Side effects based network construction and drug repositioning of ropinirole as a potential molecule for Alzheimer's disease: an in-silico, in-vitro, and in-vivo study.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Drug repositioning is a process of finding new therapeutic applications for existing drugs. One of the methods in drug repositioning is to use the side-effect profile of a drug to identify a new therapeutic indication. The drugs with similar side-effects may act on similar biological targets and could affect the same biochemical process. In this study, we explored the Food and Drug Administration-approved drugs using PROMISCUOUS database to find those that have adverse effects profile comparable with the ligands being studied or used to treat AD. Here, we found that the ropinirole, a dopamine receptor agonist, shared a maximum number of side-effects with the drugs proven beneficial for treating AD. Furthermore, molecular modelling demonstrated that ropinirole exhibited strong binding affinity (-9.313 kcal/mol) and best ligand efficiency (0.49) with sigma-1 receptor. Here, we observed that the quaternary amino group of ropinirole is essential for binding with sigma-1 receptor. Molecular dynamic simulation indicated that the movement of the carboxy-terminal helices (α4/α5) could play a major role in the receptor's physiological functions. The neurotoxicity induced by Aß25-35 in SH-SY5Y cells was reduced by ropinirole at concentrations 10, 30, and 50 µM. The effect on spatial learning and memory was examined in mice with Aß25-35 induced memory deficit using the radial arm maze. Ropinirole (10 and 20 mg/kg) significantly improved the short and long-term memories in the radial arm maze test. Our results suggest that ropinirole has the potential to be repositioned for AD treatment.Communicated by Ramaswamy H. Sarma.

G-Lymphatic, Vascular and Immune Pathways for Aß Clearance Cascade and Therapeutic Targets For Alzheimer's Disease.

Alzheimer's disease is an age-related neurodegenerative disease. The factors causing Alzheimer's disease are numerous. Research on humans and rodent models predicted various causative factors involved in Alzheimer's disease progression. Among them, neuroinflammation, oxidative stress, and apoptosis play a major role because of the accumulation of extracellular amyloid-beta peptides. Here, the clearance of amyloid beta-peptide plays a major role because of the imbalance in the production and clearance of the amyloid beta-peptide. Additionally, neuroinflammation by microglia, astrocytes, cytokines, chemokines, and the complement system also has a major role in Alzheimer's disease. The physiological clearance pathways involved in amyloid beta-peptide are glymphatic, vascular, and immune pathways. Amyloid precursor protein, low-density lipoprotein receptor-related protein 1, receptor for the advanced glycation end product, apolipoprotein E, clusterin, aquaporin 4, auto-antibodies, complement system, cytokines, and microglia are involved in amyloid beta-peptide clearance pathways across the blood-brain barrier. The plaque formation in the brain by alternative splicing of amyloid precursor protein and production of misfolded protein results in amyloid-beta agglomeration. This insoluble amyloid-beta leads to a neurodegenerative cascade and neuronal cell death occurs. Studies had shown that disturbed sleep may be a risk factor for dementia and cognitive decline. In this review, the therapeutic targets for Alzheimer'sdisease via focusing on pathways for amyloid-beta clearance are discussed.

Reinforced tension line suture closure after midline laparotomy in emergency surgery.

Midline laparotomy is an emergency surgical operation frequently performed in cases of intra-abdominal pathology. Closure of the incision is usually done by continuous suturing by mass closure. In an emergency operation the intra-abdominal milieu is usually contaminated leading to gut oedema and, hence, an increase in postoperative intra-abdominal pressure. It is complicated by wound dehiscence, burst abdomen, etc. The cause of this complication is an increase in horizontal tensile forces on the site of the insertion of sutures which cuts the sheath. In this technique of reinforced tension line suture peak tensile forces are distributed from the suture base to the surrounding tissue through a horizontal suture, thereby preventing the suture from cutting through the tissue. From July 2007 to June 2009 patients requiring laparotomy were randomly divided into test and control groups by a 'closed envelope' technique. Their postoperative intra-abdominal pressure was recorded by urinary bladder catheter manometry. The result of this technique was compared with the incidence of burst abdomen in cases where it was closed by continuous suture. A total of 190 patients underwent laparotomy. In 90 the abdomen was closed by reinforced tension line (RTL) and in 100 patients by continuous suturing. None of the RTL group had a burst abdomen. Thirteen who had closure by continuous suture had a burst abdomen. The analysis of the results was done using the chi-square test. On comparing the incidence of burst abdomen in cases operated by continuous suture technique and by RTL, the P value was found to be 0.0026 which is highly significant. On analysis of the incidence of burst abdomen in cases having a grade II intra-abdominal pressure the P value was found to be 0.0009 which is highly significant. Closure of midline incision by RTL reduces the incidence of burst abdomen. Registration No. PROVCTRI/2008/091/000269 (http://www.ctri.in).

Doctor patient communication-a vital yet neglected entity in Indian medical education system.

Doctor patient communication is the most important and an integral part of any treatment regimen. Properly carried out it has been shown to have a therapeutic effect equivalent to drugs. Despite being so important part of treatment it is more than often taken and carried out casually. Apart from apathy towards this practice, its omission in the medical study curriculum is an important factor. This study was carried in amongst the surgical residents of surgical departments of various medical colleges to assess the attitude of surgical residents towards patient doctor communication. A questionnaire was forwarded by mail and email and the response was assessed: The responses of the surgical residents from various residents from different medical colleges were similar. Most of the residents prefer inclusion of communication skill in medical education curriculum.