Multiple Neural Oscillators and Muscle Feedback Are Required for the Intestinal Fed State Motor Program

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40–60 s and separated by quiescent episodes lasting 40–200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle

A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis

Introduction: Bone is an integral part of the osteoarthritis (OA) process. We conducted a systematic literature review in order to understand the relationship between non-conventional radiographic imaging of subchondral bone, pain, structural pathology and joint replacement in peripheral joint OA. Methods: A search of the Medline, EMBASE and Cochrane library databases was performed for original articles reporting association between non-conventional radiographic imaging-assessed subchondral bone pathologies and joint replacement, pain or structural progression in knee, hip, hand, ankle and foot OA. Each association was qualitatively characterised by a synthesis of the data from each analysis based upon study design, adequacy of covariate adjustment and quality scoring. Results: In total 2456 abstracts were screened and 139 papers were included (70 cross-sectional, 71 longitudinal analyses; 116 knee, 15 hip, six hand, two ankle and involved 113 MRI, eight DXA, four CT, eight scintigraphic and eight 2D shape analyses). BMLs, osteophytes and bone shape were independently associated with structural progression or joint replacement. BMLs and bone shape were independently associated with longitudinal change in pain and incident frequent knee pain respectively. Conclusion: Subchondral bone features have independent associations with structural progression, pain and joint replacement in peripheral OA in the hip and hand but especially in the knee. For peripheral OA sites other than the knee, there are fewer associations and independent associations of bone pathologies with these important OA outcomes which may reflect fewer studies; for example the foot and ankle were poorly studied. Subchondral OA bone appears to be a relevant therapeutic target. Systematic review: PROSPERO registration number: CRD 4201300500

Development and validation of the Multi-dimensional University Research Workplace Inventory (MDURWI)

WOS:000454839600005This study describes the development and validation of an instrument aimed toward measuring organizational features of an academic research workplace. The question pool was developed based on data from a pilot study (N = 43). The survey was deployed to academic researchers in the field of higher education research worldwide (N = 850). An exploratory factor analysis conducted on 36 questions, followed by confirmatory factor analysis, which lead to a final pool of 27 questions in five subscales, one of which divided into three lower-order factors. The final model exhibited very good fit (X2/df = 2.561; CFI = 0.972; PCFI = 0.784; RMSEA = 0.043; P[rmsea ? 0.05] < 0.001; AIC = 891.018; BCC = 987.839) and psychometric properties, in the form of factorial, convergent, and discriminant validity, as well as reliability and sensitivity. Implications of this instrument for research and policymaking are discussed, as well as future research directions.info:eu-repo/semantics/acceptedVersio

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Postnatal development of the dopaminergic signaling involved in the modulation of intestinal motility in mice

Background:Since antidopaminergic drugs are pharmacological agents employed in the management of gastrointestinal motor disorders at all ages, we investigated whether the enteric dopaminergic system may undergo developmental changes after birth.Methods:Intestinal mechanical activity was examined in vitro as changes in isometric tension.Results:In 2-d-old (P2) mice, dopamine induced a contractile effect, decreasing in intensity with age, replaced, at the weaning (day 20), by a relaxant response. Both responses were tetrodotoxin (TTX)-insensitive. In P2, dopaminergic contraction was inhibited by D1-like receptor antagonist and mimicked by D1-like receptor agonist. In 90-d-old (P90) mice, the relaxation was reduced by both D1- and D2-like receptor antagonists, and mimicked by D1- and D2-like receptor agonists. In P2, contraction was antagonized by phospholipase C inhibitor, while in P90 relaxation was antagonized by adenylyl cyclase inhibitor and potentiated by phospholipase C inhibitor. The presence of dopamine receptors was assessed by immunofluorescence. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed a significant increase in D1, D2, and D3 receptor expression in proximal intestine with the age.Conclusion:In mouse small intestine, the response to dopamine undergoes developmental changes shifting from contraction to relaxation at weaning, as the consequence of D2-like receptor recruitment and increased expression of D1 receptors

The association between California Verbal Learning Test performance and fibre impairment in multiple sclerosis: evidence from diffusion tensor imaging

Contains fulltext : 90644.pdf (publisher's version ) (Closed access)The California Verbal Learning Test (CVLT) is recognized as a standard clinical tool for assessing episodic memory difficulties in multiple sclerosis (MS), but its neural correlates have not yet been examined in detail in this patient population. We combined neuropsychological examination and diffusion tensor imaging (DTI) analysis in a group of MS patients (N = 50) and demographically matched healthy participants (N = 20). We investigated the degree of impairment of the uncinate fascicle (UF), the superior longitudinal fascicle (SLF), the fornix (FX) and the cingulum (CG). The patients were impaired on all CVLT parameters and the DTI parameters correlated moderately with disease-related variables. Regression analyses in the complete study sample showed that CVLT learning scores correlated with impairment of the right UF. This association reached marginal significance in the patient sample. In contrast to other studies claiming retrieval deficits, our results suggest that encoding and consolidation deficits may play a major role in verbal memory impairments in MS. The findings also provide evidence for an association between degree of myelination of prefrontal fibre pathways and encoding efficiency. Finally, DTI-derived measurements appear to reflect disease progression in MS. The results are discussed in light of functional MRI studies investigating compensatory brain activity during cognitive processing in MS