bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimized Damping Device Configuration Design of a Steel Frame Structure Based on Building Performance Indices
Authors: Liu Wei , Tong Mai , Wu Yihui , Lee George C.
Published: March 2004

Energy dissipation devices (EDDs) have been accepted as one of the viable strategies for enhancing the seismic performance of building structures. However, the current design provisions do not provide guidelines for optimizing the EDD configurations on structures. For many building structures an efficient configuration of EDDs may provide considerable performance improvement. Similarly, an optimized configuration may reduce the number of EDDs required to achieve a target performance objective. In this paper an existing building with added linear viscous dampers is redesigned based on different performance index optimization. The results indicate that the optimal device configurations are highly related to the dynamic properties of the structure and its required performance index. In one instance, where the cost is the major concern and a performance requirement is placed on story drift limitation, the total device damping coefficient can be reduced by 26%.
Probabilistic Benefit-Cost Analysis for Earthquake Damage Mitigation: Evaluating Measures for Apartment Houses in Turkey
Authors: Smyth Andrew W. , Altay Gülay , Deodatis George , Erdik Mustafa , Franco Guillermo , Gülkan Polat , Kunreuther Howard , Luş Hilmi , Mete Esra , Seeber Nano , Yüzügüllü özal
Published: March 2004

In the wake of the 1999 earthquake destruction in Turkey, the urgent need has arisen to evaluate the benefits of loss mitigation measures that could be undertaken to strengthen the existing housing stock. In this study, a benefit-cost analysis methodology is introduced for the comparative evaluation of several seismic retrofitting measures applied to a representative apartment building located in Istanbul. The analysis is performed probabilistically through the development of fragility curves of the structure in its different retrofitted configurations. By incorporating the probabilistic seismic hazard for the region, expected direct losses can be estimated for arbitrary time horizons. By establishing realistic cost estimates of the retrofitting schemes and costs of direct losses, one can then estimate the net present value of the various retrofitting measures. The analysis in this work implies that, even when considering only direct losses, all of the retrofitting measures considered are desirable for all but the very shortest time horizons. This conclusion is valid for a wide range of estimates regarding costs of mitigation, discount rates, number of fatalities, and cost of human life. The general methodology developed here for a single building can be extended to an entire region by incorporating additional structural types, soil types, retrofitting measures, more precise space- and time-dependent seismic hazard estimates, etc. It is hoped that this work can serve as a benchmark for more realistic and systematic benefit-cost analyses for earthquake damage mitigation.
Using High-Resolution Satellite Images for Post-Earthquake Building Damage Assessment: A Study following the 26 January 2001 Gujarat Earthquake
Authors: Saito Keiko , Spence Robin J. S. , Going Christopher , Markus Michael
Published: March 2004

Newly available optical satellite images with 1-m ground resolution such as IKONOS mean that rapid postdisaster damage assessment might be made over large areas. Such surveys could be of great value to emergency management and post-event recovery operations and have particular promise for earthquake areas, where damage distribution is often very uneven. In this paper three satellite images taken before and after the 26 January 2001 Gujarat earthquake were studied for damage assessment purposes. The images comprised a post-earthquake cover of the city of Bhuj, which was close to the epicenter, and pre- and post-earthquake cover of the city Ahmedabad. The assessment data was then compared with damage surveys actually made on-site. Three separate experiments were conducted. In the first, the satellite image of Bhuj was compared with detailed ground photos of 28 severely damaged buildings taken at about the same time as the satellite image, to investigate the levels and types of damage that can and cannot be identified. In the second experiment, the whole city center of Bhuj was damage mapped using only the satellite image. This was subsequently compared with a map produced from a building-by-building damage survey. In the third experiment, pre- and post-earthquake images for a large area of Ahmedabad were compared and totally collapsed buildings were identified. These sites were subsequently visited to confirm the accuracy of the observations. The experiment results indicate that rapid visual screening can identify areas of heavy damage and individual collapsed buildings, even when comparative cover does not exist. The need to develop a tool with direct application to support emergency response is discussed.
Management of Infertility in a Patient Presenting with Ovarian Dysfunction and McCune-Albright Syndrome
Authors: Laven Joop S. E. , Lumbroso Serge , Sultan Charles , Fauser Bart C. J. M.
Published: March 2004

Persistent autonomous ovarian dysfunction in McCune-Albright syndrome (MAS) patients is associated with the development of multiple dominant follicles, premature luteinization, cyst formation, and anovulatory infertility. Due to the mosaic distribution of the mutation, ovaries may be unequally affected. In the current patient, the least affected ovary became quiescent upon GnRH agonist-induced gonadotropin suppression. Normoovulatory cycles were restored after subsequent removal of the affected right ovary, and a pregnancy was established within 3 months. A healthy unaffected girl was born at term after an uneventful pregnancy. The placental tissue was normal, and the mutation was not detected in the placenta, umbilical cord structures, or umbilical cord blood. GnRH analog administration may help to identify those MAS patients who might benefit from unilateral ovariectomy. Because a healthy baby was born, evidence is provided suggesting that MAS is not passed on to the children from the parents.
The Relationship between Obesity and Serum 1,25-Dihydroxy Vitamin D Concentrations in Healthy Adults
Authors: Parikh Shamik J. , Edelman Marni , Uwaifo Gabriel I. , Freedman Renee J. , Semega-Janneh Mariama , Reynolds James , Yanovski Jack A.
Published: March 2004

