Combined high-voltage pulsed radiofrequency and ozone therapy versus ozone therapy alone in treating postherpetic neuralgia: a retrospective comparison.

Postherpetic neuralgia (PHN) is a devastating disease with extraordinarily poor treatment outcomes. Both pulsed radiofrequency (PRF) and ozone have good effects on the treatment of the disease. However, whether PRF and ozone have a synergistic effect on PHN remains unclear. Therefore, this study aimed to assess the therapeutic effects of ozone alone and in combination with PRF in the treatment of PHN. Ninety-one patients with PHN were assigned into two groups: PRF combined with ozone (PRF + ozone group, n = 44) and ozone therapy alone (ozone group, n = 47). In PRF + ozone group, the high-voltage, long-duration PRF was applied to the target dorsal root ganglions. Then ozonated water (11.5 µg/mL) was injected through the inner cannula. In the ozone group, all other processes were the same as those in the PRF + ozone group apart from the electrical stimulation. The therapeutic efficacy was evaluated by visual analog scale and tactile sensation at pre-treatment and post-treatment 3, 6, and 12 months. Compared with pre-treatment data, the visual analog scale score was significantly decreased in both groups after treatment. Compared with the ozone group, the visual analog scale score was significantly decreased in the PRF + ozone group at 3, 6, and 12 months. Similarly, the tactile sensation was also significantly decreased at post-treatment when compared to pre-treatment. However, there were no statistical differences between the two groups. Regression analysis results showed that the history of diabetes mellitus and age had significant negative and positive effects, respectively, on the treatment results. To conclude, the administration of PRF + ozone and ozone therapy alone could both improve pain symptoms. Moreover, treatment effects and total efficacy rates tended to be higher for the combination of PRF and ozone than ozone alone. This conclusion was especially true for long-term therapeutic effects.

Electroacupuncture Alleviates Thalamic Pain in Rats by Suppressing ADCY1 Protein Upregulation.

BACKGROUND: Thalamic pain (TP), also known as central post-stroke pain, is a chronic neuropathic pain syndrome that follows a stroke and is a severe pain that is usually intractable. No universally applicable and effective therapies have been proposed. Emerging studies have reported that electroacupuncture (EA) can potentially be used as an effective therapy for the treatment of neuropathic pain. However, whether EA influences TP and if so, by what potential mechanism, remains poorly understood. OBJECTIVE: The aim of this study was to detect the efficacy of EA and explore possible mechanisms for treating TP. STUDY DESIGN: Controlled animal study. SETTING: The laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine. METHODS: Male Sprague Dawley rats were randomly divided into 3 groups (n = 15 / group): sham-operated (SH) group, thalamic pain model (TP) group, EA treatment (EA) group. After the TP rat model was successfully established, EA was used for intervention. During the experiment, the mechanical pain thresholds of rats were detected among the groups. The right thalamus of the rats was extracted on postoperative day 28 for RNA-sequencing (RNA-Seq) analysis to find the changes in gene expression in different groups of rats. The key genes were screened using reverse transcription-polymerase chain reaction (RT-PCR) detection and subsequently identified with western blotting and immunofluorescence. RESULTS: The mechanical withdrawal threshold (MWT) value of the right facial skin in the TP group and the EA group decreased significantly on the 3rd day after surgery, compared to the SH group (P < 0.01). From 7 to 28 days, the MWT value increased continually in the EA group; however, there was no significant change in the TP group. The results of RNA-seq showed that compared to the TP group, 377 genes changed in the EA group. Moreover, ADCY1 expression increased significantly in the TP group as compared to the SH group, while EA treatment reversed the expression of ADCY1. LIMITATIONS: In addition to ADCY1, the mechanism(s) of other signaling pathways in TP need to be explored in future research. CONCLUSIONS: EA treatment may promote the recovery of TP model rat by regulating ADCY1 expression.

Potential Molecular Mechanisms of Electroacupuncture With Spatial Learning and Memory Impairment Induced by Chronic Pain on a Rat Model.

