors declare no conflict interests. Authors declare that the results of the present study do not constitute endorsement by ACSM and that the data are presented clearly without inappropriate manipulation. Accepted for publication: 25 January 2019. © 2019 American College of Sports Medicine

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No further evidence for paternal leakage of mitochondrial DNA in humans yet [Biological Sciences]

Recently in PNAS, Luo et al. (1) report the observation of heteroplasmic mixtures of mitochondrial DNA (mtDNA) in the blood of three unrelated patients suffering from different mitochondrial disorders. The affected mixed positions coincide with signature mutations of established haplogroups (2), suggesting that each mixture consists of a different pair...

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A bipartite boundary element restricts UBE3A imprinting to mature neurons [Genetics]

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is...

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Reply to Lutz-Bonengel et al.: Biparental mtDNA transmission is unlikely to be the result of nuclear mitochondrial DNA segments [Biological Sciences]

In Luo et al. (1), we report the transmission of paternal mtDNA in 17 individuals across three unrelated families. In their letter responding to this paper, Lutz-Bonengel et al. (2) argue that these results do not provide sufficient evidence for paternal inheritance of mtDNA. Instead, they propose that these biparental...

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Chromatin features constrain structural variation across evolutionary timescales [Genetics]

The potential impact of structural variants includes not only the duplication or deletion of coding sequences, but also the perturbation of noncoding DNA regulatory elements and structural chromatin features, including topological domains (TADs). Structural variants disrupting TAD boundaries have been implicated both in cancer and developmental disease; this likely occurs...

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Core Concept: Solving Peto’s Paradox to better understand cancer [Genetics]

Cancer is as ancient as multicellularity itself. But not all animals get cancer at the same rate. Some, such as elephants and naked mole rats, rarely get it at all, whereas others, such as ferrets and dogs, have cancer at unusually high rates. The question is why. Despite their size...

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Triparental inheritance in Dictyostelium [Genetics]

Sex promotes the recombination and reassortment of genetic material and is prevalent across eukaryotes, although our knowledge of the molecular details of sexual inheritance is scant in several major lineages. In social amoebae, sex involves a promiscuous mixing of cytoplasm before zygotes consume the majority of cells, but for technical...

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Prp8 impacts cryptic but not alternative splicing frequency [Genetics]

Pre-mRNA splicing must occur with extremely high fidelity. Spliceosomes assemble onto pre-mRNA guided by specific sequences (5′ splice site, 3′ splice site, and branchpoint). When splice sites are mutated, as in many hereditary diseases, the spliceosome can aberrantly select nearby pseudo- or "cryptic" splice sites, often resulting in nonfunctional protein....

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The challenges in managing perioperative hypoglycemia in a child on modified Atkins diet

Abstract

Our patient is a 5‐year‐old boy with West syndrome, complicated by neurodevelopmental delays, scheduled for elective gastrostomy. He was started on MAD 6 months prior to surgery. His oral anti‐epileptics were converted to intravenous equivalents during fasting. Non‐dextrose containing solution was used as maintenance fluid. Blood glucose was monitored 4‐hourly when fasting commenced 6h before surgery. His serial blood glucose is summarized in Table 1.

This article is protected by copyright. All rights reserved.



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Uneven terrain exacerbates the deficits of a passive prosthesis in the regulation of whole body angular momentum in individuals with a unilateral transtibial amputation

Uneven ground is a frequently encountered, yet little-studied challenge for individuals with amputation. The absence of control at the prosthetic ankle to facilitate correction for surface inconsistencies, and...

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Locomotion and cadence detection using a single trunk-fixed accelerometer: validity for children with cerebral palsy in daily life-like conditions

Physical therapy interventions for ambulatory youth with cerebral palsy (CP) often focus on activity-based strategies to promote functional mobility and participation in physical activity. The use of activity ...

