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1.  Synthesis and evaluation of a nanoglobular dendrimer 5-aminosalicylic acid conjugate with a hydrolyzable Schiff base spacer for treating retinal degeneration 
ACS nano  2013;8(1):153-161.
Biocompatible dendrimers with well-defined nanosizes are increasingly being used as carriers for drug delivery. 5-Aminosalicylic acid (5-ASA) is an FDA approved therapeutic agent recently found effective in treating retinal degeneration of animal models. Here, a water-soluble dendrimer conjugate of 5-ASA (AGFB-ASA) was designed to treat such retinal degeneration. The drug was conjugated to a generation 2 (G2) lysine dendrimer with a silsesquioxane core (nanoglobule) by using a hydrolysable Schiff base spacer. Incubation of nanoglobular G2 dendrimer conjugates containing a 4-formylbenzoate (FB) Schiff base spacer in pH 7.4 phosphate buffers at 37 °C gradually released 5-ASA. Drug release from the dendrimer conjugate was significantly slower than from the low molecular weight free Schiff base of 5-ASA (FB-ASA). 5-ASA release from the dendrimer conjugate was dependent on steric hindrance around the spacer. After intraperitoneal injection, the nanoglobular 5-ASA conjugate provided more effective 7-day protection against light-induced retinal degeneration at a reduced dose than free 5-ASA in Abca4−/−Rdh8−/− mice. The dendrimer 5-ASA conjugate with a degradable spacer could be a good candidate for controlled delivery of 5-ASA to the eye for treatment of retinal degeneration.
PMCID: PMC4060971  PMID: 24350906
dendrimer; 5-aminosalicylic acid; Schiff base; drug delivery; controlled release
2.  Comparison of a web-based versus traditional diet recall among children 
Self-administered instruments offer a low-cost diet assessment method for use in adult and pediatric populations. This study tested whether eight to 13 year old children could complete an early version of the Automated Self Administered 24 (ASA24) hour dietary recall and how this compared to an interviewer-administered 24-hour dietary recall (24 HDR). One-hundred and twenty eight to13 year old children were recruited in Houston from June through August 2009, and randomly assigned to complete either the ASA24 or an interviewer-administered 24 HDR, followed by the other recall mode covering the same time interval. Multivariate analysis of variance, testing for differences by age, gender and ethnic/racial group, were applied to percentages of food matches, intrusions, and omissions between reports on the ASA24 and the interviewer-administered 24 HDR. For the ASA24, qualitative findings were reported regarding ease of use. Overall matches between interviewer-administered and ASA24 self-administered 24 HDR was 47.8 percent. Matches were significantly lower among younger (eight to nine year old), compared to older (10 to 13 year old) children. Omissions on ASA24 (18.9 percent overall) were most common among eight year olds and intermediate among nine year olds. Eight and nine year olds had substantial difficulties and often required aid in completing ASA24. Findings from this study suggest that a simpler version of a web-based diet recall program would be easier for children to use.
PMCID: PMC3379547  PMID: 22717216
diet assessment; computer; 24 hour recall; children
3.  Intraoperative Reported Adverse Events in Children 
Paediatric anaesthesia  2009;19(8):732-739.
Significant intra-procedural adverse events(AE) are reported in children who receive anesthesia for procedures outside the Operating Rooms(NORA). No study, so far, has characterized AE in children who receive anesthesia in the operating rooms(ORA) and NORA when anesthesia care is provided by the same team in a consistent manner.
We used the same patient-specific Quality Assurance questionnaires(QAs), to elucidate incidences of intra-operative reported AE for children receiving anesthesia in NORA and ORA locations. Through multivariate logistic regression analysis we assessed the association between patient’s AE risk and procedure’s location while adjusting for ASA status, age and unscheduled nature of the procedure.
After IRB approval, we used returned QAs of patients under 21 years; who received anesthesia from our pediatric anesthesia faculty; from May 1, 2006 through September 30, 2007. We analyzed QA data on: service location, unscheduled/schedule procedure, age, ASA status, presence and type of AE. We excluded QAs with incomplete information on date, location, age and ASA status.
We included 8,707 cases, with 3.5% incidence of reported AE. We had 1,898 NORA and 6,808 ORA cases with AE incidence of 2.5% and 3.7% respectively. Multivariate regression analysis revealed that patients with higher ASA status or younger age had higher incidence of reported AE, irrespective of location or unscheduled nature of the procedure. The most common AE type, for both sites, was respiratory-related (1.9%).
Pediatric reported AE incidence was comparable for NORA and ORA locations. Younger age or higher ASA status are associated with increased risk of AE.
PMCID: PMC2752696  PMID: 19624360
anesthesia; pediatric; adverse events; ORA; NORA
4.  Real value prediction of protein solvent accessibility using enhanced PSSM features 
BMC Bioinformatics  2008;9(Suppl 12):S12.
Prediction of protein solvent accessibility, also called accessible surface area (ASA) prediction, is an important step for tertiary structure prediction directly from one-dimensional sequences. Traditionally, predicting solvent accessibility is regarded as either a two- (exposed or buried) or three-state (exposed, intermediate or buried) classification problem. However, the states of solvent accessibility are not well-defined in real protein structures. Thus, a number of methods have been developed to directly predict the real value ASA based on evolutionary information such as position specific scoring matrix (PSSM).