BACKGROUND: It is frequently reported that neuropathic pain is associated with abnormalities in brain function and structure as well as cognitive deficits. However, the contributing mechanisms have remained elusive. OBJECTIVES: We aimed to investigate the systemic ultrastructural changes of the peripheral nervous system (PNS) and central nervous system (CNS) in rats with trigeminal neuralgia (TN) induced by cobra venom, as well as the effects and mechanisms of electroacupuncture (EA) and pregabalin (PGB) on TN. STUDY DESIGN: This study used an experimental design in rats. SETTING: The research took place in the laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine. METHODS: Male Sprague-Dawley rats were randomly divided into 4 groups (n = 12/group): cobra venom (CV), PGB, EA, and sham-operated (SHAM). The development of pain-related behaviors and spatial learning and memory abilities were measured using video recordings and Morris water maze tests, respectively. The ultrastructural changes of the PNS and CNS were examined using transmission electron microscopy. We also screened the differentially expressed genes and proteins in the prefrontal cortex  and hippocampus using  ribonucleic acid sequencing and isobaric tag for relative and absolute quantitation techniques, respectively. Data for the behavioral tests and molecular biology were analyzed with a one-way analysis of variance. RESULTS: The rats in the CV group exhibited long-lasting pain-like behaviors, cognitive deficits, and systemic ultrastructural changes. Both EA and PGB alleviated the chronic pain syndrome, but EA also inhibited the chronic pain-induced cognitive dysfunction and restored normal cellular structures, while PGB was associated with no improvements. Transcriptomic and proteomic analyses revealed marcks, pak2 and acat1 were altered in rats with TN but were adjusted back to baseline by EA but not by PGB. LIMITATIONS: We examined systemic ultrastructural alterations at different levels of the nervous system; however, the detailed timeline of the damage process was not explicitly delineated.  Moreover, the current study provides only preliminary evidence for the neurobiological mechanisms of cognitive impairment resulting from chronic pain.  Further research is still necessary (using models such as gene knockout rats and cell cultures) before a detailed mechanism can be postulated. CONCLUSIONS: EA treatment may offer significant advantages when compared to PGB for the treatment of cognitive impairment associated with chronic pain. Moreover, marcks, pak2 and acat1 may be the potential therapeutic targets of EA.

Treatment of Femoral Head Osteonecrosis with Ozone Therapy: Pilot Trial of a New Therapeutic Approach.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a progressive and painful disorder due to impaired blood supply to the femoral head, yet little is known about the effect of ozone therapy in femoral head necrosis. OBJECTIVES: We aimed to evaluate the clinical and radiographic outcomes of ozone therapy in the treatment of ONFH. STUDY DESIGN: Nonrandomized clinical trial. SETTINGS: The study was conducted in a single-center, academic institution. METHODS: A total of 71 patients (107 hip joints) with Association Research Circulation Osseous (ARCO) stage-I, II, III, and IV ONFH were included and assigned to undergo either intraarticular O2-O3 mixture hip injections with ozonated autohemotherapy (ozone therapy group, n = 39, 58 hip joints) or protected weight bearing (control group, n = 32, 49 hip joints). The primary outcomes included the Visual Analog Scale (VAS) for pain intensity and Harris Hip Score (HHS) for hip function. The secondary outcomes included bone marrow edema examination, and conversion to total hip arthroplasty (THA). RESULTS: Ozone therapy effectively improves VAS for pain intensity and HHS during the follow-up period compared to the control group. Ozone therapy showed a significant resolution of bone marrow edema of the femoral head compared to the control group (P < 0.001). Thirteen of the 49 hips (26.53%) in the control group underwent THA, whereas only 6 hips (10.34%) in the ozone therapy group required THA during a 30-month follow-up (P = 0.041). The cumulative analysis revealed a low rate of conversion to THA in the ozone therapy group (logrank test; P = 0.022). LIMITATIONS: The study is limited by a single treatment protocol in addition to the lack of a randomized design. CONCLUSIONS: Ozone therapy was associated with significant pain relief, improvement in hip function, and bone marrow edema resolution that may delay the need for THA in patients affected by ONFH.Institutional Review Board (IRB) approval number: HK2018-10-28.Clinical trials registration number: ChiCTR1900023449.

Green Tea Extract Concurrent with an Oral Nutritional Supplement Acutely Enhances Muscle Microvascular Blood Flow without Altering Leg Glucose Uptake in Healthy Older Adults.

Postprandial macro- and microvascular blood flow and metabolic dysfunction manifest with advancing age, so vascular transmuting interventions are desirable. In this randomised, single-blind, placebo-controlled, crossover trial, we investigated the impact of the acute administration of green tea extract (GTE; containing ~500 mg epigallocatechin-3-gallate) versus placebo (CON), alongside an oral nutritional supplement (ONS), on muscle macro- and microvascular, cerebral macrovascular (via ultrasound) and leg glucose/insulin metabolic responses (via arterialised/venous blood samples) in twelve healthy older adults (42% male, 74 ± 1 y). GTE increased m. vastus lateralis microvascular blood volume (MBV) at 180 and 240 min after ONS (baseline: 1.0 vs. 180 min: 1.11 ± 0.02 vs. 240 min: 1.08 ± 0.04, both p < 0.005), with MBV significantly higher than CON at 180 min (p < 0.05). Neither the ONS nor the GTE impacted m. tibialis anterior perfusion (p > 0.05). Leg blood flow and vascular conductance increased, and vascular resistance decreased similarly in both conditions (p < 0.05). Small non-significant increases in brachial artery flow-mediated dilation were observed in the GTE only and middle cerebral artery blood flow did not change in response to GTE or CON (p > 0.05). Glucose uptake increased with the GTE only (0 min: 0.03 ± 0.01 vs. 35 min: 0.11 ± 0.02 mmol/min/leg, p = 0.007); however, glucose area under the curve and insulin kinetics were similar between conditions (p > 0.05). Acute GTE supplementation enhances MBV beyond the effects of an oral mixed meal, but this improved perfusion does not translate to increased leg muscle glucose uptake in healthy older adults.

