bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacologic Blockade of the Renin‐Angiotensin System: Vascular Benefits Beyond Commonly Understood Pharmacologic Actions
Authors: Tsikouris James P. , Cox Craig D.
Published: May 2004

Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are recognized primarily for their use in hypertension, in heart failure, and after myocardial infarction. New evidence, particularly with ACE inhibitors, has shown their ability to reduce acute coronary events associated with atherosclerosis in patients without a history of the aforementioned cardiac conditions. This is likely due to inhibitory effects on the renin‐angiotensin system—a system that adversely influences fibrinolytic balance, vascular endothelial function, and vascular inflammation, all key components of atherosclerotic progression and adverse coronary outcomes. Results of various studies suggest favorable effects of ACE inhibitors and ARBs on markers of these components, including effects on plasminogen activator inhibitor‐1, endothelin‐1, and nitric oxide by ACE inhibitors, and effects on vascular cell adhesion molecule‐1 and C‐reactive protein by ARBs. Although early evidence suggests that ACE inhibitors may provide a greater beneficial effect on some of these markers compared with ARBs, and that certain ACE inhibitors may provide greater vascular benefits than others, further investigation is required to verify such findings. Overall, understanding the distinct coronary vascular benefits of these agents will emphasize the importance of using them, particularly ACE inhibitors, to improve outcomes in patients with coronary atherosclerotic disease.
A Primer for Developing Pharmacist‐Managed Clinics in the Outpatient Setting
Authors: Snella Kathleen A. , Sachdev Gloria P.
Published: May 2004

Pharmacist‐managed clinics exist in many practice settings, such as physician offices, hospital‐based outpatient clinics, and pharmacies. This article is intended to serve as a primer for pharmacists who wish to establish clinical pharmacy services in these settings. Recommendations for beginning this process are delineated. Information on building initial support, developing a needs assessment analysis, selecting the focus of new clinical services, developing a detailed clinic proposal, and marketing new services is provided. In a comprehensive review of how to develop a clinic proposal, the purpose, background information, proposed clinic structure, implications, assessment, billing issues, financial summary, and resources requested are discussed. Opportunities for financial compensation in various practice settings, such as the physician outpatient clinic, hospital‐based outpatient clinic, and community pharmacy, are also reviewed.
Superwarfarin and Glass Ingestion with Prolonged Coagulopathy Requiring High‐Dose Vitamin K1 Therapy
Authors: Tsutaoka Ben T. , Miller Michael , Fung Stacey M. , Patel Manish M. , Olson Kent R.
Published: May 2004

A 23‐year‐old man was brought to the emergency department after eating four boxes of brodifacoum‐containing rodenticide over a 4‐day interval and pieces from approximately two bottles of glass over the previous 2 weeks. He was asymptomatic but his prothrombin time was markedly elevated with an international normalized ratio (INR) of 37.8. A plain abdominal film showed diffuse radiopaque foreign bodies, presumably glass, in the large and distal small intestines. Treatment for ingested glass consisted of stool softeners and bulk‐forming laxatives. The patient developed mild gingival bleeding and received fresh frozen plasma (FFP) infusions and vitamin K1 orally. At a vitamin K1 dosage of 300 mg/day, the INR corrected to less than 2.0 and the patient was discharged taking that dosage. He returned 26 days later with hematuria and flank pain, and his INR was 189. He was administered FFP and packed red blood cells, and his vitamin K1 dosage was increased to 800 mg/day; his INR returned to baseline. Compliance with taking the vitamin K1, which required ingestion of 60–160 tablets/day, was a serious problem, requiring numerous follow‐up calls and visits to the patient at home and work. At 5‐month follow he was doing well. Compliance with large daily doses of vitamin K1 for treatment of “superwarfarin” ingestion may be poor because of the duration of treatment and large number of pills required. A more concentrated formulation may be advantageous for management of patients with brodifacoum poisoning.
From Club Drug to Orphan Drug: Sodium Oxybate (Xyrem) for the Treatment of Cataplexy
Authors: Fuller David E. , Hornfeldt Carl S.
Published: May 2004

Narcolepsy, a rare disease with a prevalence of 0.05% in the general population, affects an estimated 140,000 patients in the United States. Patients have been able to lead fuller personal and professional lives since the Food and Drug Administration approved sodium oxybate (Xyrem) in 2002 for treatment of cataplexy in patients with narcolepsy. Previously, γ‐hydroxybutyrate (GHB), the active ingredient of sodium oxybate, had been a substance of abuse, most notoriously as a date‐rape drug. Public Law 106–172, the date‐rape prohibition act enacted in 2000, was modified to allow the drug to be legally administered for medical purposes. Because of the apprehension regarding the risk of possible drug diversion after the approval of sodium oxybate and concerns about safety, the Xyrem Risk Management Program was created. This program has been successful in satisfying the needs of patients and physicians while ensuring responsible distribution of the drug.
Comparative Study of the Development of Diabetes Mellitus in Patients Taking Risperidone and Olanzapine
Authors: Fuller Matthew A. , Shermock Kenneth M. , Secic Michelle , Grogg Amy L.
Published: May 2004

Objectives.A growing body of literature suggests that certain atypical antipsychotics, especially olanzapine and clozapine, may induce glucoregulatory dysfunction. We assessed the differences in risk of developing diabetes mellitus during treatment with olanzapine and risperidone by using patients treated with haloperidol and fluphenazine as control subjects in whom we would not expect to see an increased risk.

