Enhancing selegiline hydrochloride efficacy: Box Behnken-optimized liposomal delivery via intranasal route for Parkinson's disease intervention.

The clinical use of selegiline hydrochloride in conventional dosage forms is to reduce the progression of Parkinson's disease (PD). However, its limited access to the brain, short half-life, and first-pass metabolism minimize brain uptake. Nano-based liposomes offer promising tools for brain-targeted delivery of therapeutics, especially intranasally administered cationic liposomes that target the brain region via the olfactory route and reduce biodistribution. In the present work, cationic liposomes encapsulated with selegiline hydrochloride were fabricated for intranasal administration against PD. The liposomes were initially optimized by Box Behnken design, and the selected run was coated with stearylamine to provide a cationic charge to the liposomes. The final coated liposomes, SH-LP3, demonstrated a minimum size of 173 ± 2.13 nm, an ideal zeta potential of +16 ± 1.98, and achieved a maximum entrapment efficiency of 40.14 ± 1.83%. Morphology analysis showed the spherical shape of liposomes in the size range of 100-200 nm. The in vitro cytotoxicity assay in SHSY5Y cell lines showed a significant decrease in toxicity, almost ten times less, compared to pure selegiline hydrochloride. Animal studies on rotenone-lesioned C57BL6 mice model for PD were performed to investigate the effect of intranasally administered liposomes. The SH-LP3 formulation exhibited remarkable effectiveness in relieving symptoms of PD. This extensive analysis emphasizes the possibility of intranasally administered SH-LP3 liposomes as a feasible treatment option for PD. The formulation not only delivers continuous drug release but also displays better safety and efficacy, providing a platform for additional studies and growth in the domain of PD treatment.

Measuring CP Violating Phase in Beauty Baryon Decays.

One of the outstanding problems in physics is to explain the baryon-antibaryon asymmetry observed in nature. According to the well-known Sakharov criterion for explaining the observed asymmetry, it is essential that CP violation exist. Even though CP violation has been observed in meson decays and is an integral part of the standard model (SM), measurements in meson decays indicate that CP violation in the SM is insufficient to explain the observed baryon-antibaryon asymmetry. The SM predicts the existence of yet to be observed CP violation in baryon decays. A critical test of the SM requires that CP violation be measured in baryon decays as well, in order to verify that it agrees with the measurement using meson decays. In this Letter we propose a new method to measure the CP violating phase in b baryons, using interference arising implicitly due to Bose symmetry considerations of the decaying amplitudes.

Single TRAM domain RNA-binding proteins in Archaea: functional insight from Ctr3 from the Antarctic methanogen Methanococcoides burtonii.

TRAM domain proteins present in Archaea and Bacteria have a ß-barrel shape with anti-parallel ß-sheets that form a nucleic acid binding surface; a structure also present in cold shock proteins (Csps). Aside from protein structures, experimental data defining the function of TRAM domains is lacking. Here, we explore the possible functional properties of a single TRAM domain protein, Ctr3 (cold-responsive TRAM domain protein 3) from the Antarctic archaeon Methanococcoides burtonii that has increased abundance during low temperature growth. Ribonucleic acid (RNA) bound by Ctr3 in vitro was determined using RNA-seq. Ctr3-bound M. burtonii RNA with a preference for transfer (t)RNA and 5S ribosomal RNA, and a potential binding motif was identified. In tRNA, the motif represented the C loop; a region that is conserved in tRNA from all domains of life and appears to be solvent exposed, potentially providing access for Ctr3 to bind. Ctr3 and Csps are structurally similar and are both inferred to function in low temperature translation. The broad representation of single TRAM domain proteins within Archaea compared with their apparent absence in Bacteria, and scarcity of Csps in Archaea but prevalence in Bacteria, suggests they represent distinct evolutionary lineages of functionally equivalent RNA-binding proteins.

Experiences obtaining insurance after live kidney donation.

