bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacodynamics of Long‐Acting Propranolol 60‐mg Capsules: A Comparative Evaluation
Authors: Marino Maria R. , Dey Michael , Garg Dyal C. , Jallad Nader S. , Dorick Diane M. , Martinez Juan J. , Weidler Donald J.
Published: March 2013

This double‐blind, placebo‐controlled, four‐period cross‐over study was undertaken to evaluate the sustained‐release characteristics of long‐acting propranolol hydrochloride (Inderal LA, Ayerst Laboratories, New York, NY) 60 mg qd, to compare the pharmacokinetic and pharmacodynamic properties of this formulation with conventional propranolol 20 mg tid, and to evaluate the proportionality of long‐acting propranolol 60 mg (LA 60 mg) and long‐acting propranolol 80 mg (LA 80 mg). Pharmacodynamic effects were evaluated in 34 healthy subjects by assessing heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure (double product) after exercise‐induced tachycardia following both acute (day 1) and steady state (day 4) drug administration. The Cmax following administration of LA 60 mg was 9.5 and 11.4 ng/mL on days 1 and 4, respectively, compared with 18.8 and 20.0 ng/mL with 20 mg tid (P < .0001). The tmax for LA 60 mg was significantly later (P < .0001) than for conventional propranolol. Additionally, the apparent plasma half‐life was significantly longer (P < .0001) than with conventional propranolol. The LA 60‐mg formulation was dose proportional to the LA 80‐mg formulation. Pharmacodynamic evaluations showed no significant differences between LA 60 mg and 20 mg tid at any times tested with either acute or steady state dosing. This study demonstrates that LA 60 mg displays characteristics of a sustained‐release formulation, is proportional with LA 80 mg, and produces pharmacodynamic effects that are similar to 20‐mg tid dosing.
A Comparison of the Side Effects of Atenolol and Propranolol in the Treatment of Patients with Hypertension
Authors: Fodor J. George , Chockalingam Arun , Drover Aidan , Fifield Frank , Pauls Cecil J.
Published: March 2013

A single‐blind study was conducted in 52 hypertensive patients, aged 25 to 68 years, to compare the side effects of an equally effective antihypertensive regimen of propranolol and atenolol. All patients had a history of side effects with beta‐blocker therapy. Patients were treated with propranolol 40 to 160 mg hid for 8 weeks, followed by atenolol 50 to 100 mg given once daily for 8 weeks, and then rechallenged with the required dosage of propranolol for 8 weeks. Mean systolic and diastolic blood pressures were controlled during all three treatment phases. Side effects showed a definite trend toward improvement during the atenolol treatment phase. CNS side effects, in particular, showed significantly (P < .05) reduced severity scores and overall incidence rates during the atenolol treatment phase. In conclusion, this study showed that at equally effective antihypertensive dosages the hydrophilic beta blocker atenolol produced significantly fewer CNS side effects than the lipophilic beta blocker propranolol.
Labetalol in the Treatment of Hypertension in Elderly and Younger Patients
Authors: Abernethy Darrell R. , Bartos Paul , Plachetka John R.
Published: March 2013

The efficacy and safety of labetalol therapy were evaluated in 20 patients 60 years and older with isolated systolic or diastolic hypertension and 19 patients aged younger than 60 years with diastolic hypertension. After a two‐week placebo washout period, labetalol was titrated for up to four weeks (100–400 mg bid) until blood pressure control was achieved (standing systolic < 160 mm Hg or ≥ 10% reduction from baseline, and standing diastolic < 90 mm Hg or a decrease of 10 mm Hg from baseline). Mean decreases in standing systolic and diastolic blood pressure from baseline were statistically significant for both age groups (≥60 years, −23/−13; <60 years, −18/−12,P< .01). Control criteria were met in 18 (90%) older and 15 (79%) younger patients who then entered a four‐week maintenance period. Sixteen (80%) of the older patients and six (32%) of the younger patients maintained blood pressure control on 200 mg or less of labetalol bid (P< .05). Three patients, two of whom withdrew from the study, were judged to have experienced adverse events that were drug related. It was concluded that labetalol was effective and well‐tolerated antihypertensive therapy in both elderly and younger patients. In addition, significantly less medication was required to achieve blood pressure control in the elderly.
Nifedipine in Primary Raynaud's Phenomenon and in Scleroderma: Oral Versus Sublingual Hemodynamic Effects
Authors: Wollersheim H. , Thien Th. , Laar A. van ‘t
Published: March 2013

In 16 patients with Raynaud's phenomenon a placebo‐controlled single‐dose study was performed on the hemodynamic effects of 10 mg nifedipine, sublingually administered, followed by an open eight‐week study on the therapeutic efficacy of chronic oral nifedipine, 10 mg qid. After the acute sublingual nifedipine administration, a pronounced objective improvement of finger skin (P = .013) and forearm muscle blood flow (P = .04) during a standard finger‐cooling test was found. During the chronic oral study the improvement in objective efficacy parameters disappeared, except for laser Doppler estimated shunt flow (P = .07). The acute hemodynamic effects did not predict the long‐term results in individual patients. Patients with systemic sclerosis reacted as well as patients with primary Raynaud's phenomenon. This study shows that orally administered nifedipine does not convey long‐term objective benefit to patients with Raynaud's phenomenon. The apparent increase in vasodilation during acute administration suggests that sublingual nifedipine prophylactically or during a vasospastic attack may be more useful.
Hemiplegia and Focal Convulsions as a Manifestation of Cyclosporine A Toxicity
Authors: Vellodi A. , Jayatunga R. , Hugh‐Jones K.
Published: March 2013