Several previous reports of small cohorts have found significantly higher serum 1,25-dihydroxy vitamin D (1,25-vit D) in obese compared with nonobese whites. Based on these reports and on recent in vitro studies of adipocytes which suggest that administration of 1,25-vit D can stimulate lipogenesis and inhibit lipolysis, some investigators have proposed that high 1,25-vit D may play a role in promoting or maintaining adipocyte triglyceride stores in obese adults. To test the hypothesis that obesity is commonly associated with increased 1,25-vit D, we examined the relationships between calciotropic hormones and body adiposity in a large cohort of healthy adults. Serum intact PTH, 25-hydroxy vitamin D, and 1,25-vit D were measured in the postabsorptive state in 302 healthy adults who were Caucasian (n = 190; 71% female), African-American (n = 84; 89% female), and of other race/ethnicity (n = 28; 61% female). Results from the 154 obese subjects [body mass index (BMI) 37.3 ± 5.8 kg/m2; range, 30.1–58.2 kg/m2] were compared with those from 148 nonobese (BMI 25.6 ± 2.9 kg/m2; range, 18.0–29.9 kg/m2) age-, race-, and sex-matched participants. Body composition was measured by dual energy x-ray absorptiometry. Serum intact PTH was positively correlated with both BMI (r = 0.42; P < 0.0001) and body fat mass (r = 0.37; P < 0.0001). Serum 25-hydroxy vitamin D was negatively correlated with BMI (r = −0.4; P < 0.0001) and body fat mass (r = −0.41; P < 0.0001). Serum 1,25-vit D was also negatively correlated with BMI (r = −0.26; P < 0.0001) and body fat mass (r = −0.25; P = 0.0001). Serum 1,25-vit D was significantly lower in obese than nonobese subjects (105.7 ± 41.1 vs. 124.8 ± 36.7 pmol/liter; P < 0.0001) in both Caucasian and African-American adults. We conclude that, because 1,25-vit D concentrations fall with increasing adiposity, it appears unlikely that elevation in 1,25-vit D is an important hormonal mechanism causing or maintaining obesity in adults.
Physiological Induction of Transient Receptor Potential Canonical Proteins, Calcium Entry Channels, in Human Myometrium: Influence of Pregnancy, Labor, and Interleukin-1β
Authors: Dalrymple A. , Slater D. M. , Poston L. , Tribe R. M.
Published: March 2004

This study investigated gestational regulation of transient receptor potential canonical (TrpC) proteins, putative calcium entry channels in human myometrium, and the potential modulation of TrpC expression by IL–1β, a cytokine implicated in labor. Total RNA and proteins were isolated from myometrial biopsies obtained from NP women, pregnant women at term not in labor (TNL), or term active labor (TAL) and from primary cultured human myometrial smooth muscle cells incubated with IL–1β or IL–1β with or without nimesulide. Semiquantitative RT-PCR demonstrated significant up-regulation of TrpC1 in TAL and TNL (P ≤ 0.01) and TrpC6 (P ≤ 0.01) and TrpC7 (P ≤ 0.05) in TAL samples. TrpC3 and TrpC4 mRNA expression was unaffected. Western blot demonstrated significant up-regulation of TrpC1 in TAL and TNL (P ≤ 0.05) and TrpC3 (P ≤ 0.01), TrpC4 (P ≤ 0.05), and TrpC6 (P ≤ 0.01) in TAL samples. IL–1β did not alter TrpC1, 3, 4, 6, or 7 mRNA expression; but IL–1β exclusively up-regulated TrpC3 protein expression (P ≤ 0.05). TrpC3 up-regulation was unaffected by cyclooxygenase blockade. These data demonstrate physiological regulation of TrpC mRNA and protein and suggest an important role for TrpC proteins in human myometrium during labor.
Adipose Tissue Adiponectin Production and Adiponectin Serum Concentration in Human Obesity and Insulin Resistance
Authors: Hoffstedt Johan , Arvidsson Elisabet , Sjölin Eva , Wåhlén Kerstin , Arner Peter
Published: March 2004

The role of adiponectin production for the circulating protein concentration in human obesity and insulin resistance is unclear. We measured serum concentration and sc adipose tissue secretion rate of adiponectin in 77 obese and 23 nonobese women with a varying degree of insulin sensitivity. The serum adiponectin concentration was similar in both groups. In obesity, adiponectin adipose tissue secretion rate per weight unit was reduced by 30% (P = 0.01), whereas total body fat secretion rate was increased by 100% (P < 0.0001). In the group being most insulin resistant (1/3), serum concentration (P < 0.001) and adipose tissue secretion rate per tissue weight (P < 0.05) were reduced, whereas total body fat secretion rate was increased (P < 0.01), by about 30%. The adipose tissue secretion rate of adiponectin was related to the serum concentration (P = 0.005) but explained only about 10% of the interindividual variation in circulating adiponectin and insulin sensitivity. The plasma adiponectin half life was long, 2.5 h. In conclusion, the role of protein secretion for the circulating concentration of adiponectin and insulin sensitivity under these conditions is minor because adiponectin turnover rate is slow. Although increased in obesity and insulin resistance, total body production of adiponectin is insufficient to raise the circulating concentration, may be due to reduced secretion rate per tissue unit.
Effects of Aromatase Inhibition in Elderly Men with Low or Borderline-Low Serum Testosterone Levels
Authors: Leder Benjamin Z. , Rohrer Jacqueline L. , Rubin Stephen D. , Gallo Jose , Longcope Christopher
Published: March 2004

As men age, serum testosterone levels decrease, a factor that may contribute to some aspects of age-related physiological deterioration. Although androgen replacement has been shown to have beneficial effects in frankly hypogonadal men, its use in elderly men with borderline hypogonadism is controversial. Furthermore, current testosterone replacement methods have important limitations.