The impact of kidney donation on the ability to change or initiate health or life insurance following donation is unknown. To quantify this risk, we surveyed 1046 individuals who donated a kidney at our center between 1970 and 2011. Participants were asked whether they changed or initiated health or life insurance after donation, and if they had any difficulty doing so. Among 395 donors who changed or initiated health insurance after donation, 27 (7%) reported difficulty; among those who reported difficulty, 15 were denied altogether, 12 were charged a higher premium and 8 were told they had a preexisting condition because they were kidney donors. Among 186 donors who changed or initiated life insurance after donation, 46 (25%) reported difficulty; among those who reported difficulty, 23 were denied altogether, 27 were charged a higher premium and 17 were told they had a preexisting condition because they were kidney donors. In this single-center study, a high proportion of kidney donors reported difficulty changing or initiating insurance, particularly life insurance. These practices by insurers create unnecessary burden and stress for those choosing to donate and could negatively impact the likelihood of live kidney donation among those considering donation.

Use of sclerotherapy for treatment of vascular malformation in a young girl.

Vascular malformations are difficult to treat because of poor results of treatment and recurrence of symptoms. Percutaneous and/or transluminal embolisation has refined the treatment of surface vascular lesions; especially with availability of variety of sclerosants.We report a case of a young girl with vascular malformation of right foot, which was treated with percutaneous sclerotherapy with sodium tetradecyl sulphate (STS). Result was excellent and so far the patient is free of her symptoms.

An In-silico Approach: Design, Homology Modeling, Molecular Docking, MM/GBSA Simulations, and ADMET Screening of Novel 1,3,4-oxadiazoles as PLK1inhibitors.

BACKGROUND: Breast cancer is the most commonly diagnosed and major cause of cancer-related deaths in women worldwide. Disruption of the normal regulation of cell cycle progression and proliferation are the major events leading to cancer. Human Polo-like Kinase 1 (PLK1) plays an important role in the regulation of cellular division. High PLK1 expression is observed in various types of cancer including breast cancer. 1,3,4-oxadiazoles are the fivemembered heterocycles, that serve as versatile lead molecules for designing novel anticancer agents and they mainly act by inhibiting various enzymes and kinases. OBJECTIVE: A novel series of 1,3,4-oxadiazole derivatives (A1-A26) were designed and subjected to an in-silico analysis against PLK1 enzyme (PDB ID:1q4k), targeting breast cancer. METHODS: The chemical structure of each compound (A1-26) was drawn using ChemDraw software. The 3D structure model of protein target (PDB ID:1q4k) was built using the SWISSMODEL server. Molecular docking simulation was performed to determine the designed compound's probable binding mode and affinity towards the protein target (PDB ID:1q4k). The designed compounds were subjected to ADME screening, as well as Prime MM/GBSA simulations using Schrodinger suite 2020-4. Furthermore, the safety profile of compounds was examined through the OSIRIS property explorer program and the results were compared with the standard drugs, 5-fluorouracil and cyclophosphamide. RESULTS: Based on the binding affinity scores, the compounds were found selective to target protein 1q4k through hydrogen bonding and hydrophobic interactions. The compounds A11, A12, and A13 were found to have higher G scores and binding free energy values. The ADME screening results were also found to be within the acceptable range. Moreover, the in-silico toxicity prediction assessments suggest that all designed compounds have a low risk of toxicity, and have higher efficiency for the target receptor. CONCLUSION: The study showed that the substitution of electron-donating groups at the various position of the aromatic ring, which is bonded at the second position of the substituted 1,3,4- oxadiazole nucleus resulted in compounds with good binding energy and G score compared to the standard drugs, and hence, they can be further developed as potent PLK1 enzyme inhibitors.

Virtual screening, pharmacokinetics & MD simulation study of active phytoconstituents of Ficus Carica Linn. against PPAR-γ in diabetes mellitus.