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Colocolic intussusception

Publication date: Available online 4 February 2019

Source: Arab Journal of Gastroenterology

Author(s): Nadim Mahmud, Kirk J. Wangensteen



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Metastatic melanoma to the jejunum

Publication date: Available online 4 February 2019

Source: Arab Journal of Gastroenterology

Author(s): Amer A. Alkhatib



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Colonization of intestinal microbiota with carbapenemase-producing Enterobacteriaceae in paediatric intensive care units in Cairo, Egypt

Publication date: Available online 4 February 2019

Source: Arab Journal of Gastroenterology

Author(s): Doaa M. Ghaith, Zeinat K. Mohamed, Mohamed G. Farahat, Walaa Aboulkasem Shahin, Hadeel O. Mohamed

Abstract
Background and study aims

Colonized patients with carbapenamase producing Enterobacteriaceae (CPE) are vulnerable to invasive infections from their endogenous flora. We aimed to assess faecal colonization with (CPE) among children admitted to Cairo University paediatric intensive care units (ICUs). The phenotypic and genotypic characterizations of carbapenemase-producing Enterobacteriaceae were also studied.

Patients and methods

A total of 413 Enterobacteriaceae isolates have been isolated from cultured rectal swabs of 100 children. All swabs were inoculated on ChromID™ CARBA agar to screen for carbapenem resistant Enterobacteriaceae (CRE). Disk diffusion method, Modified Hodge test (MHT) and further genotypic detection of carbapenemases genes (blaOXA-48, blaKPC and blaNDM-1, blaVIM and blaIMP) by multiplex PCR were done.

Results

Out of 413 Enterobacteriaceae isolates; 100 isolates were defined as CRE. BlaOXA-48 was detected in (33%); Escherichia coli (n = 11), Klebsiella oxytoca (n = 3) and Klebsiella pneumoniae (n = 19), while (27%) carried blaNDM-1Escherichia coli (n = 7), and Klebsiella pneumoniae (n = 20).

Conclusion

Prevalence of carbapenem resistant Enterobacteriaceae was 24%, various genes of carbapenemases were detected in 80% of carbapenem resistant Enterobacteriaceae with dominance of blaOXA-48. Understanding the colonization status of our patients with strict infection control measures can reduce the risk of horizontal gene transfer of carbapenemases.



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Primary omental malignant solitary fibrous tumour, an extremely rare malignancy: A case report and review of the literature

Publication date: Available online 4 February 2019

Source: Arab Journal of Gastroenterology

Author(s): Chang-Yeon Jung, Jung-Min Bae

Abstract

Primary omental malignant solitary fibrous tumour is an extremely rare neoplasm considering its tumour origin and pathologic characteristics. Solitary fibrous tumour (SFT) is a spindle cell neoplasm that was first described in 1931. SFT is diagnosed at immunohistochemical stain including CD34, bcl2, CD99 and STAT6. Though most of SFTs are benign in nature, 5–15% are malignant. The diagnostic criteria of malignant SFTs are high cellularity, high mitotic activity(>4/10HPF), pleomorphism, necrosis and haemorrhage.

We present the case of a 57-year-old male patient diagnosed with primary omental malignant SFT. Neither tumour origin nor pathologic diagnosis were possible based on preoperative information. Nevertheless, tumour resection was performed successfully.

Several SFT cases involving omentum without malignant potential have been reported. However, primary omental malignant SFTs are extremely rare with only 3 cases reported in the literature.



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Self-expandable metal stent for dysphagia caused by mediastinal masses in patients with lung cancer

Publication date: Available online 4 February 2019

Source: Arab Journal of Gastroenterology

Author(s): Pave Markos, Ines Sisko Markos, Hrvoje Ivekovic, Branko Bilic, Nadan Rustemovic

Abstract
Background and study aims

We intended to evaluate the role of self-expandable metal stents (SEMS) for palliation of malignant dysphagia in patients with lung cancer.

Patients and methods

During the period between May 2015 and September 2017, 42 SEMS have been placed for malignant dysphagia in patients with lung cancer. Stents have been placed under combined fluoroscopic and endoscopic guidance.