Methods.We conducted a retrospective analysis of the Veteran's Integrated Service Network 10 Veterans Affairs (VA) database. Data for patients receiving olanzapine, risperidone, haloperidol, or fluphenazine from January 1, 1997‐December 31, 2000, were included. Diabetes was defined as any health system encounter associated with theInternational Classification of Diseases, Ninth Revision, Clinical Modificationdiagnosis for diabetes (250.xx) or prescription for a hypoglycemic agent. Data of patients with markers for diabetes within 1 year before their index date, female patients, racial groups other than Caucasian or African‐American, and patients receiving clozapine were not analyzed. We performed a Cox regression, with antipsychotic therapy as a time‐dependent covariate. Other covariates considered for inclusion in the final model were number of days supply of antipsychotic drug, age, race, psychiatric diagnoses, substance abuse, lithium, valproic acid, and other typical or atypical antipsychotic agents.

Results.Data for 5837 patients were analyzed. Overall rate of developing diabetes in the study population was 6.3% (368 of 5837 patients). Olanzapine therapy was associated with a significantly higher risk of development of diabetes compared with risperidone (hazard ratio [HR] 1.37, 95% confidence interval 1.06–1.76, p=0.016) while controlling for race, age, diagnosis, substance abuse, lithium, valproic acid, and other atypical antipsychotic agents. No differences in the rate of developing diabetes were detected between fluphenazine and risperidone (HR 1.11, p=0.69), or haloperidol and risperidone (HR 0.89, p=0.41).

Conclusions.Olanzapine was associated with a 37% (HR 1.37) increased risk of development of diabetes compared with risperidone in a VA population, even after adjusting for other factors associated with the development of diabetes and temporal exposure to study drug. Because of limitations associated with database research, prospective studies should be conducted to corroborate these findings.
The Effect of Postnatal Age on Gentamicin Pharmacokinetics in Neonates
Authors: Knight Jennifer A. , Davis Estella M. , Manouilov Konstantine , Hoie Eric B.
Published: May 2004

Study Objective. To determine if gentamicin serum concentrations obtained from newborns on day 2 of life versus days 3–4 yield significantly different pharmacokinetic parameter values.

Design. Retrospective chart review.

Setting. Neonatal intensive care unit.

Patients. Two hundred and sixty‐seven infants who had peak and trough gentamicin serum concentrations determined on days 2, 3, or 4 of life.

Intervention. Determination of peak and trough serum gentamicin concentrations on days 2, 3, or 4 of life.

Measurements and Main Results. The elimination rate constant, serum half‐life, volume of distribution, and clearance of gentamicin were calculated using a one‐compartment pharmacokinetic model. Gestational age, birthweight, gentamicin dosage, peak and trough gentamicin concentrations, and hours after birth at which serum concentrations were drawn were recorded for all infants. Infants were stratified into three groups based on gestational age: 28 weeks or younger, older than 28 weeks but younger than 37 weeks, and 37 weeks or older. Birthweight and calculated pharmacokinetic parameters were compared by 2‐tailed Student t test to determine if significant differences existed between pharmacokinetics parameters determined on day 2 of life versus days 3 or 4 within each of the gestational age groups. These analyses revealed only one significant difference between parameters assessed on day 2 versus days 3 or 4: at day 2, the mean trough concentration of gentamicin in infants of gestational age between 28 and 37 weeks was 1.63 ± 0.44 mg/L, whereas at days 3 or 4, the same parameter for patients of the same gestational age was 1.4 ± 0.48 mg/L (p=0.005).

Conclusions. With one exception—elevated trough concentrations in infants in the gestational age group between 28 and 37 weeks—pharmacokinetic parameters calculated using gentamicin serum concentrations determined on day 2 of life are not significantly different from those derived from gentamicin serum concentrations determined on days 3 or 4. This suggests that gentamicin serum concentrations and subsequent dosage adjustments can be determined on day 2 of life.
Safety and Efficacy of Pegfilgrastim in Patients Receiving Myelosuppressive Chemotherapy
Authors: Crawford Jeffrey
Published: May 2004

The major dose‐limiting toxicity associated with myelosuppressive chemotherapy is neutropenia, which can be ameliorated with proactive administration of granulocyte colony‐stimulating factor (G‐CSF). Pegfilgrastim is a long‐acting G‐CSF, recently approved by the Food and Drug Administration. The efficacy and safety of pegfilgrastim administered once/chemotherapy cycle have been evaluated in clinical trials involving patients treated with myelosuppressive chemotherapy for breast cancer, lung cancer, non‐Hodgkin's lymphoma, and Hodgkin's disease. Two pivotal phase III trials in patients with breast cancer showed that pegfilgrastim is as effective as filgrastim regarding the primary efficacy end point, which was duration of grade 4 (severe) neutropenia in cycle 1 of myelosuppressive chemotherapy. Secondary end points were the frequency of fever with neutropenia (febrile neutropenia), duration of neutropenia in cycles 2–4, depth of the absolute neutrophil count (ANC) nadir, and time to ANC recovery in cycles 1–4. Once/cycle pegfilgrastim 100 μg/kg or 6 mg was as safe and effective as daily filgrastim 5 μg/kg in reducing the frequency and duration of severe neutropenia. A trend toward a greater reduction in the overall frequency of febrile neutropenia with pegfilgrastim was observed. The availability of pegfilgrastim simplifies the use of prophylactic G‐CSF, with the potential to increase patient convenience and adherence in management of chemotherapy‐induced neutropenia.
Pegylation: Engineering Improved Biopharmaceuticals for Oncology
Authors: Molineux Graham
Published: May 2004

