The neuroprotective effects of human bone marrow mesenchymal stem cells are dose-dependent in TNBS colitis

The incidence of inflammatory bowel diseases (IBD) is increasing worldwide with patients experiencing severe impacts on their quality of life. It is well accepted that intestinal inflammation associates with extensive damage to the enteric nervous system (ENS), which intrinsically innervates the gastrointestinal tract and regulates all gut functions. Hence, treatments targeting the enteric neurons are plausible for alleviating IBD and associated complications. Mesenchymal stem cells (MSCs) are gaining wide recognition as a potential therapy for many diseases due to their immunomodulatory and neuroprotective qualities. However, there is a large discrepancy regarding appropriate cell doses used in both clinical trials and experimental models of disease. We have previously demonstrated that human bone marrow MSCs exhibit neuroprotective and anti-inflammatory effects in a Guinea-pig model of 2,4,6-trinitrobenzene-sulfonate (TNBS)-induced colitis; but an investigation into whether this response is dose-dependent has not been conducted. Methods: Hartley Guinea-pigs were administered TNBS or sham treatment intra-rectally. Animals in the MSC treatment groups received either 1 × 10 5 , 1 × 10 6 or 3 × 10 6 MSCs by enema 3 hours after induction of colitis. Colon tissues were collected 72 hours after TNBS administration to assess the effects of MSC treatments on the level of inflammation and damage to the ENS by immunohistochemical and histological analyses. Results: MSCs administered at a low dose, 1 × 10 5 cells, had little or no effect on the level of immune cell infiltrate and damage to the colonic innervation was similar to the TNBS group. Treatment with 1 × 10 6 MSCs decreased the quantity of immune infiltrate and damage to nerve processes in the colonic wall, prevented myenteric neuronal loss and changes in neuronal subpopulations. Treatment with 3 × 10 6 MSCs had similar effects to 1 × 10 6 MSC treatments. Conclusions: The neuroprotective effect of MSCs in TNBS colitis is dose-dependent. Increasing doses higher than 1 × 10 6 MSCs demonstrates no further therapeutic benefit than 1 × 10 6 MSCs in preventing enteric neuropathy associated with intestinal inflammation. Furthermore, we have established an optimal dose of MSCs for future studies investigating intestinal inflammation, the enteric neurons and stem cell therapy in this model

Neuroprotective potential of mesenchymal stem cell-based therapy in acute stages of TNBS-induced colitis in Guinea-pigs

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Allogeneic Guinea pig mesenchymal stem cells ameliorate neurological changes in experimental colitis

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Human adult stem cells derived from adipose tissue and bone marrow attenuate enteric neuropathy in the guinea-pig model of acute colitis

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Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice

BACKGROUND AND PURPOSE: Oxaliplatin is a platinum‐based chemotherapeutic drug used as a first‐line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side‐effects resulting in dose limitations and/or cessation of treatment. In this study, we tested whether oxidative stress, caused by chronic oxaliplatin treatment, induces enteric neuronal damage and colonic dysmotility. EXPERIMENTAL APPROACH: Oxaliplatin (3 mg·kg(−1) per day) was administered in vivo to Balb/c mice intraperitoneally three times a week. The distal colon was collected at day 14 of treatment. Immunohistochemistry was performed in wholemount preparations of submucosal and myenteric ganglia. Neuromuscular transmission was studied by intracellular electrophysiology. Circular muscle tone was studied by force transducers. Colon propulsive activity studied in organ bath experiments and faeces were collected to measure water content. KEY RESULTS: Chronic in vivo oxaliplatin treatment resulted in increased formation of reactive oxygen species (O(2)ˉ), nitration of proteins, mitochondrial membrane depolarisation resulting in the release of cytochrome c, loss of neurons, increased inducible NOS expression and apoptosis in both the submucosal and myenteric plexuses of the colon. Oxaliplatin treatment enhanced NO‐mediated inhibitory junction potentials and altered the response of circular muscles to the NO donor, sodium nitroprusside. It also reduced the frequency of colonic migrating motor complexes and decreased circular muscle tone, effects reversed by the NO synthase inhibitor, Nω‐Nitro‐L‐arginine. CONCLUSION AND IMPLICATIONS: Our study is the first to provide evidence that oxidative stress is a key player in enteric neuropathy and colonic dysmotility leading to symptoms of chronic constipation observed in oxaliplatin‐treated mice

Attempting to Compensate for Reduced Neuronal Nitric Oxide Synthase Protein with Nitrate Supplementation Cannot Overcome Metabolic Dysfunction but Rather Has Detrimental Effects in Dystrophin-Deficient mdx Muscle

