bluuebunny/crossref_metadata_2025 huggingface dataset:
Contemporary Use of and Future Roles for Heparin in Antithrombotic Therapy
Authors: Gibaldi Milo , Wittkowsky Ann K.
Published: March 2013

Although heparin therapy is an established component of the prevention and treatment of thromboembolic disease, recent advances have resulted in improvements in the clinical use of this agent. Studies have shown that weight‐based dosing influences significantly both the time to reach a therapeutic intensity of anticoagulation and the incidence of thromboembolic recurrence. It is now considered the standard of care. A growing understanding of the variability among activated partial thromboplastin time (aPTT) reagents and the influence of these differences on aPTT outcomes has led to the use of reagent‐specific therapeutic ranges for heparin monitoring. Many practitioners now choose to adjust the therapeutic range to correspond to heparin serum concentrations of 0.2–0.4 U/mL rather than the more common practice of prolonging aPTT to 1.5–2.5 times the mean normal aPTT. Pharmaceutical companies have developed low molecular weight heparins to minimize adverse effects associated with unfractionated heparin. More specific thrombin inhibitors are also under investigation with the aim of improving clinical outcomes in coronary syndromes now treated with heparin. Low molecular weight heparins or specific thrombin inhibitors are unlikely to replace unfractionated heparin in the near future. Therefore, optimum dosing and appropriate monitoring of heparin are critically important in the management of thromboembolic disease.
Pharmacokinetics, Absolute Bioavailability, and Absorption Characteristics of Lamivudine
Authors: Yuen Geoffrey J. , Morris David M. , Mydlow Patricia K. , Haidar Sam , Hall Susan T. , Hussey Elizabeth K.
Published: March 2013

Lamivudine is a novel cytosine nucleoside analog, reverse transcriptase inhibitor that has shown activity against human immunodeficiency virus (HIV) types 1 and 2 and hepatitis B virus in vitro. This study was conducted to compare the absolute bioavailability, pharmacokinetics, and absorption characteristics of oral solution, 100‐mg capsule, and 100‐mg tablet formulations of lamivudine with those of intravenous lamivudine. Twelve patients with HIV were enrolled in a single‐center, randomized, open‐label, four‐way crossover study. Treatment arms consisted of 100 mg intravenous lamivudine (administered over 1 hour), 100 mg oral lamivudine (1 mg/mL), a 100‐mg capsule, and a 100‐mg tablet, each followed by a 3‐ to 14‐day washout period. Serial blood samples over 24 hours were obtained after each dose administration. Serum concentration data were analyzed to determine pharmacokinetic parameter estimates including area under the curve (AUC), terminal half‐life (t1/2), mean residence time (MRT) for each formulation, systemic clearance, oral clearance, and apparent volume of distribution (Vd). Absolute bioavailability and in vivo mean absorption time (MAT) and mean dissolution time (MDT) were calculated for the oral formulations. Deconvolution techniques were used to calculate the input rate for the oral solution, capsule, and tablet. The two one‐sided t test was used to determine bioequivalency among oral formulations with respect to logarithmic transformed estimates of AUC and maximum peak concentration (Cmax). Mean (CV) systemic clearance and Vd 22 after intravenous administration of lamivudine were 22.6 L/h (15%) and 99 L (28%), respectively; mean t1/2 ranged from 8.41 to 9.11 hours for all formulations; and MRT ranged from 4.42 to 5.77 hours for all formulations. Mean absolute bioavailability ranged from 86% to 88% for the oral solution, capsule, and tablet. All oral formulations were considered bioequivalent for AUC and Cmax. The MAT was 1.32 hour for the oral solution, and MDT was 0.03 and −0.11 hours for the capsule and oral solution, respectively. The oral formulations of lamivudine examined in this study demonstrated acceptable bioavailability for oral administration. The solid oral formulations (capsule and tablet) show rapid dissolution properties with an absorption rate similar to or exceeding those observed with the oral solution. This suggests that dissolution is not an important factor for the rate of absorption of lamivudine. The use of deconvolution techniques using PCDCON provides valuable insight into the absorption characteristics of lamivudine.
Absorption Pharmacokinetics of Atenolol in Patients with the Marfan Syndrome
Authors: Phelps Stephanie J. , Alpert Bruce S. , Ward Jewel L. , Pieper John A. , Lima John J.
Published: March 2013