Pegylation, the technology of polyethylene glycol (PEG) conjugation, holds significant promise in maintaining effective plasma concentrations of systemically administered drugs that might otherwise be hampered in vivo by a number of factors, such as rapid elimination by the kidneys. Mobile, nontoxic PEG chains can be conjugated to biotherapeutics, increasing their hydrodynamic volume, which can in turn prolong their plasma retention time, increase their solubility, and shield antigenic determinants on the drug from detection by the immune system. Attaching PEG molecules for optimal pharmacokinetics without obstructing the active sites that are essential for drug efficacy is a major challenge in pegylation. Current pegylation technology uses linkerless conjugation methods to produce coupling without added toxicity or immunogenicity, and may keep the innate surface charge of the pegylated molecule intact. In addition to controlling the size and complexity of PEG molecules, the attachment site can be manipulated to avoid steric hindrance of the drug's active receptor‐recognition or substrate‐interaction site. A few pegylated drugs have been engineered to have an improved pharmacokinetic profile with preserved bioactivity. They often have prolonged steady plasma concentrations in vivo, thereby making a reduced number of doses possible. Other interesting effects have also emerged, such as the self‐regulating pharmacokinetics of pegfilgrastim, a pegylated version of the granulocyte colony‐stimulating factor filgrastim that is administered for management of chemotherapy‐induced neutropenia. The improved dosing schedule, with longer intervals between administrations of the pegylated agents, will improve compliance and quality of life in patients with chronic disease.
Pharmacokinetics of Pegfilgrastim
Authors: Zamboni William C.
Published: May 2004

Pegfilgrastim is a granulocyte colony‐stimulating factor (G‐CSF) with a long half‐life and sustained duration of action. Pegfilgrastim is created with pegylation technology, whereby a 20‐kD polyethylene glycol moiety is conjugated to filgrastim (recombinant human G‐CSF), resulting in a larger molecule. Consequently, its renal clearance by glomerular filtration is minimized, making neutrophil‐mediated clearance the predominant route of elimination. Preclinical animal data have shown that the clearance of pegfilgrastim depends on dosage and absolute neutrophil count, with pegfilgrastim having a longer circulating half‐life and more sustained duration of action than filgrastim. The biologic effect of pegfilgrastim is prolonged in a neutropenic setting because few mature neutrophils are available to mediate its elimination. Clinical trials have suggested that neutrophil‐mediated clearance of pegfilgrastim may be self‐regulating and may therefore be specific to each patient's hematopoietic recovery.
B
rueckner Doubles Method and its Application to Simple Systems
Authors: Vincent M. A.
Published: May 2004

The Brueckner doubles (BD) method is derived, and by the consideration of two applications of this theory, it is shown that the standard triple excitation correction (BD(T)) can considerably increase the accuracy of the wave function. This theoretical approach is then applied to simple nitrogen and oxygen species to assess its usefulness in determining molecular properties.
The Empirical Valence Bond (
EVB
) Method
Authors: Warshel Arieh , Florián Jan
Published: May 2004

The empirical valence bond (EVB) model is a powerful conceptual and practical tool for studies of reactions of complex systems, ranging from reactions of large molecules to chemical processes in solutions and in enzymes. This method that can be viewed as an extension of force‐field approaches to chemical reactivity is related here to other hybrid quantum mechanical/molecular mechanics (QM/MM) methods and to other approaches. The review starts by pointing out the relationship between the EVB and early VB concepts. It is noted that while the VB models were developed for studies of chemical bonding in small molecules, the EVB models have provided a general and uniform way of simulating chemical reactions in large molecules and molecules in any environment. The use of the EVB approach in modeling chemical reactions is reviewed, emphasizing the effectiveness of the method in studies of enzyme catalysis. The advantages of the EVB approach are also considered, pointing out the usefulness of the analytical form of this method and its crucial importance for molecular dynamics simulations and free energy calculations of processes in condensed phases. Finally, the current proliferation of the EVB approach and its emergence under different names is discussed, clarifying the relationship between the different EVB–type models.
Recent Advances in Relativistic Density Functional Methods
Authors: Liu Wenjian , Wang Fan , Li Lemin
Published: May 2004

Relativistic density functional theory has evolved into a powerful method for the electronic structure calculations of systems containing heavy elements. This article reviews the recent developments in this area but with the focus mainly on computational methodologies. The salient features of the Beijing Density Functional (BDF) program package are discussed. BDF is a code that can perform nonrelativistic and one‐, two‐, and four‐component relativistic density functional calculations on medium‐sized molecular systems with various functionals in most compact and yet sufficient basis set expansions. The necessity for merging the whole spectrum of the Hamiltonians into a single code is twofold: on the one hand, it facilitates
direct
and
systematic
comparisons between different Hamiltonians, and on the other hand, it facilitates the construction of hybrid relativistic and nonrelativistic methods for systems consisting of only a few heavy elements but many light ligands.
Rainfall parameterization in an off‐line chemical transport model
Authors: Giannakopoulos C. , Good P. , Law K. S. , Wang K.‐Y. , Akylas E. , Koussis A.
Published: May 2004

