Amino acid solution mitigates hypothermia response and intestinal damage following exertional heat stroke in male mice.

Increased gut permeability is implicated in the initiation and extent of the cytokine inflammatory response associated with exertional heat stroke (EHS). The primary objective of this study was to determine if a five amino acid oral rehydration solution (5AAS), specifically designed for the protection of the gastrointestinal lining, would prolong time to EHS, maintain gut function and dampen the systemic inflammatory response (SIR) measured during EHS recovery. Male C57/BL6J mice instrumented with radiotelemetry were gavaged with 150 µL of 5AAS or H2 O, and ≈12 h later were either exposed to an EHS protocol where mice exercised in a 37.5°C environmental chamber to a self-limiting maximum core temperature (Tc,max) or performed the exercise control (EXC) protocol (25°C). 5AAS pretreatment attenuated hypothermia depth and length (p < 0.005), which are indicators of EHS severity during recovery, without any effect on physical performance or thermoregulatory responses in the heat as determined by percent body weight lost (≈9%), max speed (≈6 m/min), distance (≈700 m), time to Tc,max (≈160 min), thermal area (≈550°C∙min), and Tc,max (42.2°C). EHS groups treated with 5AAS showed a significant decrease in gut transepithelial conductance, decreased paracellular permeability, increased villus height, increased electrolyte absorption and changes in tight junction protein expression pattern suggestive of improved barrier integrity (p < 0.05). No differences were witnessed between EHS groups in acute phase response markers of liver, circulating SIR markers, or indicators of organ damage during recovery. These results suggest that a 5AAS improves Tc regulation during EHS recovery through maintaining mucosal function and integrity.

Computational evaluation of bioactive compounds from Viscum album (mistletoe) as inhibitors of p63 for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma is an aggressive malignancy usually detectable at the advanced stage, with a 5-year survival rate of less than 8%. It has been reported that a gene called tumor-protein 63 (TP63) is expressed in an aggressive form of pancreatic cancer with a squamous signature. Thus, inhibiting the activity of p63 can be a means of treating and managing PDA. Different studies have shown that plant constituents are rich and can be a promising source for discovering drug candidates. The extract from mistletoe (Viscum album) is known to contain anticancer compounds; however, the specific molecular mechanism of the bioactive compounds is unknown. This study examines the pancreatic cancer therapeutic potential of the bioactive compounds in the flavonoid and phenolic acid constituents of mistletoe by adopting structural bioinformatics and advanced theoretical chemistry techniques via molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, pharmacokinetic analysis, and density functional theory analysis. The six best compounds from the flavonoid constituent with the highest binding affinity ranging from -6.8 kcal/mol to -6.7 kcal/mol were selected with the control gemcitabine (-5.5 kcal/mol) for further computational analysis after molecular docking. Furthermore, MM/GBSA calculation showed the highest binding energy for the selected docked compounds, which validates their inhibitory potential. Hence, the molecular dynamics simulation, post-simulation analysis, pharmacokinetics model, and DFT results showed that mistletoe compounds are reliable due to their stable interaction with the target protein and drug-likeness properties.Communicated by Ramaswamy H. Sarma.

Energy-dense, low-volume paediatric oral nutritional supplements improve total nutrient intake and increase growth in paediatric patients requiring nutritional support: results of a randomised controlled pilot trial.

Children with or at risk of faltering growth require nutritional support and are often prescribed oral nutritional supplements (ONS). This randomised controlled trial investigated the effects of energy-dense paediatric ONS (2.4 kcal/ml, 125 ml: cONS) versus 1.5 kcal/ml, 200 ml ONS (sONS) in community-based paediatric patients requiring oral nutritional support. Fifty-one patients (mean age 5.8 years (SD 3)) with faltering growth and/or requiring ONS to meet their nutritional requirements were randomised to cONS (n = 27) or sONS (n = 24) for 28 days. Nutrient intake, growth, ONS compliance and acceptability, appetite and gastro-intestinal tolerance were assessed. Use of the cONS resulted in significantly greater mean total daily energy (+ 531 kcal/day), protein (+ 10.1 g/day) and key micronutrient intakes compared with the sONS group at day 28 and over time, due to high ONS compliance (81% of patients ≥ 75%), maintained intake from diet alone and improved appetite in the cONS group, compared with the sONS group. Although growth increased in both intervention groups, results were significant in the cONS group (weight (p = 0.007), height (p < 0.001) and height z-score (p = 0.006)).Conclusions: This study shows that use of energy-dense (2.4 kcal/ml) low-volume paediatric-specific ONS leads to improved nutrient intakes, growth and appetite in paediatric patients requiring oral nutrition support compared with standard energy density ONS.Trial registration: The trial is registered at clinicaltrials.gov , identification number NCT02419599. What is Known: • Faltering growth is the failure of children to achieve adequate growth at a normal rate for their age and requires nutritional support, including the use of oral nutritional supplements (ONS). • Energy-dense, low-volume ONS have benefits over standard ONS in adults. What is New: • This is the first RCT to investigate the effects of energy-dense, low-volume ONS (2.4 kcal/ml, 125 ml) in children with faltering growth, showing significant improvements in total nutrient intake and increased growth. • Energy-dense, low-volume ONS can play a key role in the management of faltering growth.

