Vitamin C supplementation for diabetes management: A comprehensive narrative review.

Growing evidence suggests that vitamin C supplementation may be an effective adjunct therapy in the management of people with diabetes. This paper critically reviews the current evidence on effects of vitamin C supplementation and its potential mechanisms in diabetes management. Evidence from meta-analyses of randomized controlled trials (RCTs) show favourable effects of vitamin C on glycaemic control and blood pressure that may be clinically meaningful, and mixed effects on blood lipids and endothelial function. However, evidence is mostly of low evidence certainty. Emerging evidence is promising for effects of vitamin C supplementation on some diabetes complications, particularly diabetic foot ulcers. However, there is a notable lack of robust and well-designed studies exploring effects of vitamin C as a single compound supplement on diabetes prevention and patient-important outcomes (i.e. prevention and amelioration of diabetes complications). RCTs are also required to investigate potential preventative or ameliorative effects of vitamin C on gestational diabetes outcomes. Oral vitamin C doses of 500-1000 mg per day are potentially effective, safe, and affordable for many individuals with diabetes. However, personalisation of supplementation regimens that consider factors such as vitamin C status, disease status, current glycaemic control, vitamin C intake, redox status, and genotype is important to optimize vitamin C's therapeutic effects safely. Finally, given a high prevalence of vitamin C deficiency in patients with complications, it is recommended that plasma vitamin C concentration be measured and monitored in the clinic setting.

A Comparison of Sodium Citrate and Sodium Bicarbonate Ingestion: Blood Alkalosis and Gastrointestinal Symptoms.

This study compared the recommended dose of sodium citrate (SC, 500 mg/kg body mass) and sodium bicarbonate (SB, 300 mg/kg body mass) for blood alkalosis (blood [HCO3-]) and gastrointestinal symptoms (GIS; number and severity). Sixteen healthy individuals ingested the supplements in a randomized, crossover design. Gelatin capsules were ingested over 15 min alongside a carbohydrate-rich meal, after which participants remained seated for forearm venous blood sample collection and completion of GIS questionnaires every 30 min for 300 min. Time-course and session value (i.e., peak and time to peak) comparisons of SC and SB supplementation were performed using linear mixed models. Peak blood [HCO3-] was similar for SC (mean 34.2, 95% confidence intervals [33.4, 35.0] mmol/L) and SB (mean 33.6, 95% confidence intervals [32.8, 34.5] mmol/L, p = .308), as was delta blood [HCO3-] (SC = 7.9 mmol/L; SB = 7.3 mmol/L, p = .478). Blood [HCO3-] was ≥6 mmol/L above baseline from 180 to 240 min postingestion for SC, significantly later than for SB (120-180 min; p < .001). GIS were mostly minor, and peaked 80-90 min postingestion for SC, and 35-50 min postingestion for SB. There were no significant differences for the number or severity of GIS reported (p > .05 for all parameters). In summary, the recommended doses of SC and SB induce similar blood alkalosis and GIS, but with a different time course.

Systematic review of electrophysiology procedures in patients with obstruction of the inferior vena cava.