In this paper, techniques for the modelling of both large‐scale and convective precipitation in a three‐dimensional off‐line chemical transport model are proposed. Relatively simple formulations are proposed that will yield meaningful rainfall rates to be used for the wet deposition of chemical species without compromising the computational efficiency of the model. As the profiles of humidity and temperature obtained from available meteorological analyses are too stable to produce any rainfall, we destabilize them through advection. This technique has been tested here for the large‐scale rainfall only, but can also be applied to the convective rainfall to make it less spotty and improve the comparison with observations. For an off‐line model, TOMCAT seems to capture surprisingly well the global distribution pattern of the rainfall as witnessed by observational climatologies. It performs well in capturing the dry subtropical regions and the wet Asian monsoon season as well as the mitigation of rains in the tropics with the change of season. However, it underestimates precipitation in the continents in the summer and south of 30 °S all year round. These shortcomings could be improved if we apply the advection technique to the convective rainfall as well. In addition, we could obtain the surface precipitation totals from the meteorological analyses and subsequently scale these amounts vertically using our model‐derived grid point condensation rate. Copyright © 2004 Royal Meteorological Society
Oesophagocardioplasty for residual dysphagia following multiple pneumatic dilatations for achalasia
Authors: Caporale A , Cosenza U M , Galati G , Fiori E , Benvenuto E , Giuliani A
Published: May 2004

A novel approach to a difficult problem
Randomized clinical trial of laparoscopic versus open fundoplication for gastro-oesophageal reflux disease
Authors: Ackroyd R , Watson D I , Majeed A W , Troy G , Treacy P J , Stoddard C J
Published: May 2004

Background

The aim of this study was to compare laparoscopic and open Nissen fundoplication for gastro-oesophageal reflux disease in a randomized clinical trial.

Methods

Ninety-nine patients were randomized to either laparoscopic (52) or open (47) Nissen fundoplication. Patients with oesophageal dysmotility, those requiring a concurrent abdominal procedure and those who had undergone previous antireflux surgery were excluded. Independent assessment of dysphagia, heartburn and patients' satisfaction 1, 3, 6 and 12 months after surgery was performed using multiple standardized clinical grading systems. Objective measurement of oesophageal acid exposure and lower oesophageal sphincter pressure before and after surgery, and endoscopic assessment of postoperative anatomy, were performed.

Results

Operating time was longer in the laparoscopic group (median 82 versus 46 min). Postoperative pain, analgesic requirement, time to solid food intake, hospital stay and recovery time were reduced in the laparoscopic group. Perioperative outcomes, postoperative dysphagia, relief of heartburn and overall satisfaction were equally good at all follow-up intervals. Reduction in oesophageal acid exposure, increase in lower oesophageal sphincter tone and improvement in endoscopic appearances were the same for the two groups.

Conclusion

The laparoscopic approach to Nissen fundoplication improved early postoperative recovery, with an equally good outcome up to 12 months.
Major resection for chronic pancreatitis in patients with vascular involvement is associated with increased postoperative mortality
Authors: Alexakis N , Sutton R , Raraty M , Connor S , Ghaneh P , Hughes M L , Garvey C , Evans J C , Neoptolemos J P
Published: May 2004

Background

The aim was to evaluate the outcome of major resection for chronic pancreatitis in patients with and without vascular involvement.

Methods

Of 250 patients with severe chronic pancreatitis referred between 1996 and 2003, 112 underwent pancreatic resection. The outcome of 17 patients (15·2 per cent) who had major vascular involvement was compared with that of patients without vascular involvement.

Results

The 95 patients without vascular involvement had resections comprising Beger's operation (39 patients), Kausch–Whipple pancreatoduodenectomy (28), total pancreatectomy (25) and left pancreatectomy (three). Twenty-five major vessels were involved in the remaining 17 patients. One or more major veins were occluded and/or compressed producing generalized or segmental portal hypertension, and three patients also had major arterial involvement. Surgery in these patients comprised Beger's operation (eight), total pancreatectomy (five), Kausch–Whipple pancreatoduodenectomy (two) and left pancreatectomy (two). Perioperative mortality rates were significantly different between the groups (two of 95 versus three of 17 respectively; P = 0·024). There were similar and significant improvements in long-term outcomes in both groups.

Conclusion

Resection for severe chronic pancreatitis in patients with vascular complications is hazardous and is associated with an increased mortality rate. Vascular assessment should be included in the routine follow-up of patients with chronic pancreatitis, to enable early identification of those likely to develop vascular involvement and prompt surgical intervention.
Gemcitabine‐associated thrombotic microangiopathy
Authors: Humphreys Benjamin D. , Sharman Jeff P. , Henderson Joel M. , Clark Jeffrey W. , Marks Peter W. , Rennke Helmut G. , Zhu Andrew X. , Magee Colm C.
Published: May 2004

BACKGROUND

Gemcitabine‐associated thrombotic microangiopathy (TMA) is believed to be very rare, with an estimated incidence rate of 0.015%. Indications for gemcitabine are expanding, and comprehensive characterization of this complication is therefore important.

METHODS

The authors performed a retrospective chart review of all cases with gemcitabine‐associated TMA diagnosed at Partners Healthcare System (Boston, MA) between January 1997 and February 2002.