An emerging method to noninvasively measure and identify vagal response markers to enable bioelectronic control of gastroparesis symptoms with gastric electrical stimulation.

BACKGROUND: Gastric electrical stimulation (GES) can be a life-changing, device-based treatment option for drug-resistant nausea and vomiting associated with diabetic or idiopathic gastroparesis (GP). Despite over two decades of clinical use, the mechanism of action remains unclear. We hypothesize a vagal mechanism. NEW METHOD: Here, we describe a noninvasive method to investigate vagal nerve involvement in GES therapy in 66 human subjects through the compound nerve action potential (CNAP). RESULTS: Of the 66 subjects, 28 had diabetic GP, 35 had idiopathic GP, and 3 had postsurgical GP. Stimulus charge per pulse did not predict treatment efficacy, but did predict a significant increase in total symptom score in type 1 diabetics as GES stimulus charge per pulse increased (p < 0.01), representing a notable side effect and providing a method to identify it. In contrast, the number of significant left and right vagal fiber responses that were recorded directly related to patient symptom improvement. Increased vagal responses correlated with significant decreases in total symptom score (p < 0.05). COMPARISON WITH EXISTING METHOD(S): We have developed transcutaneous recording of cervical vagal activity that is synchronized with GES in conscious human subjects, along with methods of discriminating the activity of different nerve fiber groups with respect to conduction speed and treatment response. CONCLUSIONS: Cutaneous vagal CNAP analysis is a useful technique to unmask relationships among GES parameters, vagal recruitment, efficacy and side-effect management. Our results suggest that CNAP-guided GES optimization will provide the most benefit to patients with idiopathic and type 1 diabetic gastroparesis.

Incorporating sulfur reactions and interactions with iron and phosphorus into a general plant-wide model.

Sulfur causes many adverse effects in wastewater treatment and sewer collection systems, such as corrosion, odours, increased oxygen demand, and precipitate formation. Several of these are often controlled by chemical addition, which will impact the subsequent wastewater treatment processes. Furthermore, the iron reactions, resulting from coagulant addition for chemical P removal, interact with the sulfur cycle, particularly in the digester with precipitate formation and phosphorus release. Despite its importance, there is no integrated sulfur and iron model for whole plant process optimization/design that could be readily used in practice. After a detailed literature review of chemical and biokinetic sulfur and iron reactions, a plant-wide model is upgraded with relevant reactions to predict the sulfur cycle and iron cycle in sewer collection systems, wastewater and sludge treatment. The developed model is applied on different case studies.

Burst-Modulated Waveforms Optimize Electrical Stimuli for Charge Efficiency and Fiber Selectivity.

We demonstrate an alternative method of designing electrical stimuli-termed burst modulation--for producing different patterns of nerve fiber recruitment. By delivering electrical charge in bursts of "pulsons"--miniature pulses-instead of as long continuous pulses, our method can optimize the waveform for stimulation efficiency and fiber selectivity. In our in vivo validation experiments, while maintaining C fibers of the rat vagus nerve at ∼ 50% activation with different waveforms, the burst-modulated waveform produced 11% less A fiber activation than the standard rectangular pulse waveform (rectangular: 50.8±1.5% of maximal A response, mean ± standard error of the mean; burst-modulated: 39.8 ±1.3%), which equates to a 20% reduction in A fiber response magnitude. In addition, the burst-modulated waveform required 45% less stimulus charge per phase to maintain 50% C fiber activation (rectangular: 20.7 ±0.86 µC; burst-modulated: 11.3 ±0.41 µC ). Burst-modulated waveforms produced consistent patterns of fiber recruitment within and across animals, which indicate that our methods of stimulus design and response analysis provide a reliable way to study neurostimulation and deliver therapy.