F. carica is a small tree and commonly used as a traditional medicine against several disorders. Diabetes is currently treated with insulin and oral hypoglycemic medicines such as sulphonyl urea derivatives, bigunides, thiazolidinediones and alpha-glucosidase inhibitors. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists were found to be very much beneficial in the management of diabetes by inhibiting hepatic gluconeogenesis. The aim of this study is to evaluate the bioactive phytoconstituents from Ficus carica Linn. against the target PPAR-γ agonist by in silico docking approach. We investigated 68 phytoconstituents as potential inhibitors of PPAR-γ agonists and the top 24 phytoconstituents were further selected for molecular docking studies. Drug ability, side effects, and ADMET analysis were determined by using MolSoft, toxtree freeware, and ADMET SAR web server, respectively. The phytoconstituents were docked with the target PPAR-γ (PDB ID: 4Y29, 1.98 Å) receptor. Quercetin-3-o-rutinoside possessed the highest G score -14.22 kcal/mol, followed by Angelicin with a G score of -13.56 kcal/mol. All the other phytoconstituents displayed good pharmacokinetic and toxicological parameters with values within the permissible limits. The ligand-protein interaction was calculated by molecular dynamic (MD) simulation study. Subsequently, the binding free energy of the Quercetin-3-o-rutinosideand Pioglitazone complex was calculated using MMPBSA analysis. The results indicated that some of the phytoconstituents from Ficus carica have potency as an anti-diabetic agents. So, these bioactive phytoconstituents like Quercetin-3-o-glucoside, 5-O-caffeoylquinic acids may act as a good agonist for PPAR-γ.Communicated by Ramaswamy H. Sarma.

The aggressive phenotype: center-level patterns in the utilization of suboptimal kidneys.

Despite the fact that suboptimal kidneys have worse outcomes, differences in waiting times and wait-list mortality have led to variations in the use of these kidneys. It is unknown whether aggressive center-level use of one type of suboptimal graft clusters with aggressive use of other types of suboptimal grafts, and what center characteristics are associated with an overall aggressive phenotype. United Network for Organ Sharing (UNOS) data from 2005 to 2009 for adult kidney transplant recipients was aggregated to the center level. An aggressiveness score was assigned to each center based on usage of suboptimal grafts. Deceased-donor transplant volume correlated with aggressiveness in lower volume, but not higher volume centers. Aggressive centers were mostly found in regions 2 and 9. Aggressiveness was associated with wait-list size (RR 1.69, 95% CI 1.20-2.34, p = 0.002), organ shortage (RR 2.30, 95% CI 1.57-3.37, p < 0.001) and waiting times (RR 1.75, 95% CI 1.20-2.57, p = 0.004). No centers in single-center OPOs were classified as aggressive. In cluster analysis, the most aggressive centers were aggressive in all metrics and vice versa; however, centers with intermediate aggressiveness had phenotypic patterns in their usage of suboptimal kidneys. In conclusion, wait-list size, waiting times, geographic region and OPO competition seem to be driving factors in center-level aggressiveness.

Pregnancy outcomes in kidney transplant recipients: a systematic review and meta-analysis.

Approximately 50,000 women of reproductive age in the United States are currently living after kidney transplantation (KT), and another 2800 undergo KT each year. Although KT improves reproductive function in women with ESRD, studies of post-KT pregnancies are limited to a few voluntary registry analyses and numerous single-center reports. To obtain more generalizable inferences, we performed a systematic review and meta-analysis of articles published between 2000 and 2010 that reported pregnancy-related outcomes among KT recipients. Of 1343 unique studies, 50 met inclusion criteria, representing 4706 pregnancies in 3570 KT recipients. The overall post-KT live birth rate of 73.5% (95%CI 72.1-74.9) was higher than the general US population (66.7%); similarly, the overall post-KT miscarriage rate of 14.0% (95%CI 12.9-15.1) was lower (17.1%). However, complications of preeclampsia (27.0%, 95%CI 25.2-28.9), gestational diabetes (8.0%, 95%CI 6.7-9.4), Cesarean section (56.9%, 95%CI 54.9-58.9) and preterm delivery (45.6%, 95%CI 43.7-47.5) were higher than the general US population (3.8%, 3.9%, 31.9% and 12.5%, respectively). Pregnancy outcomes were more favorable in studies with lower mean maternal ages; obstetrical complications were higher in studies with shorter mean interval between KT and pregnancy. Although post-KT pregnancy is feasible, complications are relatively high and should be considered in patient counseling and clinical decision making.