RESULTS

Nine patients with gemcitabine‐associated TMA were identified. Diagnosis was aided by clinical and laboratory features. Renal biopsy confirmed the diagnosis in two patients. The cumulative incidence of gemcitabine‐associated TMA was 0.31% (8 cases among 2586 patients) when only the 8 patients with TMA who were treated at clinics associated with the current study were considered (1 patient with a TMA syndrome was transferred from another institution). The median patient age was 53 years, and the median time to development of a TMA syndrome after the initiation of gemcitabine was 8 months (range, 3–18 months), with a cumulative dose ranging from 9 to 56 g/m2. New or exacerbated hypertension was a prominent feature in 7 of 9 patients and preceded the clinical diagnosis by 0.5–10 weeks. Treatment of TMA included discontinuation of gemcitabine, antihypertensive therapy, plasma exchange, and dialysis. Outcomes are known for all nine patients. Six patients remain alive, whereas three have died of disease progression. No patient died as a direct result of TMA, but two developed kidney failure requiring dialysis, and one developed chronic renal insufficiency.

CONCLUSIONS

In the current series, the largest single‐institution study to date, the incidence of gemcitabine‐associated TMA was higher than previously reported (0.31% vs. 0.015%). Seven of nine patients developed new or exacerbated hypertension, which could be a useful early identifier of patients with gemcitabine‐associated TMA syndromes. Cancer 2004. © 2004 American Cancer Society.
A phase I study of sequential administration of escalating doses of intravenous paclitaxel, oral topotecan, and fixed‐dose oral etoposide in patients with solid tumors
Authors: Rocha Lima Caio M. S. , Catapano Carlo V. , Pacheco Daniel , Sherman Carol A. , Oakhill Greg , Mushtaq Chaudhry , Freeman Kimberly D. , Green Mark R.
Published: May 2004

BACKGROUND

Based on preclinical findings and on the clinical antitumor efficacy of sequential paclitaxel/topotecan and topotecan/etoposide, the authors sought to define the maximum tolerated doses (MTDs) and dose‐limiting toxicities (DLTs) associated with a sequential combination of paclitaxel, topotecan, and etoposide in patients with solid tumors.

METHODS

The MTDs were determined through standard dose escalation in cohorts of three patients. Patients with refractory solid tumors and performance status ≤ 2 were treated with intravenous paclitaxel 50–110 mg/m2 (Day 1), oral topotecan 0.5–2.0 mg/m2 (Days 2–4), and oral etoposide 160 mg/m2 (Days 5–7) during every 21‐day cycle. For dose‐limiting neutropenia, granulocyte–colony‐stimulating factor (G‐CSF) was administered on Day 8 in subsequent cohorts. Blood samples were obtained before treatment during Cycle 1 (Days 1, 2, and 5) for topoisomerase I assessment.

RESULTS

Twenty‐eight patients received a combined total of 129 cycles. The MTDs were paclitaxel 80 mg/m2, topotecan 1.5 mg/m2, and etoposide 160 mg/m2 without G‐CSF. In minimally pretreated patients, G‐CSF allowed paclitaxel dose escalation to 110 mg/m2. Three patients (11%) had radiologic partial responses, and 4 patients (14%) had stable disease. Day 2 topoisomerase I levels increased by 2–15 times relative to baseline levels in 7 of 14 patients analyzed (50%).

CONCLUSIONS

The novel sequential combination that was evaluated generally was well tolerated and active in patients with refractory solid tumors. Based on hematologic DLTs, the authors recommend further evaluation of paclitaxel 110 mg/m2, topotecan 1.5 mg/m2, and etoposide 160 mg/m2 with G‐CSF support in minimally pretreated patients. Cancer 2004. © 2004 American Cancer Society.
Dynamic deactivation for advection‐dominated contaminant transport
Authors: Löhner Rainald , Camelli Fernando
Published: May 2004

A simple dynamic deactivation procedure for advection‐dominated contaminant transport is presented. The key idea is to avoid any work in regions where the solution cannot change, i.e. where sources vanish and unknowns do not exhibit any spatial change. Saving factors in CPU of 1: 3–1: 10 are commonly achieved. The procedure is general and simple to implement, and should be applicable to a large number of codes and transport problems. Copyright © 2004 John Wiley & Sons, Ltd.
Photophysical Aspects of Single‐Molecule Detection by Two‐Photon Excitation with Consideration of Sequential Pulsed Illumination
Authors: Niesner R. , Roth W. , Gericke Karl‐Heinz
Published: May 2004

An important goal in single molecule fluorescence correlation spectroscopy is the theoretical simulation of the fluorescence signal stemming from individual molecules and its autocorrelation function. The simulation approaches developed up to now are based exclusively on continuous‐wave (cw) illumination and consequently on cw‐excitation. However, this approximation is no longer valid in the case of two‐photon excitation, for which pulsed illumination is usually employed. We present a novel theoretical model for the simulation of the fluorescence signal of single molecules and its autocorrelation function with consideration of the time dependence of the excitation flux and thus of all illumination‐dependent photoprocesses: two‐photon excitation, induced emission and photobleaching. Further important characteristics of our approach are the consideration of the dependence of the photobleaching rate on illumination and the low intersystem‐crossing rates of the studied coumarins. Moreover, using our approach, we can predict quantitatively the effect of the laser pulse width on the fluorescence signal of a molecule, that is, the contributions of the photobleaching and saturation effects, and thus we can calculate the optimal laser pulse width. The theoretical autocorrelation functions were fitted to the experimental data, and we could ascertain a good agreement between the resulting and the expected parameters. The most important parameter is the photobleaching constant σ, the cross section of the transition Sn←S1, which characterises the photostability of the molecules independent of the experimental conditions. Its value is 1.7×10−23 cm2 for coumarin 153 and 5×10−23 cm2 for coumarin 314.
Dissolution of Crystallites: Surface Energetic Control and Size Effects
Authors: Tang Ruikang , Orme Christine A. , Nancollas George H.
Published: May 2004