AIMS: The objective of the study was to conduct a systematic review to describe and compare the different approaches for performing cardiac electrophysiology (EP) procedures in patients with interrupted inferior vena cava (IVC) or equivalent entities causing IVC obstruction. METHODS: We conducted a structured search to identify manuscripts reporting EP procedures with interrupted IVC or IVC obstruction of any aetiology published up until August 2020. No restrictions were applied in the search strategy. We also included seven local cases that met inclusion criteria. RESULTS: The analysis included 142 patients (mean age 48.9 years; 48% female) undergoing 143 procedures. Obstruction of the IVC was not known before the index procedure in 54% of patients. Congenital interruption of IVC was the most frequent cause (80%); and, associated congenital heart disease (CHD) was observed in 43% of patients in this setting. The superior approach for ablation was the most frequently used strategy (52%), followed by inferior approach via the azygos or hemiazygos vein (24%), transhepatic approach (14%), and retroaortic approach (10%). Electroanatomical mapping (58%), use of long sheaths (41%), intracardiac echocardiography (19%), transesophageal echocardiography (15%) and remote controlled magnetic navigation (13%) were used as adjuncts to aid performance. Ablation was successful in 135 of 140 procedures in which outcomes were reported. Major complications were only reported in patients undergoing AF ablation, including two patients with pericardial effusion, one of whom required surgical repair, and another patient who died after inadvertent entry into an undiagnosed atrioesophageal fistula from a previous procedure. CONCLUSION: The superior approach is most frequent approach for performing EP procedures in the setting of obstructed IVC. Transhepatic approach is a feasible alternative, and may provide a "familiar approach" for transseptal access when it is required. Adjunctive use of long sheaths, intravascular echocardiography, electro-anatomical mapping and remote magnetic navigation may be helpful, especially if there is associated complex CHD. With careful planning, EP procedures can usually be successfully performed with a low risk of complications.

Spurious Serum Hormone Immunoassay Results: Causes, Recognition, Management.

For over 50 years, immunoassays have been extensively used to quantitate hormones in blood, other fluids and tissues. Each assay has its own sensitivity, specificity and other analytical components. Despite the differences between commercial products, these assays provide important clinical information about hormone levels in patients. However, inaccurate results can occur because of technical issues, as well as patient-specific factors that can interfere with immunoassay hormone measurements. The latter include excessive normal blood or serum components, the presence of cross-reacting substances, extremely high levels of hormones leading to the high-dose hook effect, and interference from a variety of endogenous factors such as human antibodies that interact with the assay components or high levels of biotin in the serum from exogenous ingestion. This article briefly reviews the sources and recognition of endogenous interference, and describes methods to determine the correct serum hormone concentration.

Thalamic projections to the subthalamic nucleus contribute to movement initiation and rescue of parkinsonian symptoms.

The parafascicular nucleus (Pf) of the thalamus provides major projections to the basal ganglia, a set of subcortical nuclei involved in action initiation. Here, we show that Pf projections to the subthalamic nucleus (STN), but not to the striatum, are responsible for movement initiation. Because the STN is a major target of deep brain stimulation treatments for Parkinson's disease, we tested the effect of selective stimulation of Pf-STN projections in a mouse model of PD. Bilateral dopamine depletion with 6-OHDA created complete akinesia in mice, but Pf-STN stimulation immediately and markedly restored a variety of natural behaviors. Our results therefore revealed a functionally novel neural pathway for the initiation of movements that can be recruited to rescue movement deficits after dopamine depletion. They not only shed light on the clinical efficacy of conventional STN DBS but also suggest more selective and improved stimulation strategies for the treatment of parkinsonian symptoms.

Factors Influencing Blood Alkalosis and Other Physiological Responses, Gastrointestinal Symptoms, and Exercise Performance Following Sodium Citrate Supplementation: A Review.

This review aimed to identify factors associated with (a) physiological responses, (b) gastrointestinal (GI) symptoms, and (c) exercise performance following sodium citrate supplementation. A literature search identified 33 articles. Observations of physiological responses and GI symptoms were categorized by dose (< 500, 500, and > 500 mg/kg body mass [BM]) and by timing of postingestion measurements (in minutes). Exercise performance following sodium citrate supplementation was compared with placebo using statistical significance, percentage change, and effect size. Performance observations were categorized by exercise duration (very short < 60 s, short ≥ 60 and ≤ 420 s, and longer > 420 s) and intensity (very high > 100% VO2max and high 90-100% VO2max). Ingestion of 500 mg/kg BM sodium citrate induced blood alkalosis more frequently than < 500 mg/kg BM, and with similar frequency to >500 mg/kg BM. The GI symptoms were minimized when a 500 mg/kg BM dose was ingested in capsules rather than in solution. Significant improvements in performance following sodium citrate supplementation were reported in all observations of short-duration and very high-intensity exercise with a 500 mg/kg BM dose. However, the efficacy of supplementation for short-duration, high-intensity exercise is less clear, given that only 25% of observations reported significant improvements in performance following sodium citrate supplementation. Based on the current literature, the authors recommend ingestion of 500 mg/kg BM sodium citrate in capsules to induce alkalosis and minimize GI symptoms. Supplementation was of most benefit to performance of short-duration exercise of very high intensity; further investigation is required to determine the importance of ingestion duration and timing.