A flexible platform for biofeedback-driven control and personalization of electrical nerve stimulation therapy.

Electrical vagus nerve stimulation is a treatment alternative for many epileptic and depressed patients whose symptoms are not well managed with pharmaceutical therapy. However, the fixed stimulus, open loop dosing mechanism limits its efficacy and precludes major advances in the quality of therapy. A real-time, responsive form of vagus nerve stimulation is needed to control nerve activation according to therapeutic need. This personalized approach to therapy will improve efficacy and reduce the number and severity of side effects. We present autonomous neural control, a responsive, biofeedback-driven approach that uses the degree of measured nerve activation to control stimulus delivery. We demonstrate autonomous neural control in rats, showing that it rapidly learns how to most efficiently activate any desired proportion of vagal A, B, and/or C fibers over time. This system will maximize efficacy by minimizing patient response variability and by minimizing therapeutic failures resulting from longitudinal decreases in nerve activation with increasing durations of treatment. The value of autonomous neural control equally applies to other applications of electrical nerve stimulation.

Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability.

OBJECTIVE: To examine n-3 polyunsaturated fatty acid (PUFA) incorporation into atherosclerotic plaques and the association with plaque inflammation and stability. METHODS AND RESULTS: Patients awaiting carotid endarterectomy (n=121) were randomised to consume control capsules or n-3 PUFA ethyl ester capsules until surgery (median 21 days). The fatty acid compositions of plasma and carotid plaque phospholipids, plaque features, and expression of inflammatory genes were determined. The proportion of eicosapentaenoic acid (EPA) was higher (P<0.0001) in carotid plaque phospholipids in patients in the n-3 PUFA group. Plaques from patients in the n-3 PUFA group had fewer foam cells (P=0.0390). There were no other differences between plaques in the two groups with regard to histological characteristics or morphology. Plaque stability was not different between the two groups. However, the EPA content of plaque phospholipids was inversely associated with plaque instability (P=0.0209), plaque inflammation (P=0.0108), the number of T cells in the plaque (P=0.0097) and a summary score considering a range of plaque features (P=0.0425). Plaques from patients who received n-3 PUFAs had significantly lower levels of mRNA for matrix metalloproteinases (MMP)-7 (P=0.0055), -9 (P=0.0048) and -12 (P=0.0044) and for interleukin-6 (P=0.0395) and intercellular adhesion molecule 1 (P=0.0142). CONCLUSIONS: Atherosclerotic plaques readily incorporate EPA. A higher plaque EPA content is associated with a reduced number of foam cells and T cells, less inflammation and increased stability.

Internal barium shielding to minimize fetal irradiation in spiral chest CT: a phantom simulation experiment.

PURPOSE: To use a phantom to prospectively examine the attenuating effect of barium sulfate as an internal shield to protect the fetus. MATERIALS AND METHODS: In an adult-size phantom, 1- and 2-cm-thick acrylic slabs containing 315 or 630 mL of water, 2% or 40% barium sulfate suspension, and a 1-mm lead sheet were placed under the diaphragm. In 17 experiments, fetal dose was measured by using thermoluminescent dosimeters that were placed immediately under (near field) and 10 cm below (far field) the water slab (eight experiments), barium sulfate slab (eight experiments), and lead sheet (one experiment). In a pulmonary embolism protocol, the phantom was scanned with single-detector spiral computed tomography (CT) at 130 kVp and 230 mAs. RESULTS: The control radiation dose was 3.60 mSv+/-0.54 (standard deviation) with the water slab at near field, where the uterus dome is at near term, and 0.507 mSv+/-0.07 with the water slab at far field, the uterus position during early gestation. Scattered radiation was attenuated 13% and 21% with 2% barium sulfate and 87% and 96% with 40% barium sulfate, as calculated in the near and far fields, respectively, and 99% with the 1-mm lead sheet. The extrapolated attenuations for 5%-40% barium sulfate suspensions indicated that beyond a 30% suspension, attenuation increased further only slightly. CONCLUSION: Study results in the phantom experiment suggest that fetal irradiation during maternal chest CT can be reduced substantially with barium shielding.