Hemiplegia and focal convulsions were observed in a patient who received cyclosporine A after bone marrow transplantation. Cessation of the drug resulted in prompt reversal of the symptoms. The diagnostic problems and implications of this case are discussed.
The Effect of Itazigrel and Aspirin on the Mucosa of the Esophagus, Stomach, and Duodenum of Normal Subjects
Authors: Demke Donald M. , Luderer John R. , Wakefield Linda K. , Euler Arthur R. , Brouwer Robert D. , Metzler Carl M.
Published: March 2013

The effects of aspirin, itazigrel (U‐53,059; a new antiplatelet drug), and placebo on the mucosa of the esophagus, stomach, and duodenum were evaluated in this double‐blind, randomized, placebo‐controlled study. Six normal male subjects were included in each of five treatment groups: aspirin (325 mg each morning for five doses), aspirin (325 mg tid for 12 doses), itazigrel (25 mg each morning for five doses), itazigrel (50 mg tid for 12 doses), and placebo. Aspirin and itazigrel, at all doses investigated, significantly inhibited ex vivo, ionophore (A23187)‐stimulated thromboxane B2 synthesis. Collagen‐induced platelet aggregation was significantly inhibited on day 3 (P = .021) and day 5 (P = .002) in both aspirin and itazigrel groups as compared with placebo. Upper gastrointestinal endoscopy was performed before the first dose of drug (day 1) and two hours after the last dose (day 5) for each subject. A rating scale was used to score the amount of mucosal damage. The baseline (day 1) endoscopic scores revealed no significant differences between groups. On day 5, neither placebo nor itazigrel treatment groups showed any significant change compared with baseline. On day 5, both aspirin groups had significantly (P < .001) more mucosal damage than the placebo group and either itazigrel group. It is concluded that in this relatively acute study, at doses that produce comparable inhibition of platelet aggregation and platelet cyclo‐oxygenase, itazigrel was superior to aspirin in terms of toxicity to the upper gastrointestinal tract.
The Registration of Medicines in the Netherlands
Authors: Drost R. A. , Reijnders P. J. M.
Published: March 2013

The working methods and the results of the system for registration of medicines in the Netherlands are reviewed. The new structure of the Committee for the Evaluation of Medicines is identified. The necessity for more international cooperation is emphasized. The authors propose the establishment of a European registration committee. The current system is discussed from the viewpoints of government and industry.
Long‐term Antihypertensive Effects and Safety of Nitrendipine in Patients with Mild, Moderate, and Severe Hypertension
Authors: Kann Jules
Published: March 2013

A study of 31 patients with mild or moderate hypertension and 17 patients with severe hypertension was conducted to evaluate the long‐term safety and efficacy of nitrendipine, a new calcium channel blocker with a long duration of action. Nitrendipine (5–40 mg bid) was given as monotherapy or in combination with hydrochlorothiazide and/or propranolol. Seventeen patients (54%) with mild to moderate hypertension were controlled with nitrendipine alone, but all except one patient with severe hypertension required combination therapy. In patients with mild or moderate hypertension, nitrendipine reduced supine blood pressure from a baseline mean 154/100 mm Hg to 136/87 mm Hg after 1 year of treatment (P < .05). In patients with severe hypertension, supine blood pressure was reduced from 186/124 mm Hg to 148/91 mm Hg by the end of the planned treatment period (P < .05; mean duration, 10 weeks). During extended observation, antihypertensive effect was sustained for up to 2.5 years and 1.6 years in patients with mild or moderate and severe hypertension, respectively. Nitrendipine was well tolerated; and only one patient, a moderate hypertensive, discontinued treatment because of pedal edema. The results of this long‐term study show that nitrendipine alone or in combination with a diuretic and/or a beta blocker is a safe and effective agent for the treatment of patients with all degrees of hypertension.
The Disposition of Recainam Hydrochloride During and After Intravenous Loading and Maintenance Infusion in Cardiac Patients
Authors: Hampton Edward M. , Anastasiou‐Nana Maria I. , Nanas John N. , Nappi Jean M. , Capuzzi David M. , Anderson Jeffrey L.
Published: March 2013

Recainam hydrochloride is a newly synthesized propylurea compound demonstrating potent antidysrhythmic effects. Recainam was administered as a loading dose of 3 mg/kg/40 minutes followed by a continuous infusion of 0.9 mg/kg/hr for 23 hours and 20 minutes to ten patients with cardiac disease and frequent PVCs (more than 30/hr). A total of 15 plasma samples were drawn over 36 hours during and after the infusion. Plasma recainam concentration was determined by high performance liquid chromatography (HPLC). The mean (± SD) postload and 24‐hour plasma concentrations were 5.19 ± 0.51 and 3.41 ± 0.71 μg/mL, respectively. The data were best described by a two‐compartment model yielding the following mean (± SD) pharmacokinetic parameters: λ1 = 2.62 ± 0.68 hr−1, λ2 = 0.144 ± 0.014 hr−1, t1/2 λ2 = 4.84 ± 0.46 hr, CLT = 0.268 ± 0.057 L/hr/kg, CLR = 0.143 ± 0.052 L/kg/hr, CLNR = 0.125 ± 0.041 L/hr/kg, Vdss =1.3 ± 0.19 L/kg, and Vdλ2 = 1.9 ± 0.43 L/kg. There were no adverse reactions. Based on these data, recainam can be safely administered as a loading dose followed by a continuous infusion in patients with stable cardiac disease without significant ventricular dysfunction.
Nitrous Oxide Anesthesia in Patients with Ischemic Chest Discomfort: Effect on Beta‐Endorphins
Authors: O'Leary Una , Puglia Charles , Friehling Ted D. , Kowey Peter R.
Published: March 2013

