Impact of Extracellular Current Flow on Action Potential Propagation in Myelinated Axons.

Myelinated axons conduct action potentials, or spikes, in a saltatory manner. Inward current caused by a spike occurring at one node of Ranvier spreads axially to the next node, which regenerates the spike when depolarized enough for voltage-gated sodium channels to activate, and so on. The rate at which this process progresses dictates the velocity at which the spike is conducted and depends on several factors including axial resistivity and axon diameter that directly affect axial current. Here we show through computational simulations in modified double-cable axon models that conduction velocity also depends on extracellular factors whose effects can be explained by their indirect influence on axial current. Specifically, we show that a conventional double-cable model, with its outside layer connected to ground, transmits less axial current than a model whose outside layer is less absorptive. A more resistive barrier exists when an axon is packed tightly between other myelinated fibers, for example. We show that realistically resistive boundary conditions can significantly increase the velocity and energy efficiency of spike propagation, while also protecting against propagation failure. Certain factors like myelin thickness may be less important than typically thought if extracellular conditions are more resistive than normally considered. We also show how realistically resistive boundary conditions affect ephaptic interactions. Overall, these results highlight the unappreciated importance of extracellular conditions for axon function.

Physiological noise facilitates multiplexed coding of vibrotactile-like signals in somatosensory cortex.

Neurons can use different aspects of their spiking to simultaneously represent (multiplex) different features of a stimulus. For example, some pyramidal neurons in primary somatosensory cortex (S1) use the rate and timing of their spikes to, respectively, encode the intensity and frequency of vibrotactile stimuli. Doing so has several requirements. Because they fire at low rates, pyramidal neurons cannot entrain 1:1 with high-frequency (100 to 600 Hz) inputs and, instead, must skip (i.e., not respond to) some stimulus cycles. The proportion of skipped cycles must vary inversely with stimulus intensity for firing rate to encode stimulus intensity. Spikes must phase-lock to the stimulus for spike times (intervals) to encode stimulus frequency, but, in addition, skipping must occur irregularly to avoid aliasing. Using simulations and in vitro experiments in which mouse S1 pyramidal neurons were stimulated with inputs emulating those induced by vibrotactile stimuli, we show that fewer cycles are skipped as stimulus intensity increases, as required for rate coding, and that intrinsic or synaptic noise can induce irregular skipping without disrupting phase locking, as required for temporal coding. This occurs because noise can modulate the reliability without disrupting the precision of spikes evoked by small-amplitude, fast-onset signals. Specifically, in the fluctuation-driven regime associated with sparse spiking, rate and temporal coding are both paradoxically improved by the strong synaptic noise characteristic of the intact cortex. Our results demonstrate that multiplexed coding by S1 pyramidal neurons is not only feasible under in vivo conditions, but that background synaptic noise is actually beneficial.

The effect of Nigella sativa supplementation on cardiovascular risk factors in obese and overweight women: a crossover, double-blind, placebo-controlled randomized clinical trial.

PURPOSE: To assess the effect of Nigella sativa (N.S) oil supplements on CVD risk factors in a crossover design for the first time. METHODS: Obese and overweight healthy women were randomized to receive N.S oil (2000 mg/day) and placebo. This intervention period lasted for 8 weeks and separated by a 4-week washout period. An iso-caloric diet was given to every individual throughout the study. Blood pressure, lipid profile, atherogenic indices and liver enzymes were measured. Pkcross procedure was performed for statistical analyses using Stata software. Cohen's d was estimated as effect size for all outcomes to measure the magnitude of the effects. RESULTS: Thirty-nine participants completed the study. Capsules of N.S increased serum high-density lipoprotein cholesterol (Cohen's d = 0.47, P = 0.009), reduced low-density lipoprotein cholesterol (Cohen's d = - 0.33, P = 0.031), reduced TC/HDL-C ratio (as an atherogenic index, Cohen's d = - 0.9, P < 0.001), reduced serum glutamic-oxaloacetic transaminase (Cohen's d = 0- 0.5, P = 0.038) and reduced systolic blood pressure (Cohen's d = - 0.4, P < 0.001). There was no effect on diastolic blood pressure measures (P = 0.96). CONCLUSION: The overall improvements in cardiovascular disease (CVD) risk factors showed beneficial effects of N.S supplements among adults with obesity to prevent possible cardiovascular diseases. More studies with different designs and in other populations are suggested to clarify the exact effects of N.S as a complementary therapy for modulating CVD risk factors in individuals with overweight and obesity. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20180528039884N1, Registered on February 15th, 2019.