This study enhances the PSSM-based features for real value ASA prediction by considering the physicochemical properties and solvent propensities of amino acid types. We propose a systematic method for identifying residue groups with respect to protein solvent accessibility. The amino acid columns in the PSSM profile that belong to a certain residue group are merged to generate novel features. Finally, support vector regression (SVR) is adopted to construct a real value ASA predictor. Experimental results demonstrate that the features produced by the proposed selection process are informative for ASA prediction.
Experimental results based on a widely used benchmark reveal that the proposed method performs best among several of existing packages for performing ASA prediction. Furthermore, the feature selection mechanism incorporated in this study can be applied to other regression problems using the PSSM. The program and data are available from the authors upon request.
PMCID: PMC2638152  PMID: 19091011
5.  Lung Injury Prevention with Aspirin (LIPS-A): a protocol for a multicentre randomised clinical trial in medical patients at high risk of acute lung injury 
BMJ Open  2012;2(5):e001606.
Acute lung injury (ALI) is a devastating condition that places a heavy burden on public health resources. Although the need for effective ALI prevention strategies is increasingly recognised, no effective preventative strategies exist. The Lung Injury Prevention Study with Aspirin (LIPS-A) aims to test whether aspirin (ASA) could prevent and/or mitigate the development of ALI.
Methods and analysis
LIPS-A is a multicentre, double-blind, randomised clinical trial testing the hypothesis that the early administration of ASA will result in a reduced incidence of ALI in adult patients at high risk. This investigation will enrol 400 study participants from 14 hospitals across the USA. Conditional logistic regression will be used to test the primary hypothesis that early ASA administration will decrease the incidence of ALI.
Ethics and dissemination
Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approval of both the protocol and informed consent documents were also obtained from the institutional review board of each participating institution prior to enrolling study participants at the respective site. In addition to providing important clinical and mechanistic information, this investigation will inform the scientific merit and feasibility of a phase III trial on ASA as an ALI prevention agent. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to Pub Med Central in accordance with the National Institute of Health Public Access Policy.
PMCID: PMC3437429  PMID: 22952165
acute lung injury; acute respiratory ditress syndrome; aspirin; critical illness; prevention; clinical trial
6.  Anesthetic management of patients undergoing bariatric surgery: two year experience in a single institution in Switzerland 
BMC Anesthesiology  2014;14(1):125.
In the field of anesthesia for bariatric surgery, a wide variety of recommendations exist, but a general consensus on the perioperative management of such patients is missing. We outline the perioperative experiences that we gained in the first two years after introducing a bariatric program.
The perioperative approach was established together with all relevant disciplines. Pertinent topics for the anesthesiologists were; successful airway management, indications for more invasive monitoring, and the planning of the postoperative period and deposition. This retrospective analysis was approved by the local ethics committee. Data are mean [SD].
182 bariatric surgical procedures were performed (147 gastric bypass procedures (GBP; 146 (99.3%) performed laparascopically). GBP patients were 43 [10] years old, 78% female, BMI 45 [7] kg/m2, 73% ASA physical status of 2. 42 patients (28.6%) presented with obstructive sleep apnea syndrome. 117 GBP (79.6%) patients were intubated conventionally by direct laryngoscopy (one converted to fiber-optic intubation, one aspiration of gastric contents). 32 patients (21.8%) required an arterial line, 10 patients (6.8%) a central venous line. Induction lasted 25 [16] min, the procedure itself 138 [42] min. No blood products were required. Two patients (1.4%) presented with hypothermia (<35°C) at the end of their case. The emergence period lasted 17 [9] min. Postoperatively, 32 patients (21.8%) were transferred to the ICU (one ventilated). The other patients spent 4.1 [0.7] h in the post anesthesia care unit. 15 patients (10.2%) required take backs for surgical revision (two laparotomies).
The physiology and anatomy of bariatric patients demand a tailored approach from both the anesthesiologist and the perioperative team. The interaction of a multi-disciplinary team is key to achieving good outcomes and a low rate of complications.
Trial registration
DRKS00005437 (date of registration 16th December 2013)
PMCID: PMC4277841  PMID: 25544832
Anesthesia; Complications; Bariatric surgery; Obesity
7.  Regulation of fruit ascorbic acid concentrations during ripening in high and low vitamin C tomato cultivars 
BMC Plant Biology  2012;12:239.
To gain insight into the regulation of fruit ascorbic acid (AsA) pool in tomatoes, a combination of metabolite analyses, non-labelled and radiolabelled substrate feeding experiments, enzyme activity measurements and gene expression studies were carried out in fruits of the ‘low-’ and ‘high-AsA’ tomato cultivars ‘Ailsa Craig’ and ‘Santorini’ respectively.
The two cultivars exhibited different profiles of total AsA (totAsA, AsA + dehydroascorbate) and AsA accumulation during ripening, but both displayed a characteristic peak in concentrations at the breaker stage. Substrate feeding experiments demonstrated that the L-galactose pathway is the main AsA biosynthetic route in tomato fruits, but that substrates from alternative pathways can increase the AsA pool at specific developmental stages. In addition, we show that young fruits display a higher AsA biosynthetic capacity than mature ones, but this does not lead to higher AsA concentrations due to either enhanced rates of AsA breakdown (‘Ailsa Craig’) or decreased rates of AsA recycling (‘Santorini’), depending on the cultivar. In the later stages of ripening, differences in fruit totAsA-AsA concentrations of the two cultivars can be explained by differences in the rate of AsA recycling activities. Analysis of the expression of AsA metabolic genes showed that only the expression of one orthologue of GDP-L-galactose phosphorylase (SlGGP1), and of two monodehydroascorbate reductases (SlMDHAR1 and SlMDHAR3) correlated with the changes in fruit totAsA-AsA concentrations during fruit ripening in ‘Ailsa Craig’, and that only the expression of SlGGP1 was linked to the high AsA concentrations found in red ripe ‘Santorini’ fruits.