Relief of discomfort during acute myocardial ischemia is usually accomplished with a narcotic analgesic. Because these medications may cause unpleasant symptoms and exert a possibly adverse hemodynamic effect, the availability of alternative analgesic medication would be advantageous. Nitrous oxide is a commonly used potent analgesic gas. Nitrous oxide has been used to relieve ischemic discomfort during myocardial infarction. The current study was undertaken to corroborate that data in a randomized, blinded, cross‐over study and to begin to explore a mechanism for the analgesic effect. Twelve patients with typical ischemic chest discomfort and a suspected myocardial infarction were included in the study. Each patient received a 30‐minute inhalation treatment of 30% nitrous oxide/70% oxygen and 30 minutes of 30% room air/70% oxygen. Patients were blinded to their treatment and were randomized to receive nitrous oxide first, then room air, or vice versa. A semiquantitative assessment of the severity of chest discomfort was made before, during, and at the conclusion of each treatment together with a measurement of plasma beta‐endorphin levels using a venous blood sample. Eleven of the 12 patients reported a significant reduction in the intensity of their chest discomfort during the nitrous oxide inhalation, but none had pain relief during the control period. Beta‐endorphin levels fell to a greater extent during the inhalation of nitrous oxide than during the control period (51% versus 26%; P < .05). No significant adverse effects were noted and most patients slept during the nitrous oxide inhalation. It is concluded that nitrous oxide anesthesia is a superior method of pain relief in patients with ischemic heart disease. The analgesic effect appears to be associated with a fall in beta‐endorphins, perhaps explained by a feedback inhibition of synthesis.
Bevantolol Disposition in Patients with Hepatic Cirrhosis
Authors: Nattel Stanley , Lawand Samih , Matthews Carol , McCans John
Published: March 2013

Bevantolol is a new, cardioselective beta‐receptor antagonist that undergoes extensive hepatic biotransformation. To evaluate changes in the disposition of bevantolol produced by liver disease, a single 200‐mg oral dose of bevantolol was administered in ten patients who had hepatic cirrhosis and to ten age‐matched controls. Cirrhotic patients had a greater plasma bevantolol half‐life (6.9 ± 4.0 hr, mean ± SD) then did patients with normal liver function (2.8 ± 1.1 hr, P < .01), and they also had a longer duration of significant bevantolol‐induced heart rate slowing (for 12 hours after oral dose in cirrhotics versus three hours for controls). On the other hand, the peak concentration after the oral dose and the magnitude of bradycardiac effect were similar for both groups. Plasma bevantolol half‐life was more variable in cirrhotic patients than in controls. Some of this variability among cirrhotics was attributable to age, which was a significant determinant of bevantolol half‐life in the cirrhotic (but not in the control) patient sample. These results indicate that hepatic cirrhosis alters the disposition of bevantolol and suggest that modifications in bevantolol dose should be considered when using this drug to treat patients with liver disease.
Diltiazem Increases Steady State Digoxin Serum Levels in Patients with Cardiac Disease
Authors: Andrejak M. , Hary L. , Andrejak M.‐Th. , Lesbre J. Ph.
Published: March 2013

Diltiazem has been reported to decrease or not to affect digoxin elimination. The effects of diltiazem on steady state concentrations of digoxin was evaluated in eleven patients with congestive heart failure receiving this drug for at least two weeks. The mean trough digoxin was 1.11 ± 0.18 ng/ml before the coadministration of diltiazem (180 mg/day). This concentration increased to 1.54 ± 0.22 ng/ml after three days and to 1.54 ± 0.23 ng/ml after seven days of coadministration (P < 0.01). Clinically, no patient showed signs of digitalis toxicity. Creatinine clearance was unchanged. The present results show that when diltiazem is added to a regimen that includes digoxin, steady state concentrations of this glycoside may increase.
Pharmacodynamics of Triazolam After Intravenous Administration
Authors: Smith Randall B. , Kroboth Patricia D. , Varner Pamela D.
Published: March 2013

Triazolam pharmacokinetics and effects on sedation, short‐term amnesia, and psychomotor performance were evaluated in 25 normal volunteers as part of a safety and tolerance study of intravenous dosing of triazolam. Triazolam kinetics were linear after intravenous administration of doses up to 1.0 mg with no differences among doses in elimination half‐life, volume of distribution, or clearance. The hepatic extraction ratio ranged from 0.14 to 0.37, suggesting that triazolam should undergo moderate first‐pass metabolism after oral administration. The duration and extent of sedation, decrement in psychomotor performance test scores, and amnesia were dose related, but all subjects returned to baseline alertness and function within eight hours of dosing. The time‐course of effects on memory and psychomotor performance were related to triazolam plasma concentration profile using an Emax model for effect and a two‐compartment pharmacokinetic model. The probability of a subject being asleep was related to triazolam plasma concentrations using logistic regression. These models indicate that intravenous doses of 0.25 to 0.5 mg triazolam would be effective for use preoperatively for short surgical procedures.
Verapamil and Lithium in Maintenance Therapy of Manic Patients
Authors: Giannini A. James , Taraszewski Robert , Loiselle Robert H.
Published: March 2013

