Selective neural inhibition via photobiomodulation alleviates behavioral hypersensitivity associated with small sensory fiber activation.

OBJECTIVE: Photobiomodulation at higher irradiances has great potential as a pain-alleviating method that selectively inhibits small diameter nerve fibers and corresponding sensory experiences, such as nociception and heat sensation. The longevity and magnitude of these effects as a function of laser irradiation parameters at the nerve was explored. METHODS: In a rodent chronic pain model (spared nerve injury-SNI), light was applied directly at the sural nerve with four delivery schemes: two irradiance levels (7.64 and 2.55 W/cm2 ) for two durations each, corresponding to either 4.8 or 14.4 J total energy, and the effect on sensory hypersensitivities was evaluated. RESULTS: At emitter irradiances of 7.64 W/cm2 (for 240 s), 2.55 W/cm2 (for 720 s), and 7.64 W/cm2 (for 80 s) the heat hypersensitivity was relieved the day following photobiomodulation (PBM) treatment by 37 ± 8.1% (statistically significant, p < 0.001), 26% ± 6% (p = 0.072), and 28 ± 6.1% (statistically significant, p = 0.032), respectively, and all three treatments reduced the hypersensitivity over the course of the experiment (13 days) at a statistically significant level (mixed-design analysis of variance, p < 0.05). The increases in tissue temperature (5.3 ± 1.0 and 1.3 ± 0.4°C from 33.3°C for the higher and lower power densities, respectively) at the neural target were well below those typically associated with permanent action potential disruption. CONCLUSIONS: The data from this study support the use of direct PBM on nerves of interest to reduce sensitivities associated with small-diameter fiber activity.

The effect of post-discharge oral nutritional supplements on outcomes after gastrointestinal surgery: A systematic review and meta-analysis.

BACKGROUND: Malnutrition is a risk-factor for adverse postoperative outcomes. This systematic review and meta-analysis evaluated the impact of post-discharge oral nutritional supplements (ONS) on outcomes in patients undergoing gastrointestinal surgery. METHODS: The Medline and Embase databases were searched for randomised clinical trials in patients undergoing gastrointestinal surgery who had received ONS for at least two weeks after discharge from hospital. The primary endpoint was weight change. Secondary endpoints included quality of life, total lymphocyte count, total serum protein and serum albumin. Analysis was performed using RevMan5.4 software. RESULTS: Fourteen studies with 2480 participants (1249 ONS/1231 controls) were included. Pooling of results revealed that a reduction in postoperative weight loss in patients taking ONS, when compared with control: overall weighted mean difference (WMD) -1.69 kg, 95% CI -2.98 to -0.41, P = 0.01. Serum albumin concentration was increased in the ONS group: WMD = 1.06 g/L, 95% CI 0.04 to 2.07, P = 0.04. Haemoglobin was also increased: WMD = 2.91 g/L, 95% CI 0.58 to 5.25, P = 0.01. Total serum protein, total lymphocyte count, total cholesterol and quality of life did not differ between the groups. Patient compliance was relatively poor across the studies and there was variability in the composition of ONS, volume consumed and surgical procedures performed. CONCLUSIONS: There was a reduction in postoperative weight loss and an improvement in some biochemical parameters in patients receiving ONS after gastrointestinal surgery. Future RCTs with more consistent methodologies are needed to investigate the efficacy of ONS after discharge from hospital following gastrointestinal surgery.

D-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception.

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of D-cystine diethyl ester (D-cystine diEE) or D-cystine dimethyl ester (D-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of D-cystine diEE (500 µmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by D-cystine diME (500 µmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by D-cystine diEE. D-cystine diEE and D-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the D-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation.

Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling.

S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase-independent (sGC-independent) effects are stereoselective - that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) - and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays - followed by unbiased proteomic analysis - to identify voltage-gated K+ channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO-Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvß2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance.

Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes.

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in ß-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.

Immunonutrition for patients undergoing surgery for head and neck cancer.