Neuropathic Pain Creates Systemic Ultrastructural Changes in the Nervous System Corrected by Electroacupuncture but Not by Pregabalin.

PURPOSE: It is unclear whether neuropathological structural changes in the peripheral nervous system and central nervous system can occur in the spared nerve injury model. In this study, we investigated the pathological changes in the nervous system in a model of neuropathic pain as well as the effects of electroacupuncture (EA) and pregabalin (PGB) administration as regards pain relief and tissue repair. PATIENTS AND METHODS: Forty adult male SD rats were equally and randomly divided into 4 groups: spared nerve injury group (SNI, n = 10), SNI with electroacupuncture group (EA, n = 10), SNI with pregabalin group (PGB, n =10) and sham-operated group (Sham, n=10). EA and PGB were given from postoperative day (POD) 14 to 36. EA (2 Hz and 100 Hz alternating frequencies, intensities ranging from 1-1.5-2 mA) was applied to the left "zusanli" (ST36) and "Yanglingquan" (GB34) acupoints for 30 minutes. The mechanical withdrawal thresholds (MWTs) were tested with von Frey filaments. Moreover, the organizational and structural alterations of the bilateral prefrontal cortex, hippocampus, sciatic nerves and the thoracic, lumbar spinal cords and dorsal root ganglions (DRGs) were examined via light and electron microscopy. RESULTS: MWTs of left hind paw demonstrated a remarkable decrease in the SNI model (P < 0.05). In the SNI model, ultrastructural changes including demyelination and damaged neurons were observed at all levels of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, EA improved MWTs and restored the normal structure of neurons. However, the effect was not found in the PGB treatment group. CONCLUSION: Chronic pain can induce extensive damage to the central and peripheral nervous systems. Meanwhile, EA and PGB can both alleviate chronic pain syndromes in rats, but EA also restores the normal cellular structures, while PGB is associated with no improvement.

Cocoa Flavanols Adjuvant to an Oral Nutritional Supplement Acutely Enhances Nutritive Flow in Skeletal Muscle without Altering Leg Glucose Uptake Kinetics in Older Adults.

Ageing is associated with postprandial muscle vascular and metabolic dysfunction, suggesting vascular modifying interventions may be of benefit. Reflecting this, we investigated the impact of acute cocoa flavanol (450-500 mg) intake (versus placebo control) on vascular (via ultrasound) and glucose/insulin metabolic responses (via arterialised/venous blood samples and ELISA) to an oral nutritional supplement (ONS) in twelve healthy older adults (50% male, 72 ± 4 years), in a crossover design study. The cocoa condition displayed significant increases in m. vastus lateralis microvascular blood volume (MBV) in response to feeding at 180 and 240-min after ONS consumption (baseline: 1.00 vs. 180 min: 1.09 ± 0.03, p = 0.05; 240 min: 1.13 ± 0.04, p = 0.002), with MBV at these timepoints significantly higher than in the control condition (p < 0.05). In addition, there was a trend (p = 0.058) for MBV in m. tibialis anterior to increase in response to ONS in the cocoa condition only. Leg blood flow and vascular conductance increased, and vascular resistance decreased in response to ONS (p < 0.05), but these responses were not different between conditions (p > 0.05). Similarly, glucose uptake and insulin increased in response to ONS (p < 0.05) comparably between conditions (p > 0.05). Thus, acute cocoa flavanol supplementation can potentiate oral feeding-induced increases in MBV in older adults, but this improvement does not relay to muscle glucose uptake.

A double-blind randomized controlled trial of the effects of eicosapentaenoic acid supplementation on muscle inflammation and physical function in patients undergoing colorectal cancer resection.

BACKGROUND: Resection of colorectal cancer (CRC) initiates inflammation, mediated at least partly by NFĸB (nuclear factor kappa-light-chain-enhancer of activated B-cells), leading to muscle catabolism and reduced physical performance. Eicosapentaenoic acid (EPA) has been shown to modulate NFĸB, but evidence for its benefit around the time of surgery is limited. OBJECTIVE: To assess the effect of EPA supplementation on muscle inflammation and physical function around the time of major surgery. DESIGN: In a double-blind randomized control trial, 61 patients (age: 68.3 ± 0.95 y; 42 male) scheduled for CRC resection, received 3 g per day of EPA (n = 32) or placebo (n = 29) for 5-days before and 21-days after operation. Lean muscle mass (LMM) (via dual energy X-ray absorptiometry (DXA)), anaerobic threshold (AT) (via cardiopulmonary exercise testing (CPET)) and hand-grip strength (HG) were assessed before and 4-weeks after surgery, with muscle biopsies (m. vastus lateralis) obtained for the assessment of NF-ĸB protein expression. RESULTS: There were no differences in muscle NFĸB between EPA and placebo groups (mean difference (MD) -0.002; 95% confidence interval (CI) -0.19 to 0.19); p = 0.98). There was no difference in LMM (MD 704.77 g; 95% CI -1045.6 g-2455.13 g; p = 0.42) or AT (MD 1.11 mls/kg/min; 95% CI -0.52 mls/kg/min to 2.74 mls/kg/min; p = 0.18) between the groups. Similarly, there was no difference between the groups in HG at follow up (MD 0.1; 95% CI -1.88 to 2.08; p = 0.81). Results were similar when missing data was imputed. CONCLUSION: EPA supplementation confers no benefit in terms of inflammatory status, as judged by NFĸB, or preservation of LMM, aerobic capacity or physical function following major colorectal surgery. CLINICAL TRIALS REFERENCE: NCT01320319.