A year‐long double‐blind cross‐over study was used to compare the long‐term therapeutic effects of lithium versus verapamil in a group of 20 manic volunteers. Subjects received each medication for six months. Before cross‐over, verapamil patients showed a significant improvement after 60 days, lithium‐treated patients after 180 days. After cross‐over, verapamil‐treated subjects showed improvement at day 240. Lithium‐treated patients showed no improvement after cross‐over. The data indicate that verapamil may be effective as an agent in the maintenance treatment of manic patients.
Pharmacokinetics of Codeine After Single‐and Multiple‐Oral‐Dose Administration to Normal Volunteers
Authors: Guay D. R. P. , Awni W. M. , Halstenson C. E. , Findlay J. W. A. , Opsahl J. A. , Abraham P. A. , Jones E. C. , Matzke Gary R.
Published: March 2013

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single‐(60 mg) and multiple‐dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single‐ and last multiple‐oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple‐dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 ± 33 ng/mL/hr after single dose versus 212 ± 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple‐dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.
Pharmacokinetics of Moxonidine After Single and Repeated Daily Doses in Healthy Volunteers
Authors: Trenk D. , Jähnchen E. , Plänitz V. , Wagner F.
Published: March 2013

The pharmacokinetics of the centrally acting alpha‐2 agonist moxonidine were investigated in 12 healthy male subjects after single and repeated oral doses (q12h for five days) of moxonidine 0.2 mg. Plasma concentration‐time data followed the general characteristics of a one‐compartment model with first‐order absorption. Peak plasma concentrations of 1.29 ± 0.32 ng/mL were achieved 0.74 ± 0.35 hours after ingestion of a 0.2‐mg tablet. The terminal half‐life of elimination was 2.12 ± 0.58 hours. The oral clearance (CL/F) amounted to 830 ± 171 mL/min with renal elimination being the major route of elimination. No significant differences in pharmacokinetic parameters could he observed following repeated dosing over five days.
The Effect of Renal Function on the Pharmacokinetics of Gemfibrozil
Authors: Evans J. Robert , Forland Steven C. , Cutler Ralph E.
Published: March 2013

Study objective: to determine the effect of renal function on the pharmacokinetics of gemfibrozil following single and multiple oral doses. Design: nonrandomized; paired studies of single versus multiple doses. Setting: patients enrolled in a veterans hospital renal subspecialty clinic. Patients: 17 male patients 57 to 74 years old selected for various levels of renal function, including end‐stage renal disease, Interventions: patients initially received 600 mg of oral‐gemfibrozil followed by sequential venous blood sampling. Seven to 14 days later, the patients started receiving gemfibrozil, 600 mg bid. Venous blood samples were obtained over the following 10 days and frequently during a 24‐hour washout phase. Measurements and main results: peak gemfibrozil concentrations (mg/L) were 11.1 (3.9 SD) for the single dose and 10.2 (3.8) for the multiple‐dose study. Time to peak concentration (hr) was 2.1 (1.0) and 1.8 (0.6), respectively. The mean half‐life of elimination (hr) from the single‐dose study was 6.4 (11.8) compared with the multidose study of 3.0 (3.1), which did not reach statistical significance (P = .25). The difference between the area under the curve for the single versus the multiple‐dose study approached statistical significance (P = .054). The coefficient of determination for creatinine renal clearance versus the plasma clearance of oral gemfibrozil was 0.009 (P = .72) for the single‐dose regimen and 0.331 (P = .016) for the multiple‐dose study. Conclusion: the half‐life of gemfibrozil is independent of renal function for both single‐ and multiple‐dose regimens. Dosing schedules do not require alteration for renal insufficiency.
Pharmacokinetics of Nifedipine After Oral Administration in Chronic Liver Disease
Authors: Ene M. D. , Roberts C. J. C.
Published: March 2013

Presented are the results of a study in whch ten healthy subjects and seven patients with hepatic cirrhosis were given 10 mg nifedipine orally; plasma concentrations of the drug were measured over 24 hours. The drug was also administered intravenously, but those results were unsatisfactory for presentation. The rate of absorption and peak plasma concentrations were similar in the two groups. There was a fourfold increase in the elimination half‐life (434 ± 74 minutes in the cirrhotics compared with 102 ± 11 minutes in the healthy subjects). A twofold increase in the area under the plasma concentration‐time curve occurred in the cirrhotic group. The study confirmed that there is clinically significant alteration in the kinetics of nifedipine in patients who have hepatic cirrhosis and that there is considerable risk of accumulation. No adverse effects were observed despite high plasma levels of nifedipine.
Distribution of Tranexamic Acid to Plasma and Saliva After Oral Administration and Mouth Rinsing: A Pharmacokinetic Study
Authors: Sindet‐Pedersen Steen
Published: March 2013