We investigated the ability of the orally administered aromatase inhibitor, anastrozole, to increase endogenous testosterone production in 37 elderly men (aged 62–74 yr) with screening serum testosterone levels less than 350 ng/dl. Subjects were randomized in a double-blind fashion to the following 12-wk oral regimens: group 1: anastrozole 1 mg daily (n = 12); group 2: anastrozole 1 mg twice weekly (n = 11); and group 3: placebo daily (n = 14). Hormone levels, quality of life (MOS Short-Form Health Survey), sexual function (International Index of Erectile Function), benign prostate hyperplasia severity (American Urological Association Symptom Index Score), prostate-specific antigen, and measures of safety were compared among groups.

Mean ± sd bioavailable testosterone increased from 99 ± 31 to 207 ± 65 ng/dl in group 1 and from 115 ± 37 to 178 ± 55 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.054 group 1 vs. group 2). Total testosterone levels increased from 343 ± 61 to 572 ± 139 ng/dl in group 1 and from 397 ± 106 to 520 ± 91 ng/dl in group 2 (P < 0.001 vs. placebo for both groups and P = 0.012 group 1 vs. group 2). Serum estradiol levels decreased from 26 ± 8 to 17 ± 6 pg/ml in group 1 and from 27 ± 8 to 17 ± 5 pg/ml in group 2 (P < 0.001 vs. placebo for both groups and P = NS group 1 vs. group 2). Serum LH levels increased from 5.1 ± 4.8 to 7.9 ± 6.5 U/liter and from 4.1 ± 1.6 to 7.2 ± 2.8 U/liter in groups 1 and 2, respectively (P = 0.007 group 1 vs. placebo, P = 0.003 group 2 vs. placebo, and P = NS group 1 vs. group 2). Scores for hematocrit, MOS Short-Form Health Survey, International Index of Erectile Function, and American Urological Association Symptom Index Score did not change. Serum prostate-specific antigen levels increased in group 2 only (1.7 ± 1.0 to 2.2 ± 1.5 ng/ml, P = 0.031, compared with placebo).

These data demonstrate that aromatase inhibition increases serum bioavailable and total testosterone levels to the youthful normal range in older men with mild hypogonadism. Serum estradiol levels decrease modestly but remain within the normal male range. The physiological consequences of these changes remain to be determined.
BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms
Authors: Xing M. , Vasko V. , Tallini G. , Larin A. , Wu Gujun , Udelsman R. , Ringel M. D. , Ladenson P. W. , Sidransky D.
Published: March 2004

A high prevalence of activating mutation of the B type Raf kinase (BRAF) gene was recently reported in papillary thyroid cancer (PTC). However, the frequency of this mutation in several other types of thyroid neoplasms was not thoroughly investigated. In the present study, in addition to PTC, we evaluated various thyroid tumor types for the most common BRAF T1796A mutation by direct genomic DNA sequencing. We found a high and similar frequency (45%) of the BRAF T1796A mutation in two geographically distinct PTC patient populations: one composed of sporadic cases from North America, and the other from Kiev, Ukraine, that included individuals who were exposed to the Chernobyl nuclear accident. In contrast, we found BRAF mutation in only 20% of anaplastic thyroid cancers and no mutation in medullary thyroid cancers and benign thyroid hyperplasia. We also confirmed previous reports that the BRAF T1796A mutation did not occur in benign thyroid adenomas and follicular thyroid cancers. Specific analysis of the Ukraine patients with confirmed history of radiation exposure failed to show a higher incidence of BRAF mutation. Our results suggest that frequent occurrence of BRAF mutation is inherently associated with PTC, irrespective of geographic origin, and is apparently not a radiation-susceptible mutation. The lack or low prevalence of BRAF mutation in other thyroid neoplasms is consistent with the notion that other previously defined genetic alterations on the same signaling pathway are sufficient to cause tumorigenesis in most thyroid neoplasms.
Validation of Insulin Sensitivity Indices from Oral Glucose Tolerance Test Parameters in Obese Children and Adolescents
Authors: Yeckel Catherine W. , Weiss Ram , Dziura James , Taksali Sara E. , Dufour Sylvie , Burgert Tania S. , Tamborlane William V. , Caprio Sonia
Published: March 2004