Results indicate that ‘Ailsa Craig’ and ‘Santorini’ use complementary mechanisms to maintain the fruit AsA pool. In the low-AsA cultivar (‘Ailsa Craig’), alternative routes of AsA biosynthesis may supplement biosynthesis via L-galactose, while in the high-AsA cultivar (‘Santorini’), enhanced AsA recycling activities appear to be responsible for AsA accumulation in the later stages of ripening. Gene expression studies indicate that expression of SlGGP1 and two orthologues of SlMDHAR are closely correlated with totAsA-AsA concentrations during ripening and are potentially good candidates for marker development for breeding and selection.
PMCID: PMC3548725  PMID: 23245200
Ascorbate biosynthesis; Ascorbate recycling; Ascorbate turnover; Candidate gene; GDP-L-galactose phosphorylase; Gene expression; Monodehydroascorbate reductase
8.  Safety of 5-Aminosalicylic Acid Derivatives in Patients with Sensitivity to Acetylsalicylic Acid and Nonsteroidal Anti-inflammatory Drugs 
One of the cornerstones of the management of inflammatory bowel disease is the use of 5-aminosalicylic acid (5-ASA) compounds for treatment of flares and as maintenance therapy during remission. There are concerns about using 5-ASA in patients with a history of hypersensitivity to acetylsalicylic acid (ASA).
To assess the literature with respect to the safety of 5-ASA compounds in patients with documented sensitivity to ASA or nonsteroidal anti-inflammatory drugs (NSAIDs).
Data Sources:
A literature search was conducted in the MEDLINE and Embase databases, using various search terms, including “aminosalicylic acids”, “non-steroidal anti-inflammatory agents,” “hypersensitivity”, and “allergy”. The search was limited to articles (of any study design) published in English. Abstracts, full articles, and reference lists from retrieved articles were assessed to identify further relevant literature.
Study Selection and Data Extraction:
Of 485 citations identified in the initial search, 4 case reports were relevant to the study objective and were analyzed in detail.
Data Synthesis:
Three of the case reports described the successful use of 5-ASA compounds in patients with prior sensitivity to ASA or an NSAID. The fourth report described a reaction to 5-ASA in a patient who had previously tolerated ASA. All of the reports were limited by lack of investigation into the validity of the reported sensitivity to ASA or 5-ASA.
There is a dearth of evidence demonstrating cross-reactivity between ASA or NSAID and 5-ASA. This lack of information may relate to the mechanism of action of 5-ASA. This agent controls inflammation by inhibiting prostaglandin E2 and leukotrienes. In contrast, ASA-induced or NSAID-induced reactions are due to inhibition of the cycloxygenase-1 enzyme and subsequent release of histamine and synthesis of leukotrienes. Further reports describing the safety of 5-ASA use in patients with sensitivity to ASA or NSAIDs are needed before safety in this situation can be definitively determined. In patients with sensitivity to ASA or NSAID who require 5-ASA, a test dose of 5-ASA (to rule out potential cross-reactivity) or further investigation of the ASA or NSAID sensitivity is recommended.
PMCID: PMC3952906  PMID: 24634525
5-ASA; acetylsalicylic acid; nonsteroidal anti-inflammatory drug; hypersensitivity; 5-ASA; acide acétylsalicylique; anti-inflammatoires non stéroïdiens; hypersensibilité
9.  Pharmacological and Non-Pharmacological Recanalization Strategies in Acute Ischemic Stroke 
According to the guidelines of the European Stroke Organization (ESO) and the American Stroke Association (ASA), acute stroke patients should be managed at stroke units that include well organized pre- and in-hospital care. In ischemic stroke the restoration of blood flow has to occur within a limited time window that is accomplished by fibrinolytic therapy. Newer generation thrombolytic agents (alteplase, pro-urokinase, reteplase, tenecteplase, desmoteplase) have shorter half-life and are more fibrin-specific. Only alteplase has Food and Drug Administration (FDA) approval for the treatment of acute stroke (1996). The National Institute of Neurological Disorders and Stroke (NINDS) trial proved that alteplase was effective in all subtypes of ischemic strokes within the first 3 h. In the European cooperative acute stroke study III trial, intravenous (IV) alteplase therapy was found to be safe and effective (with some restrictions) if applied within the first 3–4.5 h. In middle cerebral artery (MCA) occlusion additional transcranial Doppler insonication may improve the breakdown of the blood clot. According to the ESO and ASA guidelines, intra-arterial (IA) thrombolysis is an option for recanalization within 6 h of MCA occlusion. Further trials on the IA therapy are needed, as previous studies have involved relatively small number of patients (compared to IV trials) and the optimal IA dose of alteplase has not been determined (20–30 mg is used most commonly in 2 h). Patients undergoing combined (IV + IA) thrombolysis had significantly better outcome than the placebo group or the IV therapy alone in the NINDS trial (Interventional Management of Stroke trials). If thrombolysis fails or it is contraindicated, mechanical devices [e.g., mechanical embolus removal in cerebral ischemia (MERCI)- approved in 2004] might be used to remove the occluding clot. Stenting can also be an option in case of acute internal carotid artery occlusion in the future. An intra-aortic balloon was used to increase the collateral blood flow in the Safety and Efficacy of NeuroFlo™ Technology in Ischemic Stroke trial (results are under evaluation). Currently, there is no approved effective neuroprotective drug.
