Drug addiction is one of the major public health concerns around the world. Addiction to prescription medications has been growing due to the psychoactive effects of these medications, ...availabilities, low price and no legal consequences were practiced against the abusers. One of these prescription medications is mirtazapine (MIRT). MIRT is an antidepressant that is recently reported in different case studies to be abused and could induce withdrawal symptoms. No previous study has investigated its abuse potential in animal model of drug addiction. Here we conducted a free‐choice drinking paradigm to investigate the voluntary drinking of MIRT in two different concentrations. Male bulb/c mice were allowed free access to two bottles of water for five days and their intake and body weight were recorded daily to calculate, based on consumed fluid, the concentrations of MIRT solutions. Mice were then divided into three groups; the first group had free access to two bottles of water. The second group (MIRT‐10) had free access to one bottle of water and one bottle of MIRT in a concentration that might yield daily intake of (10 mg/kg). The third group (MIRT‐20) had free access to one bottle of water and one bottle of MIRT in a concentration that might yield daily intake of (20 mg/kg). Interestingly, animals in MIRT‐20 showed a significant increase in MIRT intake as compared to MIRT‐10 group indicating that MIRT in higher doses can induce drug seeking effects. Following the drinking phase, and to confirm any effects on memory and recognition, animals underwent Novel Object Recognition test (NORT). Animals in MIRT‐20 showed a significant deterioration in the recognition of the novel objects as compared to the control and MIRT‐10 groups. This indicates the destructive nature of abusing MIRT on recognition and memory which is consistent with the effects of different drugs of abuse. All animals were then only exposed to two bottles of water to induce withdrawal symptoms. After five days of abstinence, animals in MIRT‐20 group showed a significant increase in the immobility time in forced swimming test and tail suspension test as compared to the control and MIRT‐10. This indicates that animals in MIRT‐20 might have depressive‐like symptoms as one of the indicators of withdrawal symptoms related to drug addiction. Together, MIRT was able to induce drug seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has potential for inducing drug dependence and its use should be controlled by legal authorities. Further studies are needed to investigate the neurobiological basis of MIRT‐induced drug seeking behavior.
Summary Background Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those ...individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. Methods In this pooled analysis, we studied 133 118 individuals (63 559 with hypertension and 69 559 without hypertension), median age of 55 years (IQR 45–63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4·2 years (IQR 3·0–5·0) and blood pressure. Findings Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2·08 mm Hg change per g sodium increase) compared with individuals without hypertension (1·22 mm Hg change per g; pinteraction <0·0001). In those individuals with hypertension (6835 events), sodium excretion of 7 g/day or more (7060 11% of population with hypertension: hazard ratio HR 1·23 95% CI 1·11–1·37; p<0·0001) and less than 3 g/day (7006 11% of population with hypertension: 1·34 1·23–1·47; p<0·0001) were both associated with increased risk compared with sodium excretion of 4–5 g/day (reference 25% of the population with hypertension). In those individuals without hypertension (3021 events), compared with 4–5 g/day (18 508 27% of the population without hypertension), higher sodium excretion was not associated with risk of the primary composite outcome (≥7 g/day in 6271 9% of the population without hypertension; HR 0·90 95% CI 0·76–1·08; p=0·2547), whereas an excretion of less than 3 g/day was associated with a significantly increased risk (7547 11% of the population without hypertension; HR 1·26 95% CI 1·10–1·45; p=0·0009). Interpretation Compared with moderate sodium intake, high sodium intake is associated with an increased risk of cardiovascular events and death in hypertensive populations (no association in normotensive population), while the association of low sodium intake with increased risk of cardiovascular events and death is observed in those with or without hypertension. These data suggest that lowering sodium intake is best targeted at populations with hypertension who consume high sodium diets. Funding Full funding sources listed at end of paper (see Acknowledgments).
Prescription drug abuse is an issue that is rapidly growing globally. Pregabalin, an anticonvulsant, analgesic, and anxiolytic medication, is effective in the management of multiple neurological ...disorders; however, there is increasing concern regarding its widespread illicit use. It has been previously reported in mice that pregabalin can induce conditioned place preference. In this current investigation, the potential of pregabalin to elicit free-choice drinking in a mouse model of drug addiction, and its effect on recognition and withdrawal behaviors after forced abstinence, were studied. Twenty-two male BALB/c mice were randomly divided into three groups (n = 7–8/group); control, pregabalin-30, and pregabalin-60. The study had three phases: habituation (days 1–5) with free water access, free-choice drinking (days 6–13) with pregabalin groups receiving one water and one pregabalin bottle, and forced abstinence (days 14–21) with free water access. On day 13, the first open field test was conducted, followed by the Novel Object Recognition Test. On day 21, the second open field test was performed, followed by the Tail Suspension Test and Forced Swimming Test. Pregabalin elicited voluntary drinking in the higher-dose group, concurrently causing a decline in recognition memory performance in the novel object recognition test. Moreover, pregabalin induced withdrawal behavior after a period of forced abstinence in the forced swimming and tail suspension tests. This is the first report to establish an animal model of free-choice pregabalin drinking that may be used for further molecular studies and targeted therapy for pregabalin addiction.