The effect of Nigella sativa on the measures of liver and kidney parameters: A systematic review and meta-analysis of randomized-controlled trials.

The aim of this systematic review and dose-response meta-analysis was to determine the effect of Nigella sativa (N.S) supplementation on liver and kidney parameters. We searched PubMed, Scopus, ISI Web of Science, Cochrane central register for controlled trials and Google Scholar from database inception to April 2019 for relevant controlled trials. Mean differences and standard deviations for each outcome were pooled using a random-effects model and a dose-response analysis was performed using a fractional polynomial model. Quality of evidence was evaluated using Cochrane Collaboration Risk of Bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Nineteen trials (n = 1295 participants) were included in the meta-analysis. We observed that N.S supplements had significant reducing effects on alkaline-phosphatase (ALP) [9 trials, n = 710 participants, weighted mean difference (WMD)= -10.825; 95 %CI: -19.658, -1.992 U/L; P = 0.016; I2 = 75.7 %; P-heterogeneity = 0.000) and blood urea nitrogen (BUN) (12 trials, n = 821 participants, WMD= -1.016; 95 % CI: -1.760, -0.273 U/L; P = 0.007; I2 = 87.7 %; P-heterogeneity = 0.000) concentrations. Subgroup analysis showed that, an intervention of more than 12 weeks was found to have a reducing effect on aspartate- aminotransferase (AST) measures (2 trials, n = 201 participants, WMD= -11.317; 95 % CI: -15.007, -7.626; P = 0.000; I2 = 0.0 %; P-heterogeneity = 0.977). Creatinine levels increased significantly in studies that considered adjusted analysis based on covariates (3 trials, n = 152 participants, WMD = 0.070; 95 % CI: 0.027, 0.112 U/L; P = 0.001; I2 = 0.0 %; P-heterogeneity = 0.788). A daily dose of 1100-1500 mg of N.S supplements was observed to have a substantial reducing effect on ALP levels (5 trials, n = 340 participants, WMD= -11.323; 95 % CI: -21.418, -1.229 U/L; P = 0.028; I2 = 0.00 %; P-heterogeneity = 0.686), while a dosage of more than 2000 mg per day led to a significant increase in BUN concentrations (2 trials, n = 101 participants, WMD= -1.016; 95 % CI: -1.760, -0.273 U/L; P = 0.007; I2 = 87.7 %; P-heterogeneity = 0.000). Our data suggested that N.S supplementation had significant impacts on liver and kidney parameters leading to a decrease in ALP and BUN levels. Longer duration of intervention and normal daily dosages of N.S supplements led to significant reductions in ALP and AST concentrations, respectively, while higher daily dosages increased BUN levels. Hence, in spite of favorable impacts of N.S supplements on liver and kidney parameters, due to the herbal nature of N.S, more studies with high-quality, large-scale, long-term intervention and precise baseline characteristics are needed to assess the exact effective dose, duration and efficacy of N.S supplementation on kidney and liver parameters.

Association between adherence to a dietary approach to stop hypertension and the Mediterranean diets and risk of colorectal cancer: A matched case-control study.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers and is currently the third leading cause of cancer-related deaths worldwide. This study aimed to evaluate whether the dietary approach to stop hypertension (DASH) and Mediterranean (MED) diets are associated with CRC in Iranian adults. METHODS: This hospital-based case-control study was conducted on 71 cases and 142 controls (40-75 years old) in three general hospitals in Tehran, Iran. The dietary intakes of individuals were collected through face-to-face interviews using a semi-quantitative food frequency questionnaire (FFQ) that included 125 food items. The DASH and MED diet scores were calculated according to food items based on guidelines. Two logistic regression models were applied to evaluate the association between DASH and MED score adherence. RESULTS: After adjusting for confounding factors, a negative association between DASH diet adherence and CRC risk was observed in the second and last tertile compared to the first tertile (T) (T2: odds ratio (OR) = 0.33; 95% confidence interval (CI): 0.14-0.77 - T3: OR = 0.09; 95% CI: 0.03-0.27). There was no significant association between the MED diet and the risk of CRC. CONCLUSIONS: In conclusion, the current study's findings presented that adherence to a DASH diet could reduce the odds of CRC.

Absence of paresthesia during high-rate spinal cord stimulation reveals importance of synchrony for sensations evoked by electrical stimulation.