PMCID: PMC3105226  PMID: 21660098
intravenous thrombolysis; intra-arterial thrombolysis; acute stroke; mechanism of recanalization; thrombectomy; alteplase; stroke unit; therapeutic time window
10.  Computational Analysis of N-acetyl transferase in Tribolium castaneum 
Bioinformation  2013;9(14):715-717.
N-acetyl transferase (NAT) is responsible to catalyze the transfer of acetyl groups to arylamines from acetyl-CoA. Aralkylamine Nacetyl transferase (AANAT), which belongs to GCN5-related N-acetyl transferase member, is a globular 23-kDa cytosolic protein that forms a reversible regulatory complex with 14-3-3 proteins, AANAT regulates the daily cycle of melatonin biosynthesis in mammals, making it an attractive target for therapeutic control of abnormal melatonin production in mood and sleep disorders. There is no evidence available regarding α and β subunits, active site and their ASA value in Dopamine N-acetyl transferase. Therefore, we describe the development of Dopamine N-acetyl transferase model in Tribolium castaneum. We further document the predicted active sites in the structural model with solvent exposed ASA residues. During this study, the model was built by CPH program and validated through PROCHECK, Verify 3D, ERRAT and ProSA for reliability. The active sites were predicted in the model with further ASA analysis of active site residues. The discussed information thus provides insight to the predicted active site and ASA values of Dopamine N-acetyl transferase model in Tribolium castaneum.
PMCID: PMC3746093  PMID: 23976826
Protein selection and validation; Active site; ASA analysis
11.  In silico analysis of Myoglobin in Channa striata 
Bioinformation  2014;10(1):19-22.
Myoglobin is a cytoplasmic hemoprotein, expressed solely in cardiac myocytes and oxidative skeletal muscle fibers, that reversibly binds O2 by its heme residue. Myoglobin is an essential oxygen-storage hemoprotein capable of facilitating oxygen transport and modulating nitric oxide homeostasis within cardiac and skeletal myocytes. Functionally, myoglobin is well accepted as an O2- storage protein in muscle, capable of releasing O2 during periods of hypoxia or anoxia. There is no evidence available regarding active sites, ligand binding sites, antigenic determinants and the ASA value of myoglobin in Channa striata. We further document the predicted active sites in the structural model with solvent exposed ASA residues. During this study, the model was built by CPH program and validated through PROCHECK, Verify 3D, ERRAT and ProSA for reliability. The active sites were predicted in the model with further ASA analysis of active site residues. The discussed information thus provides the predicted active sites, ligand binding sites, antigenic determinants and ASA values of myoglobin model in Channa striata.
PMCID: PMC3916814  PMID: 24516321
Validation; Active Sites Prediction; Ligand Binding Sites; Antigenic Determinants and ASA analysis
12.  Complications following Surgery for Lumbar Stenosis in a Veteran Population 
Spine  2013;38(19):1695-1702.
Study Design
Secondary analysis of the prospectively collected Veterans Affairs National Surgical Quality Improvement Program (VASQIP) database.
Determine rates of major medical complications, wound complications, and mortality among patients undergoing surgery for lumbar stenosis; and examine risk factors for these complications.
Summary of Background Data
Surgery for spinal stenosis is concentrated among older adults, for whom complications are more frequent than among middle-aged patients. Many studies have focused on infections or device complications, but fewer have focused on major cardiopulmonary complications, using prospectively collected data.
We identified patients who underwent surgery for a primary diagnosis of lumbar stenosis between 1998 and 2009 from the VASQIP database. We created a composite of major medical complications, including acute myocardial infarction, stroke, pulmonary embolism, pneumonia, systemic sepsis, coma, and cardiac arrest.
Among 12,154 eligible patients, major medical complications occurred in 2.1% ; wound complications in 3.2%; and 90-day mortality in 0.6%. Major medical complications, but not wound complications, were strongly associated with age. American Society of Anesthesiologists (ASA) class was a strong predictor of complications. Insulin use, chronic corticosteroid use, and preoperative functional status were also significant predictors. Fusion procedures were associated with higher complication rates than decompression alone. In logistic regressions, ASA class and age were the strongest predictors of major medical complications (OR for ASA class 4 vs. classes 1 or 2: 2.97, 95% CI 1.68, 5.25, p=0.0002). After adjustment for comorbidity, age, and functional status, fusion procedures remained associated with higher medical complication rates than decompression alone (OR 2.85, 95% CI 2.14, 3.78, p<0.0001).
ASA class, age, type of surgery, insulin or corticosteroid use, and functional status were independent risk factors for major medical complications. These factors may help in selecting patients and planning procedures, improving patient safety.
PMCID: PMC3865062  PMID: 23778366
spinal stenosis; lumbar stenosis; lumbar fusion; Complications; surgical complications; postoperative mortality; prediction rule; patient safety; risk prediction; receiver operating characteristic (ROC)
13.  Time and Cost Analysis: Pediatric Dental Rehabilitation with General Anesthesia in the Office and the Hospital Settings 
Anesthesia Progress  2012;59(4):147-153.