The negative inotropic and chronotropic effects of β‐blocker therapy have been reported to reduce morbidity and mortality in patients with Marfan syndrome; however, little is known about the pharmacokinetics of atenolol after oral administration of multiple doses to patients with the Marfan syndrome. We studied the pharmacokinetics of atenolol in 13 such patients aged 18.7 ± 2.9 years who were receiving 1.78 ± 0.58 mg/kg/day (70.1 ± 20.3 mg/m2/day) of atenolol for 6 weeks or longer. Mean ± SD percentage change in baseline heart rate after the administration of atenolol was −18.03 ± 16.59% and mean ± SD percentage change in exercise heart rate after atenolol was −33.22 ± 14.75% (P < .01). Six to 8 atenolol serum concentrations were collected in each patient during a 12‐hour dosing interval and were determined by high‐performance liquid chromatography with ultraviolet detection. Serum atenolol concentrations at 0 (123 ± 70 μg/L) and 12 (116 ± 66 μg/L) hours were within 20% of each other and were thus assumed to be at steady‐state. A one‐compartment, steady‐state pharmacokinetic model with first‐order absorption and elimination was fitted to the concentration‐time data for each patient using nonlinear regression. Maximal concentration was 343 ± 120 μg/L, and the mean half‐life was 4.72 hours. Pharmacokinetic parameters were as follows: Absorption rate constant (ka>) was 1.03 ± 1.34 hr−1; elimination rate constant (k) was 0.230 ± 0.220 hr−1; the ratio of bioavailability to volume of distribution (f/Vd) was 0.00612 ± 0.00214 L−1; area under the concentration‐time curve at steady‐state (AUC) was 2919 ± 1175 μghr/L; and the time at which the highest concentration occurred (tmax) was 1.87 ± 0.16 hours. Additionally, the dose‐normalized AUC ranged from 20.9 to 57.8 μg hr/L. Although there was considerable variability in the pharmacokinetics of atenolol in patients with the Marfan syndrome, the variability was similar to that reported in patients without Marfan syndrome.
Relationship Between Pharmacokinetics and Pharmacodynamics of Eptastigmine in Young Healthy Volunteers
Authors: Imbimbo B. P. , Licini M. , Schettino M. , Mosca A. , Onelli E. , Zecca L. , Giustina A.
Published: March 2013

Eptastigmine is a long‐lasting acetyl‐cholinesterase inhibitor, currently being developed for the symptomatic treatment of Alzheimer's disease. In the present study, we investigated the relationship between pharmacokinetics and pharmacodynamics of eptastigmine in young healthy volunteers. Eight male subjects received single oral doses of 10, 20, and 30 mg of eptastigmine and placebo according to a double‐blind, randomized, crossover design. Blood was collected before and 0.5, 1, 1.5, 2, 3, 4, 6, and 24 hours after drug administration. Cholinesterase activity was measured using a potentiometric method in both plasma (butyryl‐cholinesterase) and in red blood cells (acetyl‐cholinesterase). Eptastigmine plasma levels were measured by a very sensitive high‐performance liquid chromatography method (limit of quantitation 0.2 ng/mL). Eptastigmine plasma concentrations increased proportionally with the dose (mean ± SEM AUC0–24 was 0.74 ± 0.58, 3.61 ± 1.15, and 6.25 ± 1.51 ng • h/mL with 10, 20, and 30 mg, respectively) and were undetectable at 24 hours. The inhibition of acetyl‐cholinesterase was dose‐dependent (peak inhibition was 15 ± 2%, 30 ± 4%, and 36 ± 6% with 10, 20, and 30 mg, respectively) and long‐lasting, with a residual inhibition of 8 to 11% at 24 hours. Acetyl‐cholinesterase inhibition and drug plasma levels were related over time with a counterclockwise hysteresis curve, suggesting the formation of active metabolites and/or a slow association to and dissociation from the enzyme in red blood cells. Butyryl‐cholinesterase inhibition was weak and not dose‐dependent (peak inhibition was 12 ± 4%, 13 ± 3%, and 12 ± 2% with 10, 20, and 30 mg, respectively). The drug was well tolerated by all subjects. These results indicate that after oral administration, eptastigmine is absorbed linearly and produces a dose‐dependent, long‐lasting inhibition of acetyl‐cholinesterase.
Potassium Channel Modulation: Effect of Pinacidil on Insulin Release in Healthy Volunteers
Authors: Links Thera P. , Smit Andries J. , Reitsma Wepco D.
Published: March 2013

The effect of a potassium (K+) channel opener (pinacidil) on serum insulin levels and blood glucose levels was investigated in normal volunteers during glucose loading. An intravenous glucose load was used with and without oral pretreatment: pinacidil (25 mg) 11 hours and 1 hour before the 25‐g glucose loading. Serum insulin, C‐peptide, blood glucose, and plasma catecholamines were measured between t = 0 and t = 180 minutes. Pinacidil led to significantly lower insulin levels, especially in the first phase. Serum C‐peptide levels were not significantly lowered, and glucose levels were not changed. Pinacidil inhibits the first phase of insulin release after glucose administration in healthy volunteers. These findings suggest that the safety of the drug regarding glucose tolerance, should be tested separately in patients with diabetes mellitus and essential hypertension.
Antiinflammatory Mechanism of Cordiachromene A Action
Authors: Benslimane Abdel Fattah , Pouchus Yves François , Verbist Jean‐François , Petit Jean‐Yves , Brion Jean Daniel , Welin Lucien
Published: March 2013

The mechanism of antiinflammatory action of cordiachromene A, isolated from the chloromethylenic extract of the ascidian Aplidium antillense or chemically synthesized, was studied using different in vivo and in vitro inhibition tests on enzymes of the cyclooxygenase cascade. Cordiachromene A inhibits prostacyclin synthesis and arachidonic acid metabolism but not phospholipase A2 and peroxidase. The mechanism of action, already known to be stereospecific, operates by cyclooxygenase inhibition.
Benefit/Risk of Estrogen Therapy in Cardiovascular Disease: Current Knowledge and Future Challenges
Authors: Chow Moses S. S.
Published: March 2013