Electrically activating mechanoreceptive afferents inhibits pain. However, paresthesia evoked by spinal cord stimulation (SCS) at 40-60 Hz becomes uncomfortable at high pulse amplitudes, limiting SCS "dosage." Kilohertz-frequency SCS produces analgesia without paresthesia and is thought, therefore, not to activate afferent axons. We show that paresthesia is absent not because axons do not spike but because they spike asynchronously. In a pain patient, selectively increasing SCS frequency abolished paresthesia and epidurally recorded evoked compound action potentials (ECAPs). Dependence of ECAP amplitude on SCS frequency was reproduced in pigs, rats, and computer simulations and is explained by overdrive desynchronization: spikes desychronize when axons are stimulated faster than their refractory period. Unlike synchronous spikes, asynchronous spikes fail to produce paresthesia because their transmission to somatosensory cortex is blocked by feedforward inhibition. Our results demonstrate how stimulation frequency impacts synchrony based on axon properties and how synchrony impacts sensation based on circuit properties.

The Relationship between Plant-Based Diet Index and Semen Parameters of Men with Infertility: A Cross-Sectional Study.

BACKGROUND: Infertility is a major clinical problem that affects people psychologically and medically. For the past 40 years, studies have linked nearly 50% of childlessness to male infertility. It is worth noting that unlike other factors contributing to infertility, diet is a tunable factor and can be applied in counseling infertile men. The goal of this study was to determine the relationship between plant diet index (PDI) and semen parameters in Iranian infertile men. MATERIALS AND METHODS: In this cross-sectional study, dietary intake was determined by a valid 168-item questionnaire (FFQ). In this study, four dependent semen parameters, including total sperm motility (TSM), sperm concentration (SC), normal sperm morphology (NSM), and semen volume (SV) were measured. RESULTS: Results of this study stated that greater adherence to the healthful plant-based diet index (hPDI), can significantly increase sperm density and motility in men, as well as greater adherence to the PDI dietary pattern is related to a lower risk of sperm volume deficiency, and ultimately more adherence to the unhealthful plant-based diet index (uPDI), can reduce the risk of sperm motility. CONCLUSION: In this study, for the first time, the relationship between PDI, hPDI, uPDI and male infertility was evaluated. Altogether, this study demonstrated that nutrition has an impact on semen quality and fertility of men.

The relationship between plant and animal based protein with semen parameters: A cross-sectional study in infertile men.

OBJECTIVE: Infertility is a global challenge, affecting 15% of non-contracepting couples that have intercourse. Recent studies have shown that diet can directly affect sperm quality. Protein is one of the most important components of an adequate diet that can regulate metabolic profile and send signals to the reproductive axis. This study aimed to determine the relationship between plant and animal protein intake and infertility in Iranian men. METHODS AND MATERIALS: In this cross-sectional study, 270 infertile men aged 18-55 years were selected from Isfahan Infertility clinic in 2018. Semen assessment was performed according to the fifth edition of the WHO laboratory manual and a 168-item questionnaire was used to determine the amount of dietary intakes of participants. Statistical analyses were carried out using SPSS for Windows software (version 20.0), SPSS Inc, and Chicago IL. P-value < 0.05 was considered statistically significant. RESULTS: There was significant association between concentration and plant protein tertiles in the crude model (OR = 0.38; 95% CI: 0.19, 0.75; P = 0.004), which became significant in the both adjusted model and participants in highest tertile had a lower risk (OR = 0.36; 95% CI: 0.18, 0.72; P = 0.003 and OR = 0.31; 95% CI: 0.14, 0.65; P = 0.002). Also, there was a significant association between sperm concentration and animal protein in the crude model, and participants in the highest tertile had a higher risk (OR = 2.32; 95% CI: 1.13, 4.76; P = 0.02). Participants in highest animal protein tertile had a higher risk (OR = 2.38; 95% CI: 1.16, 4.91; P = 0.02 and OR = 2.42; 95% CI: 1.13, 5.19; P = 0.02) in adjusted model. Furthermore, there was a significant association between morphology and animal protein in the crude model, and participants in the highest tertile had a higher risk (OR = 3.68; 95% CI: 0.97, 13.91; P = 0.04). CONCLUSION: In this cross-sectional study, the relationship between plant and animal protein with semen parameters was evaluated. Although this study demonstrated the relationship between plant and animal based protein with semen parameters, more researches need to be done in this area.

The effect of Nigella sativa on TAC and MDA in obese and overweight women: secondary analysis of a crossover, double blind, randomized clinical trial.