The objective of the study was to investigate the content of tranexamic acid in plasma and in mixed, unstimulated whole saliva after oral administration and mouth rinsing. Ten healthy volunteers each received 1 g of tranexamic acid orally, whereas 20 healthy volunteers rinsed their mouths with 10 mL of a 5% aqueous tranexamic acid solution for two minutes. Blood and saliva were collected 30, 60, 120, 240, 360, and 480 minutes after administration of tranexamic acid. Samples of blood and saliva were analyzed for tranexamic acid content by electron capture gas chromatography. After oral administration, the mean plasma concentration of tranexamic acid reached its maximum after 120 minutes at approximately 7 μg/mL, whereas none of the saliva samples contained tranexamic acid at detectable levels. After mouth rinse, the plasma concentrations remained below 2 μg/mL, whereas the concentrations found in saliva initially were very high (after 30 minutes mean concentration above 200 μg/mL) and remained at a therapeutic level for more than two hours. These findings indicate, that fibrinolysis in the oral cavity can be inhibited only by local administration of tranexamic acid. This finding may be of significance when the drug is used for prevention and treatment of Weeding in the oral cavity in patients with coagulation defects.
Ambient ion/molecule reactions in low‐temperature plasmas (LTP): reactive LTP mass spectrometry
Authors: Benassi Mario , Garcia‐Reyes Juan F. , Spengler Bernhard
Published: March 2013

RATIONALE

Ion/molecule reactions are commonly used to characterize structures due to their high specificity. Herein, we present ambient ion/molecule reactions performed in the course of low‐temperature plasma (LTP) ionization of condensed‐phase analytes in order to increase the specificity of LTP‐based ambient analysis.

METHODS

The ion population of the cold plasma is modified by addition of a reagent to the plasma before it is directed at a surface bearing the analyte. Desorbed ions were analyzed using linear ion trap‐Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS).

RESULTS

Acylium ions generated from tetramethylurea react with 1,3‐dioxane analyte to afford distinctive Eberlin product ions. Reactions of alkylamines, such as n‐hexylamine and n‐octylamine, with benzaldehyde produce the corresponding imines. Reaction of ruthenocene with trifluoroacetic anhydride forms the unusual trifluoroacetate ruthenocene.

CONCLUSIONS

A LTP source can be used to generate reagent ions that can undergo ion/molecule reactions in the ambient environment with an analyte at condensed phase on a surface. The experiment is a 'reactive' version of the standard low‐temperature plasma (LTP) ambient ionization experiment. This approach provides additional information by combining ion/molecule chemistry with conventional MS and MS/MS data to characterize particular analytes. Copyright © 2013 John Wiley & Sons, Ltd.
Structural characterization of biocompatible lipoic acid–oligo‐(3‐hydroxybutyrate) conjugates by electrospray ionization mass spectrometry
Authors: Maksymiak Magdalena , Debowska Renata , Jelonek Katarzyna , Kowalczuk Marek , Adamus Grazyna
Published: March 2013

RATIONALE

Currently, most of the antioxidants and free radical neutralizers used in cosmetic compositions are absorbed quickly into deeper layers of skin, and then carried away by the blood stream. It would be beneficial to delay the penetration of antioxidants to the deeper layers of skin to control their delivery and release.

METHODS

Recently, growing attention has been paid to the attachment of cosmetics to specific polymer carriers. Biodegradable and biocompatible conjugates of oligo‐3‐hydroxybutyrate with lipoic acid were obtained via the anionic ring‐opening oligomerization of (R,S)‐β‐butyrolactone initiated by lipoic acid potassium salt. The structure of the resulting conjugates as well as their water‐soluble hydrolytic degradation products were established at the molecular level by electrospray ionization mass spectrometry (ESI‐MSn) supported by 1H NMR analyses.

RESULTS

The structural studies, performed with the aid of ESI‐MSn, confirmed that the lipoic acid was covalently bound to oligo‐3‐hydroxybutyrate chains through hydrolyzable ester bonds. Furthermore, hydrolytic degradation studies of the bioconjugates provided detailed insight into the hydrolysis process, allowing the identification of the degradation products and confirming the release of α‐lipoic acid. Cytotoxicity tests demonstrated that the conjugates were non‐toxic.

CONCLUSIONS

Detailed molecular structural studies of new polymeric delivery systems of lipoic acid were performed by ESI‐MS. ESI‐MS proved to be an excellent technique for the evaluation of hydrolytic degradation products of the conjugates and for monitoring the release of lipoic acid. The results obtained contribute significantly to the characterization of biocompatible LA‐OHB conjugates with potential applications in cosmetology. Copyright © 2013 John Wiley & Sons, Ltd.
Mass spectrometric characterization of organosulfates related to secondary organic aerosol from isoprene
Authors: Safi Shalamzari Mohammad , Ryabtsova Oxana , Kahnt Ariane , Vermeylen Reinhilde , Hérent Marie‐France , Quetin‐Leclercq Joëlle , Van der Veken Pieter , Maenhaut Willy , Claeys Magda
Published: March 2013

RATIONALE

A considerable fraction of atmospheric particulate fine matter consists of organosulfates, with some of the most polar ones originating from the oxidation of isoprene. Their structural characterization provides insights into the nature of gas‐phase precursors as well as into formation pathways.

METHODS

The structures of unknown polar organosulfates present in ambient particulate fine matter were characterized using liquid chromatography/(−)electrospray ionization mass spectrometry (LC/(−)ESI‐MS), including ion trap MSn and accurate mass measurements, derivatization of the carbonyl group into 2,4‐dinitrophenylhydrazones, detailed interpretation of the MS data, and in a selected case comparison of their LC and MS behavior with that of synthesized reference compounds.