Pediatric dental patients who cannot receive dental care in the clinic due to uncooperative behavior are often referred to receive dental care under general anesthesia (GA). At Stony Brook Medicine, dental patients requiring treatment with GA receive dental care in our outpatient facility at the Stony Brook School of Dental Medicine (SDM) or in the Stony Brook University Hospital ambulatory setting (SBUH). This study investigates the time and cost for ambulatory American Society of Anesthesiologists (ASA) Class I pediatric patients receiving full-mouth dental rehabilitation using GA in these 2 locations, along with a descriptive analysis of the patients and dental services provided. In this institutional review board–approved cross-sectional retrospective study, ICD-9 codes for dental caries (521.00) were used to collect patient records between July 2009 and May 2011. Participants were limited to ASA I patients aged 36–60 months. Complete records from 96 patients were reviewed. There were significant differences in cost, total anesthesia time, and recovery room time (P < .001). The average total time (anesthesia end time minus anesthesia start time) to treat a child at SBUH under GA was 222 ± 62.7 minutes, and recovery time (time of discharge minus anesthesia end time) was 157 ± 97.2 minutes; the average total cost was $7,303. At the SDM, the average total time was 175 ± 36.8 minutes, and recovery time was 25 ± 12.7 minutes; the average total cost was $414. After controlling for anesthesia time and procedures, we found that SBUH cost 13.2 times more than SDM. This study provides evidence that ASA I pediatric patients can receive full-mouth dental rehabilitation utilizing GA under the direction of dentist anesthesiologists in an office-based dental setting more quickly and at a lower cost. This is very promising for patients with the least access to care, including patients with special needs and lack of insurance.
PMCID: PMC3522492  PMID: 23241037
Pediatric dentistry; Dental anesthesia; Cost analysis; Operating room; Office-based anesthesia; Health economics
14.  Incidence of and factors associated with perioperative cardiac arrest within 24 hours of anesthesia for emergency surgery 
To determine the incidence of and factors associated with perioperative cardiac arrest within 24 hours of receiving anesthesia for emergency surgery.
Patients and methods
This retrospective cohort study was approved by the ethical committee of Maharaj Nakorn Chiang Mai Hospital, Thailand. We reviewed the data of 44,339 patients receiving anesthesia for emergency surgery during the period from January 1, 2003 to March 31, 2011. The data included patient characteristics, surgical procedures, American Society of Anesthesiologists (ASA) physical status classification, anesthesia information, location of anesthesia performed, and outcomes. Data of patients who had received topical anesthesia or monitoring anesthesia care were excluded. Factors associated with cardiac arrest were identified by univariate analyses. Multiple regressions for the risk ratio (RR) and 95% confidence intervals (CI) were used to determine the strength of factors associated with cardiac arrest. A forward stepwise algorithm was chosen at a P-value <0.05.
The incidence (within 24 hours) of perioperative cardiac arrest in patients receiving anesthesia for emergency surgery was 163 per 10,000. Factors associated with 24-hour perioperative cardiac arrest in emergency surgery were age of 2 years or younger (RR =1.46, CI =1.03–2.08, P=0.036), ASA physical status classification of 3–4 (RR =5.84, CI =4.20–8.12, P<0.001) and 5–6 (RR =33.98, CI =23.09–49.98, P<0.001), the anatomic site of surgery (upper intra-abdominal, RR =2.67, CI =2.14–3.33, P<0.001; intracranial, RR =1.74, CI =1.35–2.25, P<0.001; intrathoracic, RR =2.35, CI =1.70–3.24, P<0.001; cardiac, RR =3.61, CI =2.60–4.99, P<0.001; and major vascular; RR =3.05, CI =2.22–4.18, P<0.001), respiratory or cardiovascular comorbidities (RR =1.95, CI =1.60–2.38, P<0.001 and RR =1.38, CI =1.11–1.72, P=0.004, respectively), and patients in shock prior to receiving anesthesia (RR =2.62, CI =2.07–3.33, P<0.001).
The perioperative incidence of cardiac arrest within 24 hours of anesthesia for emergency surgery was high and associated with multiple factors such as young age (≤2 years old), cardiovascular and respiratory comorbidities, increasing ASA physical status classification, preoperative shock, and surgery site. Perioperative care providers, including surgeons, anesthesiologists, and nurses, should be prepared to manage promptly this high risk group of surgical patients.
PMCID: PMC4159363  PMID: 25214804
risk factors; retrospective cohort; anesthetic care; perioperative cardiac arrest; emergency surgery
15.  Nitrates and NO-NSAIDs in Cancer Chemoprevention & Therapy: In Vitro Evidence Querying the NO Donor Functionality 
Properties of the NO-ASA family of NO-donating NSAIDs (NO-NSAIDs), notably NCX 4016 (mNO-ASA) and NCX 4040 (pNO-ASA), reported in more than a hundred publications, have included positive preclinical data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA; mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural “linker” as NCX 4040 and NCX 4016 are anticipated to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery.
PMCID: PMC2572831  PMID: 18485921
Chemoprevention; quinone oxidoreductase; hybrid drugs; antioxidant response element; quinone methide; nitrates; inflammation; NO-ASA; NO-NSAID
16.  Long-distance transport of L-ascorbic acid in potato 
BMC Plant Biology  2004;4:16.
Following on from recent advances in plant AsA biosynthesis there is increasing interest in elucidating the factors contributing to the L-ascorbic acid (AsA) content of edible crops. One main objective is to establish whether in sink organs such as fruits and tubers, AsA is synthesised in situ from imported photoassimilates or synthesised in source tissues and translocated via the phloem. In the current work we test the hypothesis that long-distance transport is involved in AsA accumulation within the potato tuber, the most significant source of AsA in the European diet.
Using the EDTA exudation technique we confirm the presence of AsA in the phloem of potato plants and demonstrate a correlation between changes in the AsA content of source leaves and that of phloem exudates. Comparison of carboxyflourescein and AgNO3 staining is suggestive of symplastic unloading of AsA in developing tubers. This hypothesis was further supported by the changes in AsA distribution during tuber development which closely resembled those of imported photoassimilates. Manipulation of leaf AsA content by supply of precursors to source leaves resulted in increased AsA content of developing tubers.