Given the extreme increase in prediabetes, type 2 diabetes, and the potential for metabolic syndrome in obese youth, identifying simplified indexes for assessing stimulated insulin sensitivity is critical. The purpose of this study was validation of two surrogate indexes of insulin sensitivity determined from the oral glucose tolerance test (OGTT): the composite whole body insulin sensitivity index (WBISI) and the insulin sensitivity index (ISI). An obese population (aged 8–18 yr) of normal and impaired glucose tolerance individuals was studied. One group (n = 38) performed both the euglycemic-hyperinsulinemic clamp and OGTT for comparison of insulin sensitivity measurements as well as 1H-magnetic resonance spectroscopy estimates of intramyocellular lipid content. Another larger (n = 368) cohort participated only in an OGTT. Both the WBISI and ISI represented good estimates (r = 0.78 and 0.74; P < 0.0005) for clamp-derived insulin sensitivity (glucose disposed, M-value), respectively. In the large cohort, the surrogate indexes demonstrated the shift toward poorer function and increased risk profile as a function of insulin resistance. Additionally, the WBISI and ISI correlated with intramyocellular lipid content (r = −0.74 and −0.71; P < 0.0001), a tissue marker for insulin resistance. Insulin sensitivity can be estimated using plasma glucose and insulin responses derived from the OGTT in obese youth with normal and impaired glucose tolerance.
Effects of the Peroxisomal Proliferator-Activated Receptor-γ Agonist Pioglitazone on Renal and Hormonal Responses to Salt in Healthy Men
Authors: Zanchi Anne , Chiolero Arnaud , Maillard Marc , Nussberger Jürg , Brunner Hans-Rudolf , Burnier Michel
Published: March 2004

Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.
Gastric Bypass Surgery for Morbid Obesity Leads to an Increase in Bone Turnover and a Decrease in Bone Mass
Authors: Coates Penelope S. , Fernstrom John D. , Fernstrom Madelyn H. , Schauer Philip R. , Greenspan Susan L.
Published: March 2004

Little is known about the effects on the skeleton of laparoscopic Roux-en-Y gastric bypass (LRGB) surgery for morbid obesity and subsequent weight loss. We compared 25 patients who had undergone LRGB 11 ± 3 months previously with 30 obese controls matched for age, gender, and menopausal status. Compared with obese controls, patients post LRGB had significantly lower weight (92 ± 16 vs. 133 ± 20 kg; P < 0.001) and body mass index (31 ± 5 vs. 48 ± 7 kg/m2; P < 0.001). Markers of bone turnover were significantly elevated in patients post LRGB compared with controls (urinary N-telopeptide cross-linked collagen type 1, 93 ± 38 vs. 24 ± 11 nmol bone collagen equivalents per mmol creatinine; and osteocalcin, 11.6 ± 3.4 vs. 7.6 ± 3.6 ng/ml; both P < 0.001). Fifteen patients were studied prospectively for an average of 9 months after LRGB. They lost 37 ± 9 kg and had a 29 ± 8% fall in body mass index (both P < 0.001). Urinary N-telopeptide cross-linked collagen type 1 increased by 174 ± 168% at 3 months (P < 0.01) and 319 ± 187% at 9 months (P < 0.01). Bone mineral density decreased significantly at the total hip (7.8 ± 4.8%; P < 0.001), trochanter (9.3 ± 5.7%; P < 0.001), and total body (1.6 ± 2.0%; P < 0.05), with significant decreases in bone mineral content at these sites.

In summary, within 3 to 9 months after LRGB, morbidly obese patients have an increase in bone resorption associated with a decrease in bone mass. Additional studies are needed to examine these findings over the longer term.
Physical Properties of Monofluorodimethyl Carbonate
Authors: Takehara Masahiro , Watanabe Susumu , Nanbu Noritoshi , Ue Makoto , Sasaki Yukio
Published: March 2004

Partial fluorination of solvents can improve various physical properties because of the polar effect. We have investigated the temperature dependence of relative permittivity (εr), viscosity (η), refractive index (nd), and density (ρ) of monofluorodimethyl carbonate (MFDMC) over a range of 10 to 70 °C and compared the physical properties with those of dimethyl carbonate (DMC). The εr, η, and ρ of the MFDMC are higher than those of the DMC, whereas the nd becomes lower.
Pendleian (early Serpukhovian) marine carbonates from SW Spain: sedimentology, biostratigraphy and depositional model
Authors: Cózar P. , Rodríguez S.
Published: March 2004

The San Antonio–La Juliana tectono‐sedimentary unit contains the only Namurian marine carbonates in the southwestern part of the Iberian Peninsula. The analysis of this unit is fundamental in understanding the sedimentary evolution and tectonic movements which operated during the Namurian in this area. Using foraminifera the succession has been assigned to two biozones (Zones 17 and 18), both occurring in the Pendleian (early Namurian). Seven stratigraphic sections have been analysed: San Antonio, Burjadillo, Lavadero de la Mina, Cornuda, Lozana, Caridad and Via Crucis. The stratigraphic succession of the San Antonio–La Juliana Unit consists of olistolites in the basal part, with common debris‐flow deposits (mainly of carbonates, with minor siliciclastic rocks), and turbidites, all of them embedded in shales. These rocks, interpeted as slope deposits, pass up into shallow‐water platform facies, with sediments characteristic of the inner platform and tidal flats. Above these rocks, terrigenous deltaic deposits occur. Thus, the stratigraphic sections show an overall shallowing‐upward trend. The isolation of some outcrops, and the duplication and absence of some parts of the stratigraphic succession are explained by tectonic movements. Overall, tectonic factors seem to be the main control rather than glacio‐eustatic or autocyclic processes, and sedimentation took place in a strike‐slip regime. Copyright © 2004 John Wiley & Sons, Ltd.
Magnitude of lateral displacement on the Crevillente Fault Zone (Betic Cordillera, SE Spain): stratigraphical and sedimentological considerations
Authors: Nieto L. M. , Rey J.
Published: March 2004