In the United States, cardiovascular disease represents the leading cause of death among women. A majority of the deaths are due to coronary disease. In addition, the incidence of heart attacks increases with age. Among those who are 65 years of age or older, the estimated heart attack rate is 374,000 per year for women, compared with 440,000 per year for men. In the past three decades, a number of observational studies have suggested that estrogen therapy can reduce the risk of coronary disease in postmenopausal women. This protective effect appears to be much greater in women who have existing coronary disease than in those without coronary disease. These observational data point to the potential usefulness of estrogen therapy in preventing cardiovascular death among women. Although large, well‐controlled, clinical trials are needed to confirm the benefit of estrogen therapy, several important findings strongly support the cardioprotective effect of estrogen therapy. For example, in monkeys estrogen prevents the accumulation of low‐density lipoprotein (LDL) cholesterol (a known risk factor for heart disease) in coronary arteries, and estrogen has also been shown to increase high‐density lipoprotein (HDL) cholesterol (a known cardioprotective factor). Estrogen also possesses a vasodilating property, which can improve cardiac performance in ischemic heart disease. In addition, recent studies have demonstrated that estrogens (especially equilin) exhibit a high antioxidant effect, which may also be related to cardioprotectivity. Although estrogen therapy has been observed to decrease the risk of coronary disease, long‐term estrogen therapy has also been found to increase the risk of uterine carcinoma; the addition of progesterone to estrogen therapy may lessen this undesirable risk, however. On the other hand, the addition of progesterone to estrogen therapy may decrease estrogen's beneficial effect on HDL cholesterol. What should be the present position on estrogen therapy in postmenopausal women? What is the best dosage regimen? Should it be used alone or in combination with a progesterone? These important issues are discussed, as are several current clinical trials addressing the issue of estrogen therapy in postmenopausal women.
Future Therapeutic Developments of Estrogen Use
Authors: Fillit Howard
Published: March 2013

The potential long‐term benefits of estrogen replacement therapy (ERT) in the prevention of osteoporosis and heart disease have been reasonably well established. However, the favorable effects of ERT on cognitive function and prevention of senile dementia in old age now represents a revitalized area of clinical research. A growing body of experimental evidence has recently provided the neurobiologic basis to support the hypothesis that gonadal hormones such as estrogen have psychologic effects on human brain function and behavior. Studies in women who have undergone surgical menopause have demonstrated that the menopause is associated with subclinical cognitive and affective dysfunction, which is improved by ERT. In addition, a growing body of evidence suggests that estrogen may be an effective therapy for senile dementia in some elderly women. Recent epidemiologic studies have indicated that long‐term postmenopausal ERT may prevent late‐life cognitive dysfunction in older women. Several clinical trials employing oral estrogen therapy have also observed that some aged women with senile dementia have improved cognitive and affective function after estrogen therapy. Estrogen loss resulting in cognitive disorders, including menopausal cognitive dysfunction and senile dementia in late life, may act via several mechanisms. Estrogen may be an important growth factor for estrogen‐responsive neurons. Estrogen therapy may also have substantial neurochemical effects, direct effects on the vasculature, and effects on the generation of free radicals, which may be toxic to neurons. At this time, several important clinical questions need to be answered regarding the role of ERT in the cognitive and affective dysfunctions associated with menopause and senile dementia. Should estrogen be used for menopausal women whose sole complaint is cognitive or affective dysfunction? Does long‐term ERT prevent cognitive decline in late life if initiated at the time of menopause? Can ERT improve cognition and affective function in postmenopausal women with Alzheimer's disease, and does estrogen therapy prevent the progression of Alzheimer's disease in these patients? Finally, do the vascular effects of estrogen play a role in the treatment or prevention of both Alzheimer's disease and vascular dementia?
Effects of Yohimbine on Autonomic Measures are Determined by Individual Values for Area Under the Concentration—Time Curve
Authors: Grasing Kenneth , Sturgill Marc G. , Rosen Raymond C. , Trout J. Richard , Thomas T. J. , Kulkarni Gayathri D. , Maines Peggy , Seibold James R.
Published: March 2013