Duchenne muscular dystrophy arises from the loss of dystrophin and is characterized by calcium dysregulation, muscular atrophy, and metabolic dysfunction. The secondary reduction of neuronal nitric oxide synthase (nNOS) from the sarcolemma reduces NO production and bioavailability. As NO modulates glucose uptake, metabolism, and mitochondrial bioenergetics, we investigated whether an 8-week nitrate supplementation regimen could overcome metabolic dysfunction in the mdx mouse. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were supplemented with sodium nitrate (85 mg/l) in drinking water. Following the supplementation period, extensor digitorum longus and soleus were excised and radioactive glucose uptake was measured at rest (basal) and during contraction. Gastrocnemius was excised and mitochondrial respiration was measured using the Oroboros Oxygraph. Tibialis anterior was analyzed immunohistochemically for the presence of dystrophin, nNOS, nitrotyrosine, IgG and CD45+ cells, and histologically to assess areas of damage and regeneration. Glucose uptake in the basal and contracting states was normal in unsupplemented mdx muscles but was reduced following nitrate supplementation in mdx muscles only. The mitochondrial utilization of substrates was also impaired in mdx gastrocnemius during phosphorylating and maximal uncoupled respiration, and nitrate could not improve respiration in mdx muscle. Although nitrate supplementation reduced mitochondrial hydrogen peroxide emission, it induced mitochondrial uncoupling in red gastrocnemius, increased muscle fiber peroxynitrite (nitrotyrosine), and promoted skeletal muscle damage. Our novel data suggest that despite lower nNOS protein expression and likely lower NO production in mdx muscle, enhancing NO production with nitrate supplementation in these mice has detrimental effects on skeletal muscle. This may have important relevance for those with DMD

Semantic Congruency Across Development

Multisensory processing often results in facilitation and/or interference effects, yet the mechanisms remain unclear. The two reported experiments used a Stroop-like task to examine how congruent, incongruent, and irrelevant information presented in one sensory modality (e.g., visual) affects processing and responding in a different modality (e.g., auditory). Across two experiments, adults (E1) and 5-year-olds (E2) were presented with pictures and sounds, and they had to determine if what they saw or heard was an animal or vehicle. Experiment 1 with adults showed evidence of both facilitation on congruent trials and interference on incongruent trials, with unattended visual stimuli having a larger effect on auditory processing than vice versa. Results in 5-year-olds were slightly more symmetrical than adults but there was no evidence that auditory input dominated visual processing. Possible mechanisms underlying these effects are discussed

Effect of vaginal antiseptic prior to caesarean section on the rate of post-caesarean complications: a blinded randomised controlled trial

BACKGROUND: Rates of caesarean section (CS) delivery are increasing worldwide. CS delivery is often complicated by post-surgical infection, estimated to have ten times higher risk of infections than that of vaginal delivery. While widespread use of prophylactic antibiotics with CS has reduced post-CS infection, incidence may be reduced further by cleansing the vagina with betadine antiseptic wash prior to CS. However, reports are not consistent, and different antiseptics have been practised variably. Therefore, in order to ensure that the risks to the mother are as minimal as possible, it is important to determine whether vaginal irrigation with antiseptic wash reduces post-CS infection rate, and if so, which antiseptic is paramount. METHODS: Women giving birth by elective or emergency CS will be assigned into either the intervention (1% povidone iodine (n = 125) or chlorhexidine (n = 125)) or the control (no-irrigation (n = 125)) group by using a block randomisation technique. Participants will receive vaginal cleansing with an intervention or no vaginal cleansing prior to CS. Follow-up will occur at day 14 and day 28 post-CS. A predeveloped questionnaire will be completed with patients’ socio-demographic characteristics and required clinical and pregnancy-related information. All the fever, infection and readmission-related information will be completed from either the patient’s or their record or at follow-up visits. Occurrence of post-CS infection, as measured by primary and secondary outcomes, will be compared between the groups. DISCUSSION: The results of this study may provide important data to define the future uniform use of vaginal antiseptic wash immediately prior to CS and to determine the best antiseptic wash details in reducing post-operative infections or complications. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000971932p. Registered on 28 September 202

Krill Oil and Its Bioactive Components as a Potential Therapy for Inflammatory Bowel Disease: Insights from In Vivo and In Vitro Studies

Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the development of a range of chronic conditions, including inflammatory bowel disease (IBD). Krill oil is enriched with long-chain n-3 polyunsaturated fatty acids, especially eicosapentaenoic and docosahexaenoic acids, and the potent antioxidant astaxanthin, contributing to its therapeutic properties. The possible underlying mechanisms of krill oil’s health benefits include anti-inflammatory and antioxidant actions, maintaining intestinal barrier functions, and modulating gut microbiota. This review aims to provide an overview of the beneficial effects of krill oil and its bioactive components on intestinal inflammation and to discuss the findings on the molecular mechanisms associated with the role of krill oil in IBD prevention and treatment

Child and Adolescent Mental Health Training Programs for Non-specialist Mental Health Professionals in Low and Middle Income Countries: A Scoping Review of Literature

Large treatment deficits in child and adolescent mental health (CAMH) care exist in low and middle income countries (LMICs). This study reviewed CAMH training programs for non-specialist health professionals (NSHPs) in LMICs. Multiple databases were searched for peer-reviewed articles describing programs from 2005 to 2018. Educational source materials, trainee evaluation methods, and perspectives on teaching methods, course content and scheduling were studied. Six programs were identified. NSHPs were most appreciative of training which included case-based discussions, role plays and clinical demonstrations that were relevant to local contexts. A need for less intense and more flexible timetables to enable reflection was identified. WHO’s mental health gap action program intervention guide (mhGAP-IG) and international association of child and adolescent psychiatrists and allied professionals resources should be used; they are free, easily accessible, and developed with extensive international contributions. Additionally, mhGAP-IG assessment tool encourages mutual learning, thereby iteratively enhancing training programs