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1.  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.
doi:10.1016/j.jada.2011.10.002
PMCID: PMC3379547  PMID: 22717216
diet assessment; computer; 24 hour recall; children
2.  Intraoperative Reported Adverse Events in Children 
Paediatric anaesthesia  2009;19(8):732-739.
Background
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.
Objective/Aim
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.
Methods/Materials
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.
Results
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%).
Conclusions
Pediatric reported AE incidence was comparable for NORA and ORA locations. Younger age or higher ASA status are associated with increased risk of AE.
doi:10.1111/j.1460-9592.2009.03066.x
PMCID: PMC2752696  PMID: 19624360
anesthesia; pediatric; adverse events; ORA; NORA
3.  Real value prediction of protein solvent accessibility using enhanced PSSM features 
BMC Bioinformatics  2008;9(Suppl 12):S12.
Background
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).
Results
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.
Conclusion
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.
doi:10.1186/1471-2105-9-S12-S12
PMCID: PMC2638152  PMID: 19091011
4.  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.
Introduction
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.
doi:10.1136/bmjopen-2012-001606
PMCID: PMC3437429  PMID: 22952165
acute lung injury; acute respiratory ditress syndrome; aspirin; critical illness; prevention; clinical trial
5.  Regulation of fruit ascorbic acid concentrations during ripening in high and low vitamin C tomato cultivars 
BMC Plant Biology  2012;12:239.
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2229-12-239
PMCID: PMC3548725  PMID: 23245200
Ascorbate biosynthesis; Ascorbate recycling; Ascorbate turnover; Candidate gene; GDP-L-galactose phosphorylase; Gene expression; Monodehydroascorbate reductase
6.  Safety of 5-Aminosalicylic Acid Derivatives in Patients with Sensitivity to Acetylsalicylic Acid and Nonsteroidal Anti-inflammatory Drugs 
Background:
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).
Objective:
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.
Conclusions:
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
7.  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.
doi:10.6026/97320630009715
PMCID: PMC3746093  PMID: 23976826
Protein selection and validation; Active site; ASA analysis
8.  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.
doi:10.6026/97320630010019
PMCID: PMC3916814  PMID: 24516321
Validation; Active Sites Prediction; Ligand Binding Sites; Antigenic Determinants and ASA analysis
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.
doi:10.3389/fneur.2011.00032
PMCID: PMC3105226  PMID: 21660098
intravenous thrombolysis; intra-arterial thrombolysis; acute stroke; mechanism of recanalization; thrombectomy; alteplase; stroke unit; therapeutic time window
10.  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.
doi:10.2344/0003-3006-59.4.147
PMCID: PMC3522492  PMID: 23241037
Pediatric dentistry; Dental anesthesia; Cost analysis; Operating room; Office-based anesthesia; Health economics
11.  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.
doi:10.1016/j.niox.2008.04.013
PMCID: PMC2572831  PMID: 18485921
Chemoprevention; quinone oxidoreductase; hybrid drugs; antioxidant response element; quinone methide; nitrates; inflammation; NO-ASA; NO-NSAID
12.  Long-distance transport of L-ascorbic acid in potato 
BMC Plant Biology  2004;4:16.
Background
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2229-4-16
PMCID: PMC521686  PMID: 15377389
13.  Enhanced recovery program in total hip arthroplasty 
Indian Journal of Orthopaedics  2012;46(4):407-412.
Background:
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).
Results:
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.
Conclusion:
The ER protocol is universally beneficial and confers an advantage regardless of the patients’ preoperative condition.
doi:10.4103/0019-5413.98829
PMCID: PMC3421930  PMID: 22912515
Enhanced recovery program; length of stay; total hip arthroplasty
14.  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
15.  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.
doi:10.2119/2007-00063.Matzner
PMCID: PMC1933260  PMID: 17660863
16.  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.
Results
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.
Conclusion
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.