A study was conducted to examine tolerability and pharmacodynamics of single doses of yohimbine in healthy volunteers using measures of mood, heart rate, blood pressure, and serum catecholamine levels. Participants were given single oral doses of yohimbine hydrochloride as high as 21.6 mg. Plasma concentrations of yohimbine, epinephrine, norepinephrine, and MHPG (3‐methoxy‐4‐hydroxyphenylethylene‐glycol) were quantified by means of high‐performance liquid chromatography with electrochemical detection. Mood was assessed by visual analogue scale (VAS), the Profile of Mood States, and the Spielberger State Anxiety Index. Yohimbine was well tolerated and rapidly absorbed and eliminated. Dose‐related increases in area under the concentration—time curve (AUC) were observed. Administration of yohimbine in the presence of a high fat meal diminished both the rate and extent of drug absorption. Significant intersubject variability in the pharmacokinetic parameters of yohimbine was observed, with some individuals exhibiting greatly increased oral bioavailability of yohimbine. Increases in blood pressure, respiratory rate, plasma catecholamine levels, and total VAS score were observed in participants with elevated AUC values. The AUC of yohimbine had the largest effect on total VAS score. The results indicate that higher doses of yohimbine are both well tolerated and produce dose‐related increases in AUC, which are associated with more pronounced autonomic effects. Increases in respiratory rate and plasma MHPG appear to be the most reliable pharmacodynamic measures for single oral doses of yohimbine. Individual differences in the pharmacokinetics of yohimbine are important in determining pharmacodynamic effects and should be considered in evaluations of its clinical effectiveness.
Pharmacokinetics of Single Intravenous and Oral Doses of Dolasetron Mesylate in Healthy Elderly Volunteers
Authors: Dempsey Ellen , Bourque Stéphane , Spénard Jean , Landriault Hélène
Published: March 2013

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5‐HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half‐life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vdβ) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the [+]‐enantiomer of the reduced metabolite, which accounted for 25.35% (± 7.79%) and 18.88% (± 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high‐dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.
Olanzapine: Interaction Study with Imipramine
Authors: Callaghan John T. , Cerimele Benito J. , Kassahun Kelem J. , Nyhart Eldon H. , Hoyes‐Beehler Pamela J. , Kondraske George V.
Published: March 2013

Olanzapine is an “atypical” antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open‐label, three‐way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two‐way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor‐speed tasks (finger tapping and visual‐arm random reach) compared with baseline or imipramine treatment. Peak 6‐hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were <19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6. J Clin Pharmacol 1997;37:971–978.
Analgesic Dose‐Response Relationship of Ibuprofen 50, 100, 200, and 400 mg after Surgical Removal of Third Molars: A Single‐Dose, Randomized, Placebo‐Controlled, and Double‐Blind Study of 304 Patients
Authors: Schou Søren , Nielsen Henrik , Nattestad Anders , Hillerup Søren , Ritzau Martin , Branebjerg Poul Erik , Bugge Christine , Skoglund Lasse A.
Published: March 2013

The purpose of this single‐dose, randomized, placebo‐controlled, and double‐blind study was to evaluate the analgesic dose‐response relationship of 50‐mg, 100‐mg, 200‐mg, and 400‐mg doses of ibuprofen after third molar surgery. Patients were instructed to take a single dose of either placebo or 50 mg, 100 mg, 200 mg, or 400 mg of ibuprofen when the postoperative pain was moderate to severe. Acetaminophen 500 mg was used as a rescue medication. Pain intensity, pain relief, and any possible adverse events were recorded on self‐administered questionnaires hourly for 6 hours after intake of study medication. If rescue medication was taken, the time of intake was registered. A total of 304 patients entered the study, and 258 complied with the protocol. A positive analgesic dose‐response relationship of 50‐mg, 100‐mg, 200‐mg, and 400‐mg doses of ibuprofen was observed when evaluated by pain intensity difference, sum of pain intensity difference, pain relief, total pain relief, and survival distribution of patients not taking rescue medication. Although significant pain relief was seen after a dose of 50 mg ibuprofen, ibuprofen 400 mg provided maximum pain relief and the longest duration of analgesic effect. Mild transient adverse events were reported by 6.8% of the patients. However, there was no significant difference in frequency between the placebo and 50 mg, 100 mg, 200 mg, and 400 mg ibuprofen dose groups.
Pharmacokinetics and Pharmacodynamics of Diphenhydramine 25 mg in Young and Elderly Volunteers
Authors: Scavone Joseph M. , Greenblatt David J. , Harmatz Jerold S. , Engelhardt Nina , Shader Richard I.
Published: March 2013

Thirty‐seven young and elderly male and female volunteers 21 to 76 years of age received a single 25‐mg oral dose of diphenhydramine or matching placebo in a double‐blind, randomized, two‐way crossover study. Plasma diphenhydramine concentrations, self‐ratings of sedation, mood, and autonomic effects, performance on the digit‐symbol substitution test (DSST), and heart rate were determined for 24 hours after administration. Information acquisition and recall were tested at 2.5 and 24 hours after administration. Age and gender did not significantly influence diphenhydramine peak plasma concentration, time of peak concentration, elimination half‐life, area under the plasma concentration curve, or apparent oral clearance. Effects on psychomotor performance, sedation, mood, and memory did not differ between diphenhydramine and placebo in either group. Thus, the pharmacokinetics of single 25‐mg oral doses of diphenhydramine are not influenced by age or gender. This dose of diphenhydramine produces essentially undetectable pharmacodynamic effects in both the young and elderly.
Whispering‐gallery mode lasing from patterned molecular single‐crystalline microcavity array
Authors: Fang Hong‐Hua , Ding Ran , Lu Shi‐Yang , Yang Yue‐De , Chen Qi‐Dai , Feng Jing , Huang Yong‐Zhen , Sun Hong‐Bo
Published: March 2013