Hypothalamic-Extended Amygdala Circuit Regulates Temporal Discounting.

Choice behavior is characterized by temporal discounting, i.e., preference for immediate rewards given a choice between immediate and delayed rewards. Agouti-related peptide (AgRP)-expressing neurons located in the arcuate nucleus of the hypothalamus (ARC) regulate food intake and energy homeostasis, yet whether AgRP neurons influence choice behavior and temporal discounting is unknown. Here, we demonstrate that motivational state potently modulates temporal discounting. Hungry mice (both male and female) strongly preferred immediate food rewards, yet sated mice were largely indifferent to reward delay. More importantly, selective optogenetic activation of AgRP-expressing neurons or their axon terminals within the posterior bed nucleus of stria terminalis (BNST) produced temporal discounting in sated mice. Furthermore, activation of neuropeptide Y (NPY) type 1 receptors (Y1Rs) within the BNST is sufficient to produce temporal discounting. These results demonstrate a profound influence of hypothalamic signaling on temporal discounting for food rewards and reveal a novel circuit that determine choice behavior.SIGNIFICANCE STATEMENT Temporal discounting is a universal phenomenon found in many species, yet the underlying neurocircuit mechanisms are still poorly understood. Our results revealed a novel neural pathway from agouti-related peptide (AgRP) neurons in the hypothalamus to the bed nucleus of stria terminalis (BNST) that regulates temporal discounting in decision-making.

Effects of Vitamin C Supplementation on Glycemic Control and Cardiovascular Risk Factors in People With Type 2 Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Evidence suggests that vitamin C supplementation could be a potential therapy in type 2 diabetes. However, its effectiveness and evidence quality require further evaluation. PURPOSE: To investigate the efficacy of oral vitamin C supplementation in improving glycemic control, cardiovascular risk factors, and oxidative stress in people with type 2 diabetes. DATA SOURCES: Databases (PubMed, Embase, Scopus, Cochrane Library) and clinical trial registries were searched for randomized controlled trials up to 8 September 2020. STUDY SELECTION: Trials in adults with type 2 diabetes were included. Trials were excluded if supplements were not exclusive to vitamin C and if <2 weeks in duration. DATA EXTRACTION: Primary outcomes were HbA1c, glucose, cholesterol, triglycerides, and blood pressure (BP). Data were extracted for changes in outcomes between vitamin C and control groups. Evidence certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluation methods. DATA SYNTHESIS: Twenty-eight studies (N = 1,574 participants) were included in the review. Outcomes that changed to a statistically and clinically significant extent with vitamin C were systolic BP (mean difference -6.27 [95% CI -9.60, -2.96] mmHg; P = 0.0002), with moderate evidence certainty, and HbA1c (-0.54% [-0.90, -0.17]; P = 0.004) and diastolic BP (-3.77 [-6.13, -1.42] mmHg; P = 0.002) with very low evidence certainty. LIMITATIONS: Studies were predominantly short term (<6 months) with a small number of participants (n < 100). CONCLUSIONS: While evidence from short-term studies suggests that vitamin C supplementation may improve glycemic control and BP in people with type 2 diabetes, vitamin C supplementation cannot currently be recommended as a therapy until larger, long-term, and high-quality trials confirm these findings.

A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.

BACKGROUND: Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. METHODS: Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. FINDINGS: Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. CONCLUSION: Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.

