The present study established a novel mouse model of a runway drug self-administration in our laboratory. The operant runway apparatus consisted of three long runways arranged in a zig-zag manner. The methodology consisted of six distinct phases: habituation, preconditioning, conditioning, post-conditioning, extinction and reinstatement. The effects of saline were compared with escalating doses of either ethanol (0.5-4.0 g/kg, i.p), heroin (5-40 mg/kg, i.p), or nicotine (0.1-0.5mg/kg, i.p) administered in the goal box during the conditioning phase (day 1 to day 5). A significant decrease in the time of trained (conditioned) mice to reach the goal box confirmed the subjects' motivation to seek those drugs on day 6 (expression). The mice were then subjected to non-rewarded extinction trials for 5 days over which run times were significantly increased. After 5 days of abstinence, a priming dose of ethanol or heroin (1/5th of maximum dose used in conditioning) significantly reinstated the drug-seeking behavior. These results suggest that the modified runway model can serve as a powerful behavioral tool for the study of the behavioral and neurobiological bases of drug self-administration and, as such, is appropriate simple but powerful tool for investigating the drug-seeking behavior of laboratory mice.
Morinda citrifolia L. commonly known as noni or Indian mulberry belongs to the family Rubiaceae. Noni fruit juice has recently become a very popular remedy for the treatment of several diseases, including psychiatric disorders. This study aimed to investigate the anticraving effect of Tahitian Noni® Juice (TNJ) against ethanol seeking behavior in ICR male mice using the conditioned place preference (CPP) test. The CPP procedure consisted of four phases: preconditioning, conditioning, extinction, and reinstatement. During conditioning, intraperitoneal (i.p.) injections of ethanol (2 g/kg body weight (bw)) and normal saline (10 ml/kg bw) were given on alternate days for 12 days. Then, the animals were subjected to extinction trials for the next 12 days to weaken CPP. Finally, CPP was reinstated in the extinguished animals by a single low-dose priming injection of ethanol (0.4 g/kg bw, i.p.). The effect of TNJ (as a source of drinking water) on different phases of ethanol CPP in mice was studied. TNJ-treated mice showed a significant reduction in ethanol seeking behavior in the CPP test. The reference drug, acamprosate (ACAM) also showed a similar effect in the CPP test. The outcome of this study suggests that TNJ is effective in attenuating ethanol craving in mice and could be utilized for the treatment of alcohol dependence. Further clinical studies in this direction are warranted to support the present preclinical findings.
Phytotherapy is an emerging field successfully utilized to treat various chronic diseases including alcohol dependence. In the present study, we examined the effect of the standardized methanolic extract of Morinda citrifolia Linn. unripe fruit (MMC), on compulsive ethanol-seeking behavior using the mouse conditioned place preference (CPP) test. CPP was established by injections of ethanol (2 g/kg, i.p.) in a 12-day conditioning schedule in mice. The effect of MMC and the reference drug, acamprosate (ACAM), on the reinforcing properties of ethanol in mice was studied by the oral administration of MMC (1, 3, and 5 g/kg) and ACAM (300 mg/kg) 60 min prior to the final CPP test postconditioning. Furthermore, CPPs weakened with repeated testing in the absence of ethanol over the next 12 days (extinction), during which the treatment groups received MMC (1, 3, and 5 g/kg, p.o.) or ACAM (300 mg/kg, p.o.). Finally, a priming injection of a low dose of ethanol (0.4 g/kg, i.p.) in the home cage (Reinstatement) was sufficient to reinstate CPPs, an effect that was challenged by the administration of MMC or ACAM. MMC (3 and 5 g/kg, p.o.) and ACAM (300 mg/kg, p.o.) significantly reversed the establishment of ethanol-induced CPPs and effectively facilitated the extinction of ethanol CPP. In light of these findings, it has been suggested that M. citrifolia unripe fruit could be utilized for novel drug development to combat alcohol dependence.