Organic single‐crystalline materials have attracted great attention for laser applications. However, the fabrication of laser resonators and pattern of crystals are still intractable problems. Organic single crystals have been limited to fundamental property studies despite their superior photonic characteristics. In this work, whispering‐gallery mode (WGM) resonators of BP1T and BP2T crystalline materials have been fabricated through a combination method with improved lithography and dry etching. Crystalline microresonators with different geometries over a large area are top‐down fabricated with submicrometer spatial resolution. WGM lasing oscillation from circular, hexagonal, pentagonal and square resonators is definitively observed. The BP1T and BP2T crystals are characterized with high refractive index, and stable lasing in aqueous solution is demonstrated besides in the air environment. It is expected that organic crystalline materials would be used for the practical applications in a variety of organic electronic and optical devices.
Conformational preference and mechanism of decarboxylation of levodopa. A quantum dynamics/quantum mechanics study
Authors: Elroby Shabaan A. K. , Ahmed Ashour A. , Hilal Rifaat H.
Published: March 2013

The present study addresses the conformational preferences and the mechanism of decarboxylation of levodopa (LD). LD is used to increase dopamine concentrations in the treatment of Parkinson's disease. LD crosses the protective blood–brain barrier, where it is converted into dopamine by the process of decarboxylation. Molecular dynamics simulation has been carried out at the DFT/6‐31++G level of theory to identify the global minimum structure of LD. Conformational preferences of the amino acid side chain of LD has been investigated at the B3LYP/6‐311++G** level of theory. Fourier transform analysis has been performed to identify the origin of the rotational barriers. Electrostatic dipole moment and bond interactions underlie the observed potential energy barriers for rotation of the amino acid side chain of LD. The vital biological process of decarboxylation of LD has been examined in the gas phase and in aqueous solution. Without the presence of water, there is only one possible route for the decarboxylation of LD. In this concerted mechanism, a proton transfer and breakage of the C10—C18 bond, take place simultaneously (ΔE# = 73.2 kcal/mol). In solution, however, two possible decarboxylation routes are available for LD. The first involve the formation of a zwitterionic intermediate (ΔE# = 72.4 kcal/mol). The zwitterionic form of LD have been localized using explicitly bound water molecules to model short‐range solvent effects and self‐consistent reaction field polarized continuum model to estimate long‐range solvent interactions. The second route involve the formation of a cyclic structure in which a water molecule acts as a bridge linking the anticarboxylic hydrogen and α‐position carbon atom (ΔE# = 59.8 kcal/mol). Natural bond orbital (NBO) analysis reveals that the conformational and overall stability of the amino acid side chain is facilitated by the antiperiplanar interactions between the phenyl moiety C—H and C—C bonds and C—X bonds of the amino acid side chain. However, much of the major donor–acceptor interactions is of the lone pair type and is localized within the amino acid side chain itself. Results of the present work reveal that NBO data reflect nicely and identify clearly reaction coordinates at the transition species. © 2013 Wiley Periodicals, Inc.
Serine protease inhibitor Kazal type 1 and epidermal growth factor receptor are expressed in pancreatic tubular adenocarcinoma, intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia
Authors: Ozaki Nobuyuki , Ohmuraya Masaki , Ida Satoshi , Hashimoto Daisuke , Ikuta Yoshiaki , Chikamoto Akira , Hirota Masahiko , Baba Hideo
Published: March 2013

Background

Serine protease inhibitor Kazal type 1 (SPINK1) is expressed in normal human pancreatic acinar cells and in a variety of tumors, and binds to the epidermal growth factor receptor (EGFR), mediating cell proliferation through the mitogen‐activated protein kinase cascade in pancreatic cancer cell lines. Here, we aimed to assess SPINK1 and EGFR expression in various neoplastic lesions, including tissues demonstrating precancerous changes.

Methods

Surgical specimens of pancreatic ductal adenocarcinoma (n = 23), intraductal papillary mucinous neoplasm (IPMN;n = 21), pancreatic neoplasms other than ductal adenocarcinoma (n = 8), chronic pancreatitis (n = 11), and pancreatic intraepithelial neoplasia (PanIN) lesions within the resected specimens were analyzed immunohistochemically for SPINK1 and EGFR expression.

Results

Sixty‐five PanIN‐1A, 32 PanIN‐1B, 17 PanIN‐2, and 6 PanIN‐3 were identified. Both SPINK1 and EGFR were expressed in almost all PanIN lesions. All tubular ductal adenocarcinoma, IPMN, and mucinous cystadenocarcinoma samples (neoplasms of ductal origin) expressed SPINK1, whereas acinar cell carcinoma, anaplastic carcinoma, adenosquamous carcinoma, insulinoma, and islet cell carcinoma did not. EGFR was expressed in 87 % of tubular adenocarcinoma and 48 % of IPMN lesions. Among IPMN lesions, malignant lesions (IPMC) expressed EGFR more often than benign lesions (IPMA) did. Scattered expression of EGFR was observed in normal pancreatic ducts and within the tubular complex within chronic pancreatitis lesions.