Results

Data from 42 patient were analysed. 35 patients (83%) were males and the mean age was 68,4 years (range 52–80 y). In 26 patients (61%) cause of dysphagia was extraluminal mediastinal lymphadenopathy and in others direct tumour infiltration of the oesophagus. A tracheo-oesophageal fistula (TEF) was seen in 8 patients (19%). Most of the patients (32 patients; 76%) had stage 3 dysphagia (able to swallow liquids only) and the rest (10 patients; 24%) stage 4 (unable to swallow saliva). Thirty stents (71%) were partially covered and 12 (29%) were fully covered. Five (12%) stents have been placed across the oesophagogastric junction due to infiltration of the cardia. There were no immediate complications except for aspiration pneumonia in 3 (7%) and minor bleeding in 2 (5%) patients which resolved spontaneously. Dysphagia score improved in all patients to stage 1 (dysphagia with certain solid food in 16 patients-38%) or stage 2 (able to swallow semi solid in 26 patients-62%). In 3 (7%) patients during the follow-up we encountered tumour overgrowth and in 1 patients the TEF was not sealed so they have been referred for gastrostomy. No other long term complications were recorded. Most of the patients (30 patients- 71%) died during the follow-up, with mean survival of 4 months (range 2–9) after the stent placement.

Conclusion

Placing SEMS in patients with lung cancer is safe and highly effective in relieving dysphagia with significant improvement in quality of life.



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Incomplete cold snare polypectomy for rectal carcinoid tumour

Publication date: Available online 4 February 2019

Source: Arab Journal of Gastroenterology

Author(s): Yuichiro Hirai, Toshihiro Nishizawa, Toshio Uraoka



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The importance of deriving adequate wildlife benchmark values to optimize radiological protection in various environmental exposure situations

Publication date: Available online 5 February 2019

Source: Journal of Environmental Radioactivity

Author(s): Almudena Real, Jacqueline Garnier-Laplace

Abstract

The actions to be taken to demonstrate that the environment is adequately protected against the detrimental effects of ionising radiation, and if needed to protect it, must be commensurate with the overall level of risk to non-human biota. To judge the level of risk, the estimated dose rates absorbed by animals and plants need to be compared with dose criteria, a benchmark or reference value.

A variety of aspects will influence the final value of the derived benchmark, including: the aim of the application of the benchmark, the protection goals of the assessment, the data on radiation-induced biological effects considered, and the methodology used.

Benchmark values have been proposed by several international organizations (UNSCEAR, ICRP, IAEA), countries (USA, Canada) and research projects (ERICA, PROTECT), for different application purposes and protection goals and using a variety of methodologies.

This paper describes the aspects that need to be considered in the derivation of numerical benchmarks, the approaches used by different organizations and the benchmark values they have proposed for the radiation protection of the environment. The benchmark values proposed are compared with the dose-rates at which radiation-induced biological effects have been described in animals and plants.



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Dynamic balance measurements can differentiate fallers from non-fallers in patients with idiopathic normal pressure hydrocephalus

Publication date: Available online 4 February 2019

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Yasutaka Nikaido, Yoshinaga Kajimoto, Toshihiro Akisue, Hideyuki Urakami, Yuki Kawami, Kenji Kuroda, Hiroshi Ohno, Ryuichi Saura

Abstract
Objectives

To investigate which clinical assessments are suitable for differentiating fallers from non-fallers in patients with idiopathic normal pressure hydrocephalus (iNPH).

Design

Prospective observational study.

Setting

Medical College Hospital.

Participants

Sixty-eight patients with a cerebrospinal fluid tap test (TT) result meeting the diagnosis criteria for iNPH.

Interventions

Not applicable.

Main Outcome Measures

Participants were assessed before the TT based on the following: Timed Up & Go (TUG), 10-meter walk test (10MWT), Functional Gait Assessment (FGA), Berg Balance Scale (BBS), isometric quadriceps strength (QS), and a history of falls within the past 6 months.