Addiction to various drugs and chemicals is a significant public health concern worldwide. Addiction to prescription medications has increased due to the psychoactive effects of these medications, ...their availability, low price, and the lack of legal consequences for abusers. One of such prescription medication is mirtazapine (MIRT). MIRT is an antidepressant that has recently been reported to be abused and could induce withdrawal symptoms in different case studies. No previous study has investigated its abuse potential in animal models of drug addiction. Here, we conducted a free-choice drinking paradigm to investigate voluntary drinking of MIRT at two different concentrations. Male BALB/c mice were given unlimited access to two water bottles for five days before being divided into three groups: the first group had free access to two water bottles. The second group (MIRT10) and the third group (MIRT20) was allowed unlimited choice to one bottle of water and one bottle of MIRT at concentrations of 0.03 and 0.06 mg/mL, respectively. The average daily MIRT intake in the MIRT20 group was significantly higher on all tested days than that in the MIRT10 group. Moreover, mice in the MIRT20 group preferred to self-administer MIRT over water, indicating that MIRT can induce drug-seeking behavior. To further investigate the addictive potential of MIRT and its possible deterioration of memory and recognition, as reported with several known drugs of abuse, animals underwent a novel object recognition test. Mice in the MIRT20 group demonstrated significant deterioration in memory and recognition, indicating its effects on different brain regions involved in recognition, similar to other known drugs of abuse. The forced swimming test and tail suspension test were used to test MIRT-induced withdrawal symptoms after forced abstinence. After eight days of abstinence, mice in the MIRT20 group demonstrated significant depression-like symptoms in both the TST and FST, manifested by a significant increase in immobility time. MIRT was shown to induce drug-seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has the potential to induce drug dependence and further studies are warranted to explore the neurobiological basis of MIRT-induced drug-seeking behavior.
A facile, cost-effective, surfactant-free chemical route has been demonstrated for the fabrication of porous β-Co(OH)2 hierarchical nanostructure in gram level simply by adopting cobalt acetate as a ...precursor salt and ethanolamine as a hydrolyzing agent at room temperature. A couple of different morphologies of β-Co(OH)2 have been distinctly identified by varying the mole ratio of the precursor and hydrolyzing agent. The cyclic voltammetry measurements on β-Co(OH)2 displayed significantly high capacitance. The specific capacitance obtained from charge–discharge measurements made at a discharge current of 1 A/g is 416 F/g for the Co(OH)2 sample obtained at room temperature. The charge–discharge stability measurements indicate retention of specific capacitance about 93% after 500 continuous charge–discharge cycles at a current density of 1 A g–1. The capacitive behavior of the other synthesized morphology was also accounted. The nanoflower-shaped porous β-Co(OH)2 with a characteristic three-dimensional architecture accompanied highest pore volume which made it promising electrode material for supercapacitor application. The porous nanostructures accompanied by high surface area facilitates the contact and transport of electrolyte, providing longer electron pathways and therefore giving rise to highest capacitance in nanoflower morphology. From a broad view, this study reveals a low-temperature synthetic route of β-Co(OH)2 of various morphologies, qualifying it as supercapacitor electrode material.
This study investigated the effects of a synbiotic Lacto Forte on growth performance, haemato‐immunological responses, plasma bactericidal capacity, histological profiles and resistance of ...Oreochromis niloticus to Pseudomonas fluorescens. The experimental fish were divided into three groups; two of them (T1 and T2) were given Lacto Forte incorporated diets at increasing level (0.7 and 1.5 g/kg, respectively) and an additive‐free basal diet served as the control (T0) for 30 and 45 days. At the end of the feeding trial, a challenge was performed using a virulent strain of P. fluorescens and mortalities were recorded over an additional 14‐days period. The results showed that Lacto Forte has a pronounced effect on haematological and growth performance parameters at 1.5 g/kg rather than 0.5 g/kg (p < 0.05). Plasma lysozyme, proteases, antiproteases and bactericidal capacity were significantly enhanced (p < 0.05) in Lacto Forte‐treated groups, particularly after 45 days of supplementation. Long‐term supplementation with Lacto Forte (1.5 g/kg) induced degenerative changes in the liver, spleen and intestine. Additionally, a significant increase (p < 0.05) in survival rates were found in Lacto Forte‐treated groups compared to the control one 14 days post‐challenge. As a result, Lacto Forte fortifies tilapia immune response and can be used as a surrogate for antibiotics to control P. fluorescens.
The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven.
We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' ...cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event.