Purpose: Since obesity is a risk factor for various diseases and is associated with increased oxidative stress conditions, some herbs are considered to be effective in reducing obesity and its complications. Methods: This secondary analysis investigates the effect of Nigella sativa (N.S) oil supplement on total antioxidant capacity (TAC) and malondialdehyde (MDA) levels in obese/overweight women. Obese and overweight healthy women were randomized to receive 2,000 mg/d of N.S supplement and placebo. The intervention periods lasted 8 weeks and were separated by a 4-week washout period. Also, each participant was given an iso-calorie diet. Baseline characteristics and TAC and MDA levels were measured. Pkcross analysis was performed for statistical analysis using Stata software. Also, Cohen's d was estimated as effect size for all results to assess the magnitude of the effects. Results: 39 women completed the study. N.S oil supplementation at a dose of 2000 mg/d significantly increased serum TAC (P effect = 0.017, Cohen's d = 1.81) and reduced serum MDA (P effect < 0/001, Cohen's d = - 0.32). Conclusion: Based on our findings taking N.S supplementation for 8 weeks can improve antioxidant conditions in obese and overweight adults. However, more studies with a larger population and the presence of both genders need to be done to confirm the results.Registration number: IRCT20180430039475N1.

The effect of Nigella sativa on appetite, anthropometric and body composition indices among overweight and obese women: A crossover, double-blind, placebo-controlled, randomized clinical trial.

OBJECTIVES: Obesity is a global concern which is associated with several complications and disease. DESIGN: Present study is the first crossover, double-blind, placebo-controlled, randomized clinical trial aimed to evaluate the effect of Nigella Sativa (N. sativa) intervention on anthropometric and body composition parameters as well as dietary intake and appetite in a crossover design. METHOD: Forty-five healthy women with obesity or overweight were randomized into two groups of intervention and placebo, and the study conducted in two 8-week periods of intervention separated by a 4-week washout period. Anthropometric and body composition indices and dietary intake were measured. Also, appetite sensation was evaluated via a standard visual analog scale (VAS) questionnaire. Pkcross procedure was performed for statistical analysis using STATA. Cohen's d effect size was estimated for all outcomes to determine the magnitude of the effects. RESULTS: Supplementation with 2000 mg of N. sativa oil found to have a considerable increment in the measures of body mass index (P < 0.001, Cohen's d = 0.5), body weight (P < 0.001, Cohen's d = 0.6) and waist circumference (P = 0.020, Cohen's d = 0.4) with a medium effect size measure, and a significant decrease in body fat mass (P = 0.019, Cohen's d = 0.2), body fat percent (P < 0.001, Cohen's d = 0.2) and visceral fat area (P = 0.011, Cohen's d = 0.2) with a small effect size measure. CONCLUSION: The overall improvements in anthropometric and body composition parameters and a significant decrease in appetite represents the beneficial effects of N. sativa supplements in the treatment of obesity. More studies with different dosages, a larger number of participants, and longer intervention duration are recommended to illustrate the exact effects of N. sativa as a complementary therapy for obesity.

Effects of oral Nigella sativa oil on the expression levels and serum concentrations of adiponectin, PPAR-γ, and TNF-α in overweight and obese women: a study protocol for a crossover-designed, double-blind, placebo-controlled randomized clinical trial.

BACKGROUND: Obesity is a major public health problem in recent decades. The accumulation of excessive fat promotes inflammatory status. Meanwhile, herbal products are marketed for their weight-loss properties, such as Nigella sativa (N. Sativa) which has been used for centuries to treat rheumatoid arthritis, diabetes, and asthma; recently, the anti-obesity characteristics of N. sativa have also been indicated. However, the exact mechanisms and cellular-related pathways are still unclear. Thus, we will aim to assess the effects of oral N. sativa on the gene expression of inflammatory and adipogenesis-related factors, including TNF-α, PPAR-γ, and adiponectin as well as assessing their serum concentrations among obese and overweight individuals. METHODS: Obese and overweight women aged 25-55 years with a body mass index (BMI) of 25-35 kg/m2 will be recruited from the Obesity Clinic in Shahid Sadoughi University of Medical Sciences and will be assessed for eligibility against inclusion criteria. They will be randomly assigned into two groups to receive either two capsules of N. sativa or two capsules of placebo per day for eight weeks (each capsule contains 1000 mg of N. sativa or placebo). There will be a four-week wash-out period and then participants will receive the reverse supplements for another eight weeks. Biochemical assessments and gene expressions (using real-time polymerase chain reaction) will be conducted at the beginning and at the end of every intervention period. DISCUSSION: The present study will investigate the probable cellular pathways for the anti-obesity effects of N. sativa in overweight/obese women. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20180528039884N1 . Registered on 2nd of July, 2018.