RESULTS

Polar organosulfates with molecular weights (MWs) of 156, 170, 184 and 200 were attributed to/or confirmed as derivatives of glycolic acid (156), lactic acid (170), 1,2‐dihydroxy‐3‐butanone (184), glycolic acid glycolate (200), 2‐methylglyceric acid (200), and 2,3‐dihydroxybutanoic acid (200). In the case of the MW 184 compound an unambiguous assignment was obtained through synthesis of reference compounds.

CONCLUSIONS

A more complete structural characterization of polar organosulfates that originate from isoprene secondary organic aerosol was achieved. An important atmospheric finding is the presence of an organosulfate that is related to methyl vinyl ketone, a major gas‐phase oxidation product of isoprene. In addition, minor polar organosulfates related to crotonaldehyde were identified. Copyright © 2013 John Wiley & Sons, Ltd.
Analysis of novel melphalan hydrolysis products formed under isolated lung perfusion conditions using liquid chromatography/tandem mass spectrometry
Authors: Boschmans Jasper , de Bruijn Ernst , Van Schil Paul , Lemière Filip
Published: March 2013

RATIONALE

Melphalan is a widely used cytotoxic agent in cancer treatments. This phenylalanine analog has been shown an effective drug in the treatment of breast cancer, multiple myeloma and melanoma of the extremities. A good knowledge of the drug's degradation and metabolism are crucial for understanding its activity during cancer treatments.

METHODS

The formation of hydrolysis products of melphalan is studied using ultra‐performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS). Aqueous melphalan solutions were incubated at elevated temperatures and analyzed by UPLC/MS/MS. Two previously described hydrolysis products, mono‐ and dihydroxymelphalan (MOH and DOH), were formed in vitro and could be characterized during MS/MS and high‐resolution experiments.

RESULTS

Novel compounds with m/z values >500 Da were discovered. Comparison of the fragmentation patterns of these new molecules with those of MOH and DOH show great similarities. The higher masses are explained by the presence of two or more melphalan units. In total, more than 15 new hydrolysis products were found. Experiments were set up to study the formation and the chemical structures of these molecules.

CONCLUSIONS

The hydrolysis of melphalan is studied in the scope of a phase II clinical trial (isolated lung perfusion, ILuP). Patient samples were screened for the presence of all documented and novel melphalan hydrolysis products. This study reports the formation of a new class of oligomeric compounds in both in vivo and in vitro samples. Copyright © 2013 John Wiley & Sons, Ltd.
Petroleum crude oil analysis using low‐temperature plasma mass spectrometry
Authors: Benassi Mario , Berisha Arton , Romão Wanderson , Babayev Elbay , Römpp Andreas , Spengler Bernhard
Published: March 2013

RATIONALE

The analysis of crude oil is a challenging task due to sample complexity. In mass spectrometry, several ionization techniques can be used to perform this task. Herein, we report the use of an atmospheric pressure low‐temperature plasma (LTP) probe to desorb and ionize compounds of petroleum crude oil from different sources and residual fuel oil standard reference materials (SRMs). LTP is used to perform rapid screening of low molecular weight and relatively volatile components enabling characterization and differentiation of crude oil samples relying solely on mass spectrometric data.

METHODS

Crude oil samples were analyzed without sample preparation or dilution directly from sampling surfaces of different materials such as polytetrafluorethylene, glass and polyethylene. Analyses were performed using Fourier transform ion cyclotron resonance mass spectrometry (FTICR‐MS) with high mass accuracy and high resolving power of 400 000 at m/z 400 to estimate the elemental composition of the ions produced by LTP. Principal components analysis (PCA) was performed on the LTP data for statistical analysis.

RESULTS

LTP was found to generate positive ions of lower mass compounds of low to moderate polarity. Three‐dimensional PCA plots efficiently differentiated between SRMs and Azerbaijan crude oil samples. Standards of alkanes, nitrogen heterocycles, sulfur heterocycles, hydrocarbon polycyclic aromatics and saturated acids were investigated for their behavior in LTP ionization. Alkanes were found to form oxidized products to some extent. The LTP probe worked particularly well in the characterization of sulfur compounds.

CONCLUSIONS

LTP ionization of crude oils was found to advantageously complement analysis by electrospray ionization. The LTP probe in combination with miniaturized mass spectrometers has the potential to provide direct composition analysis and source identification of crude oil contaminations in the future. Copyright © 2013 John Wiley & Sons, Ltd.
Re: Does antenatal ultrasound labeling predict birth order in twin pregnancies? F. D'Antonio, T. Dias and B. Thilaganathan on behalf of the Southwest Thames Obstetric Research Collaborative (STORK). Ultrasound Obstet Gynecol 2013; 41: 274–277
Authors: Khalil A.
Published: March 2013

Linked Comment: Ultrasound Obstet Gynecol 2013:41:274–277
Re: Intra‐ and interobserver agreement when describing adnexal masses using the International Ovarian Tumor Analysis terms and definitions: a study on three‐dimensional ultrasound volumes. P. Sladkevicius and L. Valentin. Ultrasound Obstet Gynecol 2013; 41: 318–327
Authors: Jurkovic D.
Published: March 2013

Linked Comment: Ultrasound Obstet Gynecol 2013:41:318–327
Gauge threshold corrections for $ \mathcal{N}=2 $ heterotic local models with flux, and mock modular forms
Authors: Carlevaro Luca , Israël Dan
Published: March 2013

