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1.
Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?
van Eijk, RPA, Eijkemans, MJC, Nikolakopoulos, S, Jansen, MD, Westeneng, HJ, van Eijk, KR, van der Spek, RAA, van Vugt, JJFA, Piepers, S, Groeneveld, GJ, et al
The pharmacogenomics journal. 2020;(2):220-226
Abstract
Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.4%). The UNC13A genotype affected mortality (p = 0.012), whereas C9orf72 repeat-expansion carriers exhibited a faster rate of decline in overall (p = 0.051) and bulbar functioning (p = 0.005). A dose-response pharmacogenetic interaction was identified between creatine and the A allele of the MOBP genotype (p = 0.027), suggesting a qualitative interaction in a recessive model (HR 3.96, p = 0.015). Not taking genetic information into account may mask evidence of response to treatment or be an unrecognized source of bias. Incorporating genetic data could help investigators to identify critical treatment clues in patients with ALS.
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2.
Effects of upper-body resistance exercise training on serum nesfatin-1 level, insulin resistance, and body composition in obese paraplegic men.
Mogharnasi, M, TaheriChadorneshin, H, Papoli-Baravati, SA, Teymuri, A
Disability and health journal. 2019;(1):29-34
Abstract
BACKGROUND As a recently discovered adipokine, nesfatin-1 is conducive to insulin sensitivity, lipid profile, energy balance, and probably obesity. OBJECTIVE The aim of the present study was to investigate the effect of upper-body resistance exercise training (RET) on nesfatin-1 levels, insulin resistance, lipid profile, and body composition in obese paraplegic men. METHODS Twenty obese paraplegic men were randomly assigned into control and upper-body RET groups. Upper-body RET was performed for 8 weeks, 3 sessions per week at an intensity corresponding to 60-80% maximum amount of force that can be generated in one maximal contraction in 5 stations (bench press, seated rows, sitting lat pulldown, arm extension, and arm curls). Body fat percentage was determined according to 4-sites skinfold protocol of Durnin and Womersley and Siri equation. Obesity for spinal cord injury patients in the current study was set at BMI >22 kg/m2. Data were statistically analyzed by paired and independent t-test (P < 0.05). RESULTS We found significant improvements in serum levels of nesfatin-1 (21.13%), insulin sensitivity (8.95%), and high-density lipoprotein (10.87%). Other lipid profile markers, i.e. low-density lipoprotein (4.32%), cholesterol (8.20%), and triglyceride (15.10%) reduced significantly after upper-body RET. Moreover, upper-body RET led to a significant reduction in body mass index (2.36%), body fat percentage (2.79%), and waist-to-hip ratio (2.40%). CONCLUSION Upper-body RET improved insulin sensitivity, lipid profile, and body composition in paraplegic men. Serum nefastin-1 may be a potential marker of success in weight management in this population.
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3.
Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine.
Mullen, SA, Carney, PW, Roten, A, Ching, M, Lightfoot, PA, Churilov, L, Nair, U, Li, M, Berkovic, SF, Petrou, S, et al
Neurology. 2018;(1):e67-e72
Abstract
OBJECTIVE To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1. METHODS A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. RESULTS Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3-5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10-18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval -1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. CONCLUSION Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. CLINICAL TRIALS REGISTRATION Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.
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4.
The effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis: a randomized controlled trial.
Farhangi, MA, Dehghan, P, Tajmiri, S, Abbasi, MM
BMC complementary and alternative medicine. 2016;(1):471
Abstract
BACKGROUND Hashimoto's thyroiditis is an autoimmune disorder and the most common cause of hypothyroidism. The use of Nigella sativa, a potent herbal medicine, continues to increase worldwide as an alternative treatment of several chronic diseases including hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM). The aim of the current study was to evaluate the effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis. METHODS Forty patients with Hashimoto's thyroiditis, aged between 22 and 50 years old, participated in the trial and were randomly allocated into two groups of intervention and control receiving powdered Nigella sativa or placebo daily for 8 weeks. Changes in anthropometric variables, dietary intakes, thyroid status, serum VEGF and Nesfatin-1 concentrations after 8 weeks were measured. RESULTS Treatment with Nigella sativa significantly reduced body weight and body mass index (BMI). Serum concentrations of thyroid stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) antibodies decreased while serum T3 concentrations increased in Nigella sativa-treated group after 8 weeks. There was a significant reduction in serum VEGF concentrations in intervention group. None of these changes had been observed in placebo treated group. In stepwise multiple regression model, changes in waist to hip ratio (WHR) and thyroid hormones were significant predictors of changes in serum VEGF and Nesgfatin-1 values in Nigella sativa treated group (P < 0.05). CONCLUSIONS Our data showed a potent beneficial effect of powdered Nigella sativa in improving thyroid status and anthropometric variables in patients with Hashimoto's thyroiditis. Moreover, Nigella sativa significantly reduced serum VEGF concentrations in these patients. Considering observed health- promoting effect of this medicinal plant in ameliorating the disease severity, it can be regarded as a useful therapeutic approach in management of Hashimoto's thyroiditis. TRIAL REGISTRATION Iranian registry of clinical trials (registration number IRCT2015021719082N4 - Registered March-15-2015).