doi:10.1007/s13224-011-0034-7
PMCID: PMC3394564
serum antisperm antibody; post coital test; ELISA
17.  Inhibitory Effect of Flavonoids on the Efflux of N-Acetyl 5-Aminosalicylic Acid Intracellularly Formed in Caco-2 Cells 
N-acetyl 5-aminosalicylic acid (5-AcASA) that was intracellularly formed from 5-aminosalicylic acid (5-ASA) at 200 μM was discharged 5.3, 7.1, and 8.1-fold higher into the apical site than into the basolateral site during 1, 2, and 4-hour incubations, respectively, in Caco-2 cells grown in Transwells. The addition of flavonols (100 μM) such as fisetin and quercetin with 5-ASA remarkably decreased the apically directed efflux of 5-AcASA. When 5-ASA (200 μM) was added to Caco-2 cells grown in tissue culture dishes, the formation of 5-AcASA decreased, and, in addition, the formed 5-AcASA was found to be accumulated within the cells in the presence of such flavonols. Thus, the decrease in 5-AcASA efflux by such flavonols was attributed not only to the inhibition of N-acetyl-conjugation of 5-ASA but to the predominant cellular accumulation of 5-AcASA. Various flavonoids also had both of the effects with potencies that depend on their specific structures. The essential structure of flavonoids was an absence of a hydroxyl substitution at the C5 position on the A-ring of flavone structure for the inhibitory effect on the N-acetyl-conjugation of 5-ASA, and a presence of hydroxyl substitutions at the C3′ or C4′ position on the B-ring of flavone structure for the promoting effect on the cellular accumulation of 5-AcASA. Both the decrease in 5-AcASA apical efflux and the increase in 5-AcASA cellular accumulation were also caused by MK571 and indomethacin, inhibitors of MRPs, but not by quinidine, cyclosporin A, P-glycoprotein inhibitors, and mitoxantrone, a BCRP substrate. These results suggest that certain flavonoids suppress the apical efflux of 5-AcASA possibly by inhibiting MRPs pumps located on apical membranes in Caco-2 cells.
doi:10.1155/2009/467489
PMCID: PMC2726441  PMID: 19688110
18.  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.
Methods
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.
Conclusions
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.
doi:10.1093/aob/mcn233
PMCID: PMC2707328  PMID: 19033285
Ascorbate; fruit quality; irradiance; shading; Solanum lycopersicon; sugars; tomato; vitamin C
19.  Cost-Effectiveness of Ulcerative Colitis Surveillance in the Setting of 5-Aminosalicylates 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1038/ajg.2009.264
PMCID: PMC2764368  PMID: 19491824
Chemoprevention; Colonic Neoplasms; Decision Support Techniques; Surveillance; Ulcerative Colitis
20.  The Antineoplastic Effect of Nitric Oxide-Donating Acetylsalicylic Acid (NO-ASA) in Chronic Lymphocytic Leukemia (CLL) Cells is Highly Dependent on its Positional Isomerism 
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
doi:10.1177/2040620711416272
PMCID: PMC3573417  PMID: 23556096
chronic lymphocytic leukemia (CLL); isomerism; nonsteroidal anti-inflammatory drugs (NSAIDs); nitric-oxide-donating acetylsalicylic acid (NO-ASA); xenograft
21.  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.
Objective
To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO).
Patients/Methods
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).
Results
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.
Conclusions
Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser1177.
doi:10.1371/journal.pone.0082574
PMCID: PMC3869699  PMID: 24376548
22.  Changing Risk of Perioperative Myocardial Infarction 
The Permanente Journal  2012;16(4):4-9.
Introduction: Years ago, patients with recent myocardial infarction (MI) were reported to be at high risk of reinfarction (27%) and death after surgery. Therapy has changed in the 3 decades since those reports, so we reexamined that risk as well as other cardiac comorbidities and surgical work values in predicting adverse outcome.
Methods: We used the National Surgical Quality Improvement Program Participant Use Data File for 2005 to 2009. We included all patients of all included specialties, for outpatient and inpatient surgery. Cardiac comorbidities included history of congestive heart failure (30 days) or MI (6 months), percutaneous coronary intervention, previous cardiac surgery, and history of angina (30 days). Other predictors included a frailty index and American Society of Anesthesiologists (ASA) class. Adverse cardiac events included cardiac arrest requiring cardiopulmonary resuscitation, MI, and death. Cases were stratified according to surgical work units. Univariate χ2 analysis and multivariate logistic regression established simple relationships and interactions, with p < 0.05 significant.
Results: Of patients who had recent MI, 2.1% had reinfarction perioperatively and 26% of those died. The odds ratio for infarction with vs without recent MI in inpatients age 40 years and older was 4.6. Frailty and ASA class were stronger predictors of perioperative MI and cardiac arrest than was history of MI, and risk increased as surgical work increased.
Discussion: The risk caused by preoperative MI has improved by an order of magnitude in the last 30 years. The ASA class and especially frailty are better predictors of adverse cardiac events.
PMCID: PMC3523933  PMID: 23251110
23.  Preoperative drug dispensing as predictor of surgical site infection. 
Emerging Infectious Diseases  2001;7(1):57-65.