Conclusions

These results indicate that SPINK1 plays a role as a growth factor, signaling through the EGFR pathway in pancreatic ductal adenocarcinoma and neoplasms, and that the EGFR is involved in the malignant transformation of IPMN.
Analysis of species coexistence co‐mediated by resource competition and reproductive interference
Authors: Kishi Shigeki , Nakazawa Takefumi
Published: March 2013

Reproductive interference is any interspecific sexual interaction that reduces the reproductive success of females through promiscuous reproductive activities of heterospecific individuals. This phenomenon is ubiquitous in nature in both plants and animals, and is frequently observed in biological invasions. However, its effects on interspecific competition remain incompletely understood despite growing concern. To study the interactive effects of resource competition and reproductive interference on species coexistence and exclusion, we analyzed a unified competition model including both processes in symmetric and asymmetric scenarios. The results of our model showed that resource competition and reproductive interference act synergistically to promote competitive exclusion. We also found that when the two processes are asymmetric, the species that is superior in reproductive interference can coexist with or even exclude the species that is superior in resource competition. Therefore, coexistence is possible via an unbalanced trade‐off between resource use and reproduction. Our results suggest that integration of reproductive interference and resource competition will contribute to a better understanding of interspecific competition and to more effective biodiversity conservation against management of biological invasions.
Basophile: Accurate Fragment Charge State Prediction Improves Peptide Identification Rates
Authors: Wang Dong , Dasari Surendra , Chambers Matthew C. , Holman Jerry D. , Chen Kan , Liebler Daniel C. , Orton Daniel J. , Purvine Samuel O. , Monroe Matthew E. , Chung Chang Y. , Rose Kristie L. , Tabb David L.
Published: March 2013

In shotgun proteomics, database search algorithms rely on fragmentation models to predict fragment ions that should be observed for a given peptide sequence. The most widely used strategy (Naive model) is oversimplified, cleaving all peptide bonds with equal probability to produce fragments of all charges below that of the precursor ion. More accurate models, based on fragmentation simulation, are too computationally intensive for on-the-fly use in database search algorithms. We have created an ordinal-regression-based model called Basophile that takes fragment size and basic residue distribution into account when determining the charge retention during CID/higher-energy collision induced dissociation (HCD) of charged peptides. This model improves the accuracy of predictions by reducing the number of unnecessary fragments that are routinely predicted for highly-charged precursors. Basophile increased the identification rates by 26% (on average) over the Naive model, when analyzing triply-charged precursors from ion trap data. Basophile achieves simplicity and speed by solving the prediction problem with an ordinal regression equation, which can be incorporated into any database search software for shotgun proteomic identification.
MYC‐y mice: From tumour initiation to therapeutic targeting of endogenous MYC
Authors: Morton Jennifer P. , Sansom Owen J.
Published: March 2013

MYC is one of the best‐studied oncogenes in terms of mouse models of malignancy. MYC overexpression has been targeted to several tissues using transgenic constructs, and more recently as mouse models have evolved, conditional systems have been developed to allow the regulation of MYC expression or activity in vivo. The ability to target MYC expression to specific tissues and cell lineages, as well as the ability to regulate that expression, has made genetically engineered mouse models (GEMM) a valuable resource for studying the importance of MYC in the process of tumourigenesis. Here we review how these models have been used to address the role of MYC in tumour initiation and maintenance, how subtle changes in levels of MYC can influence tumourigenesis, and finally the ongoing efforts to target endogenous MYC genetically and with novel therapies.
Bernoulli measure of complex admissible kneading sequences
Authors: BRUIN HENK , SCHLEICHER DIERK
Published: March 2013

Iterated quadratic polynomials give rise to a rich collection of different dynamical systems that are parametrized by a simple complex parameter $c$. The different dynamical features are encoded by the kneading sequence, which is an infinite sequence over $\{ \mathtt{0} , \mathtt{1} \} $. Not every such sequence actually occurs in complex dynamics. The set of admissible kneading sequences was described by Milnor and Thurston for real quadratic polynomials, and by the authors in the complex case. We prove that the set of admissible kneading sequences has positive Bernoulli measure within the set of sequences over $\{ \mathtt{0} , \mathtt{1} \} $.
An articulated hindlimb of a basal iguanodont (Dinosauria, Ornithopoda) from the Early Cretaceous Las Hoyas Lagerstätte (Spain)
Authors: SERRANO MERCEDES LLANDRES , VULLO ROMAIN , MARUGÁN-LOBÓN JESÚS , ORTEGA FRANCISCO , BUSCALIONI ÁNGELA D.
Published: March 2013

An isolated, fully articulated hindlimb of a basal iguanodont from the Spanish Las Hoyas Lagerstätte is described. It probably belonged to a juvenile or subadult individual. Despite some slight differences, anatomical features, as well as the late Barremian age of this specimen, would suggest that it belongs toMantellisaurus atherfieldensis. The exquisite preservation of this specimen provides information on the foot anatomy of basal iguanodonts. This is the first report of a non-theropod dinosaur from Las Hoyas. From a palaeoecological point of view, this discovery indicates that potential prey of the carcharodontosaurian theropodConcavenatorwere present at Las Hoyas, thus complementing our knowledge of the trophic structure of this Early Cretaceous palaeocommunity.
A NOTE ON THE BUSINESS CYCLE IMPLICATIONS OF TRADE IN INTERMEDIATE GOODS
Authors: Eyquem Aurélien , Kamber Güneş
Published: March 2013