A New Rat Model of Thalamic Pain Produced by Administration of Cobra Venom to the Unilateral Ventral Posterolateral Nucleus.

BACKGROUND: Thalamic pain is a neuropathic pain syndrome that occurs as a result of thalamic damage. It is difficult to develop therapeutic interventions for thalamic pain because its mechanism is unclear. To better understand the pathophysiological basis of thalamic pain, we developed and characterized a new rat model of thalamic pain using a technique of microinjecting cobra venom into the ventral posterolateral nucleus (VPL) of the thalamus. OBJECTIVES: This study will establish a new thalamic pain rat model produced by administration of cobra venom to the unilateral ventral posterolateral nucleus. STUDY DESIGN: This study used an experimental design in rats. SETTING: The research took place in the laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine. METHODS: Male Sprague-Dawley rats were subjected to the administration of cobra venom or saline into the left VPL. The development of mechanical hyperalgesia and changes in pain-related behaviors and motor function were measured after intrathalamic cobra venom microinjection using the von Frey test, video recording, and cylinder test, respectively. On postoperative days 7 to 35, both electroacupuncture and pregabalin (PGB) were administered to verify that the model reproduced the findings in humans. Moreover, the organizational and structural alterations of the thalamus were examined via transmission electron microscopy (TEM). RESULTS: The threshold for mechanical stimuli in the left facial skin was significantly decreased on day 3 after thalamic pain modeling as compared with pre-venom treatment. Furthermore, the ultrastructural alterations of neurons such as indented neuronal nuclei, damaged mitochondria and endoplasmic reticulum, and dissolved surrounding tissues were observed under TEM. Moreover, electroacupuncture treatment ameliorated mechanical hyperalgesia, pain-like behaviors, and motor dysfunction, as well as restore normal structures of neurons in the thalamic pain rat model. However, no such beneficial effects were noted when PGB was administered. LIMITATIONS: The pathophysiological features were different from the present model and the patients in clinical practice (in most cases strokes, either ischemic or hemorrhagic). CONCLUSION: The cobra venom model may provide a reasonable model for investigating the mechanism of thalamic pain and for testing therapies targeting recovery and pain after thalamic lesions. KEY WORDS: Thalamic pain, cobra venom, electroacupuncture, pregabalin, indented neuronal nuclei, damaged mitochondria, dissolved endoplasmic reticulum, golgi body.

Enhanced Pain Sensitivity with Systemic Ultrastructural Changes of the Nervous Systems after Cobra Venom Injection is Reversed by Electroacupuncture Treatment.

BACKGROUND: Electroacupuncture (EA) has been proved to be effective in treating certain neuropathic pain conditions. The mechanisms of pain relief by EA are not fully understood. There have been sporadic reports of damage in the peripheral nervous system (PNS) and regions of the central nervous system (CNS) at the ultrastructural level following peripheral nerve injury. However, information about possible systemic changes in the PNS and CNS after nerve injury is scarce. OBJECTIVES: The goal of this study was to examine the ultrastructural changes of the nervous system induced by a local injection of cobra venom into the sciatic nerve and to compare the ultrastructural changes in rats with or without treatment with EA or pregabalin. STUDY DESIGN: An experimental study. SETTING: Department of Anesthesiology, Pain Medicine, and Critical Care Medicine, Aviation General Hospital of China Medical University. METHODS: In this study, using an established model of sciatic neuralgia induced by local injection of cobra venom into the sciatic nerve, we examined ultrastructural changes of the PNS and CNS and how they respond to EA and pregabalin treatment. EA and pregabalin were given daily from postoperative day (POD) 14 to 36. Based on previous works, the frequency of EA stimulation of the ST36 and GB34 acupoints was held to 2/100 Hz variable. Pain sensitivity in the sciatic neuralgia rats with and without treatments was assessed using the von Frey test. Ultrastructural alterations were examined bilaterally in the prefrontal cortex, hippocampus, medulla oblongata; and the cervical, thoracic, and lumbar spinal cords on PODs 14, 40, and 60. Ultrastructural examinations were also carried out on the bilateral sciatic nerves and dorsal root ganglion (DRG) at the cervical, thoracic and lumbar levels. In rats treated with EA or pregabalin, the ultrastructure was examined on PODs 40 and 60. RESULTS: Behavioral signs of pain and systemic ultrastructural changes including demyelination were observed at all levels of the PNS and CNS in rats with sciatic neuralgia. After intervention, the mechanical withdrawal thresholds of the EA group and pregabalin group were significantly higher than that of the cobra venom group (P < 0.05). Both EA and pregabalin treatments partially reversed increased cutaneous sensitivity to mechanical stimulation. However, only the EA treatment was able to repair the ultrastructural damages caused by cobra venom. LIMITATIONS: The results confirm that peripheral nerve injury led to the ultrastructural damage at different levels of the CNS as demonstrated with electron microscopy; however, we need to further verify this at both the molecular level and in light microscope level. Sciatic neuralgia induced by cobra venom is a chemical injury, and whether this exactly mimics a peripheral nerve mechanical injury is still unclear. CONCLUSIONS: Local cobra venom injection leads to systemic neurotoxicity. EA and pregabalin alleviate pain via different mechanisms. KEY WORDS: Sciatic neuralgia, cobra venom, demyelination, electroacupuncture, pregabalin, rat model.