Our data provide strong support to the hypothesis that long-distance transport of AsA occurs in potato. We also show that phloem AsA content and AsA accumulation in sink organs can be directly increased via manipulation of AsA content in the foliage. We are now attempting to establish the quantitative contribution of imported AsA to overall AsA accumulation in developing potato tubers via transgenic approaches.
PMCID: PMC521686  PMID: 15377389
17.  Enhanced recovery program in total hip arthroplasty 
Indian Journal of Orthopaedics  2012;46(4):407-412.
Enhanced recovery program (ERP) was implemented to optimize the hospital stay in total hip arthroplasty. This study assessed the effects of optimizing preoperative and perioperative care using enhanced recovery (ER) on patients undergoing Total hip arthroplasty.
Materials and Methods:
We compared a prospective group of 64 patients on the ER program with a historic cohort of 63 patients that received conventional care (non ER).
ER patients were discharged earliest from hospital [mean length of stay (LOS) 5.3 days, median 4; P < 0.001] as compared to a mean of 8.3 days among non ER patients. Comparison based on American Association of Anesthesiologists (ASA) grades, preoperative hemoglobin, and body mass index (BMI) revealed that patients with ASA grade 3, preoperative hemoglobin of <14 g/dl, and BMI >30 on ER program spent shorter time in hospital as compared to the non ER's conventionally treated patients with more favorable physiological parameters of ASA grade 1 and 2, preoperative hemoglobin of >14 g/dl, and BMI <30.
The ER protocol is universally beneficial and confers an advantage regardless of the patients’ preoperative condition.
PMCID: PMC3421930  PMID: 22912515
Enhanced recovery program; length of stay; total hip arthroplasty
18.  Evaluation of serum antisperm antibodies in infertility 
Aims and Objective
To evaluate the role of serum antisperm antibody (ASA) in infertility.
Method and Material
This study was conducted in the Department of Obstetrics and Gynecology, Pt. J.N.M. Medical College, Raipur (C.G.), India, from December 2006 to July 2008 over 105 selected couples with primary and secondary infertility attending the infertility clinic. Their detailed clinical history was taken. Physical examination and routine as well as special investigations like pelvic USG, follicular study, and hysterosalpingography were done in the female. Complete physical examination and semen analysis of male partners were done. Couples were subjected to post coital test (PCT) 2–6 hours after intercourse to rule out cervical factor. Serum ASA titer in both partners was detected by ELISA. Results were interpreted for qualitative evaluation. ASA-positive cases were treated with low-dose daily oral prednisolone for 3 months and evaluated in terms of ASA titer, semen analysis, PCT result, and conception rate. The results were analyzed by statistical methods.
Out of 105 couples, serum ASA-positive males were 38 (39.19%), of which definite serum ASA positive were 9 (8.57%), borderline (equivocal) were 29 (27.61%), and negative were 67 (63.08%). Among females serum ASA positive were 42 (40%), in which definite ASA positive were 19 (18.09%), borderline 23 (21.9%), and negative 63 (60%). Asthenospermia was found more common in ASA-positive men (55.56%, p=0.0001). Poor PCT was most commonly associated in husband ASA negative and wife ASA positive. Treatment with low-dose oral prednisolone resulted in significant increase in motility of sperms in male partners and decrease in ASA titer in both the patients. Pregnancy was achieved in 45.23% ASA-positive females, while among couples with ASA-positive husbands, 31.57% of wives conceived.
Serum ASA are considered to be cause of unexplained infertility and unexplained abnormal PCT. Antibodies against sperm prevent their motility through female reproductive tract and hamper the process of fertilization. Low-dose prednisolone was useful in infertility associated with ASA by improving sperm quality and giving rise to pregnancies.
PMCID: PMC3394564
serum antisperm antibody; post coital test; ELISA
19.  Use of acetylsalicylic acid by physicians and in the community. 
OBJECTIVE: To determine physicians' attitudes toward prescribing acetylsalicylic acid (ASA), physicians' own use of ASA and the prevalence of ASA use in the community following the trials of ASA for primary prevention of coronary heart disease. DESIGN: Random sample surveys of physicians and the general public by mail and telephone respectively and a mail survey of a selected panel of expert cardiologists and neurologists. SETTING: London, Ont., and surrounding Middlesex County. PARTICIPANTS: A total of 210 physicians (77% of eligible subjects), including family practitioners and most types of specialists, with an active medical licence and 666 English-speaking people (75% of eligible subjects) aged 18 years or more living in a household with active, listed telephone service. MAIN OUTCOME MEASURE: Long-term ASA use (at least 80 mg on alternate days for 4 or more consecutive weeks) for the treatment of atherosclerosis. MAIN RESULTS: Sampled physicians and experts agreed that long-term ASA therapy was indicated in patients with unstable angina, a transient ischemic episode or recent myocardial infarction but not for primary prevention in healthy middle-aged men and women at low risk for ischemic vascular disease. Both groups were uncertain about the role of ASA in primary prevention in asymptomatic people with risk factors for atherosclerosis. Nine (16%) of the 55 male physicians aged 50 years or more took ASA routinely for primary prevention. In the community survey almost all those who used ASA routinely were 50 years or older. The proportions of men and women in this age group who used ASA routinely for any reason were 19% (95% confidence limits [CLs] 11 and 28) and 14% (95% CLs 8 and 19) respectively; the proportions of men and women who used ASA routinely and apparently for primary prevention were 8% and 1% respectively. A total of 43% (95% CLs 30 and 57) of those with apparent ischemic vascular disease took ASA routinely. Medically unsupervised long-term ASA use for primary or secondary prevention of ischemic vascular disease was uncommon (reported by 2% of those who used the drug routinely). CONCLUSIONS: Physicians generally agree on a role for long-term ASA therapy in the secondary prevention of ischemic vascular disease. However, the prevalence of long-term ASA use in people with overt atherosclerosis in the community may be less than optimal. The role of the drug in the primary prevention of ischemic vascular disease is less accepted. Long-term ASA use in the community for primary prevention is uncommon but detectable.