BACKGROUND: Patients with head and neck cancer are often malnourished. Surgery for such cancers is complex and may be undertaken after a course of radiotherapy. As a result, patients may have postoperative complications such as fistulae and wound infections, as well as more generalised infections such as pneumonia. One possible way to enhance recovery, and reduce the incidence of these complications, is by improving nutrition. Nutritional formulas that deliver basic nutrients as well as amino acids (arginine and glutamine), ribonucleic acid (RNA) and/or lipids (omega-3 fatty acids) are known as immunonutrition. OBJECTIVES: To assess the effects of immunonutrition treatment, compared to standard feeding, on postoperative recovery in adult patients undergoing elective (non-emergency) surgery for head and neck cancer. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 February 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing immunonutrition given either preoperatively, postoperatively or perioperatively to adult patients (18 years of age or older) undergoing an elective surgical procedure for head and neck cancer, compared with a control group receiving either standard polymeric nutritional supplements or no supplements. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were: length of hospital stay (days), wound infection, fistula formation and adverse events/tolerance of feeds, as defined by trial authors. Secondary outcomes were: all-cause mortality and postoperative complications (as defined by trial authors). We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 19 RCTs (1099 participants). The mean age of participants ranged from 47 to 66 years. Most studies (12/19) had fewer than 25 patients in each treatment group. Most studies (16/19) used immunonutrition formulas containing arginine, but there was variation in the actual products and amounts used, and in the length of intervention postoperatively. Follow-up time for outcome measurement varied considerably across studies, ranging from five days to greater than or equal to 16 months.Primary outcomesWe found no evidence of a difference in the length of hospital stay (mean difference -2.5 days, 95% confidence interval (CI) -5.11 to 0.12; 10 studies, 757 participants; low-quality evidence). Similarly, we found no evidence of an effect of immunonutrition on wound infection (risk ratio (RR) 0.94, 95% CI 0.70 to 1.26; 12 studies, 812 participants; very low-quality evidence). Fistula formation may be reduced with immunonutrition; the absolute risks were 11.3% and 5.4% in the standard care and immunonutrition groups, with a RR of 0.48 (95% CI 0.27 to 0.85; 10 studies, 747 participants; low-quality evidence). We found no evidence of a difference in terms of tolerance of feeds ('adverse events') between treatments (RR 1.33, 95% CI 0.86 to 2.06; 9 studies, 719 participants; very low-quality evidence).Secondary outcomesWe found no evidence of a difference between treatments in all-cause mortality (RR 1.33, 95% CI 0.48 to 3.66; 14 studies, 776 participants; low-quality evidence). Other postoperative complications such as pneumonia and urinary tract infections were not commonly reported. AUTHORS' CONCLUSIONS: The risk of postoperative fistula formation may be reduced with immunonutrition, but we found no evidence of an effect of immunonutrition on any of the other outcomes that we assessed. The studies included in this review were generally small or at high risk of bias (or both). We judged the overall quality of the evidence to be low for the outcomes length of hospital stay and all-cause mortality, and very low for wound infection and adverse events. Further research should include larger, better quality studies.

Evaluation of the possible role of prostaglandin F(2 alpha) in laminitis induced in horses by nasogastric administration of black walnut heartwood extract.

OBJECTIVE: To provide insights into the role of prostaglandin F(2 alpha) (PGF(2 alpha)) in the developmental stages of laminitis induced in horses by ingestion of black walnut heartwood extract (BWHE). SAMPLE POPULATION: 10 adult mixed-breed horses. PROCEDURES: Horses were separated into 2 groups and were euthanatized at 12 hours after placebo (water) administration (control horses) or after BWHE administration and development of Obel grade 1 laminitis. Blood samples were obtained to determine plasma PGF(2 alpha) concentrations hourly for the first 4 hours and subsequently every 2 hours after substance administration. Laminar arteries and veins were isolated, and responses to increasing concentrations of PGF(2 alpha) were measured before and after preincubation of blood vessels with prostanoid and thromboxane receptor antagonists SQ 29,548, SC-19220, and AH 6809. RESULTS: Plasma PGF(2 alpha) concentrations increased in horses given BWHE; the WBC count decreased concurrently. In control horses, PGF(2 alpha) was a potent contractile agonist for laminar veins but not for laminar arteries. In horses given BWHE, PGF(2 alpha) was similarly selective for laminar veins; however, the magnitude of PGF(2 alpha)-induced venoconstriction was less than that in control horses. After preincubation with SQ 29,548, laminar veins from control horses responded to PGF(2 alpha) with a small degree of dilation, whereas laminar veins from horses given BWHE did not. CONCLUSIONS AND CLINICAL RELEVANCE: PGF(2 alpha) may play a role in the inflammatory and vascular dysfunction associated with the prodromal stages of laminitis. Prostanoids such as PGF(2 alpha) may be viable targets for the prevention of acute laminitis in horses.