Baseline Morphine Consumption May Explain Between-Study Heterogeneity in Meta-analyses of Adjuvant Analgesics and Improve Precision and Accuracy of Effect Estimates.

BACKGROUND: Statistical heterogeneity can increase the uncertainty of results and reduce the quality of evidence derived from systematic reviews. At present, it is uncertain what the major factors are that account for heterogeneity in meta-analyses of analgesic adjuncts. Therefore, the aim of this review was to identify whether various covariates could explain statistical heterogeneity and use this to improve accuracy when reporting the efficacy of analgesics. METHODS: We searched for reviews using MEDLINE, EMBASE, CINAHL, AMED, and the Cochrane Database of Systematic Reviews. First, we identified the existence of considerable statistical heterogeneity (I > 75%). Second, we conducted meta-regression analysis for the outcome of 24-hour morphine consumption using baseline risk (control group morphine consumption) and other clinical and methodological covariates. Finally, we constructed a league table of adjuvant analgesics using a novel method of reporting effect estimates assuming a fixed consumption of 50 mg postoperative morphine. RESULTS: We included 344 randomized controlled trials with 28,130 participants. Ninety-one percent of analyses showed considerable statistical heterogeneity. Baseline risk was a significant cause of between-study heterogeneity for acetaminophen, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, tramadol, ketamine, α2-agonists, gabapentin, pregabalin, lidocaine, magnesium, and dexamethasone (R = 21%-100%; P < .05). There was some evidence that the methodological limitations of the trials explained some of the residual heterogeneity. Type of surgery was not independently associated with analgesic efficacy. Assuming a fixed baseline risk of 50 mg (in order of efficacy), gabapentin, acetaminophen, α2-agonists, nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, pregabalin, tramadol, magnesium, and lidocaine demonstrated moderate clinically significant reductions (>10 mg). We could not exclude a moderate clinically significant effect with ketamine. Dexamethasone demonstrated a small clinical benefit (>5 mg). CONCLUSIONS: We empirically identified baseline morphine consumption as the major source of heterogeneity in meta-analyses of adjuvant analgesics across all surgical interventions. Controlling for baseline morphine consumption, clinicians can use audit data to estimate the morphine-reducing effect of adding any adjuvant for their local population, regardless which surgery they undergo. Moreover, we have utilized these findings to present a novel method of reporting and an amended method of graphically displaying effect estimates, which both reduces confounding from variable baseline risk in included trials and is able to adjust for other clinical and methodological confounding variables. We recommend use of these methods in clinical practice and future reviews of analgesics for postoperative pain.

Effects of leucine-enriched essential amino acid and whey protein bolus dosing upon skeletal muscle protein synthesis at rest and after exercise in older women.

BACKGROUND & AIMS: Impaired anabolic responses to nutrition and exercise contribute to loss of skeletal muscle mass with ageing (sarcopenia). Here, we tested responses of muscle protein synthesis (MPS), in the under represented group of older women, to leucine-enriched essential amino acids (EAA) in comparison to a large bolus of whey protein (WP). METHODS: Twenty-four older women (65 ± 1 y) received (N = 8/group) 1.5 g leucine-enriched EAA supplements (LEAA_1.5), 6 g LEAA (LEAA_6) in comparison to 40 g WP. A primed constant I.V infusion of 13C6-phenylalanine was used to determine MPS at baseline and in response to feeding (FED) and feeding-plus-exercise (FED-EX; 6 × 8 unilateral leg extensions; 75%1-RM). We quantified plasma insulin/AA concentrations, leg femoral blood flow (LBF)/muscle microvascular blood flow (MBF), and anabolic signalling via immunoblotting. RESULTS: Plasma insulineamia and EAAemia were greater and more prolonged with WP than LEAA, although LEAA_6 peaked at similar levels to WP. Neither LEAA or WP modified LBF or MBF. FED increased MPS similarly in the LEAA_1.5, LEAA_6 and WP (P < 0.05) groups over 0-2 h, with MPS significantly higher than basal in the LEAA_6 and WP groups only over 0-4 h. However, FED-EX increased MPS similarly across all the groups from 0 to 4 h (P < 0.05). Only p-p70S6K1 increased with WP at 2 h in FED (P < 0.05), and at 2/4 h in FED-EX (P < 0.05). CONCLUSIONS: In conclusion, LEAA_1.5, despite only providing 0.6 g of leucine, robustly (perhaps maximally) stimulated MPS, with negligible trophic advantage of greater doses of LEAA or even to 40 g WP. Highlighting that composition of EAA, in particular the presence of leucine rather than amount is most crucial for anabolism.