Traditional understanding of dissolution assumes that the reaction is spontaneous and continues until equilibrium is reached. This paper presents theoretical and experimental data to support a dissolution mechanism that involves the existence of critical conditions for dissolution, in which the reaction is accompanied by the formation of pits and the subsequent displacement of pit steps. The accompanying increase in surface roughness leads to changes in surface energy with losses of crystal mass that are positive rather than negative and the existence of critical dissolution conditions. Critical pits and dissolution steps are verified experimentally and a relationship between the size and rate of displacement of steps is also demonstrated, in which the rate decreases with size and approaches zero at a critical size, r*. These microscopic step dynamics are consistent with the observed size‐effects in bulk dissolution, which cannot be explained using traditional dissolution theories. The observed size effects include self‐inhibition, in which the dissolution rate decreases with extent of reaction, dissolution suppression, and periodic resumption. These interesting dissolution phenomena are only readily displayed when the sizes of dissolving crystallites fall in the same range as the critical size (i.e., within 50r*). It is interesting to note that natural biominerals and many nanoparticles fall into this category, so that their suspensions can be dynamically stabilized without dissolution in undersaturated supporting media. The current research implies that dissolution kinetics cannot be understood well without appealing to fundamental physical concepts about the energetic control of dissolution steps on a molecular level. A new dissolution model for crystallites is introduced systemically.
Comparison of Properties of Aib‐Rich Peptides in Crystal and Solution: A Molecular Dynamics Study
Authors: Yu Haibo , Ramseier Maaike , Bürgi Roland , van Gunsteren Wilfred F.
Published: May 2004

In order to study the differences of the structural properties of Aib‐rich peptides in solution and in the crystalline state, molecular dynamics (MD) simulations of the Aib‐containing peptide II (pBrBz‐(Aib)5‐Leu‐(Aib)2‐OMe) were performed in the crystalline state, starting from two different conformers obtained experimentally by X‐ray diffraction. The structural properties as derived from X‐ray crystallography (e.g., torsional angles and hydrogen bonds) are well‐reproduced in both constant‐volume and constant‐pressure simulations, although the force‐field parameters used result in a too‐high density of the crystals. Through comparison with the results from previous MD and nuclear magnetic resonance (NMR) studies of the very similar peptide I (Z‐(Aib)5‐Leu‐(Aib)2‐OMe) in dimethylsulfoxide (DMSO) solution, it is found that, in the crystal simulation, the conformational distribution of peptide II is much narrower than that in the solution simulation of peptide I. This leads to a significant difference in 3J(HN, HCα) coupling constant values, in agreement with experimental data, whereas the NOE intensities or proton–proton distance bounds appear insensitive to the difference in conformational distribution. For small peptides the differences between their conformational distribution in the crystalline form and in solution may be much larger than for proteins, a fact which should be kept in mind when interpretating molecular properties in the solution state by using X‐ray crystallographic data.
Quantum Dynamics of Gas‐Phase SN2 Reactions
Authors: Schmatz Stefan
Published: May 2004

Understanding the state‐resolved dynamics of elementary chemical reactions involving polyatomic molecules, such as the well‐known reaction mechanism of nucleophilic bimolecular substitution (SN2), is one of the principal goals in chemistry. In this Review, the progress in the quantum mechanical treatment of SN2 reactions in the gas phase is reviewed. The potential energy profile of this class of reactions is characterized by two relatively deep wells, which correspond to pre‐ and post‐reaction charge–dipole complexes. As a consequence, the complex‐forming reaction is dominated by Feshbach resonances. Calculations in the energetic continuum constitute a major challenge because the high density of resonance states imposes considerable requirements on the convergence and the energetic resolution of the scattering data. However, the effort is rewarding because new insights into the details of multimode quantum dynamics of elementary chemical reactions can be obtained.
Electronic Structure and Chemical Reactivity of Carbon Nanotubes: A Chemist's View
Authors: Joselevich Ernesto
Published: May 2004

A qualitative description of the electronic structure of single‐wall carbon nanotubes from a chemical perspective is presented using real‐space orbital representations and traditional concepts of aromaticity, orbital symmetry and frontier orbitals. This unusual view of carbon nanotubes allows us to merge the solid‐state physics description of band structures with the molecular orbitals framework of reaction mechanisms used in organic chemistry and to predict intriguing chemical selectivity based on electronic structure.
Kinetics and Mechanism of the C6H5 + CH3CHO Reaction: Experimental Measurement and Theoretical Prediction of the Reactivity toward Four Molecular Sites
Authors: Choi Y. M. , Park J. , Lin M. C.
Published: May 2004