Determination of weak amplitudes using Bose symmetry and Dalitz plots.

We present a new method using Dalitz plots and Bose symmetry of pions that allows the complete determination of the magnitudes and phases of weak decay amplitudes. We apply the method to processes such as B→K*π, with the subsequent decay of K*→Kπ. Our approach enables the additional measurement of an isospin amplitude without any theoretical assumption. This advance will help in measuring the weak phase and probing for new physics beyond the standard model with fewer assumptions.

Recent advances in the management of acute myocardial infarction.

Recently the reperfusion therapy in the form of Primary Percutaneous Coronary intervention (PPCI) has become the gold standard for the treatment of Acute Myocardial Infarction. In spite of rapid revascularization either with PPCI or thrombolytic therapy, the significant number of patients develops decreased left ventricular function leading to heart failure which can increase long-term mortality and morbidity. The number of strategies are being evolved and evaluated to reduce this post infarct heart failure. They are being developed at the level of optimizing the outcomes of PPCI, protection against the reperfusion injury, and novel therapies like cardiac repair and regeneration and sonothrombolysis. Thrombus aspiration using simple aspiration catheters during PPCI are getting established as a useful adjunct tool to reduce distal embolisation and consequently improving myocardial salvage. The newer antiplatelet drugs like Prasugrel and Ticagrelor may replace the Clopidogrel to reduce ischemic complications. The reduction in reperfusion injury using drugs has shown mixed results. The newer modalities like cardiac repair and regeneration using stem cell therapy looks promising but are yet to be established.

Molecular ultrasound imaging: current status and future directions.

Targeted contrast-enhanced ultrasound (molecular ultrasound) is an emerging imaging strategy that combines ultrasound technology with novel molecularly-targeted ultrasound contrast agents for assessing biological processes at the molecular level. Molecular ultrasound contrast agents are nano- or micro-sized particles that are targeted to specific molecular markers by adding high-affinity binding ligands onto the surface of the particles. Following intravenous administration, these targeted ultrasound contrast agents accumulate at tissue sites overexpressing specific molecular markers, thereby enhancing the ultrasound imaging signal. High spatial and temporal resolution, real-time imaging, non-invasiveness, relatively low costs, lack of ionising irradiation and wide availability of ultrasound systems are advantages compared to other molecular imaging modalities. In this article we review current concepts and future directions of molecular ultrasound imaging, including different classes of molecular ultrasound contrast agents, ongoing technical developments of pre-clinical and clinical ultrasound systems, the potential of molecular ultrasound for imaging different diseases at the molecular level, and the translation of molecular ultrasound into the clinic.

Strain effect on orbital and magnetic structures of Mn ions in epitaxial Nd0.35Sr0.65MnO3/SrTiO3 films using X-ray diffraction and absorption.

This study probes the temperature-dependent strain that is strongly correlated with the orbital and magnetic structures of epitaxial films of Nd0.35Sr0.65MnO3 (NSMO) that are fabricated by pulsed laser deposition with two thicknesses, 17 (NS17) and 103 nm (NS103) on SrTiO3 (STO) substrate. This investigation is probed using X-ray diffraction (XRD) and absorption-based techniques, X-ray linear dichroism (XLD) and the X-ray magnetic circular dichroism (XMCD). XRD indicates a significant shift in the (004) peak position that is associated with larger strain in NS17 relative to that of NS103 at both 30 and 300 K. Experimental and atomic multiplet simulated temperature-dependent Mn L3,2-edge XLD results reveal that the stronger strain in a thinner NS17 film causes less splitting of Mn 3d eg state at low temperature, indicating an enhancement of orbital fluctuations in the band above the Fermi level. This greater Mn 3d orbital fluctuation can be the cause of both the enhanced ferromagnetism (FM) as a result of spin moments and the reduced Néel temperature of C-type antiferromagnetism (AFM) in NS17, leading to the FM coupling of the canted-antiferromagnetism (FM-cAFM) state in NSMO/STO epitaxial films at low temperature (T = 30 K). These findings are also confirmed by Mn L3,2-edge XMCD measurements.