The Crevillente Fault Zone (CFZ) comprises a system of northeast to southwest oriented dextral faults that extend for some 600 km in the External Zones of the Betic Cordillera (SE Spain). The magnitude of lateral displacement related to this fault zone is not well constrained, and it is considered to be between 20 and 400 km. The stratigraphical and sedimentological criteria used in this work have proven effective in quantifying the magnitude of the displacement along this structure. We have analysed an oolitic turbidite facies in the Middle Jurassic of the Sierra de Ricote (Median Subbetic of Murcia Province). A detailed revision of ooidal limestone outcrops has revealed that the source area of these deposits was to the Internal Subbetic zone, north of Vélez Rubio (Almería Province). These two tectonic units, the Median and Internal Subbetic, are currently 75 km from each other and separated by the CFZ. The conclusions arising from our stratigraphical, petrological and sedimentological studies favour interpretation of a 75–100 km lateral displacement. After restoring the Late Jurassic–Cretaceous anticlockwise rotation of Iberia, the CFZ appears to belong to the E–W palaeofault system that is related to the extension of the South Iberian Continental Margin (SICM). Copyright © 2004 John Wiley & Sons, Ltd.
New designer drug 1‐(3,4‐methylenedioxybenzyl) piperazine (MDBP): studies on its metabolism and toxicological detection in rat urine using gas chromatography/mass spectrometry
Authors: Staack Roland F. , Maurer Hans H.
Published: March 2004

Studies are described on the metabolism and toxicological analysis of the piperazine‐derived designer drug 1‐(3,4‐methylenedioxybenzyl)piperazine (MDBP) in rat urine using gas chromatography/mass spectrometry (GC/MS). The identified metabolites indicated that MDBP was metabolized by demethylenation and subsequent methylation to N‐(4‐hydroxy‐3‐methoxybenzyl)piperazine followed by partial glucuronidation or sulfation. Additionally, degradation of the piperazine moiety to N‐(3,4‐methylenedioxybenzyl)ethylenediamine and 3,4‐methylenedioxybenzylamine and N‐dealkylation to piperazine were observed. The authors' systematic toxicological analysis (STA) procedure using full‐scan GC/MS after acid hydrolysis, liquid/liquid extraction and microwave‐assisted acetylation allowed the detection of MDBP and its above‐mentioned metabolites in rat urine after single administration of a dose calculated from the doses commonly taken by drug users. Assuming similar metabolism, the described STA procedure should be suitable for proof of an intake of MDBP by analysis of human urine. Copyright © 2004 John Wiley & Sons, Ltd.
Protonated silanoic acid HSi(OH)2+ and its neutral counterpart: a tandem mass spectrometric and CBS‐QB3 computational study
Authors: Srikanth R. , Bhanuprakash K. , Srinivas R. , Wong Cathy Y. , Terlouw Johan K.
Published: March 2004

Protonated silanoic acid, HSi(OH)2+, 1a+, is cleanly generated by the dissociative electron ionization of triethoxysilane, HSi(OC2H5)3, and tetraethoxysilane, Si(OC2H5)4. This follows from tandem mass spectrometric experiments and CBS‐QB3 model chemistry calculations. The calculations predict that 1a+ (ΔHf(298 K) = 205 kJ mol−1) is separated by high barriers from its isomers HOSiOH2+, 1b+ and HSi(O)OH2+, 1c+. Low‐energy (metastable) ions 1a+ dissociate by loss of H2O via the pathway 1a+ → 1b+ → SiOH+ + H2O. Analysis of the metastable peak for this process confirms that the isomerization step 1a+ → 1b+ is rate determining. The calculations further predict that the incipient ions 1b+ communicate via a low barrier with the proton‐bound dimer SiO···H···OH2+, 1d+. This dimer ion is much lower in energy than its counterpart OSi···H···OH2+, 1e+, which is calculated to be only marginally stable. A comparison of the potential energy diagram for the silicon‐containing ions 1a+–1e+ with that of their carbon analogues reveals that the dissociation chemistries of HSi(OH)2+ and HC(OH)2+ are only superficially similar. Neutralization–reionization experiments confirm the theoretical prediction that the HSi(OH)2• radical (ΔHf(298 K) = −455 kJ mol−1) is a stable species in the rarefied gas phase. However, owing to a mismatch of Franck–Condon factors a large fraction of the neutralized ions dissociates by loss of H• yielding Si(OH)2. Copyright © 2004 John Wiley & Sons, Ltd.
A Top‐down method for the determination of residue‐specific solvent accessibility in proteins
Authors: Novak Petr , Kruppa Gary H. , Young Malin M. , Schoeniger Joe
Published: March 2004