PMCID: PMC1335868  PMID: 1751930
20.  Induction of Tolerance to Human Arylsulfatase A in a Mouse Model of Metachromatic Leukodystrophy 
Molecular Medicine  2007;13(9-10):471-479.
A deficiency of arylsulfatase A (ASA) causes metachromatic leukodystrophy (MLD), a lysosomal storage disorder characterized by accumulation of sulfatide, a severe neurological phenotype and early death. The efficacy of enzyme replacement therapy (ERT) has previously been determined in ASA knockout (ASA−/−) mice representing the only available animal model for MLD. Repeated intravenous injection of human ASA (hASA) improved the nervous system pathology and function, but also elicited a progressive humoral immune response leading to treatment resistance, anaphylactic reactions, and high mortality. In contrast to ASA−/− mice, most MLD patients express mutant hASA which may entail immunological tolerance to substituted wildtype hASA and thus protect from immunological complications. To test this notion, a cysteine-to-serine substitution was introduced into the active site of the hASA and the resulting inactive hASA-C69S variant was constitutively expressed in ASA−/− mice. Mice with sub-to supranormal levels of mutant hASA expression were analyzed. All mice, including those showing transgene expression below the limit of detection, were immunologically unresponsive to injected hASA. More than 100-fold overexpression did not induce an overt new phenotype except occasional intralysosomal deposition of minor amounts of glycogen in hepatocytes. Furthermore, long-term, low-dose ERT reduced sulfatide storage in peripheral tissues and the central nervous system indicating that high levels of extracellular mutant hASA do not prevent cellular uptake and lysosomal targeting of substituted wildtype hASA. Due to the tolerance to hASA and maintenance of the MLD-like phenotype, the novel transgenic strain may be particularly advantageous to assess the benefit and risk of long-term ERT.
PMCID: PMC1933260  PMID: 17660863
21.  Regulation of tomato fruit ascorbate content is more highly dependent on fruit irradiance than leaf irradiance 
Annals of Botany  2008;103(3):495-504.
Background and Aims
The mechanisms involving light control of vitamin C content in fruits are not yet fully understood. The present study aimed to evaluate the impact of fruit and leaf shading on ascorbate (AsA) accumulation in tomato fruit and to determine how fruit sugar content (as an AsA precursor) affected AsA content.
Cherry tomato plants were grown in a glasshouse. The control treatment (normally irradiated fruits and irradiated leaves) was compared with the whole-plant shading treatment and with leaf or fruit shading treatments in fruits harvested at breaker stage. In a second experiment, the correlation between sugars and AsA was studied during ripening.
Key Results
Fruit shading was the most effective treatment in reducing fruit AsA content. Under normal conditions, AsA and sugar content were correlated and increased with the ripening stage. Reducing fruit irradiance strongly decreased the reduced AsA content (−74 %), without affecting sugars, so that sugar and reduced AsA were no longer correlated. Leaf shading delayed fruit ripening: it increased the accumulation of oxidized AsA in green fruits (+98 %), whereas it decreased the reduced AsA content in orange fruits (−19 %), suggesting that fruit AsA metabolism also depends on leaf irradiance.
Under fruit shading only, the absence of a correlation between sugars and reduced AsA content indicated that fruit AsA content was not limited by leaf photosynthesis or sugar substrate, but strongly depended on fruit irradiance. Leaf shading most probably affected fruit AsA content by delaying fruit ripening, and suggested a complex regulation of AsA metabolism which depends on both fruit and leaf irradiance and fruit ripening stage.
PMCID: PMC2707328  PMID: 19033285
Ascorbate; fruit quality; irradiance; shading; Solanum lycopersicon; sugars; tomato; vitamin C
22.  Cost-Effectiveness of Ulcerative Colitis Surveillance in the Setting of 5-Aminosalicylates 
Colorectal cancer (CRC) is a feared complication of chronic ulcerative colitis (UC). Annual endoscopic surveillance is recommended to detect early neoplasia. 5-aminosalicylates (5-ASAs) may prevent some UC-associated CRC. Therefore, in patients prescribed 5-ASAs for maintenance of remission, annual surveillance might be overly burdensome and inefficient. We aimed to determine the ideal frequency of surveillance in patients with UC maintained on 5-ASAs.
We performed systematic reviews of the literature, and created a Markov computer model simulating a cohort of 35 year-old men with chronic UC, followed until age 90. Twenty-two strategies were modeled: Natural History (no 5-ASA or surveillance), surveillance without 5-ASA at intervals of 1 to 10 years, 5-ASA plus surveillance every 1 to 10 years, and 5-ASA alone. The primary outcome was the ideal interval of surveillance in the setting of 5-ASA maintenance, assuming a third-party payer was willing to pay $100,000 for each quality-adjusted life-year (QALY) gained.