Trade in intermediate goods is an important feature of trade in developed small open economies. We show that a model that assumes trade in intermediate goods brings the dynamics of an otherwise standard small open economy closer to what is observed in the data. With trade in intermediate goods, movements of international relative prices affect the economy through an additional channel, denoted the “cost channel.” A model embedding this channel comes closer to business cycle data in several dimensions compared to models with trade in final goods only. It increases the share of output variance explained by foreign shocks, lowers the exchange rate pass-through, and delivers a positive international correlation of outputs. In addition, the matching of other business cycle moments is at least as good as in a model with trade in final goods only.
Improving measurement in nutrition literacy research using Rasch modelling: examining construct validity of stage-specific ‘critical nutrition literacy’ scales
Authors: Guttersrud Øystein , Dalane Jorån Østerholt , Pettersen Sverre
Published: March 2013

Objective

Critical nutrition literacy (CNL), as an increasingly important area in public health nutrition, can be defined as the ability to critically analyse nutrition information, increase awareness and participate in action to address barriers to healthy eating behaviours. Far too little attention has been paid to establishing valid instruments for measuring CNL. The aim of the present study was to assess the appropriateness of utilizing the latent scales of a newly developed instrument assessing nursing students’ ‘engagement in dietary habits’ (the ‘engagement’ scale) and their level of ‘taking a critical stance towards nutrition claims and their sources’ (the ‘claims’ scale).

Design

Data were gathered by distributing a nineteen-item paper-and-pencil self-report questionnaire to university colleges offering nursing education. The study had a cross-sectional design using Rasch analysis. Data management and analysis were performed using the software packages RUMM2030 and SPSS version 20.

Setting

School personnel handed out the questionnaires.

Subjects

Four hundred and seventy-three students at ten university colleges across Norway responded (52 % response rate).

Results

Disordered thresholds were rescored, an under-discriminating item was discarded and one item showing uniform differential item functioning was split. The assumption of item locations being differentiated by stages was strengthened. The analyses demonstrated possible dimension violations of local independence in the ‘claims’ scale data and the ‘engagement’ scale could have been better targeted.

Conclusions

The study demonstrates the usefulness of Rasch analysis in assessing the psychometric properties of scales developed to measure CNL. Qualitative research designs could further improve our understanding of CNL scales.
Structural Mapping of Disordered Materials by Nanobeam Diffraction Imaging and Multivariate Statistical Analysis
Authors: Lu Ping , Gauntt Bryan D.
Published: March 2013

A hybrid nanobeam diffraction/imaging method, which combines well-developed diffraction imaging with nanobeam diffraction (NBD) pattern analysis, is described for structural mapping of disordered materials. Spatially resolved crystallographic information is obtained by NBD imaging by collecting NBD patterns at predefined intervals within a field of interest. The resulting dataset of NBD patterns is preprocessed to produce a spectral-imaging-like dataset and is further analyzed via multivariate statistical analysis methods in order to extract the relevant structural components and their distribution within the area of the sample under study without prior knowledge. Additional radial distribution function analysis of either the principal components or averaged data provides real-space maps of short-range order within the field of interest. This technique is demonstrated for two systems, one with multiple amorphous phases and one with multiple phases (amorphous and nanocrystalline) with similar chemistry.
Assessment of tariff equivalents for services considering the zero flows
Authors: GUILLIN AMÉLIE
Published: March 2013

Measuring trade barriers in services is complex due to all the non-tariff barriers that exist. In this paper we rely on quantity measures using gravity equation. In order to take into consideration the presence of zero flows in the database, we use a sample selection model. Then, we use the results of both stages of the model to derive tariff equivalents based on the distribution of the estimated residuals. Applying this methodology to the Eurostat database, we obtain tariff equivalents for a large number of countries and for 11 services sectors. Our main conclusions are that protection is not homogeneous among sectors for a country and that services openness is not directly linked with the level of development. Our results are robust to changes in specification, but we do find that OLS estimations overestimate the commercial openness of the countries with many zero flows.
Micro/Nano-CT for Visualization of Internal Structures
Authors: Singhal Anjali , Grande James C. , Zhou Ying
Published: March 2013