Indo Heart Survey on latent abnormal glucose regulation in patients with coronary artery disease without diabetes across India.

BACKGROUND: The Euro Heart Survey on diabetes and heart has demonstrated high prevalence of latent glucose abnormalities in non-diabetic patients with coronary artery disease (CAD) in the European population. The aim of our survey was to assess the prevalence of latent abnormal glucose regulation in adult non-diabetic CAD patients in India. METHODS AND RESULTS: Seven centers distributed across India recruited 350 patients. The diagnosis of CAD was done by coronary angiography showing >50% stenosis in any major epicardial coronary artery or its branches. Oral glucose tolerance test (OGTT) and fasting glucose levels were used to characterize glucose metabolism. Venous plasma glucose was measured before (fasting) and 2 hours after ingestion of glucose. Impaired fasting glucose (IFG) was defined as OGTT (0 minute)>or=100 mg/dl but <126 mg/dl and OGTT (2 hours)<140 mg/dl. Impaired glucose tolerance (IGT) was defined as OGTT (0 minute)<126 mg/dl and OGTT (2 hours)>or=140 mg/dl but <200 mg/dl. Of the 350 patients studied, 176 (50.28%) had impaired glucose regulation (IFG-28 [8%]; IGT-148[42.28%]) and 75 (21.42%) had newly detected Diabetes. In all 251 (71.7%) patients with CAD had previously undetected abnormal glucose regulation. CONCLUSION: This survey demonstrates the presence of abnormal glucose regulation in almost three quarters of the non-diabetic Indian CAD patients. OGTT should be recommended as routine screening test for detecting latent glucose abnormalities in all CAD patients.

Variability in platelet response to a single daily dose of 150 mg enteric coated aspirin in a high risk population.

PURPOSE: Previous studies have reported inadequate anti-platelet effect in 0.4-35% of patients taking aspirin. Such studies have arbitrarily defined the terms "semi-responders", "non-responders" or "resistant" to variable doses of aspirin on the basis of absolute values derived from different ex-vivo platelet aggregation (PA) methods. Our objective was to define response to 150-mg dose of aspirin in terms of normally distributed values using an ex-vivo measure of PA in a population at high risk for vascular events. METHODS: We prospectively studied high risk patients with either established coronary artery disease (CAD) or stroke or transient ischemic attack (TIA) or peripheral vascular disease or with multiple atherothrombotic risk factors like diabetes plus one of the following-- hypertension, increased total cholesterol, cigarette smoking, micro-albuminuria, low-high density lipoprotein (HDL), family history of CAD and receiving single 150 mg dose of aspirin daily. PA was assessed by chronolog lumi-aggregometer (490-2D) using arachidonic acid (AA) reagent. RESULTS: 130 patients were studied. The response of subjects to aspirin followed a normal, bell shaped distribution curve with a mean and standard deviation (S.D.) of 13.1 +/- 4.4%. 3.1% patients had PA values more than 2 S.D. of the mean, hence termed as hypo-responders to aspirin while another 3.1% patients had PA values less than 2 S.D. of the mean, hence termed as hyper-responders to aspirin. CONCLUSION: There is minimal inter-individual variability in the response to aspirin when tested with AA as the reagent. The response to aspirin follows a normal Gaussian distribution. The prevalence of hypo-responders to aspirin in high risk population is only 3.1%. This is the first study to document "hypo" and "hyper-responders" to single daily dose of 150 mg aspirin. The clinical relevance of these findings remains to be determined.

Optimal platelet inhibition in patients undergoing PCI: data from the Multicenter Registry of High-Risk Percutaneous Coronary Intervention and Adequate Platelet Inhibition (MR PCI) study.