The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval CI, 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons). The effect of treatment on PCR conversion varied according to geographic region: in Brazil, the odds ratio for PCR conversion was 3.03 (95% CI, 2.12 to 4.34) at 2 years and 1.87 (95% CI, 1.33 to 2.63) at 5 or more years; in Colombia and El Salvador, the odds ratio was 1.33 (95% CI, 0.90 to 1.98) at 2 years and 0.96 (95% CI, 0.63 to 1.45) at 5 or more years; and in Argentina and Bolivia, the odds ratio was 2.63 (95% CI, 1.89 to 3.66) at 2 years and 2.79 (95% CI, 1.99 to 3.92) at 5 or more years (P<0.001 for interaction). However, the rates of PCR conversion did not correspond to effects on clinical outcome (P=0.16 for interaction).
Trypanocidal therapy with benznidazole in patients with established Chagas' cardiomyopathy significantly reduced serum parasite detection but did not significantly reduce cardiac clinical deterioration through 5 years of follow-up. (Funded by the Population Health Research Institute and others; ClinicalTrials.gov number, NCT00123916; Current Controlled Trials number, ISRCTN13967269.).
Quetiapine, an atypical antipsychotic, is effective in the management of schizophrenia, depression, and anxiety. Although quetiapine overdosage and misuse have been reported, its abuse potential has ...not been investigated in animals. In this study, the abuse potential of quetiapine was assessed based on the conditioned place preference (CPP) paradigm of drug addiction in a mouse model. First, mice received intraperitoneal injections of quetiapine (40, 80, or 120 mg/kg) every other day during the conditioning phase. In the second experiment, mice were pretreated with 0.03 mg/kg SKF-35866, a D1 receptor antagonist, before receiving saline or quetiapine (120 mg/kg) during the conditioning phase. No significant changes in time spent in the quetiapine-paired chamber were observed compared with time spent in the saline-paired chamber in mice treated with 40 or 80 mg/kg. In contrast, the preference to the quetiapine-paired chamber was significantly increased in mice treated with 120 mg/kg quetiapine, and this effect was blocked by SKF-35866 pretreatment. These results demonstrated, for the first time, the abuse potential of quetiapine in an animal model of drug addiction. Interestingly, this CPP-inducing effect was likely mediated by activating D1 receptors.
We have accomplished a low temperature sol–gel synthesis of nanocrystalline M-type hexaferrites BaCoxZrxFe(12−2x)O19 (x=0, 0.2, 0.4, 0.6, 0.8 and 1.0). These compounds were characterized by TGA–DTA, ...FT-IR, XRD, EDS and TEM. X-ray diffraction patterns demonstrate that the compounds are single phase M-type barium hexagonal ferrites (BHF) and maximum substitution is attained at x=1.0. The average size of the hexagonal platelets is 41.62nm. MS is employed to probe the magnetic properties at microscopic levels. MS studies suggest that both the nature and concentration of dopant ions control site preferences in the crystal lattice. Substitution is preferred at 4f2 and 2b sites at x=0.4, 4f1 and 4f2 sites at x=0.6 and 2a and 2b sites at x=1.0 levels. M vs H studies reveal that on substitution MS vary only slightly from 63.63 to 56.94emu/g while a drastic reduction has been observed in HC from 5428 to 630Oe. High MS and low HC values of these materials make them particularly suitable for application in data recording. Our results also show that HC can be monitored independently while retaining high saturation magnetization of BHF by making coupled substitution of divalent (Co2+) and tetravalent (Zr4+) cations for Fe3+ ions.
•Nanosized M-type BHF have been synthesized via the sol–gel method.•MS and M vs H results show that MS and HC are related to the distribution of dopant ions on the five sites.•Both the nature and concentration of dopant control the site preferences.•MS remains nearly constant (56.94–63.63emu/g) whereas HC shows stricking fall (5428–630Oe).•High MS and low HC make these compounds highly suitable for data recording application.
Abstract
Understanding exotic forms of magnetism in quantum spin systems is an emergent topic of modern condensed matter physics. Quantum dynamics can be described by particle-like carriers of ...information, known-as quasiparticles that appear from the collective behaviour of the underlying system. Spinon excitations, governing the excitations of quantum spin-systems, have been accurately calculated and precisely verified experimentally for the antiferromagnetic chain model. However, identification and characterization of novel quasiparticles emerging from the topological excitations of the spin system having periodic exchange interactions are yet to be obtained. Here, we report the identification of emergent composite excitations of the novel quasiparticles doublons and quartons in spin-1/2 trimer-chain antiferromagnet Na
2
Cu
3
Ge
4
O
12
(having periodic intrachain exchange interactions
J
1
-
J
1
-
J
2
) and its topologically protected quantum 1/3 magnetization-plateau state. The characteristic energies, dispersion relations, and dynamical structure factor of neutron scattering as well as macroscopic quantum 1/3 magnetization-plateau state are in good agreement with the state-of-the-art dynamical density matrix renormalization group calculations.
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