Abstract

We determine threshold corrections to the gauge couplings in local models of$ \mathcal{N}=2 $smooth heterotic compactifications with torsion, given by the direct product of a warped Eguchi-Hanson space and a two-torus, together with a line bundle. Using the worldsheet cft description previously found and by suitably regularising the infinite target space volume divergence, we show that threshold corrections to the various gauge factors are governed by the non-holomorphic completion of the Appell-Lerch sum. While its holomorphic Mock-modular component captures the contribution of states that localise on the blown-up two-cycle, the non-holomorphic correction originates from non-localised bulk states. We infer from this analysis universality properties for$ \mathcal{N}=2 $heterotic local models with flux, based on target space modular invariance and the presence of such non-localised states. We finally determine the explicit dependence of these one-loop gauge threshold corrections on the moduli of the two-torus, and by S-duality we extract the corresponding string-loop and E1-instanton corrections to the Kähler potential and gauge kinetic functions of the dual type i model. In both cases, the presence of non-localised bulk states brings about novel perturbative and non-perturbative corrections, some features of which can be interpreted in the light of analogous corrections to the effective theory in compact models.
On the tuning and the mass of the composite Higgs
Authors: Panico Giuliano , Redi Michele , Tesi Andrea , Wulzer Andrea
Published: March 2013

Abstract

We analyze quantitatively the tuning of composite Higgs models with partial compositeness and its interplay with the predicted Higgs mass. In this respect we identify three classes of models, characterized by different quantum numbers of the fermionic colored resonances associated with the top quark, the so-called top partners. The main result of this classification is that in all models with moderate tuning a light Higgs, of 125 GeV mass, requires the presence of light top partners, around 1 TeV. The minimal tuning is comparable to the one of the most attractive supersymmetric models in particular the ones realizing Natural SUSY. This gives further support to an extensive program of top partners searches at the LHC that can already probe the natural region of composite Higgs models.
Interplay between Fermi gamma-ray lines and collider searches
Authors: Lee Hyun Min , Park Myeonghun , Sanz Verónica
Published: March 2013

Abstract

We explore the interplay between lines in the gamma-ray spectrum and LHC searches involving missing energy and photons. As an example, we consider a singlet Dirac fermion dark matter with the mediator for Fermi gamma-ray line at 130 GeV. A new chiral or local U(1) symmetry makes weak-scale dark matter natural and provides the axion or Z
′ gauge boson as the mediator connecting between dark matter and electroweak gauge bosons. In these models, the mediator particle can be produced in association with a monophoton at colliders and it produces large missing energy through the decays into a DM pair or ZZ, Zγ with at least one Z decaying into a neutrino pair. We adopt the monophoton searches with large missing energy at the LHC and impose the bounds on the coupling and mass of the mediator field in the models. We show that the parameter space of the Z
′ mediation model is already strongly constrained by the LHC 8TeV data, whereas a certain region of the parameter space away from the resonance in axion-like mediator models are bounded. We foresee the monophoton bounds on the Z
′ and axion mediation models at the LHC 14 TeV.
Investigation of the bacterial retting community of kenaf (Hibiscus cannabinus) under different conditions using next-generation semiconductor sequencing
Authors: Visi David K , D’Souza Nandika , Ayre Brian G , Webber III Charles L , Allen Michael S
Published: March 2013

The microbial communities associated with kenaf (Hibiscus cannabinus) plant fibers during retting were determined in an effort to identify possible means of accelerating this process for industrial scale-up. Microbial communities were identified by semiconductor sequencing of 16S rRNA gene amplicons from DNA harvested from plant-surface associated samples and analyzed using an Ion Torrent PGM. The communities were sampled after 96 h from each of three different conditions, including amendments with pond water, sterilized pond water, or with a mixture of pectinolytic bacterial isolates. Additionally, plants from two different sources and having different pretreatment conditions were compared. We report that the best retting communities are dominated by members of the order Clostridiales. These bacteria appear to be naturally associated with the plant material, although slight variations between source materials were found. Additionally, heavy inoculations of pectinolytic bacteria established themselves and in addition their presence facilitated the rapid dominance of the original plant-associated Clostridiales. These data suggest that members of the order Clostridiales dominate the community and are most closely associated with efficient and effective retting. The results further suggest that establishment of the community structure is first driven by the switch to anaerobic conditions, and subsequently by possible competition for nitrogen. These findings reveal important bacterial groups involved in fiber retting, and suggest mechanisms for the manipulation of the community and retting efficiency by modifying nutrient availability.
Detection of a novel active transposable element in Caldicellulosiruptor hydrothermalis and a new search for elements in this genus
Authors: Chung Daehwan , Farkas Joel , Westpheling Janet
Published: March 2013

We show that a previously annotated hypothetical protein is the transposase of a new and active IS element, ISCahy1, widespread in Caldicellulosiruptor species. Transposition generated an 11-bp direct repeat at the insertion site in Caldicellulosiruptor hydrothermalis, suggesting a cut-and-paste mechanism. The discovery of an active insertion sequence in Caldicellulosiruptor species led to a survey of potential IS elements in the genome sequences of eight Caldicellulosiruptor species that identified several new elements, including one novel to this genus.
Sexual and reproductive health and HIV services: Integrating HIV/AIDS and cervical cancer prevention and control
Authors: Belhadj Hedia , Rasanathan Jennifer J.K. , Denny Lynette , Broutet Nathalie
Published: March 2013