Methanolic extract of Morinda citrifolia unripe fruit (MMC) was tested against heroin addiction using a mouse modified runway model of drug‑seeking. Habituation sessions were carried out for 10 min/d for 3 days. On day 0, the total run time of each mouse was noted (the start box to goal box) during the preconditioning test. This was followed by the conditioning session (30 min), in which the animals were conditioned with escalating doses of heroin hydrochloride (5, 10, 20, 40 and 40 mg/kg) for 5 days upon entry into the goal box. On day 6, the run time of each mouse, from start to goal box, was recorded during the post conditioning test. Extinction trials were performed for the next 5 days, in which no drug/saline was injected upon goal box entry. On day 13, a priming dose of heroin (8 mg/kg) was given to reinstate drug seeking in the mice. MMC given as oral doses (1, 3 and 5 g/kg) dose‑dependently prolonged the run time to reach the goal box, indicating MMC attenuated heroin reinforcement. Moreover, MMC (5 g/kg) was found to reverse the heroin‑seeking on extinction trial 1 and 2. MMC was also found to reverse heroin‑induced reinstatement in mice. This study demonstrates that MMC attenuated heroin seeking at different phases of drug self‑administration in a mouse modified runway model.
Despite explicit warning from the National Institute of Health, Pakistan experienced its first chikungunya outbreak in the metropolis of Karachi. We underscore the attention of health authorities and healthcare professionals towards contributing factors associated with this outbreak and the measures required to combat this viral disease.
Frank-Ter Haar syndrome (FTHS) is a rare genetic hereditary autosomal recessive disorder characterized by defective malformation of cardiovascular, craniofacial, and skeletal system. Mutations in the SH3PXD2B gene are a common cause in the development of FTHS. We recruited a family with two affected individuals (3-year-old female and 2-month-old male infant) having bilateral clubfoot. Family pedigree shows an autosomal recessive mode of inheritance. DNA was extracted from the blood samples of six members of the family. Whole exome sequencing was done for the two affected individuals and the variant was validated in the whole family by using Sanger sequencing approach. Whole exome sequencing (WES) data analysis identified a rare homozygous variant (c.280C>G; p.R94G) in the SH3PXD2B gene, and Sanger sequencing showed that the same variant perfectly segregates with the phenotype in the pedigree. Moreover, the variant is predicted to be damaging and deleterious by several computation tools. Revisiting the family members for detailed clinical analysis, we diagnosed the patients as having the typical phenotype of FTHS. This study enabled us to correctly diagnose the cases of FTHS in a family initially recruited for having bilateral clubfoot by using WES. Moreover, this study identified a novel homozygous missense variant (c.280C>G; p.R94G) in (NM_001308175.2) the SH3PXD2B gene as a causative variant for autosomal recessive FTHS. This finding supports the evidence that homozygous mutations in the SH3PXD2B gene are the main cause in the development of FTHS.
A recently introduced bendable concrete having hundred times greater strain capacity provides promising results in repair of engineering structures, known as strain hardening cementitious composites (SHHCs). The current research creates new empirical prediction models to assess the mechanical properties of strain-hardening cementitious composites (SHCCs) i.e., compressive strength (CS), first crack tensile stress (TS), and first crack flexural stress (FS), using gene expression programming (GEP). Wide-ranging records were considered with twelve variables i.e., cement percentage by weight (C%), fine aggregate percentage by weight (Fagg%), fly-ash percentage by weight (FA%), Water-to-binder ratio (W/B), super-plasticizer percentage by weight (SP%), fiber amount percentage by weight (Fib%), length to diameter ratio (L/D), fiber tensile strength (FTS), fiber elastic modulus (FEM), environment temperature (ET), and curing time (CT). The performance of the models was deduced using correlation coefficient (R) and slope of regression line. The established models were also assessed using relative root mean square error (RRMSE), Mean absolute error (MAE), Root squared error (RSE), root mean square error (RMSE), objective function (OBF), performance index (PI) and Nash-Sutcliffe efficiency (NSE). The resulting mathematical GP-based equations are easy to understand and are consistent disclosing the originality of GEP model with R in the testing phase equals to 0.8623, 0.9269, and 0.8645 for CS, TS and FS respectively. The PI and OBF are both less than 0.2 and are in line with the literature, showing that the models are free from overfitting. Consequently, all proposed models have high generalization with less error measures. The sensitivity analysis showed that C%, Fagg%, and ET are the most significant variables for all three models developed with sensitiveness index higher than 10 %. The result of the research can assist researchers, practitioners, and designers to assess SHCC and will lead to sustainable, faster, and safer construction from environment-friendly waste management point of view.