Results

The full area under the curve of the receiver operating characteristic curves (AUC [95% CI]) was found to be 0.651 (0.503–0.775) for the TUG, 0.692 (0.540–0.812) for the 10MWT, 0.869 (0.761–0.933) for the FGA, and 0.796 (0.663–0.886) for the BBS; except for QS, they all were identified as statistically significant predictive variables. In the TUG <20 s group (n=47), the FGA (AUC; 0.849, [0.698–0.932]) and BBS (AUC; 0.734, [0.550–0.862]) were found to be statistically significant predictive variables; however, the other assessments were not. In the TUG <15 s group (n=34), the FGA was found to be the only statistically significant predictive variable (AUC; 0.842, [0.640–0.942]), whereas the other assessments were not. The AUC of the FGA was statistically significantly greater than those of the other assessments.

Conclusions

Our findings indicate that the falls patients experience with iNPH may be associated with dynamic balance dysfunction during gait rather than lower limb muscle strength. The FGA may be more suitable than other assessments for differentiating fallers from non-fallers in patients with mild iNPH.



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Behavioral analysis of substrate texture preference in a leech, Helobdella austinensis

Abstract

Leeches in the wild are often found on smooth surfaces, such as vegetation, smooth rocks or human artifacts such as bottles and cans, thus exhibiting what appears to be a "substrate texture preference". Here, we have reproduced this behavior under controlled circumstances, by allowing leeches to step about freely on a range of silicon carbide substrates (sandpaper). To begin to understand the neural mechanisms underlying this texture preference behavior, we have determined relevant parameters of leech behavior both on uniform substrates of varying textures, and in a behavior choice paradigm in which the leech is confronted with a choice between rougher and smoother substrate textures at each step. We tested two non-exclusive mechanisms which could produce substrate texture preference: (1) a Differential Diffusion mechanism, in which a leech is more likely to stop moving on a smooth surface than on a rough one, and (2) a Smoothness Selection mechanism, in which a leech is more likely to attach its front sucker (prerequisite for taking a step) to a smooth surface than to a rough one. We propose that both mechanisms contribute to the texture preference exhibited by leeches.



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Blunted neural response to gains versus losses associated with both risk‐prone and risk‐averse behavior in a clinically diverse sample

Abstract

Reduced responsiveness to reward has been associated with both risk‐prone and risk‐averse behavior, common features of externalizing and internalizing psychopathology, respectively. Thus, evidence has suggested a potential quadratic relationship (i.e., inverted U) between reward sensitivity and risk‐taking propensity. Blunted response to reward compared to loss may therefore demonstrate transdiagnostic utility as it relates to different patterns of maladaptive risk behavior. The current study sought to disentangle the relationship between risk and reward in a clinically diverse sample. In a sample of 210 adults (aged 18–30), the RewP (an ERP indexing differentiation between rewards and losses) was measured during a monetary guessing game, and risk‐taking propensity was measured with a behavioral task (i.e., BART) that simulates real‐world risk taking. Participants also completed clinical assessments to assess for lifetime psychopathology. Results indicated that there was no linear association between the RewP and risk‐taking propensity; however, there was a significant quadratic relationship. Thus, a reduced sensitivity to reward receipt was associated with both risk‐prone and risk‐averse behavior. There was also a significant quadratic relationship between the RewP and money won during the BART, indicating that being too risk prone or risk averse is disadvantageous and leads to missed reward. Overall, these findings suggested that blunted neural differentiation between gains and losses may contribute to deficits in effectively weighing reward and loss and result in maladaptive risk‐taking behavior. These findings support continued examination of reward dysfunction dimensionally in order to better characterize behavioral profiles implicated in clinical phenotypes.