A practice-based evidence investigation of God representations in spiritually integrated psychotherapies.

OBJECTIVE: This practice-based evidence study examined trajectories of God representations and psychological distress among Christians participating in spiritually integrated psychotherapies (SIPs). METHODS: In total, 17 clinicians practicing SIPs in a mid-sized city on the US Gulf Coast implemented session-to-session assessments of these outcomes with 158 clients over a 4-month period and also reported their use of specific spiritual interventions after each session (e.g., affirmed client's divine worth). RESULTS: Multivariate growth modeling revealed clients' psychological distress decreased over the study period whereas authoritarian God representations increased and benevolent God representations remained stable. In addition, clients who increased in benevolent representations of God had a greater likelihood of experiencing alleviation of psychological distress. CONCLUSION: These findings affirm the potential efficacy of SIPs and cultural importance of belief in a benevolent deity as a source of strength, identity, and potential healing among Christians clients who prefer a spiritually integrated approach in psychotherapy.

Antioxidant supplements and endurance exercise: Current evidence and mechanistic insights.

Antioxidant supplements are commonly consumed by endurance athletes to minimize exercise-induced oxidative stress, with the intention of enhancing recovery and improving performance. There are numerous commercially available nutritional supplements that are targeted to athletes and health enthusiasts that allegedly possess antioxidant properties. However, most of these compounds are poorly investigated with respect to their in vivo redox activity and efficacy in humans. Therefore, this review will firstly provide a background to endurance exercise-related redox signalling and the subsequent adaptations in skeletal muscle and vascular function. The review will then discuss commonly available compounds with purported antioxidant effects for use by athletes. N-acetyl cysteine may be of benefit over the days prior to an endurance event; while chronic intake of combined 1000 mg vitamin C + vitamin E is not recommended during periods of heavy training associated with adaptations in skeletal muscle. Melatonin, vitamin E and α-lipoic acid appear effective at decreasing markers of exercise-induced oxidative stress. However, evidence on their effects on endurance performance are either lacking or not supportive. Catechins, anthocyanins, coenzyme Q10 and vitamin C may improve vascular function, however, evidence is either limited to specific sub-populations and/or does not translate to improved performance. Finally, additional research should clarify the potential benefits of curcumin in improving muscle recovery post intensive exercise; and the potential hampering effects of astaxanthin, selenium and vitamin A on skeletal muscle adaptations to endurance training. Overall, we highlight the lack of supportive evidence for most antioxidant compounds to recommend to athletes.

High-dose folic acid and its effect on early stage diabetic foot ulcer wound healing.

High-dose folic acid (HDFA; vitamin B9)-5 mg, given daily, has not been evaluated as a treatment to improve early stage-diabetic foot ulcer (ES-DFU) wound healing. However, HDFA has been demonstrated to correct: (a) endothelial dysfunction and decreased nitric oxide (NO) bioavailability, associated with type-2 diabetes mellitus (T2DM); and (b) hyperhomocysteinemia (HHcy) that may promote impaired DFU-wound healing. Measures of wound area (cm2 ) reduction (wound closure; WC), over a 4-week period (4 W-WC), greater than 50% of the wound area, have been reported as a robust indicator of the potential for DFU-wound healing. By using this model, we examined the effectiveness of a wound treatment in promoting progressive healing and complete wound closure for the chronic, nonhealing DFU-wound. To investigate this possible relationship between HDFA and ES-DFU wound healing, a retrospective cohort study of medical records, between November 2018 and April 2019, was performed for Veterans with T2DM and ES-DFUs following treatment with HDFA. During the study period 29 (n = 29) Veterans with ES-DFU wounds who received HDFA treatment were identified. Medical record reviews of this retrospective cohort of ES-DFU Veterans receiving HDFA report 90% (26/29) experiencing complete DFU-wound closure during the study period. Of the 29 Veterans with ES-DFUs receiving HDFA, the medical records of nine (30%), with healed wounds, provided documentation suitable for 4 W-WC, pre- and post-HDFA treatment study comparisons. This study documents significant (P < .05) improvements comparing 4 W-WC values for standard treatment for Veterans with poorly progressing, worsening or stagnating ES-DFU-wounds to those for the same subjects following HDFA treatment. These observations suggest that chronic ES-DFUs treated with HDFA may experience significantly improved wound closure and complete healing (re-epithelialization) when compared with standard treatments without HDFA. With validation from RCTs, HDFA may be established as an effective treatment to promote wound healing and closure for nonhealing ES-DFUs.