The kinetics and mechanism of the reaction of C6H5 with CH3CHO have been investigated experimentally and theoretically. The total rate constant for the reaction has been measured by means of the cavity ring‐down spectrometry (CRDS) in the temperature range 299–501 K at pressures covering 20–75 Torr. The overall bimolecular rate constant can be represented by the expression k=(2.8±0.2)×1011 exp[−(700±30)/T] cm3 mol−1 s−1, which is slightly faster than for the analogous C6H5+CH2O reaction determined with the same method in the same temperature range. The reaction mechanism for the C6H5+CH3CHO reaction was also explored with quantum‐chemical calculations at various hybrid density functional theories (DFTs) and using ab initio high‐level composite methods. The theories predict that the reaction may occur by two hydrogen‐abstraction and two addition channels with the aldehydic hydrogen‐abstraction reaction being dominant. The rate constant calculated by the transition state theory for the aldehydic hydrogen‐abstraction reaction is in good agreement with the experimental result after a very small adjustment of the predicted reaction barrier (+0.3 kcal mol−1). Contributions from other product channels are negligible under our experimental conditions. For combustion applications, we have calculated the rate constants for key product channels in the temperature range of 298–2500 K under atmospheric‐pressure conditions; they can be represented by the following expressions in units of cm3 mol−1 s−1: k1,cho=8.8×103 T2.6 exp(−90/T), k2,ch3=6.0×101 T3.3 exp(−950/T), k3a(C6H5COCH3+H)=4.2×105 T0.6 exp(−410/T) and k3b(C6H5CHO+CH3)=6.6×109 T−0.5 exp(−310/T).
Ultrafast Proton‐Coupled Electron‐Transfer Dynamics in Pyrene‐Modified Pyrimidine Nucleosides: Model Studies towards an Understanding of Reductive Electron Transport in DNA
Authors: Raytchev Milen , Mayer Elke , Amann Nicole , Wagenknecht Hans‐Achim , Fiebig Torsten
Published: May 2004

5‐(Pyren‐1‐yl)‐2′‐deoxyuridine (PydU) and 5‐(Pyren‐1‐yl)‐2′‐deoxycytidine (PydC) were used as model nucleosides for DNA‐mediated reductive electron transport (ET) in steady‐state fluorescence and femtosecond time‐resolved transient absorption spectroscopy studies. Excitation of the pyrene moiety in PydU and PydC leads to an intramolecular electron transfer that yields the pyrenyl radical cation and the corresponding pyrimidine radical anion (dU.− and dC.−. By comparing the excited state dynamics of PydC and PydU, we derived information about the energy difference between the two pyrimidine radical anion states. To determine the influence of protonation on the rates of photoinduced intramolecular ET, the spectroscopic investigations were performed in acetonitrile, MeCN, and in water at different pH values. The results show a significant difference in the basicity of the generated pyrimidine radical anions and imply an involvement of proton transfer during electron hopping in DNA. Our studies revealed that the radical anion dC.− is being protonated even in basic aqueous solution on a picosecond time scale (or faster). These results suggest that protonation of dC.− may also occur in DNA. In contrast, efficient ET in PydU could only be observed at low pH values (<5). In conclusion, we propose—based on the free energy differences and the different basicities—that only dT.− but not dC.− can participate as an intermediate charge carrier for excess electron migration in DNA.
Cover Picture: Molecular Beams and Model Catalysis: Activity and Selectivity of Specific Reaction Centers on Supported Nanoparticles (ChemPhysChem 5/2004)
Authors: Libuda Jörg
Published: May 2004

The cover picture shows time‐resolved surface IR spectra (top) acquired during a molecular beam experiment on a supported model catalyst (bottom). Using this approach, the microscopic role of different types of sites simultaneously present on a catalyst surface can be probed during a catalytic reaction. Moreover, detailed information on the activities and selectivities of specific reactive centers on the well‐defined nanocrystallites of the catalyst can be obtained. Find out more in the Concept by Libuda on p. 625.
Electronic gel protein transfer and identification using matrix‐assisted laser desorption/ionization‐mass spectrometry
Authors: Cooper Jonathan W. , Gao Jun , Lee Cheng S.
Published: May 2004

An electronic protein transfer technique is described for achieving the rapid and efficient recovery of sodium dodecyl sulfate (SDS)‐protein complexes from polyacrylamide gels. This process involves the use of small‐dimension capillaries in physical contact with a resolved protein band within the polyacrylamide gel, providing a large potential drop and high electric field strength at the capillary/gel interface. Several factors controlling the electronic protein transfer, including the applied electric field strength, the electrophoresis buffer concentration, and the capillary dimension, are studied to further enhance the use of field‐amplification for sample stacking of extracted SDS‐protein complexes. As a result of sample stacking, the extracted proteins from a 50 ng gel loading are present in a narrow (∼80 nL) and highly concentrated (0.46 mg/mL or 3.3×10−5 M for cytochrome c) solution plug. Three model proteins with molecular mass ranging from 14 kDa (cytochrome c) to 116 kDa (β‐galactosidase) are stained by Coomassie blue and electrophoretically extracted from gels with protein loadings as low as 50 ng. The capillary format of the electronic protein transfer technique allows direct deposition of extracted proteins onto a matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) target. Various matrices and solvent compositions are evaluated for the analysis of extracted and concentrated SDS‐protein complexes using MALDI‐MS. The electronic protein transfer technique, when operated under optimized conditions, is demonstrated for the effective (>70% recovery), speedy (less than 5 min), and sensitive MS identification of gel resolved proteins (as low as 50 ng).
Analysis of the sinusitis nasal lavage fluid proteome using capillary liquid chromatography interfaced to electrospray ionization‐quadrupole time of flight‐ tandem mass spectrometry
Authors: Casado Begona , Pannell Lewis K. , Viglio Simona , Iadarola Paolo , Baraniuk James N.
Published: May 2004