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Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features and intellectual disability caused by haploinsufficiency of the NSD1 gene. Genotype–phenotype correlations have been observed, with major anomalies seen more frequently in patients with 5q35 deletions than those with point mutations in NSD1. Though endocrine features have rarely been described, transient hyperinsulinemic hypoglycemia (HI) of the neonatal period has been reported as an uncommon presentation of Sotos syndrome. Eight cases of 5q35 deletions and one patient with an intragenic NSD1 mutation with transient HI have been reported. Here, we describe seven individuals with HI caused by NSD1 gene mutations with three having persistent hyperinsulinemic hypoglycemia. These patients with persistent HI and Sotos syndrome caused by NSD1 mutations, further dispel the hypothesis that HI is due to the deletion of other genes in the deleted 5q35 region. These patients emphasize that NSD1 haploinsufficiency is sufficient to cause HI, and suggest that Sotos syndrome should be considered in patients presenting with neonatal HI. Lastly, these patients help extend the phenotypic spectrum of Sotos syndrome to include HI as a significant feature.



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Physiological properties of the lamina I spinoparabrachial neurons in the mouse

Key points

Spinal cord lamina I neurons receiving dense input from nociceptors, and projecting to the parabrachial area at the ponto‐mesencephalic junction form the major ascending pain‐related pathway in rodents. Lamina I spinoparabrachial neurons have never been characterised in mice, despite the growing and extensive use of this species to understand the contribution of lamina I spinoparabrachial neurons in chronic pain. The electrophysiological properties of lamina I spinoparabrachial neurons recorded here in the anaesthetized mice are comparable to those of rat or cat, forming a nociceptive and thermoreceptive pathway. It was confirmed "on line" that lamina I spinoparabrachial neurons that normally encode noxious stimuli can receive input from low threshold mechanoreceptors in certain conditions. The present work indicates that the study of lamina I spinoparabrachial neurons in vivo could take advantage of the use of genetically modified mice.

Abstract

Ongoing studies investigating the role of lamina I projection neurons in the generation of chronic pain are mainly based on the use of genetically modified mice. However, lamina I projection neurons have never been physiologically characterized in this species. The present work aimed to fill this gap in information, and to assess the effect of spinal "disinhibition" that may occur in chronic pain states on the responses of these neurons to light touch. Seventy lamina I spinoparabrachial neurons were characterized in anaesthetized mice. These neurons showed low central conduction velocities (<12.4 m.s−1) and wide range of responses. Fifty six neurons responded equally to noxious mechanical and thermal (heat) stimuli (16 % responded consistently to light touch). Modality specific neurons responded preferentially to thermal (cold) stimuli (n = 10) and pinch (n = 2), or specifically to heat (n = 2). Spinal bicuculline and strychnine application induced responses to brush in half of the neurons tested, confirming directly the potential connection between low threshold mechanoreceptors and nociceptive‐specific neurons, responsible for mechanical allodynia. Remarkably, the effect of the treatment was highly variable and apparently independent of the initial profile of the neurons. The present data confirms that mice lamina I spinoparabrachial neurons have the expected characteristics to form a nociceptive and thermoreceptive pathway, but they constitute a highly heterogeneous group. The differential effect of spinal disinhibition observed here suggests that a subgroup of lamina I spinoparabrachial neurons might be responsible for abnormal pain in pathological conditions, and emphasizes the importance of in vivo recording, a neglected approach.

This article is protected by copyright. All rights reserved



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Sensory coding is impaired in rat absence epilepsy

Key points

Absence epilepsy is characterized by the occurrence of spike‐and‐wave discharges concomitant with an alteration of consciousness and is associated with cognitive comorbidities. In a genetic model of absence epilepsy in the rat, the genetic absence epilepsy rat from Strasbourg (GAERS), spike‐and‐wave discharges are shown to be initiated in the barrel field primary somatosensory cortex that codes whisker‐related information, therefore playing an essential role in the interactions of rodents with their environment. Sensory‐information processing is impaired in the epileptic barrel field primary somatosensory cortex of GAERS, with a delayed sensory‐evoked potential and a duplicated neuronal response to whisker stimulation in in vivo extracellular recordings. Yet, GAERS present no defaults of performance in a texture discrimination task, suggesting the existence of a compensatory mechanism within the epileptic neuronal network. The results of the present study indicate that physiological primary functions are processed differently in an epileptic cortical network.