Multidisciplinary Tumor Boards in Dermatologic Surgery.

BACKGROUND: Recent advances in diagnostic and therapeutic modalities have made oncologic care ever more challenging, and multidisciplinary tumor boards (MTBs) are increasingly being used as a forum to discuss and coordinate care for complex oncology patients. Literature on the use of MTBs specific to cutaneous oncology and dermatologic surgery remains limited. OBJECTIVE: To share our experiences with cutaneous oncology MTBs at the University of Vermont Medical Center (UVMMC). METHODS: We describe the formation, timing, participation, clinical discussion, case follow-up, and coordination of care of our MTBs. RESULTS: A log of all cases discussed at cutaneous oncology MTBs from August 2018 to August 2019 is presented as an example. Five specific cases are described in further detail to demonstrate critical components of multidisciplinary care. CONCLUSION: The MTBs at UVMMC has created a collaborative environment for providers in multiple specialties to jointly formulate and coordinate optimal treatment plans for difficult cases, particularly when treatment guidelines do not exist or are insufficient. Furthermore, MTBs can serve as an educational forum for all participants.

Sodium citrate ingestion protocol impacts induced alkalosis, gastrointestinal symptoms, and palatability.

To compare the effect of 500 mg·kg-1 body mass (BM) sodium citrate ingested in solution or capsules on induced alkalosis, gastrointestinal symptoms and palatability. Twenty-four healthy and active participants completed two testing sessions, ingesting 500 mg·kg-1 BM sodium citrate within solution or capsules. Capillary blood samples were collected pre-ingestion, and every 30-min for 240-min post-ingestion; samples were analyzed for blood pH and [HCO3- ]. A validated questionnaire was used to quantify gastrointestinal symptoms at the same 30-min intervals. Palatability was quantified immediately after ingestion using a validated scale. There was a greater peak and change from baseline for capsules versus solution for blood pH (P < 0.001) and [HCO3- ] (P = 0.013). Blood pH and [HCO3- ] time to peak was 199 and 204 min, respectively, after capsule ingestion, both significantly later than after solution (P = 0.034, P = 0.001). Gastrointestinal symptoms were significantly elevated above baseline for both ingestion modes at each time point between 30 and 120 min after ingestion (P = 0.003), with no differences between modes at any time point (P = 0.644). Capsules were significantly more palatable than solution (P < 0.001). We recommend 500 mg·kg-1 BM sodium citrate ingestion in capsules, at least 200 min before exercise, to achieve greater alkalosis, minimize gastrointestinal symptoms, and maximize.

Ascorbic acid supplementation improves postprandial glycaemic control and blood pressure in individuals with type 2 diabetes: Findings of a randomized cross-over trial.