Thromboxane and isoprostanes as inflammatory and vasoactive mediators in black walnut heartwood extract induced equine laminitis.

Inflammation and vascular dysfunction occur concurrently during the prodromal stages of equine laminitis. The aim of this study was to provide insights into the role that thromboxane and isoprostanes may play in the development of black walnut heartwood extract (BWHE)-induced laminitis. Horses were divided into two groups, either control or BWHE-administered horses. Plasma concentrations of thromboxane increased transiently after administration of BWHE and coincided with the nadir in white blood cell counts, whereas plasma concentrations of iso-prostaglandin PGF(2alpha) (iso-PGF(2alpha)) did not change in either group. At 12h (for the control group) or Obel grade 1 laminitis (for the BWHE group) the horses were euthanized and laminar tissue collected. Laminar arteries and veins were used in functional studies with vasoconstrictor substances and tissue samples were used for the determination of laminar iso-PGF(2alpha) concentrations. Laminar tissue concentrations of iso-PGF(2alpha) were significantly greater in BWHE horses when compared to control horses. In parallel studies concentrations of iso-PGF(2alpha) in laminar tissue samples obtained 1.5 and 3h after administration of BWHE were indistinguishable from those for control horses at 3 or 12h after administration of an equal volume of water. Laminar vessel constrictor responses to either a thromboxane mimetic (U46619), iso-prostaglandin PGE(2) (iso-PGE(2)) or iso-PGF(2alpha) were determined using small vessel myographs. In some vessels, the effects of putative prostanoid and thromboxane receptor antagonists, SQ 29,548, SC-19220 and AH 6809, upon contractile responses were determined. In control horses, U46619, iso-PGF(2alpha) and iso-PGE(2) more potently and efficaciously constricted laminar veins when compared to laminar arteries. Responses of laminar veins from BWHE horses to iso-PGE(2) were similar to those of laminar veins from control horses, whereas iso-PGF(2alpha) elicited significantly greater responses in laminar veins from BWHE horses when compared to controls. In contrast, responses to U46619 were smaller in laminar veins isolated from BWHE horses when compared to those in laminar veins from control horses. In the presence of SQ 29,548, iso-PGF(2alpha) elicited a small dilation in laminar veins from control horses, which was not apparent in laminar veins from BWHE horses. These results are consistent with both systemic and local inflammatory events occurring during the prodromal stages of BWHE-induced laminitis. Because laminar veins are sensitive to thromboxane and isoprostanes, these substances may act as conduits between the inflammatory and vascular events occurring in laminitis and may be therapeutic targets for this crippling condition.

Effect of Lactobacillus acidophilus supernatants on body weight and leptin expression in rats.

BACKGROUND: Lactobacillus extracts and supernatants have been used as probiotics in human and veterinary medicine for their ability to enhance wound healing and immunity. Previous data from our laboratory demonstrated that Lactobacillus supernatant (LS) stimulated wound healing, angiogenesis and proliferation of embryonic cells after topical application. This current study shows that LS after its administration into the cerebral ventricles of male rats exerts systemic effects. METHODS: The right lateral cerebral ventricle of young male rats was accessed through intracerebroventricular cannulation (ICV) under anesthesia and aseptic conditions. One group of control rats received saline solution, a second control group received 0.8 M lactic acid solution (to control for acidity of LS), and a third group received LS. The animals were sacrificed 12, 24, 48, 96 and 120 hours after the injection. Selected tissues were collected, fixed in 10% buffered formalin and used for immunohistochemistry and in situ hybridization. Other tissues were frozen and extracted for immunoblotting RESULTS: LS-injected animals had a slight decrease in body weight when compared to their initial weight and to both control groups. Using immunohistochemistry and in situ hybridization leptin expression was studied in multiple brain sections and peripheral adipose tissue of control and LS-injected rats. Strong cytoplasmic stain was observed by both techniques in neurons of the cerebral cortex, thalamus, hypothalamus, hippocampus and, to lesser degree, in the cells of the choroid plexus in the LS-injected rats. Control animals demonstrated much less intense staining in neurons located in the same regions using immunohistochemistry and almost no staining with in situ hybridization technique. Adipose tissue exhibited slight presence of leptin in LS-treated animals. In contrast no immunohistochemical staining for GM-CSF and TNFalpha was observed in brains from control and treated rats. Western blotting showed mild increase in leptin and leptin receptors in intestines and retroperitoneal adipose tissues of LS-injected rats. CONCLUSION: This study demonstrates that direct administration of LS into rat CNS leads to a decrease in body weight of rats and an increase in the expression of leptin in specific areas of the brain and retroperitoneal adipose tissue.