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5.
Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers.
Olsen, RV, Andersen, HH, Møller, HG, Eskelund, PW, Arendt-Nielsen, L
European journal of pain (London, England). 2014;(9):1333-42
Abstract
BACKGROUND Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination. METHODS Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design. RESULTS Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01). CONCLUSION This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.
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6.
Plasma nesfatin-1 level in obese patients after acupuncture: a randomised controlled trial.
Guo, Y, Xing, M, Sun, W, Yuan, X, Dai, H, Ding, H
Acupuncture in medicine : journal of the British Medical Acupuncture Society. 2014;(4):313-7
Abstract
BACKGROUND Nesfatin-1 is an anorexigenic hormone suggested to regulate obesity. OBJECTIVE To investigate the relationship between nesfatin-1 level and anthropometric and metabolic parameters in obese patients, and examine the change in plasma nesfatin-1 level after acupuncture treatment. METHODS 64 obese adult patients without diabetes and 58 normal weight control subjects were enrolled in this study. The obese patients were randomly divided into an acupuncture plus diet group (n=32) and a diet only group (n=32). Measurements were repeated after 45 days. RESULTS Body mass index (BMI), waist and hip circumferences, serum insulin, lipoprotein and insulin resistance measures were significantly higher, and plasma nesfatin-1 level was significantly lower, in obese patients than in normal weight controls. In addition, negative correlations were found between plasma nesfatin-1 level and BMI, waist and hip circumferences. Weight reduction in participants after acupuncture and diet restriction was 7.0% and 4.3%, respectively. Plasma nesfatin-1 level increased from 2.75±1.16 to 3.44±1.28 ng/mL and from 2.86±1.07 to 3.23±1.06 ng/mL in acupuncture and diet groups, respectively; the difference was significant, p<0.05. CONCLUSIONS Plasma nesfatin-1 level is reduced in obese adults, and is increased after acupuncture. The beneficial effect of acupuncture on obesity is associated with increased plasma nesfatin-1 level.
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7.
Effect of oral piperine on the swallow response of patients with oropharyngeal dysphagia.
Rofes, L, Arreola, V, Martin, A, Clavé, P
Journal of gastroenterology. 2014;(12):1517-23
Abstract
BACKGROUND Oropharyngeal dysphagia (OD) is a major gastrointestinal motility disorder that causes severe nutritional and respiratory complications in elderly and neurological patients. In an earlier study, we found that stimulation of pharyngeal sensory neurons by capsaicinoids acting on transient receptor potential vanilloid 1 (TRPV1) improved the swallow response of dysphagic patients. The aim of this study was to explore the effect of piperine, a dual TRPV1/TRPA1 agonist, on the swallow response of dysphagic patients. METHODS A videofluoroscopic study was performed to assess the signs of impaired safety and efficacy of swallow and the swallow response of 40 dysphagic patients while swallowing one series of nectar control boluses and two series of nectar boluses supplemented with piperine. Patients were randomized into two groups: one group received 150 μM piperine and the other group received 1 mM. RESULTS Piperine improved the safety of swallow by: (a) reducing the prevalence of unsafe swallows by -34.48% (P = 0.004) at 150 μM and -57.19% (P < 0.001) at 1 mM, and the severity score of the penetration-aspiration scale from 3.25 ± 0.51 to 1.85 ± 0.27 (P = 0.003, 1 mM); and (b) shortening the time to laryngeal vestibule closure from 0.366 ± 0.024 to 0.270 ± 0.022 s with 150 μM piperine (P < 0.001) and from 0.380 ± 0.032 to 0.306 ± 0.028 s with 1 mM piperine (P < 0.05). CONCLUSIONS Supplementing the alimentary bolus with piperine speeds swallow response and strongly improves safety of swallow in patients with OD, with a maximal therapeutic effect at 1 mM. Our results suggest that activation of TRPV1/A1 in oropharyngeal sensory neurons is a very promising neurostimulation strategy for dysphagic patients.