We present a method employing top‐down Fourier transform mass spectrometry (FTMS) for the rapid profiling of amino acid side‐chain reactivity. The reactivity of side‐chain groups can be used to infer residue‐specific solvent accessibility and can also be used in the same way as H/D exchange reactions to probe protein structure and interactions. We probed the reactivity of the N‐terminal and ε‐lysine amino groups of ubiquitin by reaction with N‐hydroxysuccinimidyl acetate (NHSAc), which specifically acetylates primary amines. Using a hybrid Q‐FTMS instrument, we observed several series of multiply acetylated ubiquitin ions that varied with the NHSAc : protein stoichiometry. We isolated and fragmented each member of the series of acetylated ubiquitin ions in the front end of the instrument and measured the fragment ion masses in the FTMS analyzer cell to determine which residue positions were modified. As we increased the NHSAc : protein stoichiometric ratio, identification of the fragments from native protein and protein with successively increasing modification allowed the assignment of the complete order of reactivity of the primary amino groups in ubiquitin (Met 1 ≈ Lys 6 ≈ Lys 48 ≈ Lys 63 > Lys 33 > Lys 11 > Lys 27, Lys 29). These results are in excellent agreement with the reactivity expected from other studies and predicted from the known crystal structure of ubiquitin. The top‐down approach eliminates the need for proteolytic digestion, high‐performance liquid chromatographic separations and all other chemical steps except the labeling reaction, making it rapid and amenable to automation using small quantities of protein. Copyright © 2004 John Wiley & Sons, Ltd.
Solid‐phase microextraction: a powerful sample preparation tool prior to mass spectrometric analysis
Authors: Vas György , Vékey Károly
Published: March 2004

Sample preparation is an essential step in analysis, greatly influencing the reliability and accuracy of resulted the time and cost of analysis. Solid‐Phase Microextraction (SPME) is a very simple and efficient, solventless sample preparation method, invented by Pawliszyn in 1989. SPME has been widely used in different fields of analytical chemistry since its first applications to environmental and food analysis and is ideally suited for coupling with mass spectrometry (MS). All steps of the conventional liquid–liquid extraction (LLE) such as extraction, concentration, (derivatization) and transfer to the chromatograph are integrated into one step and one device, considerably simplifying the sample preparation procedure. It uses a fused‐silica fibre that is coated on the outside with an appropriate stationary phase. The analytes in the sample are directly extracted to the fibre coating. The SPME technique can be routinely used in combination with gas chromatography, high‐performance liquid chromatography and capillary electrophoresis and places no restriction on MS. SPME reduces the time necessary for sample preparation, decreases purchase and disposal costs of solvents and can improve detection limits. The SPME technique is ideally suited for MS applications, combining a simple and efficient sample preparation with versatile and sensitive detection. This review summarizes analytical characteristics and variants of the SPME technique and its applications in combination with MS. Copyright © 2004 John Wiley & Sons, Ltd.
Identification of MRI and 1H MRSI parameters that may predict survival for patients with malignant gliomas
Authors: Li Xiaojuan , Jin Hua , Lu Ying , Oh Joonmi , Chang Susan , Nelson Sarah J.
Published: March 2004

Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre‐treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly‐diagnosed malignant glioma were examined with MRI and three‐dimensional proton (1H) MRSI. Thirty‐nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N‐acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan–Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho‐to‐Cr, higher Cho‐to‐NAA, higher LL and lower Cr‐to‐NAA abnormalities. The survival functions were significantly different between the sub‐groups of patients obtained from the survival tree for both pre‐surgery and post‐surgery data. The results of this study suggest that pre‐treatment MRI and three‐dimensional 1H‐MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques. Copyright © 2004 John Wiley & Sons, Ltd.
Magnetic resonance angiography of collateral vessels in a murine femoral artery ligation model
Authors: Wagner Shawn , Helisch Armin , Ziegelhoeffer Tibor , Bachmann Georg , Schaper Wolfgang
Published: March 2004

The in vivo detection of growing collateral vessels following arterial occlusion is difficult in small animals. We have addressed the feasibility of performing high resolution time‐of‐flight angiograms to monitor the growth of collateral vessels after femoral artery occlusion in mice. We will also present a low‐pass quadrature birdcage coil construction with a sufficient signal‐to‐noise ratio to produce high resolution. After a 4‐month recovery period a C57BL/6 mouse with a surgical occlusion of the right femoral artery was used to assess the image quality and time requirements to produce magnetic resonance angiograms sufficient to assess collateral artery development using a two‐dimensional gradient echo sequence. At a resolution of 100 × 100 × 100 μm and a matrix size of 256 × 128 × 256 for a 2.56 cm isometric volume, three scans were performed with one, two and four repetitions resulting in signal‐to‐noise ratios for the femoral artery proximal to the ligation site of 58, 126 and 194, respectively. Five C57BL/6 mice were additionally measured 4 weeks after occlusion using two repetitions and the visual collateral vessels were assessed for number and location: 2.0 ± 1.2 in quadriceps muscle, 0.6 ± 0.5 in adductor (deep adductor vessel), 0.0 ± 0.0 in adductor (surface adductor vessels). The results showed a significant difference, two‐sided t‐test, p < 0.05, in number of vessels in all the locations. We have shown that this method can be utilized to elucidate the contribution of collateral vessels to arterial flow. Copyright © 2004 John Wiley & Sons, Ltd.
Effects of temperature on intracellular sodium, pH and cellular energy status in RIF‐1 tumor cells
Authors: Babsky Andriy , Hekmatyar S. K. , Wehrli Suzanne , Nelson David , Bansal Navin
Published: March 2004