People living with HIV are at an increased risk of acquiring HPV and of developing evolutive cervical cancers (women) and penile and anal cancers (men). Low‐cost screening—visual inspection with acetic acid, HPV DNA diagnostics and primary care level treatment, cryotherapy for cervical intraepithelial neoplasia (CIN 2), and primary prevention through HPV vaccination of girls aged 9–13 years—makes the goal of eliminating cervical cancer possible in the long term. Integration of cervical cancer screening and treatment into a sexual and reproductive health service package raises programmatic questions and calls for a continuum of care. The latter is only possible when adequate cytopathology skills and treatment for advanced cancer conditions are available. The present paper highlights the role of member societies of the International Federation of Gynecology and Obstetrics (FIGO) in developing the base for an integrated package that responds to women's sexual and reproductive health needs.
Dual decentralization in China's transitional economy: Welfare regionalism and policy implications for central–local relationship
Authors: Mok Ka Ho , Wu Xiao Fang
Published: March 2013

In the last three decades, China has experienced dual decentralization in transforming its economy, resulting in decentralization and deconcentration in public administration and social service delivery. Under the policy framework of decentralization, particularly when welfare financing has been decentralized to local governments, the emergence of welfare regionalism is evident in China. This paper sets out against this policy context to examine how three local governments in eastern coastal areas in China handle changing labour welfare needs by institutionalizing social and labour protection measures to meet the local needs instead of implementing central policy. With particular reference to examine why regional variations exist in welfare provision even though the socio-economic development status is similar in these areas, this paper shows how different forms of capitals, government's governance style and diversity of industries have affected welfare arrangements for labour in China.
Simple
piggyBac
transposon-based mammalian cell expression system for inducible protein production
Authors: Li Zhijie , Michael Iacovos P. , Zhou Dongxia , Nagy Andras , Rini James M.
Published: March 2013

Reported here is a
piggyBac
transposon-based expression system for the generation of doxycycline-inducible, stably transfected mammalian cell cultures for large-scale protein production. The system works with commonly used adherent and suspension-adapted mammalian cell lines and requires only a single transfection step. Moreover, the high uniform expression levels observed among clones allow for the use of stable bulk cell cultures, thereby eliminating time-consuming cloning steps. Under continuous doxycycline induction, protein expression levels have been shown to be stable for at least 2 mo in the absence of drug selection. The high efficiency of the system also allows for the generation of stable bulk cell cultures in 96-well format, a capability leading to the possibility of generating stable cell cultures for entire families of membrane or secreted proteins. Finally, we demonstrate the utility of the system through the large-scale production (140–750 mg scale) of an endoplasmic reticulum-resident fucosyltransferase and two potential anticancer protein therapeutic agents.
Stiffened lipid platforms at molecular force foci
Authors: Anishkin Andriy , Kung Ching
Published: March 2013

How mechanical forces are sensed remains largely mysterious. The forces that gate prokaryotic and several eukaryotic channels were found to come from the lipid membrane. Our survey of animal cells found that membrane force foci all have cholesterol-gathering proteins and are reinforced with cholesterol. This result is evident in overt force sensors at the tips of stereocilia for vertebrate hearing and the touch receptor of
Caenorhabditis elegans
and mammalian neurons. For less specialized cells, cadherins sustain the force between neighboring cells and integrins between cells and matrix. These tension bearers also pass through and bind to a cholesterol-enriched platform before anchoring to cytoskeleton through other proteins. Cholesterol, in alliance with sphingomyelin and specialized proteins, enforces a more ordered structure in the bilayer. Such a stiffened platform can suppress mechanical noise, redirect, rescale, and confine force. We speculate that such platforms may be dynamic. The applied force may allow disordered-phase lipids to enter the platform-staging channel opening in the thinner mobile neighborhood. The platform may also contain specialized protein/lipid subdomains enclosing mechanosensitive channels to open with localized tension. Such a dynamic stage can mechanically operate structurally disparate channels or enzymes without having to tie them directly to cadherin, integrin, or other protein tethers.
High-resolution metabolic mapping of cell types in plant roots
Authors: Moussaieff Arieh , Rogachev Ilana , Brodsky Leonid , Malitsky Sergey , Toal Ted W. , Belcher Heather , Yativ Merav , Brady Siobhan M. , Benfey Philip N. , Aharoni Asaph
Published: March 2013

Significance

Analyzing metabolite composition offers a powerful tool for understanding gene function and regulatory processes. Here, we present nontargeted metabolomics assays of five Arabidopsis GFP-tagged lines representing core cell types in the plant root, providing a metabolic map of an organ, composed of its different cell types. Fifty metabolites were putatively identified. The most prominent groups were glucosinolates, phenylpropanoids, and dipeptides. Metabolites were differentially abundant across root cell types and in many cases, this abundance did not correlate with transcript expression, suggesting non–cell-autonomous mechanisms responsible for their targeted localization.
New mandates? No problem for The Rockefeller University Press
Authors: Rossner Mike
Published: March 2013

The existing public access policy for our three journals—The Journal of Cell Biology, The Journal of Experimental Medicine, and The Journal of General Physiology—is fully compliant with new policies from the Research Councils UK (RCUK) and the Wellcome Trust. In addition to mandating public access, the new policies specify licensing terms for reuse of content by third parties, in particular for text and data mining. We question the need for these specific terms, and we have added a statement to our licensing policy stipulating that anyone, including commercial entities, is permitted to mine our published text and data.