Molecular Dynamics of Rab7::REP1::GGTase-II Ternary Complex and Identification of Their Putative Drug Binding Sites

The structure-function correlation of membrane proteins have been a difficult task, particularly in context to transient protein complexes. The molecular simulation of ternary complex of Rab7::REP1::GGTase-II was carried out to understand the basic structural events occurring during the prenylation event of Rab proteins, using the software YASARA. The study suggested that the C-terminus of Rab7 has to be in completely extended conformation during prenylation to reach the active site of RabGGTase-II. Also, attempt was made to find putative drug binding sites on the ternary complex of Rab7::REP1::GGTase-II using Q-SiteFinder programme. The comprehensive consensus probe generated by the program revealed a total of 10 major pockets as putative drug binding sites on Rab7::REP:: GGTase-II ternary complex. These pockets were found on REP protein and GGTase protein subunits. The Rab7 was found to be devoid of any putative drug binding sites in the ternary complex. The phylogenetic analysis of 60 Rab proteins of human was carried out using PHYLIP and study indicated the close phylogenetic relationship between Rab7 and Rab9 proteins of human and hence with further in silico study, the present observations can be extrapolated to Rab9 proteins. The study paves a good platform for further experimental verifications of the findings and other in silico studies like identifying the potential drug targets by searching the putative drug binding sites, generating pharmacophoric pattern, searching or constructing suitable ligand and docking studies.     

Fifteen years' experience of treating atherosclerotic renal artery stenosis by interventional nephrologists in India

Atherosclerotic renal artery stenosis (ARAS) is an important cause of kidney disease, accelerated hypertension (HTN), and its treatment is controversial. Our aim was to evaluate the outcomes, safety, and efficacy of percutaneous transluminal angioplasty (PTA) for ARAS. Retrospective analysis of ARAS was performed among 470 angiographies during 1995–2010. Patients with nonatherosclerotic RAS and renal transplant were excluded. We assessed preintervention and postintervention mean arterial pressure (MAP), antihypertensive medications, and renal function to classify as deteriorated (>10% increase in MAP/increase in drugs/>20% reduced GFR), improved (>10% reduced MAP/reduced drugs/>20% increased eGFR), or stabilized (<10% change in MAP/same antihypertensive drugs/<20% change in eGFR) at last follow‐up. A total of 220 subjects with mean age of 57.6 ± 10.4 years underwent PTA and/or stenting. The average follow‐up was 23.07 ± 21.2 months. Accelerated HTN, HTN onset >50 years, unexplained renal failure, and unilateral small kidney were the most common presentations. In all, 255 significant stenotic lesions in 220 patients (119 unilateral, 66 single functioning kidney, and 35 bilateral) were observed. In total, 255 PTA were performed, including 177 stenting. Technical success was seen in 220/243 (90.5%) subjects. Combined MAP and antihypertensive drugs improved in 154/220 (70%) patients. Renal function improved/stabilized in 175/220 (79.5%). Angioplasty and stenting are relatively safe and feasible tools for control of blood pressure (BP) in ARAS. Angioplasty produced improvement/stabilization of BP in 70%, and the renal function in 79.5% subjects.     

Back to the Future: How Biology and Technology Could Change the Role of PTFE Grafts in Vascular Access Management

Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF maturation failure remains a huge clinical problem, often resulting in a prolonged duration of use of tunneled dialysis catheters. In contrast, polytetrafluoroethylene (PTFE) grafts do not suffer from early failure, but have significant problems with later stenosis and thrombosis. This review will initially summarize the pathology and pathogenesis of PTFE graft dysfunction and will then use this as a basis for describing some novel therapies, which may have the potential to reduce PTFE graft dysfunction. Finally, we will emphasize that the introduction of such therapies could be an important first step toward individualizing overall vascular access care.     

Effect of osteoporosis medications on fracture healing

Antiosteoporotic medications are often used to concurrently treat a patient’s fragility fractures and underlying osteoporosis. This review evaluates the existing literature from animal and clinical models to determine these drugs’ effects on fracture healing. The data suggest that these medications may enhance bone healing, yet more thorough prospective studies are warranted. Pharmacologic agents that influence bone remodeling are an essential component of osteoporosis management. Because many patients are first diagnosed with osteoporosis when presenting with a fragility fracture, it is critical to understand how osteoporotic medications influence fracture healing. Vitamin D and its analogs are essential for the mineralization of the callus and may also play a role in callus formation and remodeling that enhances biomechanical strength. In animal models, antiresorptive medications, including bisphosphonates, denosumab, calcitonin, estrogen, and raloxifene, do not impede endochondral fracture healing but may delay repair due to impaired remodeling. Although bisphosphonates and denosumab delay callus remodeling, they increase callus volume and result in unaltered biomechanical properties. Calcitonin increases cartilage formation and callus maturation, resulting in improved biomechanical properties. Parathyroid hormone, an anabolic agent, has demonstrated promise in animal models, resulting in accelerated healing with increased callus volume and density, more rapid remodeling to mature bone, and improved biomechanical properties. Clinical data with parathyroid hormone have demonstrated enhanced healing in distal radius and pelvic fractures as well as postoperatively following spine surgery. Strontium ranelate, which may have both antiresorptive and anabolic properties, affects fracture healing differently in normal and osteoporotic bone. While there is no effect in normal bone, in osteoporotic bone, strontium ranelate increases callus bone formation, maturity, and mineralization; forms greater and denser trabeculae; and improves biomechanical properties. Further clinical studies with these medications are needed to fully understand their effects on fracture healing in order to simultaneously treat fragility fractures and underlying osteoporosis.     