Most perfused tumor cell experiments are performed at 37°C, the normal healthy body temperature. However, the temperature of subcutaneously implanted tumors in small animals is generally 29–33°C when the rectal temperature of the animal is maintained at 37°C. We have investigated the acute effects of increasing the temperature of perfused radiation‐induced‐fibrosarcoma (RIF‐1) tumor cells from 33 to 37°C (30 min) on intracellular sodium $({\rm Na}_{\rm i}^+)$, intracellular pH (pHi), and bioenergetic status. Heating the cells by 4°C produced a reversible increase in ${\rm Na}_{\rm i}^+$, slight acidification and no change in nucleotide triphosphate to inorganic phosphate ratio (NTP/Pi) as measured by shift‐reagent‐aided 23Na and 31P NMR spectroscopy. In the presence of 3 μM 5‐(N‐ethyl‐N‐isopropyl) amiloride (EIPA), a potent and specific inhibitor of Na+/H+ antiporter, the increase in ${\rm Na}_{\rm i}^+$ during the heating was completely abolished suggesting that the heat induced increase in ${\rm Na}_{\rm i}^+$ was caused by an increase in Na+/H+ antiporter activity. However, the changes in pHi with the heating were identical with or without EIPA, indicating that pHi is controlled by other ion exchange mechanisms in addition to Na+/H+ antiporter. NTP/Pi was significantly higher in presence of EIPA for some time points during the heating suggesting that both NTP production and consumption rates may be altered during the heating. These results indicate that a slight increase in temperature from 33 to 37°C induces significant changes in Na+ physiology largely because of activation of Na+/H+ antiporter but other ion exchange mechanisms are also involved in maintaining pHi in the RIF‐1 tumor cells. Thus, care must be taken in choosing the temperature for perfused cell studies. Copyright © 2004 John Wiley & Sons, Ltd.
St John's wort induces both cytochrome P450 3A4–catalyzed sulfoxidation and 2C19–dependent hydroxylation of omeprazole
Authors: Wang Lian‐Sheng , Zhou Gan , Zhu Bing , Wu Jun , Wang Jian‐Gang , El‐Aty A. M. Abd , Li Tong , Liu Jie , Yang Tian‐Lun , Wang Dan , Zhong Xiang‐Yang , Zhou Hong‐Hao
Published: March 2004

Objective

St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4–mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites.

Methods

Twelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a 2‐phase randomized crossover design. In each phase the volunteers received placebo or a 300‐mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20‐mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection.

Results

Omeprazole and its metabolites all exhibit CYP2C19 genotype–dependent pharmacokinetic profiles. After a 14‐day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (Cmax) significantly decreased by 37.5% ± 13.3% (P = .001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6% ± 20.7% (P = .017) in CYP2C19*1/CYP2C19*1; the area under the concentration‐time curve extrapolated to infinity [AUC(0‐∞)] decreased by 37.9% ± 21.3% (P = .014) and 43.9% ± 23.7% (P = .011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the Cmax and AUC(0‐∞) of omeprazole sulfone increased by 160.3% ± 45.5% (P = .001) and by 136.6% ± 84.6% (P = .014), 155.5% ± 58.8% (P = .001), and 158.7% ± 101.4% (P = .017) in mutant and wild genotypes, respectively. St John's wort increased the Cmax of 5‐hydroxyomeprazole by 38.1% ± 30.5% (P = .028) and the AUC(0‐∞) by 37.2% ± 26% (P = .005) in CYP2C19 wild‐type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes.

Conclusion

St John's wort induces both CYP3A4‐catalyzed sulfoxidation and CYP2C19‐dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.

Clinical Pharmacology & Therapeutics (2004) 75, 191–197; doi: 10.1016/j.clpt.2003.09.014
CYP2C9 genotypes and dose requirements during the induction phase of oral anticoagulant therapy
Authors: Peyvandi Flora , Spreafico Marta , Siboni Simona Maria , Moia Marco , Mannucci Pier Mannuccio
Published: March 2004

Objective

Variant alleles of the CYP2C9 gene encoding the cytochrome P450 (CYP) enzyme (2C9*2 [Arg144Cys] and 2C9*3 [Ile359Leu]) are known to increase the anticoagulant effect of warfarin and decrease the mean daily dose required to maintain the international normalized ratio (INR) of the prothrombin time within the target therapeutic range. However, little information is available on the effect of CYP2C9 polymorphisms on dose requirements during the most critical step of anticoagulant therapy, the induction phase.

Methods

This retrospective study evaluated the dosages given to 125 patients who started therapy with warfarin in a clinical center where physicians used the same approach for dosing and frequency of monitoring. CYP2C9 allelic variants were evaluated by polymerase chain reaction followed by restriction enzyme analysis.

Results

From the time of the first INR estimate (day 4) until the end of the induction phase (arbitrarily established at day 24), patients with 2C9*2 or 2C9*3 variant alleles required lower mean daily doses than patients carrying only wild‐type alleles 2C9*1 (−17% and −40%, P < .0001). They also more frequently had INR values above the upper limit of the target range (3.0) (65% for 2C9*2/− and 66% for 2C9*3/− versus 33% for 2C9*1/*1; P = .006 and .012, respectively).

Conclusions

The requirement of smaller doses of warfarin in relation to CYP2C9 polymorphisms is already manifest on the fourth day of treatment, at the time of the first INR estimate. CYP2C9 genotyping is as yet not warranted, but frequent INR monitoring with appropriate dose adjustments is recommended during the first 3 weeks of treatment to avoid overanticoagulation and the inherent risk of bleeding in carriers of variant alleles.