AIM: The primary aim of this study was to investigate whether ascorbic acid (AA) supplementation improves postprandial glucose responses under free-living conditions in individuals with type 2 diabetes. A secondary aim was to investigate the effect of AA supplementation on blood pressure. MATERIALS AND METHODS: A total of 31 individuals with type 2 diabetes (26 males and 5 females; aged 61.8 ± 6.8 years; duration of diabetes, 5.6 ± 4.6 years; HbA1c, 7.6% ± 0.7% [mean ± SD]) were enrolled in a randomized cross-over study involving 4 months of supplementation with oral AA (2 × 500 mg/d) or placebo. Participants wore continuous glucose monitors for 48 hours and consumed standardized meals pre- and post-supplementation. Measurements included postprandial glucose incremental areas under the curve (iAUC), duration of day in hyper- and hypo-glycaemia status, average 24-hour and daily postprandial glucose concentrations, HbA1c, insulin, blood pressure (BP) and oxidative stress (F2 -isoprostanes). RESULTS: Following AA supplementation, significant decreases were observed in daily postprandial glucose iAUC (-36%), in duration of day with hyperglycaemia (-2.8 h/d) and postprandial hyperglycaemia (-1.7 h/d), in average 24-hour glucose (-0.8 mmol/L) and daily postprandial glucose (-1.1 mmol/L) concentrations, in systolic (-7 mm Hg) and diastolic (-5 mm Hg) blood pressures and in a specific fraction of free plasma F2 -isoprostanes (-47 pg/mL) as compared to placebo. CONCLUSIONS: Individuals with type 2 diabetes experienced improved postprandial and 24-hour glycaemia and decreased BP after 4 months of AA supplementation as compared to placebo. These findings offer evidence for the proposed use of AA as an adjunct therapy to improve glycaemic and BP control in individuals with type 2 diabetes.

A systematic review of the effects of modifiable risk factor interventions on the progression of multiple sclerosis.

BACKGROUND: Several risk factors are associated with multiple sclerosis (MS) progression and may be amenable to intervention. OBJECTIVE: To systematically review the evidence for interventions targeting risk factors for MS progression. METHODS: We searched six databases and existing reviews till March 2015 and consulted with experts to identify randomized controlled trials (RCTs) of interventions targeting MS risk factors (PROSPERO 2015:CRD42015016461). RESULTS: In total, 37 RCTs met inclusion criteria. Expanded Disability Status Scale (EDSS) scores after exercise interventions did not differ compared with untreated controls (standardized mean differences (SMDs): 0.02; confidence interval (CI): -0.40, 0.44; I2: 0%; seven RCTs; very low quality of evidence (QoE)). Dietary interventions did not show a statistically significant effect on the relative risk (RR) of progression (RR: 0.86; CI: 0.67, 1.05; I2: 0%; four RCTs; moderate QoE) compared to placebo. EDSS scores after vitamin D supplementation were not significantly different from placebo (SMD: -0.15; CI: -0.33, 0.02; I2: 0%; five RCTs; very low QoE). CONCLUSION: We did not identify any risk factor interventions with significant effects on MS progression, but the overall QoE was limited. More adequately powered trials are needed on vitamin D supplementation, long-term exercise, and smoking cessation.

Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis.

Radiation-induced proctitis (RIP) is the most common clinical adverse effect for patients receiving radiotherapy as part of the standard course of treatment for ovarian, prostate, colon, and bladder cancers. RIP limits radiation dosage, interrupts treatment, and lowers patients' quality of life. A prophylactic treatment that protects the gastrointestinal tract from deleterious effects of radiotherapy will significantly improve patient quality of life and may allow for higher and more regular doses of radiation therapy. Semi-synthetic glycosaminoglycan (GAG), generated from the sulfation of hyaluronic acid, are anti-inflammatory but have difficulty achieving therapeutic levels in many tissues. To enhance the delivery of GAG, we created an in situ gelling rectal delivery system using silk-elastinlike protein polymers (SELPs). Using solutions of SELP 815K (which contains 6 repeats of blocks comprised of 8 silk-like units, 15 elastin-like units, and 1 lysine-substituted elastin-like unit) with GAG GM-0111, we created an injectable delivery platform that transitioned in <5min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30min and enhanced the accumulation of GAG in the rectum compared to traditional enema-based delivery. Using a murine model of radiation-induced proctitis, the prophylactic delivery of a single dose of GAG from a SELP matrix administered prior to irradiation significantly reduced radiation-induced pain after 3, 7, and 21days by 53±4%, 47±10%, and 12±6%, respectively. Matrix-mediated delivery of GAG by SELP represents an innovative method for more effective treatment of RIP and promises to improve quality of life of cancer patients by allowing higher radiotherapy doses with improved safety.