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8.
Effect of dopamine D₃ receptor antagonism on approach responses to food cues in overweight and obese individuals.
Mogg, K, Bradley, BP, O'Neill, B, Bani, M, Merlo-Pich, E, Koch, A, Bullmore, ET, Nathan, PJ
Behavioural pharmacology. 2012;(5-6):603-8
Abstract
The aim of the study was to examine the effect of manipulating the brain dopamine system, using a D₃ receptor antagonist, on approach responses to food cues in overweight and obese individuals. Twenty-six healthy overweight and obese participants were randomly assigned to receive either a single dose of dopamine D₃ receptor antagonist, GSK598809 (175 mg), or placebo in the first assessment session and vice versa in the second session. Using a stimulus-response compatibility task, approach bias was indexed by response latency to move an image of a manikin towards, versus away from, pictures of food, relative to nonfood stimuli. Data from the first session (which were unaffected by repeated testing) indicated that approach bias scores were significantly reduced in overweight and obese participants who received GSK598809, compared with those who received placebo. Data from the second session were confounded by an effect of treatment order and, consequently, were uninformative for the hypotheses. Between-participant comparison of drug versus placebo conditions indicated that GSK598809 attenuated approach bias to food cues, which is consistent with the reduction in their motivational attractiveness. The findings, albeit preliminary, are in agreement with the view that D₃ receptor antagonists may prove useful as therapeutic agents for reducing appetitive responses to food cues in obesity.
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9.
Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury.
Namer, B, Kleggetveit, IP, Handwerker, H, Schmelz, M, Jorum, E
Pain. 2008;(1):63-72
Abstract
Local cold injury often induces hypersensitivity to cold and cold allodynia. Sensitisation of TRPM8 or TRPA1 could be the underlying mechanisms. This was evaluated by psychophysics and axon-reflex-flare induction following topical menthol and cinnamaldehyde application in cold injury patients and healthy subjects. The patients had no signs of neuropathy except cold allodynia. We applied 20% cinnamaldehyde and 40% menthol solutions in the cold-allodynic area of the patients and in a corresponding area in healthy subjects and obtained sensory ratings during application. Thermotesting and Laser Doppler Imaging were performed before and after exposure to the compounds. Menthol did not induce axon-reflex-erythema in patients or in controls. After menthol cold pain threshold was decreased in healthy subjects; however, no further sensitisation was observed in the patients moreover in some patients an amelioration of their cold allodynia was observed. Cinnamaldehyde-induced pain sensation did not differ between patients and controls. Heat pain thresholds following cinnamaldehyde were lowered to a similar extent in patients and controls (43-39.8 and 44-39 degrees C) and also the axon-reflex-flare responses were comparable. No evidence for sensitisation of responses to TRPM8 or TRPA1-stimulation was found in patients with cold injury-induced cold allodynia. The lack of TRPM8 induced axon-reflex indicates that also de-novo expression of TRPM8 on mechano-insensitive C-nociceptors does not underlie cold allodynia in these patients. We conclude from these data that the mechanisms for the induction of cold allodynia in the patients with cold injury are independent of TRPM8 or TRPA1 and differ therefore from neuropathic pain patients.
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10.
Reversed diurnal variation in depression: associations with a differential antidepressant response, tryptophan: large neutral amino acid ratio and serotonin transporter polymorphisms.
Joyce, PR, Porter, RJ, Mulder, RT, Luty, SE, McKenzie, JM, Miller, AL, Kennedy, MA
Psychological medicine. 2005;(4):511-7
Abstract
BACKGROUND Although diurnal variation of mood is a widely recognized symptom of depression, the clinical, neurobiological and psychopharmacological significance of this symptom has not previously been reported. METHOD A total of 195 depressed out-patients underwent a detailed clinical and neurobiological assessment, and were then randomized to treatment with either fluoxetine or nortriptyline. RESULTS Of the 195 depressed patients, 62 had a pattern of reversed diurnal variation (i.e. worse in the evening). Those with reversed diurnal variation had a poorer response to a serotonergic anti-depressant, were less likely to have bipolar II disorder, had a higher tryptophan: large neutral amino acid ratio and had different allele frequencies of the polymorphisms in the promoter region of the serotonin transporter. CONCLUSIONS These findings raise the possibility of serotonergic influence on diurnal variation, and that the symptom of reversed diurnal variation is of relevance to antidepressant prescribing.