Abstract

Several neurodevelopmental pathologies are associated with disorganized cortical circuits that may alter primary functions such as sensory processes. In the present study, we investigated whether the function of a cortical area is altered in the seizure onset zone of absence epilepsy, a prototypical form of childhood genetic epilepsy associated with cognitive impairments. We first combined in vivo multichannel electrophysiological recordings and histology to precisely localize the seizure onset zone in the genetic absence epilepsy rat from Strasbourg (GAERS). We then investigated the functionality of this epileptic zone using extracellular silicon probe recordings of sensory‐evoked local field potentials and multi‐unit activity, as well as a behavioural test of texture discrimination. We show that seizures in this model are initiated in the barrel field part of the primary somatosensory cortex and are associated with high‐frequency oscillations. In this cortex, we found an increased density of parvalbumin‐expressing interneurons in layer 5 in GAERS compared to non‐epileptic Wistar rats. Its functional investigation revealed that sensory abilities of GAERS are not affected in a texture‐discrimination task, whereas the intracortical processing of sensory‐evoked information is delayed and duplicated. Altogether, these results suggest that absence seizures are associated with an increase of parvalbumin‐inhibitory neurons, which may promote the functional relationship between epileptic oscillations and high‐frequency activities. Our findings suggest that cortical circuits operate differently in the epileptic onset zone and may adapt to maintain their ability to process highly specialized information.



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Increased circulating microparticles in streptozotocin‐induced diabetes propagate inflammation contributing to microvascular dysfunction

Key points

Circulating microparticles (MPs) are elevated in many cardiovascular diseases and have been considered as biomarkers of disease prognosis; however, current knowledge of MP functions has been mainly derived from in vitro studies and their precise impact on vascular inflammation and disease progression remains obscure. Using a diabetic rat model, we identified a >130‐fold increase in MPs in plasma of diabetic rats compared to normal rats, the majority of which circulated as aggregates, expressing multiple cell markers and largely externalized phosphatidylserine; vascular images illustrate MP biogenesis and their manifestations in microvessels of diabetic rats. Using combined single microvessel perfusion and systemic cross‐transfusion approaches, we delineated how diabetic MPs propagate inflammation in the vasculature and transform normal microvessels into an inflammatory phenotype observed in the microvessels of diabetic rats. Our observations derived from animal studies resembling conditions in diabetic patients, providing a mechanistic insight into MP‐mediated pathogenesis of diabetes‐associated multi‐organ microvascular dysfunction.

Abstract

In various cardiovascular diseases, microparticles (MPs), the membrane‐derived vesicles released during cell activation, are markedly increased in the circulation. These MPs have been recognized to play diverse roles in the regulation of cellular functions. However, current knowledge of MP function has been largely derived from in vitro studies. The precise impact of disease‐induced MPs on vascular inflammation and disease progression remains obscure. In this study we investigated the biogenesis, profile and functional roles of circulating MPs using a streptozotocin‐induced diabetic rat model with well‐characterized microvascular functions. Our study revealed a >130‐fold increase in MPs in the plasma of diabetic rats compared to normal rats. The majority of these MPs originate from platelets, leukocytes and endothelial cells (ECs), and circulate as aggregates. Diabetic MPs show greater externalized phosphatidylserine (PS) than normal MPs. When diabetic plasma or isolated diabetic MPs were perfused into normal microvessels or systemically transfused into normal rats, MPs immediately adhered to endothelium and subsequently mediated leukocyte adhesion. These microvessels then exhibited augmented permeability responses to inflammatory mediators, replicating the microvascular manifestations observed in diabetic rats. These effects were abrogated when MPs were removed from diabetic plasma or when diabetic MPs were pre‐coated with a lipid‐binding protein, annexin V, suggesting externalized PS to be key in mediating MP interactions with endothelium and leukocytes. Our study demonstrated that the elevated MPs in diabetic plasma are actively involved in the propagation of vascular inflammation through their adhesive surfaces, providing mechanistic insight into the pathogenesis of multi‐organ vascular dysfunction that commonly occurs in diabetic patients.