Multiparametric MRI of prostate cancer: An update on state‐of‐the‐art techniques and their performance in detecting and localizing prostate cancer

Magnetic resonance (MR) examinations of men with prostate cancer are most commonly performed for detecting, characterizing, and staging the extent of disease to best determine diagnostic or treatment strategies, which range from biopsy guidance to active surveillance to radical prostatectomy. Given both the exam's importance to individual treatment plans and the time constraints present for its operation at most institutions, it is essential to perform the study effectively and efficiently. This article reviews the most commonly employed modern techniques for prostate cancer MR examinations, exploring the relevant signal characteristics from the different methods discussed and relating them to intrinsic prostate tissue properties. Also, a review of recent articles using these methods to enhance clinical interpretation and assess clinical performance is provided. J. Magn. Reson. Imaging 2013;37:1035–1054. © 2013 Wiley Periodicals, Inc.     

CT findings in pediatric blunt intestinal injury

Trauma is the leading cause of morbidity and mortality in children. Computed tomography examinations play an important role in the management of patients with major trauma. Though abdominal trauma is less common compared to head injuries, the associated morbidity and mortality are substantial. It is easier to diagnose solid abdominal injuries than intestinal or mesenteric injuries on CT examinations. However, recognition of bowel injury is very important as a delay in diagnosis increases the morbidity and mortality. Hence, with every CT of the abdomen and pelvis, the radiologist must look for signs of bowel and mesenteric injury. This pictorial review presents various CT findings of blunt intestinal injury in children.     

Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: Experience at large transplant center in New York City

Solid organ transplant (SOT) recipients may be at higher risk for poor outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Convalescent plasma is an investigational therapy that may benefit immunosuppressed patients by providing passive immunity. Convalescent plasma was administered to hospitalized patients with coronavirus disease-2019 (COVID-19) at an academic transplant center in New York City. Eligible patients were hospitalized and required to have positive nasopharyngeal polymerase chain reaction (PCR) diagnosis of SARS-CoV-2 infection, be at least 18 years old, and have either dyspnea, blood oxygen saturation ≤ 93% on ambient air, respiratory frequency ≥ 30 breaths/min, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, or lung infiltrates > 50%. Thirteen SOT recipients received convalescent plasma from April 9, 2020, to May 17, 2020. The median time from symptom onset to plasma infusion was 8 days. Eight of 13 patients (62%) had de-escalating oxygenation support by day 7 post-convalescent plasma. Nine (69%) patients were discharged, 1 (7%) patients remain hospitalized, and 3 (23%) patients died. This series supports the need for additional studies on convalescent plasma use in SOT recipients with COVID-19 to better determine efficacy and identify patients who are likely to benefit.     

The pattern of the maxillofacial fractures – A multicentre retrospective study

Aim of the present study was to report on the survey of fractures, frequency of presentation, sex and age distributions, aetiology, site distributions, associated injuries & modalities of treatment rendered at muticentres treated by the division of oral and maxillofacial surgery between 2000 and 2005 in Karnataka state of India. Study revealed that the common cause for the facial fractures was found to be traffic accidents (72.7%) with a male preponderance and peak incidence during 20–30 years of age. Isolated mandibular fractures were most frequent [1035 patients (41.7%)] followed by isolated mid face fractures [526 patients (21.2%)]. Among mid face fractures, zygomatic bone and arch were most frequently involved. Open reduction and internal fixation and closed method were used in almost the same frequency. Traffic accidents are the leading cause of the maxillofacial fractures from the observation made from the study. Legislations preventive measures to be enforced and abided by every citizen.     

Induction of ultraviolet cataracts in vitro: prevention by pyruvate.

Ultraviolet (UV) radiation is one of the important cataract risk factors. The present studies examined the hypothesis that this effect is due to the UV penetration through the cornea and subsequent induction of a photochemical generation of reactive species of oxygen (ROS) in the aqueous and lens. The hypothesis was ascertained by rat lens organ culture studies conducted under UV (365 nm), with media containing micromolar levels of riboflavin, with and without pyruvate, the latter acting as an ROS scavenger. The implication of ROS in the UV-induced damage was confirmed by measurements of peroxide generation. Damage to the lens was assessed physiologically by measuring the decrease in its active transport of rubidium ions. Biochemically, it was assessed by measuring the lowering of adenosine triphosphate and glutathione. The incorporation of pyruvate in the medium protected the lens against these deleterious effects. That the beneficial effect of pyruvate is attributable to its ROS-scavenging property was proven by the peroxide depletion in its presence, commensurate with its own utilization in parallel. A protective effect of this keto acid against UV-induced tissue damage has been shown for the first time, suggesting its clinical usefulness against UV irradiation-induced pathologies. Hence, further studies on the possible protective effects of such alpha-keto acids against UV damage are in progress.