A retrospective matched cohort study evaluating the effects of percutaneous endoscopic gastrostomy feeding tubes on nutritional status and survival in patients with advanced gastroesophageal malignancies undergoing systemic anti-cancer therapy.

BACKGROUND: Many patients with cancer or other systemic illnesses can experience malnutrition. One way to mitigate malnutrition is by insertion of a percutaneous endoscopic gastrostomy feeding tube (PEG tube). The goal of this retrospective matched cohort study is to evaluate if PEG tube placement improved nutritional status and overall survival (OS) in advanced gastroesophageal (GE) cancer patients who are undergoing anti-neoplastic therapy. METHODS: GE cancer patients who were treated and evaluated by a nutritionist and had at least 2 nutritionist follow-up visits were identified. Patients with PEG tube were matched to patients that did not undergo PEG placement (non-PEG). Clinical characteristics, GE symptoms reported at nutrition follow-up visits, and OS were recorded. RESULTS: 20 PEG and 18 non-PEG cases met criteria for further analyses. After correction for multiple testing, there were no OS differences between PEG and non-PEG, treatment naive and previously treated. However, PEG esophageal carcinoma has statistically significant inferior OS compared with non-PEG esophageal carcinoma. PEG placement did not significantly reduce the proportion of patients with weight loss between the initial nutrition assessment and 12-week follow-up. CONCLUSIONS: In this small study, PEG placement had inferior OS outcome for GE esophageal carcinoma, no improvement in OS for other evaluated groups, and did not reduce weight loss between baseline and 12-week follow-up. Unless there is prospective randomized trial that can show superiority of PEG placement in this population, PEG placement in this group cannot be endorsed.

Human skeletal muscle is refractory to the anabolic effects of leucine during the postprandial muscle-full period in older men.

Leucine modulates muscle protein synthesis (MPS), with potential to facilitate accrual/maintenance of muscle mass. Animal models suggest that leucine boluses shortly after meals may prolong MPS and delay onset of a "muscle-full" state. However, the effects of nutrient "top-ups" in humans, and particularly older adults where deficits exist, have not been explored. We determined the effects of a leucine top-up after essential amino acid (EAA) feeding on anabolic signaling, MPS, and muscle energy metabolism in older men. During 13C6-phenylalanine infusion, 16 men (∼70 years) consumed 15 g of EAA with (n=8, FED + LEU) or without (n=8, FED) 3 g of leucine top-up 90 min later. Repeated blood and muscle sampling permitted measurement of fasting and postprandial plasma EAA, insulin, anabolic signaling including mTOR complex 1 (mTORC1) substrates, cellular ATP and phosphorylocreatine, and MPS. Oral EAA achieved rapid insulinemia (12.5 iU·ml-1 25 min post-feed), essential aminoacidemia (3000 µM, 45-65 min post-feed), and activation of mTORC1 signaling. Leucine top-up prolonged plasma EAA (2800 µM, 135 min) and leucine availability (1050 µM, 135 min post-feed). Fasting FSRs of 0.046 and 0.056%·h-1 (FED and FED + LEU respectively) increased to 0.085 and 0.085%·h-1 90-180 min post-feed and returned to basal rates after 180 min in both groups. Phosphorylation of mTORC1 substrates returned to fasting levels 240 min post-feed in both groups. Feeding had limited effect on muscle high-energy phosphates, but did induce eukaryotic elongation factor 2 (eEF2) phosphorylation. We demonstrate the refractoriness of muscle to nutrient-led anabolic stimulation in the postprandial period; thus, leucine supplements should be taken outside of meals, or with meals containing suboptimal protein in terms of either amount or EAA composition.

Cognitive effects of electro-acupuncture and pregabalin in a trigeminal neuralgia rat model induced by cobra venom.