Computed tomography (CT) has been commonly used in medicine for assessing the anatomy of humans in conventional computer axial tomography (CAT) scans. It is also a very common tool for assessing the architecture of trabecular bones for diagnosis of conditions such as osteoporosis. More recently, high-resolution CT (micro-CT) has found increasing use in materials science for the evaluation of the internal structure of a variety of advanced materials for industrial applications. Knowledge of the micro-architecture of these materials is extremely important to better understand their performance. Micro-CT is a non-destructive 3D characterization tool that uses X rays to determine the internal structure of objects through imaging of different densities within the scanned object. High-resolution laboratory-based micro-CT or nano-CT provides image resolution on the order of 300 nm. Such high resolution allows one to visualize the internal 3D structure of fine-scale features. The data from micro-CT results in a virtual rendering of the object under investigation, which allows one to travel through the volume in any direction and angle, revealing complex hidden structures within the object. Thus, micro-CT can be an important complementary technique for a microscopy laboratory.
Using the TEM Condenser Lens to Switch between Image and Diffraction Modes
Authors: Rivaud Lydia
Published: March 2013

Central to the operation of the transmission electron microscope (TEM) (when used with crystalline samples) is the ability to go back and forth between an image and a diffraction pattern. Although it is quite simple to go from the image to a convergent-beam diffraction pattern or from an image to a selected-area diffraction pattern (and back), I have found it useful to be able to go between image and diffraction pattern even more quickly. In the method described, once the microscope is set up, it is possible to go from image to diffraction pattern and back by turning just one knob. This makes many operations on the microscope much more convenient. It should be made clear that, in this method, neither the image nor the diffraction pattern is “ideal” (details below), but both are good enough for many necessary procedures.
Precision Local Electrical Probing: Potential for the Analysis of Nanocontacts and Nanointerconnects
Authors: Guenther B. , Koeble J. , Chrost J. , Maier M. , Schneider C. M. , Bettac A. , Feltz A.
Published: March 2013

A major challenge in the development of novel devices in nano and molecular electronics is their interconnection with larger-scale electrical circuits required to control and characterize their functional properties. Local electrical probing by multiple probes with ultimate scanning tunneling microscopy (STM) precision can significantly improve efficiency in analyzing individual nano-electronic devices without the need for full electrical integration.
Calendar
Authors: Webster Paul
Published: March 2013

Following is a list of microscopy related meetings and courses. The editors would greatly appreciate input to this list via the electronic submission form under “events/other microscopy events” at the MSA webpage: www.microscopy.org. We will gladly add hypertext links to the notice on the web and insert a listing of the meeting in the next issue.
NetNotes
Authors: Phillips Thomas E.
Published: March 2013

Selected postings from the Microscopy Listserver from November 1, 2012 to December 31, 2012. Complete listings and subscription information can be obtained at http://www.microscopy.com. Postings may have been edited to conserve space or for clarity.
Nonadiabaticity in a Jahn-Teller system probed by absorption and resonance Raman scattering
Authors: Pae K. , Hizhnyakov V.
Published: March 2013

A theory of absorption and resonance Raman scattering of impurity centers in crystals with E⊗e-type Jahn-Teller effect in the excited state is presented. The vibronic interaction with non-totally symmetric local or pseudolocal modes and with a continuum of bath modes (phonons) is considered. A number of specific quantum effects, such as the nonadiabaticity-induced enhancement of the Raman scattering at high-energy excitation, the size effect of the final state, the interference of different channels of scattering, the Fermi resonances in the conical intersection, and others, were shown to become apparent in the calculated spectra. The vibronic interaction with phonons essentially determines the structure of the spectra.
Variational principles for relative local pressure with subadditive potentials
Authors: Ma Xianfeng , Chen Ercai
Published: March 2013

We prove two relative local variational principles of topological pressure functions \documentclass[12pt]{minimal}\begin{document}$P(T,\mathcal {F},\mathcal {U},y)$\end{document}P(T,F,U,y) and \documentclass[12pt]{minimal}\begin{document}$P(T,\mathcal {F},\mathcal {U}|Y)$\end{document}P(T,F,U|Y) for a given factor map π: (X, T) → (Y, S) between two topological dynamical systems, an open cover \documentclass[12pt]{minimal}\begin{document}$\mathcal {U}$\end{document}U of X and a subadditive potential \documentclass[12pt]{minimal}\begin{document}$\mathcal {F}$\end{document}F in \documentclass[12pt]{minimal}\begin{document}$C(X,\mathbb {R})$\end{document}C(X,R). By proving the upper semi-continuity and affinity of the entropy maps \documentclass[12pt]{minimal}\begin{document}$\mu \rightarrow h_{\mu }(T,\mathcal {U}\mid Y)$\end{document}μ→hμ(T,U∣Y) and \documentclass[12pt]{minimal}\begin{document}$\mu \rightarrow h^+_{\mu }(T,\mathcal {U}\mid Y)$\end{document}μ→hμ+(T,U∣Y) on the space of all invariant Borel probability measures, we show that the relative local topological pressure with subadditive potentials determines the local measure-theoretic conditional entropies.
On Pauli pairs
Authors: Shkarin Stanislav
Published: March 2013

The state of a system in classical mechanics can be uniquely reconstructed if we know the positions and the momenta of all its parts. In 1958 Pauli has conjectured that the same holds for quantum mechanical systems. The conjecture turned out to be wrong. In this paper we provide a new set of examples of Pauli pairs, being the pairs of quantum states indistinguishable by measuring the spatial location and momentum. In particular, we construct a new set of spatially localized Pauli pairs.