Development of Time- and Voltage-Domain Mapping (V-T-Mapping) to Localize Ventricular Tachycardia Channels During Sinus Rhythm.

BACKGROUND: In ventricular scar, impulse spread is slow because it traverses split and zigzag channels of surviving muscle. We aimed to evaluate scar electrograms to determine their local delay (activation time) and inequality in voltage splitting (entropy), and their relationship to channels. We reasoned that unlike innocuous channels, which are often short with multiple side branches, ventricular tachycardia (VT) supporting channels have very slow impulse spread and possess low entropy because of their longer protected length and relative lack of side-branching. METHODS AND RESULTS: Patients with ischemic cardiomyopathy and multiple VT were studied. In initial mapping stage (16 patients and 58 VTs), left ventricular endocardial mapping was performed in sinus rhythm. Detailed pace mapping was used to identify VT channels and confirmed, when feasible, by entrainment. Scar electrograms were analyzed in time and voltage domains to determine mean activation time, dispersion in activation time, and entropy. Predictive performances of these properties to detect VT channels were tested. In the application stage (7 patients and 20 VTs), these properties were prospectively tested to guide catheter ablation. A mean number of 763±203 sampling points were taken. From 1770 pace maps, 47 channels corresponded to VTs. A combination of scar electrograms with the latest mean activation time and minimum entropy, in a high activation dispersion region, accurately recognized regions containing VT channels (κ=0.89, sensitivity=86%, specificity=100%, positive predictive value=93%, and negative predictive value=100%). Finally, focused ablation within 5-mm rim of the prospective channel regions eliminated 18 of 20 inducible VTs. CONCLUSIONS: Activation time and entropy mapping in the scar accurately identify VT channels during sinus rhythm. The method integrates principles of reentry formation to recognize VT channels without pace mapping or mapping during VT.

Muscle redox signalling pathways in exercise. Role of antioxidants.

Recent research highlights the importance of redox signalling pathway activation by contraction-induced reactive oxygen species (ROS) and nitric oxide (NO) in normal exercise-related cellular and molecular adaptations in skeletal muscle. In this review, we discuss some potentially important redox signalling pathways in skeletal muscle that are involved in acute and chronic responses to contraction and exercise. Specifically, we discuss redox signalling implicated in skeletal muscle contraction force, mitochondrial biogenesis and antioxidant enzyme induction, glucose uptake and muscle hypertrophy. Furthermore, we review evidence investigating the impact of major exogenous antioxidants on these acute and chronic responses to exercise. Redox signalling pathways involved in adaptive responses in skeletal muscle to exercise are not clearly elucidated at present, and further research is required to better define important signalling pathways involved. Evidence of beneficial or detrimental effects of specific antioxidant compounds on exercise adaptations in muscle is similarly limited, particularly in human subjects. Future research is required to not only investigate effects of specific antioxidant compounds on skeletal muscle exercise adaptations, but also to better establish mechanisms of action of specific antioxidants in vivo. Although we feel it remains somewhat premature to make clear recommendations in relation to application of specific antioxidant compounds in different exercise settings, a bulk of evidence suggests that N-acetylcysteine (NAC) is ergogenic through its effects on maintenance of muscle force production during sustained fatiguing events. Nevertheless, a current lack of evidence from studies using performance tests representative of athletic competition and a potential for adverse effects with high doses (>70mg/kg body mass) warrants caution in its use for performance enhancement. In addition, evidence implicates high dose vitamin C (1g/day) and E (≥260 IU/day) supplementation in impairments to some skeletal muscle cellular adaptations to chronic exercise training. Thus, determining the utility of antioxidant supplementation in athletes likely requires a consideration of training and competition periodization cycles of athletes in addition to type, dose and duration of antioxidant supplementation.