The nasal lavage fluids (NLFs) from four subjects with acute sinusitis were analyzed to investigate the amount of proteins expressed in this pathology at the beginning of the event (day 1) and after 6 days of treatment with antibiotics and a nasal steroid spray. The protein identification was performed with capillary liquid chromatography‐electrospray‐quadrupole time of flight‐(LC‐ESI‐Q‐TOF)‐mass spectrometry. The samples collected on the first day contained high‐abundant plasma proteins, such as albumin and immunoglobulins, glandular serous cell proteins (lysozyme, lactoferrin, and polymeric immunoglobulin receptor), epithelial keratins, and inflammatory cell proteins (myeloperoxidase, IL‐16, and IL‐17E). After six days of therapy, the complexity of the proteome was reduced to plasma proteins and lysozyme with no inflammatory markers. The presence of hemoglobin, however, suggested that significant squamous metaplasia with breaches in the epithelial barrier, or nasal steroid‐related bleeding, had occurred. The proteomic approach presented here allowed us to identify, in the high complexity of acute sinusitis nasal secretions, the proteins that respond to a pharmacological treatment and that could be suitable as markers of this pathology.
Chiral cyclodextrin‐modified microemulsion electrokinetic chromatography
Authors: Mertzman Melissa D. , Foley Joe P.
Published: May 2004

Cyclodextrin (CD)‐modified microemulsion electrokinetic chromatography (MEEKC) or CD‐MEEKC has not previously been applied to the area of chiral separations. Herein, the results of investigations of various microemulsions with CD additives are presented. Two different microemulsions are explored: an ethyl acetate sodium dodecyl sulfate microemulsion, and a chiral dodecoxycarbonylvaline (DDCV) microemulsion. Each microemulsion is paired separately with a neutral CD (hydroxypropyl‐β‐CD) and an anionic CD (sulfated‐β‐CD). In addition, the chiral DDCV microemulsion is investigated in both the R‐ and S‐ form. By varying simple parameters such as buffer system, applied voltage, surfactant enantiomer, and type of cyclodextrin, dramatic improvements in the chiral separations were noted. Resolution was found to be highly dependent on buffer identity and concentration, and somewhat dependent on whether the CDs used were randomly or highly sulfated. Under optimized conditions, the resolution ranged from 0.8 to 4.8, with plate counts ranging from 4000 to 26 000. Additionally, S‐ and R‐levetiracetam, which had never before been enantioseparated via capillary electrophoresis (CE) methodologies, were separated in less than 8 min, with a resolution of 1.1.
Capillary electrophoresis of cationic random coil peptide standards: Effect of anionic ion‐pairing reagents and comparison with reversed‐phase chromatography
Authors: Popa Traian V. , Mant Colin T. , Hodges Robert S.
Published: May 2004

The present study compares a charge/hydrophobicity capillary electrophoresis (CE) approach to reversed‐phase high‐performance liquid chromatography (RP‐HPLC) for the separation of three series of four synthetic, random coil peptide standards. Each series has peptides of the same positive charge (+1, +2 and +3 series) and length but differing in hydrophobicity. Complete resolution of the 12 peptides was achieved via a novel CE approach: a capillary zone electrophoresis (CZE) mode effected a separation of identically charged peptides; within each charged group of peptides, the addition of perfluorinated acid anionic ion‐pairing reagents allowed resolution of the peptides through a mechanism based on peptide hydrophobicity which we have termed ioninteraction (II)‐CZE. The peak capacity and peptide resolution of this CE approach was superior to that of RP‐HPLC and stresses an important role for CE for peptide/proteomic applications.
Single‐isomer sulfated α‐cyclodextrins for capillary electrophoresis. Part 2. Hexakis(6‐O‐sulfo)‐α‐cyclodextrin: Synthesis, analytical characterization, and initial screening tests
Authors: Li Shulan , Vigh Gyula
Published: May 2004

The second member of the family of single‐isomer sulfated α‐cyclodextrins, the sodium salt of hexakis(6‐O‐sulfo)‐α‐cyclodextrin (HxS), has been synthesized, analytically characterized, and used as the resolving agent for the capillary electrophoretic separation of the enantiomers of nonionic, weak‐acid and weak‐base analytes present in our initial screening kit. HxS interacted less strongly with many of the analytes tested than the larger‐ring analogs, heptakis(6‐O‐sulfo)‐β‐cyclodextrin (HS) and octakis(6‐O‐sulfo)‐γ‐cyclodextrin (OS). For some of the analytes, the separation selectivities obtained with HxS were complementary to those observed with hexakis(2,3‐di‐O‐acetyl‐6‐O‐sulfo)‐α‐cyclodextrin (HxDAS), HS, and OS. For all analytes, the effective mobilities and separation selectivities as a function of the background electrolyte concentration of HxS followed the trends that were found for HxDAS, HS, and OS.
Determination of dissociation constants for a heparin‐binding domain of amyloid precursor protein and heparins or heparan sulfate by affinity capillary electrophoresis
Authors: McKeon Jocelyn , Holland Lisa A.
Published: May 2004

Dynamic affinity capillary electrophoresis (ACE) was used for determining the binding constants between heparin‐like glycosaminoglycans and the (96–110) heparin‐binding domain of amyloid precursor protein (APP). The migration time shift of the (96–110) APP peptide was monitored as the concentration of heparin was increased in the background electrolyte. The compounds investigated included low‐molecular‐weight heparin, porcine mucosa heparin, and heparan sulfate. Change in mobility as a function of glycosaminoglycan concentration was plotted using both linear regression (Scatchard analysis) and nonlinear regression. Dissociation constants (Kd) were determined and compared for both sets of analyses with the low‐molecular‐weight heparin giving the most reproducible results and best fit with a Kd value of 3.9 μM.