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Impaired pressure natriuresis and non‐dipping blood pressure in rats with early type 1 diabetes mellitus

Key points

Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long‐term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow. Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes.

Abstract

Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague‐Dawley rats were injected with streptozotocin (30–45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non‐diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non‐diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.



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Sleep disordered breathing in children disrupts the maturation of autonomic control of heart rate and its association with cerebral oxygenation

Key points

Sleep disordered breathing (SDB) affects 4–11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control. The relationship between heart rate variability (HRV; a measure of autonomic control) and age found in non‐snoring control children was absent during sleep in children with SDB. Age significantly predicted increasing cerebral oxygenation during wake in non‐snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation. Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep. SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non‐snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow.

Abstract

The repetitive episodes of hypoxia that are features of sleep disordered breathing (SDB) in children are associated with alterations in autonomic control of heart rate in an age‐dependent manner. We aimed to relate heart rate variability (HRV) parameters to age and measures of cerebral oxygenation in children (3–12 years old) with SDB and non‐snoring controls. Children (SDB, n = 117; controls, n = 42; 3–12 years) underwent overnight polysomnography. Total (TP), low‐ (LF) and high‐frequency (HF) power, tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were analysed during wake and sleep. Pearson's correlations determined the association between age and HRV parameters, and multiple linear regressions between HRV, age and cerebral oxygenation parameters. During wake, age had a positive association with LF power, reflecting increased parasympathetic and sympathetic activity with increasing age for both control and SDB groups. This association was also evident during sleep in controls, but was absent in children with SDB. In controls, during wake TOI had a positive, and FTOE a negative association with age. During sleep, TP, LF and HF power were significant, negative determinants of TOI and positive determinants of FTOE. These associations were not seen in children with SDB during wake or sleep. SDB disrupts the normal maturation of the autonomic control of heart rate and the association between HRV and cerebral oxygenation exhibited by non‐snoring control children of primary school age. These results highlight the impact SDB has on cardiovascular control and the potential impact on adverse cardiovascular outcomes.



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Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice

Key points summary

Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases (CVD). To investigate whether age‐related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad‐spectrum, poorly‐absorbed antibiotics in drinking water for 3–4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age‐related changes in gut microbiota that may underlie these observations, we show that aging altered abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine‐N‐oxide. Our results provide the first proof‐of‐concept evidence that the gut microbiome is an important mediator of age‐related arterial dysfunction and therefore may be a promising therapeutic target to preserve arterial function with ageing, thereby reducing CVD risk.

Abstract

Oxidative stress‐mediated arterial dysfunction, e.g. endothelial dysfunction and large elastic artery stiffening, is the primary mechanism driving age‐related cardiovascular disease. Accumulating evidence suggests the gut microbiome modulates host physiology, as dysregulation ("gut dysbiosis") has systemic consequences, including promotion of oxidative stress. Aim: To determine whether the gut microbiome modulates arterial function with ageing. Methods: We measured arterial function in young and older mice following 3–4 weeks treatment with broad‐spectrum, poorly‐absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age‐related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut‐derived metabolite trimethylamine‐N‐oxide (TMAO). Results: In old mice, antibiotics reversed endothelial dysfunction (area‐under‐the‐curve carotid artery dilation to acetylcholine in young: 345±16A.U. vs. old control [OC]: 220±34A.U., p<0.01; vs. old antibiotic‐treated [OA]: 334±15A.U.; p<0.01 vs. OC), and arterial stiffening (aortic pulse wave velocity in young: 3.62±0.15m.s−1 vs. OC: 4.43±0.38m.s−1 vs. OA: 3.52±0.35m.s−1; p = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6±0.4 vs. OC: 7.2±2.0μmol.L−1; p<0.0001) and suppressed by antibiotic treatment (OA: 1.2±0.2μmol.L−1; p<0.0001 vs. OC). Conclusion: Our results provide the first evidence for the gut microbiome as an important mediator of age‐related arterial dysfunction and oxidative stress and suggest therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans.

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