In the Natural History strategy, the CRC incidence was 30%. Without 5-ASA, annual surveillance was the ideal strategy, preventing 89% of CRC and costing $69,100 per QALY gained compared to surveillance every 2 years. 5-ASA alone prevented 49% of CRC. In the setting of 5-ASA, surveillance every 3 years was ideal, preventing 87% of CRC. 5-ASA with surveillance every 2 years cost an additional 147,500 per QALY gained, and 5-ASA with annual surveillance cost nearly $1 million additional per QALY gained compared to every 2 years. In Monte Carlo simulations, surveillance every 2 years or less often was ideal in 95% of simulations.
If 5-ASA is efficacious chemoprevention for UC-associated CRC, endoscopic surveillance might be safely performed every 2 years or less often. Such practice could decrease burdens to patients and to endoscopic resources with a minimal decrease in quality-adjusted length of life, since 5-ASA with annual surveillance may cost nearly $1 million per additional QALY gained.
PMCID: PMC2764368  PMID: 19491824
Chemoprevention; Colonic Neoplasms; Decision Support Techniques; Surveillance; Ulcerative Colitis
23.  The Antineoplastic Effect of Nitric Oxide-Donating Acetylsalicylic Acid (NO-ASA) in Chronic Lymphocytic Leukemia (CLL) Cells is Highly Dependent on its Positional Isomerism 
Chronic Lymphocytic Leukemia (CLL) is not curable in patients that are not eligible for allogeneic stem cell transplantation. Therefore, new treatment options are highly desirable. Chemically modified nonsteroidal anti-inflammatory drugs (NSAIDs), such as nitric-oxide-donating acetylsalicylic acid (NO-ASA), have been described to possess antineoplastic capacity. Recently, we could demonstrate a potent apoptosis induction in primary CLL cells in vitro and tumor growth inhibition by para-NO-ASA in a xenograft mouse model. However, little is known about the impact of positional isomerism of NO-ASA on its antineoplastic capacity in CLL.
Primary CLL cells were treated with the meta-or para-isomer of NO-ASA at varying concentrations and durations. Viability was assessed flow cytometrically by annexin V-FITC/PI staining and by CellTiter-Glo luminescence cell viability assay. Caspase and PARP cleavage as well as involvement of β-catenin/Lef-1 signaling was determined by immunoblotting. For caspase inhibition, BD™ ApoBlock was used. Nude mice were xenografted with JVM3 cells and treated with meta-NO-ASA, para-NO-ASA or vehicle control.
The meta-isomer was entirely ineffective in inducing CLL cell apoptosis in concentrations up to 100 μM, while para-NO-ASA acted in the low micromolar range. meta-NO-ASA, in contrast to para-NO-ASA, did not alter caspase activity. While para-NO-ASA action involved inhibition of β-catenin/Lef-1 signaling, meta-NO-ASA did not show any impact on this signaling pathway. Further, meta-NO-ASA did not significantly reduce tumor growth in a CLL xenograft mouse model, while para-NO-ASA was highly potent.
We conclude that positional isomerism is crucial for the antineoplastic effect of NO-ASA in CLL. It can be suggested that the para-isomer, but not the meta-isomer, generates a chemical structure which is essential for the neoplastic effect of NO-ASA.
PMCID: PMC3573417  PMID: 23556096
chronic lymphocytic leukemia (CLL); isomerism; nonsteroidal anti-inflammatory drugs (NSAIDs); nitric-oxide-donating acetylsalicylic acid (NO-ASA); xenograft
24.  Platelet Content of Nitric Oxide Synthase 3 Phosphorylated At Serine1177 Is Associated with the Functional Response of Platelets to Aspirin 
PLoS ONE  2013;8(12):e82574.
To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO).
Platelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100).
ASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position −786 (T−786→C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)1177, an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser1177 phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser1177. On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser1177. During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets.
Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser1177.
PMCID: PMC3869699  PMID: 24376548
25.  Therapeutic Efficacy of pH-Dependent Release Formulation of Mesalazine on Active Ulcerative Colitis Resistant to Time-Dependent Release Formulation: Analysis of Fecal Calprotectin Concentration 
BioMed Research International  2014;2014:342751.
Purpose. Few reports have compared the clinical efficacy of a pH-dependent release formulation of mesalazine (pH-5-ASA) with a time-dependent release formulation (time-5-ASA). We examined whether pH-5-ASA is effective for active ulcerative colitis (UC) in patients resistant to time-5-ASA. Methods. We retrospectively and prospectively analyzed the efficacy of pH-5-ASA in mildly to moderately active UC patients in whom time-5-ASA did not successfully induce or maintain remission. The clinical efficacy of pH-5-ASA was assessed by clinical activity index (CAI) before and after switching from time-5-ASA. In addition, the efficacy of pH-5-ASA on mucosal healing (MH) was evaluated in a prospective manner by measuring fecal calprotectin concentration. Results. Thirty patients were analyzed in a retrospective manner. CAI was significantly reduced at both 4 and 8 weeks after switching to pH-5-ASA. In the prospective study (n = 14), administration of pH-5-ASA also significantly reduced CAI scores at 4 and 8 weeks in these patients who were resistant to time-5-ASA. In addition, fecal calprotectin concentration was significantly decreased along with improvement in CAI after switching to pH-5-ASA. Conclusions. Our results suggest that pH-5-ASA has clinical efficacy for mildly to moderately active patients with UC in whom time-5-ASA did not successfully induce or maintain remission.
PMCID: PMC4251321  PMID: 25478568

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