OBJECTIVE: The objective of this study was to investigate the effects of electro-acupuncture (EA) and pregabalin on cognition impairment induced by chronic trigeminal neuralgia (TN) in rats. DESIGN: Controlled animal study. SETTING: Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University. SUBJECTS: Forty adult male Sprague Dawley rats. METHODS: Rats were randomly divided into four groups. The TN model was induced by administration of cobra venom to the left infraorbital nerve. On postoperative day 14, either EA or pregabalin was administered, free behavioral activities were observed. Spatial learning and memory abilities were determined in the Morris water maze. The ultrastructural alterations of the Gasserian ganglion, medulla oblongata and hippocampus were examined by electron microscopy. The changes on long-term potentiation were investigated. RESULTS: After treatment, the exploratory behavior increased and the grooming behavior decreased (P<0.05) for the EA group and pregabalin group compared with the cobra venom group; moreover, demyelination of neurons in Gasserian ganglion and medulla oblongata was reversed. The number of platform site crossings, the average percentages of time in the target quadrant and the field excitatory postsynaptic potential slopes increased (P<0.05) in the EA group compared to the cobra venom group. However, the pregabalin group showed no differences compared to the cobra venom group (P>0.05). Vacuolar degeneration in the hippocampal neurons was mild in the EA group, while it was severe in the pregabalin group. CONCLUSION: EA and pregabalin could alleviate TN induced by cobra venom. EA could also inhibit the cognition deficit induced by TN, while pregabalin could not.

Supplementing essential amino acids with the nitric oxide precursor, l-arginine, enhances skeletal muscle perfusion without impacting anabolism in older men.

Postprandial limb blood flow and skeletal muscle microvascular perfusion reduce with aging. Here we tested the impact of providing bolus essential amino acids (EAA) in the presence and absence of the nitric oxide precursor, l-Arginine (ARG), upon skeletal muscle blood flow and anabolism in older men. Healthy young (YOUNG: 19.7 ± 0.5 y, N = 8) and older men (OLD, 70 ± 0.8 y, N = 8) received 15 g EAA or (older only) 15 g EAA +3 g ARG (OLD-ARG, 69.2 ± 1.2 y, N = 8). We quantified responses in muscle protein synthesis (MPS; incorporation of 13C phenylalanine into myofibrillar proteins), leg and muscle microvascular blood flow (Doppler/contrast enhanced ultrasound (CEUS)) and insulin/EAA in response to EEA ± ARG. Plasma EAA increased similarly across groups but argininemia was evident solely in OLD-ARG (∼320 mmol, 65 min post feed); increases in plasma insulin (to ∼13 IU ml-1) were similar across groups. Increases in femoral flow were evident in YOUNG >2 h after feeding; these effects were blunted in OLD and OLD-ARG. Increases in microvascular blood volume (MBV) occurred only in YOUNG and these effects were isolated to the early postprandial phase (+45% at ∼45 min after feeding) coinciding with detectable arterio-venous differences in EAA reflecting net uptake by muscle. Increases in microvascular flow velocity (MFV) and tissue perfusion (MBV × MFV) occurred (∼2 h) in YOUNG and OLD-ARG, but not OLD. Postprandial protein accretion was greater in YOUNG than OLD or OLD-ARG; the latter two groups being indistinguishable. Therefore, ARG rescues aspects of muscle perfusion in OLD without impacting anabolic blunting, perhaps due to the "rescue" being beyond the period of active EAA-uptake.

Acute cocoa flavanol supplementation improves muscle macro- and microvascular but not anabolic responses to amino acids in older men.

The anabolic effects of nutrition on skeletal muscle may depend on adequate skeletal muscle perfusion, which is impaired in older people. Cocoa flavanols have been shown to improve flow-mediated dilation, an established measure of endothelial function. However, their effect on muscle microvascular blood flow is currently unknown. Therefore, the objective of this study was to explore links between the consumption of cocoa flavanols, muscle microvascular blood flow, and muscle protein synthesis (MPS) in response to nutrition in older men. To achieve this objective, leg blood flow (LBF), muscle microvascular blood volume (MBV), and MPS were measured under postabsorptive and postprandial (intravenous Glamin (Fresenius Kabi, Germany), dextrose to sustain glucose ∼7.5 mmol·L(-1)) conditions in 20 older men. Ten of these men were studied with no cocoa flavanol intervention and a further 10 were studied with the addition of 350 mg of cocoa flavanols at the same time that nutrition began. Leg (femoral artery) blood flow was measured by Doppler ultrasound, muscle MBV by contrast-enhanced ultrasound using Definity (Lantheus Medical Imaging, Mass., USA) perflutren contrast agent and MPS using [1, 2-(13)C2]leucine tracer techniques. Our results show that although older individuals do not show an increase in LBF or MBV in response to feeding, these absent responses are apparent when cocoa flavanols are given acutely with nutrition. However, this restoration in vascular responsiveness is not associated with improved MPS responses to nutrition. We conclude that acute cocoa flavanol supplementation improves muscle macro- and microvascular responses to nutrition, independently of modifying muscle protein anabolism.

Analgesic Effects and Neuropathology Changes of Electroacupuncture on Curing a Rat Model of Brachial Plexus Neuralgia Induced by Cobra Venom.