Clinical Pharmacology & Therapeutics (2004) 75, 198–203; doi: 10.1016/j.clpt.2003.09.015
Glyburide Inhibits Dipyridamole‐induced Forearm Vasodilation but not Adenosine‐induced Forearm Vasodilation
Authors: Bijlstra Peter , van Ginneken Egidia E. M. , Huls Marc , van Dijk Rob , Smits Paul , Rongen Gerard A.
Published: March 2004

Background

The mechanism of the vasodilator response to adenosine has not been elucidated in humans. Stimulation of adenosine receptors on endothelial and vascular smooth muscle cells with subsequent endothelial release of nitric oxide and opening of adenosine triphosphate (ATP)–sensitive potassium (KATP) channels has been suggested.

Aim

The aim of this study was to investigate the involvement of KATP channels in the vasodilator response to adenosine and the nucleoside transport inhibitor dipyridamole.

Methods and results

In healthy male volunteers, adenosine (0.6, 1.9, 5.6, 19, 57, and 190 nmol · min−1 · dL−1) was infused into the brachial artery, and forearm blood flow (FBF) was measured by use of strain‐gauge plethysmography. Adenosine increased the FBF ratio (FBF in experimental arm/FBF in control arm) from 1.3 ± 0.2 to 1.2 ± 0.2, 1.5 ± 0.2, 2.8 ± 0.4, 7.3 ± 2.3, 11.1 ± 4.1, and 12.9 ± 3.7 for the six increasing adenosine doses, respectively. Simultaneous infusion of glyburide (INN, glibenclamide), a blocker of KATP channels, did not affect this response (from 1.7 ± 0.4 to 1.5 ± 0.2, 2.2 ± 0.3, 4.0 ± 1.0, 9.3 ± 4.0, 13.5 ± 6.4, and 15.9 ± 5.3 for the 6 increasing doses of adenosine, respectively; P = .439, n = 6). The increase in FBF ratio during infusion of the nucleoside transport inhibitor dipyridamole (20, 60, and 200 nmol · min−1 · dL−1) was significantly reduced by glyburide, as follows: from 1.2 ± 0.1 to 1.7 ± 0.2, 2.4 ± 0.5, and 2.9 ± 0.4, respectively, during saline solution and from 1.6 ± 0.2 to 1.8 ± 0.2, 2.1 ± 0.3, and 2.2 ± 0.4, respectively, during glyburide (P = .010 for effect of glyburide on response from baseline, ANOVA for repeated measures; n = 8). The vasodilator response to dipyridamole was significantly inhibited by the adenosine receptor antagonist theophylline.

Conclusion

Opening of vascular KATP channels is involved in the forearm vasodilator response to dipyridamole but not to adenosine. Differences in stimulated cell type (endothelium for adenosine versus smooth muscle cells for dipyridamole) may underlie this divergent pharmacologic profile.

Clinical Pharmacology & Therapeutics (2004) 75, 147–156; doi: 10.1016/j.clpt.2003.09.016
Cyclic antidepressants and the risk of sudden cardiac death
Authors: Ray Wayne A. , Meredith Sarah , Thapa Purushottam B. , Hall Kathi , Murray Katherine T.
Published: March 2004

Background

Tricyclic and other related cyclic antidepressants (TCAs), used frequently for the treatment of depression and several other indications, have cardiovascular effects that may increase the risk of sudden cardiac death. We thus sought to quantify the risk of sudden cardiac death among TCA users, according to dose, as well as among users of selective serotonin reuptake inhibitors (SSRIs).

Methods

We conducted a retrospective cohort study in Tennessee Medicaid, from Jan 1, 1988, through Dec 31, 1993, which included large numbers of antidepressant users and computer files describing medication use and comorbidity. The cohort included 1,282,091 person‐years of follow‐up for persons aged 15 to 84 years who were not in a nursing home and were free of life‐threatening noncardiac illness. This included 58,956 person‐years for current use of TCAs alone, 6291 person‐years for SSRIs only, and 96,220 person‐years for former use.

Results

The cohort included 1487 confirmed sudden cardiac deaths occurring in the community. When compared with nonusers of antidepressants, current users of TCAs had a dose‐related increase in the risk of sudden cardiac death. Rate ratios increased from 0.97 (95% confidence interval [CI], 0.72–1.29) for doses lower than 100 mg (amitriptyline or its equivalent) to 2.53 (95% CI, 1.04–6.12) for doses of 300 mg or more (P = .03, test for dose‐response). The rate ratio for SSRIs was 0.95 (95% CI, 0.42–2.15). There was no evidence that TCA doses lower than 100 mg increased the risk of sudden cardiac death in subgroups defined by pre‐existing cardiovascular disease, female sex, age 65 years or older, or use of amitriptyline.

Conclusions

Our data suggest that SSRI antidepressants and TCAs in doses of less than 100 mg (amitriptyline equivalents) did not increase the risk of sudden cardiac death. However, higher doses of TCAs were associated with increased relative risk, which suggests that such doses should be used cautiously, particularly in patients with an elevated baseline risk of sudden death.

Clinical Pharmacology & Therapeutics (2004) 75, 234–241; doi: 10.1016/j.clpt.2003.09.019