The system used by the National Nosocomial Infection Surveillance (NNIS) program to measure risk of surgical site infection uses a score of 3 on the American Society of Anesthesiologists (ASA)-physical status scale as a measure of underlying illness. The chronic disease score measures health status as a function of age, sex, and 29 chronic diseases, inferred from dispensing of prescription drugs. We studied the relationship between the chronic disease score and surgical site infection and whether the score can supplement the NNIS risk index. In a retrospective comparison of 191 patients with surgical site infection and 378 uninfected controls, the chronic disease score and ASA score were highly correlated. The chronic disease score improved prediction of infection by the NNIS risk index and augmented the ASA score for risk adjustment.
PMCID: PMC2631693  PMID: 11266295
24.  NO-donating aspirin inhibits angiogenesis by suppressing VEGF expression in HT-29 human colon cancer mouse xenografts 
Carcinogenesis  2008;29(9):1794-1798.
The inhibitory effect of NO-donating aspirin (NO-ASA) on colon cancer has been demonstrated in vivo and in vitro but its mechanism is still obscure. We investigated the effect of NO-ASA on angiogenesis. Four groups of athymic mice (N = 12) bearing subcutaneous xenotransplants of HT-29 human colon cancer cells were injected intratumorally twice a week for 3 weeks with vehicle or m-NO-ASA or p-NO-ASA; the fourth group received no injections. The necrotic area of tumors, expressed as percentage of total area, was similar in the non-injected and vehicle-injected groups (51.8 ± 2.8 versus 52.2 ± 4.1, P > 0.05; mean ± SEM for these and subsequent values). Compared with the vehicle group, the necrotic area of tumors was higher in the m-NO-ASA-treated (61.0 ± 2.7, P < 0.02) and p-NO-ASA (65.8 ± 2.4, P < 0.001)-treated groups. NO-ASA decreased microvessel density: vehicle = 11.7 ± 0.8; m-NO-ASA = 7.8 ± 0.6 (P = 0.0003 versus vehicle) and p-NO-ASA 6.2 ± 0.7 (P = 0.0001 versus vehicle). The expression of vascular endothelial growth factor (VEGF) was significantly reduced in response to NO-ASA, with the p- isomer being more potent than the m-. NO-ASA altered the spatial distribution of VGEF expression, with 16.7% of the vehicle-treated xenografts displaying diminished VEGF in the inner region of the area between necrosis and the outer perimeter of the tumor, compared with those treated with m- (58.3%) or p-NO-ASA (75%, P < 0.01 for both versus control). Our findings indicate that NO-ASA suppresses the expression of VEGF, which leads to suppressed angiogenesis. The antiangiogenic activity of NO-ASA may be part of its antineoplastic effect.
doi:10.1093/carcin/bgn127
PMCID: PMC2527643  PMID: 18544566
25.  NO-donating aspirin inhibits angiogenesis by suppressing VEGF expression in HT-29 human colon cancer mouse xenografts 
Carcinogenesis  2008;29(9):1794-1798.
The inhibitory effect of NO-donating aspirin (NO-ASA) on colon cancer has been demonstrated in vivo and in vitro but its mechanism is still obscure. We investigated the effect of NO-ASA on angiogenesis. Four groups of athymic mice (N = 12) bearing subcutaneous xenotransplants of HT-29 human colon cancer cells were injected intratumorally twice a week for 3 weeks with vehicle or m-NO-ASA or p-NO-ASA; the fourth group received no injections. The necrotic area of tumors, expressed as percentage of total area, was similar in the non-injected and vehicle-injected groups (51.8 ± 2.8 versus 52.2 ± 4.1, P > 0.05; mean ± SEM for these and subsequent values). Compared with the vehicle group, the necrotic area of tumors was higher in the m-NO-ASA-treated (61.0 ± 2.7, P < 0.02) and p-NO-ASA (65.8 ± 2.4, P < 0.001)-treated groups. NO-ASA decreased microvessel density: vehicle = 11.7 ± 0.8; m-NO-ASA = 7.8 ± 0.6 (P = 0.0003 versus vehicle) and p-NO-ASA 6.2 ± 0.7 (P = 0.0001 versus vehicle). The expression of vascular endothelial growth factor (VEGF) was significantly reduced in response to NO-ASA, with the p- isomer being more potent than the m-. NO-ASA altered the spatial distribution of VGEF expression, with 16.7% of the vehicle-treated xenografts displaying diminished VEGF in the inner region of the area between necrosis and the outer perimeter of the tumor, compared with those treated with m- (58.3%) or p-NO-ASA (75%, P < 0.01 for both versus control). Our findings indicate that NO-ASA suppresses the expression of VEGF, which leads to suppressed angiogenesis. The antiangiogenic activity of NO-ASA may be part of its antineoplastic effect.
doi:10.1093/carcin/bgn127
PMCID: PMC2527643  PMID: 18544566

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