Infective endocarditis (IE) is the one of the most important causes of increased mortality and morbidity among haemodialysis patients. The reason for this increasing prevalence of infection among these patients is the use of haemodialysis catheters during dialysis, as these patients are highly susceptible to infections that are easily transmitted via blood access points. The present case was a geriatric end stage renal disease (ESRD) patient who was readmitted to the hospital two days after her scheduled haemodialysis session with symptoms of nosocomial endocarditis. Her concurrent medical complications were hypertension, non-insulin dependent diabetes mellitus, and ischemic heart disease. Based on her previous medical history and current examination, the patient was suspected to have IE due to catheter related infection. The goal of therapy is to manage the comorbidities and infection by provision of appropriate treatment based on close monitoring of the patient condition.
The current study involves the synthesis of Schiff bases based on 1,2,4-triazoles skeleton and assessing their α-amylase and α-glucosidase profile. Furthermore, the precise structures of the synthesized derivatives were elucidated using various spectroscopic methods such as 1H-NMR, 13C-NMR and HREI-MS. Using glimepiride as the reference standard, the in vitro α-glucosidase and α-amylase inhibitory activities of the synthesized compounds were evaluated in order to determine their potential anti-diabetic properties. All analogues showed varied range of inhibitory activity having IC50 values ranging from 17.09 ± 0.72 to 45.34 ± 0.03 μM (α-amylase) and 16.35 ± 0.42 to 42.31 ± 0.09 μM (α-glucosidase), respectively. Specifically, the compounds 1, 7 and 8 were found to be significantly active with IC50 values of 17.09 ± 0.72, 19.73 ± 0.42, and 23.01 ± 0.04 μM (against α-amylase) and 16.35 ± 0.42, 18.55 ± 0.26, and 20.07 ± 0.02 μM (against α-glucosidase) respectively. The obtained results were compared with the Glimepiride reference drug having IC50 values of 13.02 ± 0.11 μM (for α-glucosidase) and 15.04 ± 0.02 μM (for α-amylase), respectively. The structure-activity relationship (SAR) studies were conducted based on differences in substituent patterns at varying position of aryl rings A and B may cause to alter the inhibitory activities of both α-amylase and α-glucosidase enzymes. Additionally, the molecular docking study was carried out to explore the binding interactions possessed by most active analogues with the active sites of targeted α-amylase and α-glucosidase enzymes.
On the 18th of March 2020, the Malaysia government declared a movement control order (MCO) due to the unprecedented COVID-19 pandemic. Although the majority of patients presented with respiratory-related symptoms, COVID-19 patients may present atypically with neurological manifestations and may even have an increased risk of stroke. The Malaysia Stroke Council is concerned regarding the level of care given to stroke patients during this pandemic. During the recent National Stroke Workflow Steering Committee meeting, a guide was made based on the currently available evidences to assist Malaysian physicians providing acute stroke care in the hospital setting in order to provide the best stroke care while maintaining their own safety. The guide comprises of prehospital stroke awareness, hyperacute stroke care, stroke care unit and intensive care unit admission, post-stroke rehabilitation and secondary prevention practice. We urge continuous initiative to provide the best stroke care possible and ensure adequate safety for both patients and the stroke care team.