Dietary structured lipids and phytosteryl esters: blood lipids and cardiovascular status in spontaneously hypertensive rats.

This study examined the dietary effects of enzymatically modified sesame oil with caprylic acid (structured lipids, SL) and phytosteryl esters (PE) on blood lipid profiles and cardiovascular parameters of spontaneously hypertensive rats (SHR) fed high-fat and high-cholesterol (HFHC) diets. The dietary groups were: normal diet (control), sesame oil (SO), SL, SO fortified with PE (SOP), and SL fortified with PE (SLP). After 9 weeks of feeding, the body weights, liver weights, and liver weight/body weight ratios in all HFHC-fed groups were higher than controls. Plasma total and LDL cholesterol levels in all HFHC-fed groups were similar to one another but higher than those in controls. Plasma HDL cholesterol levels in rats fed SOP and SLP were higher than those in controls or rats fed SO and SL. Plasma HDL/total cholesterol ratios in rats fed SOP and SLP were similar to those in controls and were higher than those in rats fed SO and SL. There was no difference in plasma lipid profiles between rats fed SO and SL. Arterial blood pressures (BP) in conscious HFHC-fed rats were similar to those in controls whereas heart rates (HR) in all HFHC-fed groups were similar to one another but were higher than that in controls. These findings demonstrate that (1) the dietary effects of SL on plasma lipid profiles and resting BP and HR are similar to those of SO, (2) PE had positive effects on plasma lipid profiles, and (3) 9-week intake of SL and PE did not have pronounced effects on resting BP but induced tachycardia in SHR.

Dietary effects of structured lipids and phytosteryl esters on cardiovascular function in spontaneously hypertensive rats.

This study examined the dietary effects of sesame oil (SO)-based structured lipids (SL) and phytosteryl esters (PE) on cardiovascular function in conscious spontaneously hypertensive rats (SHR) fed high-fat (HF) diets (20% w/w fat). The dietary groups were as follows: normal diet (4.5% w/w fat), SO, SO fortified with PE (SOP), SL, and SL fortified with PE (SLP). Mean arterial blood pressures were similar in all groups, whereas resting heart rates (HR) were higher in all HF-fed groups. The pressor responses to the alpha1-adrenoceptor agonist, phenylephrine (5 microg/kg), were similar in all groups. However, the pressor responses to phenylephrine (10 microg/kg) were diminished in SO- or SL-fed SHR, whereas they were not diminished in SOP- or SLP-fed SHR. The depressor responses elicited by the nitric oxide (NO) donor, sodium nitroprusside (5 and 10 microg/kg), were not diminished in HF-fed rats. Baroreflex-mediated changes in HR were variously decreased in the HF-fed groups, and this decrease tended to be greater in SOP and SLP than in SO and SL groups. The depressor and tachycardic responses elicited by the beta-adrenoceptor agonist, isoproterenol, were equivalent in all groups. The depressor responses elicited by the endothelium-dependent agonist, acetylcholine (0.1 microg/kg), and the hypertension elicited by the NO synthesis inhibitor, NG-nitro-L-arginine methylester (25 micromol/kg), were similar in all groups. These findings demonstrate that (1) HF diets increase resting HR and impair baroreflex function in SHR, whereas they do not obviously affect endothelium-dependent vasodilation, and (2) fortification with PE may be deleterious to cardiovascular function (eg, baroreflex activity) in SHR.