BACKGROUND: Optimal inhibition of platelet aggregation (IPA) may afford greater protection against ischemic events during percutaneous coronary intervention (PCI). The objective of this study was to test several antiplatelet regimens in elective high-risk PCI patients by comparing different combinations of glycoprotein IIb/IIIa inhibitors and clopidogrel. METHODS: The study was a randomized open-label study at 3 heart centers in India. One hundred twenty patients were enrolled between July 2006 and September 2006. Patients were randomized to 1 of the 4 groups: group A--tirofiban, group B--eptifibatide, group C--tirofiban + clopidogrel 600-mg loading dose, and group D--eptifibatide + clopidogrel 600-mg loading dose. All patients received a clopidogrel maintenance dose after PCI. The primary outcome measure was the IPA assessed at 10 minutes, at 6 to 8 hours, and at 24 hours. RESULTS: The IPA was higher with high-dose tirofiban compared with eptifibatide at 10 minutes (95.88 +/- 5.85% vs 91.22 +/- 7.52%, P = .003) and at 6 to 8 hours (93.11 +/- 7.6% vs 85.45 +/- 11.03, P < .001). Significantly more patients achieved >95% IPA with the high-dose tirofiban regimen. CONCLUSIONS: This head-to-head study comparing high-dose tirofiban with double-bolus eptifibatide demonstrated higher degree of platelet inhibition with high-dose tirofiban at 10 minutes and at 6 to 8 hours in patients undergoing elective high-risk PCI. The addition of clopidogrel did not acutely extend the IPA from intravenous glycoprotein IIb/IIIa inhibitors, but did so at 24 hours.

Mobile self-splicing group I introns from the psbA gene of Chlamydomonas reinhardtii: highly efficient homing of an exogenous intron containing its own promoter.

Introns 2 and 4 of the psbA gene of Chlamydomonas reinhardtii chloroplasts (Cr.psbA2 and Cr.psbA4, respectively) contain large free-standing open reading frames (ORFs). We used transformation of an intronless-psbA strain (IL) to test whether these introns undergo homing. Each intron, plus short exon sequences, was cloned into a chloroplast expression vector in both orientations and then cotransformed into IL along with a spectinomycin resistance marker (16S rrn). For Cr.psbA2, the sense construct gave nearly 100% cointegration of the intron whereas the antisense construct gave 0%, consistent with homing. For Cr.psbA4, however, both orientations produced highly efficient cointegration of the intron. Efficient cointegration of Cr.psbA4 also occurred when the intron was introduced as a restriction fragment lacking any known promoter. Deletion of most of the ORF, however, abolished cointegration of the intron, consistent with homing. The Cr.psbA4 constructs also contained a 3-(3,4-dichlorophenyl)-1,1-dimethylurea resistance marker in exon 5, which was always present when the intron integrated, thus demonstrating exon coconversion. Remarkably, primary selection for this marker gave >100-fold more transformants (>10,000/microgram of DNA) than did the spectinomycin resistance marker. A trans homing assay was developed for Cr.psbA4; the ORF-minus intron integrated when the ORF was cotransformed on a separate plasmid. This assay was used to identify an intronic region between bp -88 and -194 (relative to the ORF) that stimulated homing and contained a possible bacterial (-10, -35)-type promoter. Primer extension analysis detected a transcript that could originate from this promoter. Thus, this mobile, self-splicing intron also contains its own promoter for ORF expression. The implications of these results for horizontal intron transfer and organelle transformation are discussed.

Placenta in PIH.

A variety of changes in placental villi are known to occur in Pregnancy Induced Hypertension. In this study an attempt is made to study 49 placentae from PIH and its correlation to perinatal outcome. Quantification of villous lesions was carried out. The striking villious changes were cytotrophoblastic proliferation, paucity of vasculosyncytial membrane, trophoblastic basement membrane thickening and fibrinoid necrosis of villi. The changes were directly proportional to the severity of disease and perinatal outcome was worse with advancing grades of PIH.