BACKGROUND: Electroacupuncture (EA) is widely applied to treat neuropathic pain. Brachial plexus neuralgia (BPN) is a common form of chronic persistent pain. Few studies have evaluated the analgesic effects and mechanism of EA using the novel animal model of BPN. OBJECTIVE: To observe the curative effects of repeated EA on curing BPN induced by administration of cobra venom to the lower trunk of the right brachial plexus. STUDY DESIGN: Controlled animal study. SETTING: Department of Anesthesiology, Pain Medicine & Critical Care Medicine, Aviation General Hospital of China Medical University. METHODS: Sixty-six adult male Sprague-Dawley rats were equally and randomly divided into the following groups: normal control (NC), brachial plexus neuralgia (BPN), BPN with sham EA stimulation, BPN with EA stimulation starting on postoperative day 1 (EA1), and BPN with EA stimulation starting on postoperative day 12 (EA12). The BPN model was established by administration of cobra venom to the lower trunk of the right brachial plexus. On postoperative day 1 or day 12, EA (constant aquare wave, 2 Hz and 100 Hz alternating frequencies, intensities ranging from 1 - 1.5 - 2 mA) was applied to the right "Shousanli" (LI10) and "Quchi" (LI11) acupoints for 30 minutes, once every other day for 12 times in both groups. Mechanical withdrawal thresholds (MWT) were tested with von Frey filaments. Video recordings were conducted to analyze the spontaneous exploratory behaviors. Moreover, the organizational and structural alterations of the right brachial plexus and cervical cord (C8-T1) were examined via light and electron microscopy. RESULTS: Following the production of the BPN model, the MWT of both ipsilateral and contralateral paws demonstrated a profound decrease (P < 0.05). But after EA interventions, the MWT showed a significant increase (P < 0.05). In comparison to the EA12 group, the analgesic effects of the EA1 group were more significant, and similar results were observed in exploratory behaviors. However, grooming behaviors did not demonstrate significant differences. Meanwhile, on day 12 after surgery it was observed under light microscopy that the inflammatory response in the right brachial plexus and cervical cord (C8-T1) were significantly attenuated after EA stimulation. Furthermore, the demyelination of the brachial plexus and cervical cord (C8-T1) were also reversed. LIMITATIONS: Limitations include the fact that there was demyelination of the cervical cord (C8-T1) in the control group because of inappropriate manipulation. CONCLUSION: Repeated EA contributes significant analgesic effects in the treatment of BPN.

A validation of the application of D(2)O stable isotope tracer techniques for monitoring day-to-day changes in muscle protein subfraction synthesis in humans.

Quantification of muscle protein synthesis (MPS) remains a cornerstone for understanding the control of muscle mass. Traditional [(13)C]amino acid tracer methodologies necessitate sustained bed rest and intravenous cannulation(s), restricting studies to ~12 h, and thus cannot holistically inform on diurnal MPS. This limits insight into the regulation of habitual muscle metabolism in health, aging, and disease while querying the utility of tracer techniques to predict the long-term efficacy of anabolic/anticatabolic interventions. We tested the efficacy of the D2O tracer for quantifying MPS over a period not feasible with (13)C tracers and too short to quantify changes in mass. Eight men (22 ± 3.5 yr) undertook one-legged resistance exercise over an 8-day period (4 × 8-10 repetitions, 80% 1RM every 2nd day, to yield "nonexercised" vs. "exercise" leg comparisons), with vastus lateralis biopsies taken bilaterally at 0, 2, 4, and 8 days. After day 0 biopsies, participants consumed a D2O bolus (150 ml, 70 atom%); saliva was collected daily. Fractional synthetic rates (FSRs) of myofibrillar (MyoPS), sarcoplasmic (SPS), and collagen (CPS) protein fractions were measured by GC-pyrolysis-IRMS and TC/EA-IRMS. Body water initially enriched at 0.16-0.24 APE decayed at ~0.009%/day. In the nonexercised leg, MyoPS was 1.45 ± 0.10, 1.47 ± 0.06, and 1.35 ± 0.07%/day at 0-2, 0-4, and 0-8 days, respectively (~0.05-0.06%/h). MyoPS was greater in the exercised leg (0-2 days: 1.97 ± 0.13%/day; 0-4 days: 1.96 ± 0.15%/day, P < 0.01; 0-8 days: 1.79 ± 0.12%/day, P < 0.05). CPS was slower than MyoPS but followed a similar pattern, with the exercised leg tending to yield greater FSRs (0-2 days: 1.14 ± 0.13 vs. 1.45 ± 0.15%/day; 0-4 days: 1.13 ± 0.07%/day vs. 1.47 ± 0.18%/day; 0-8 days: 1.03 ± 0.09%/day vs. 1.40 ± 0.11%/day). SPS remained unchanged. Therefore, D2O has unrivaled utility to quantify day-to-day MPS in humans and inform on short-term changes in anabolism and presumably catabolism alike.