bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous CD4+BV8S2− T cells from TG BV8S2+ donors confer complete protection against spontaneous experimental encephalomyelitis (Sp‐EAE) in TCR transgenic, RAG−/− mice
Authors: Matejuk Agata , Buenafe Abigail C. , Dwyer Jami , Ito Atsushi , Silverman Marc , Zamora Alex , Subramanian Sandhya , Vandenbark Arthur A. , Offner Halina
Published: December 2002

To investigate regulatory mechanisms which naturally prevent autoimmune diseases, we adopted the genetically restricted immunodeficient (RAG‐1−/−) myelin basic protein (MBP)‐specific T cell receptor (TCR) double transgenic (T/R−) mouse model of spontaneous experimental autoimmune encephalomyelitis (Sp‐EAE). Sp‐EAE can be prevented after transfer of CD4+splenocytes from naïve immunocompetent mice. RAG‐1+ double transgenic (T/R+) mice do not develop Sp‐EAE due to the presence of a very small population (about 2%) of non‐Tg TCR specificities. In this study, CD4+BV8S2+ T cells that predominate in T/R+ mice, and three additional populations, CD4+BV8S2−, CD4−CD8−BV8S2+, and CD4−CD8+BV8S2+ T cells that expanded in T/R+ mice after immunization with MBP‐Ac1‐11 peptide, were studied for their ability to prevent Sp‐EAE in T/R− mice. Only the CD4+BV8S2− T cell population conferred complete protection against Sp‐EAE, similar to unfractionated splenocytes from non‐Tg donors, whereas CD4−CD8−BV8S2+ and CD4+BV8S2+ T cells conferred partial protection. In contrast, CD4−CD8+BV8S2+ T cells had no significant protective effects. The highly protective CD4+BV8S2− subpopulation was CD25+, contained non‐clonotypic T cells, and uniquely expressed the CCR4 chemokine receptor. Protected recipient T/R− mice had marked increases in CD4+CD25+ Treg‐like cells, retention of the pathogenic T cell phenotype in the spleen, and markedly reduced inflammation in CNS tissue. Partially protective CD4+BV8S2+ and CD4− CD8−BV8S2+ subpopulations appeared to be mainly clonotypic T cells with altered functional properties. These three Sp‐EAE protective T cell subpopulations possessed distinctive properties and induced a variety of effects in T/R− recipients, thus implicating differing mechanisms of protection. © 2002 Wiley‐Liss, Inc.
Fullerene C60 and ascorbic acid protect cultured chromaffin cells against levodopa toxicity
Authors: Corona‐Morales Aleph A. , Castell Andrés , Escobar Alfonso , Drucker‐Colín René , Zhang Limei
Published: December 2002

Adrenal chromaffin cell (ACC) transplants, alone or combined with levodopa treatment, were used in attempted therapy for Parkinson's disease (PD). In a previous study, we demonstrated that levodopa caused chromaffin cell death either by necrosis or by apoptosis in cell culture. Here we report the beneficial effect of a water‐soluble derivative of fullerene C60 (a novel molecule with potent antioxidant properties) and of ascorbic acid when applied to chromaffin cell cultures exposed to levodopa. Both antioxidants remarkably increase the ACC survival and prevent cell death, including apoptosis. Although ACC transplants are not currently considered as an option for PD treatment, these observations should help in exploring the possibilities of preventing the neurotoxicity generated by levodopa and in envisaging new strategies for PD treatment by combining the clinical use of levodopa and potent antioxidants. Chemical properties of fullerene related to biological uses are discussed. © 2002 Wiley‐Liss, Inc.
Effects of chronic dermal exposure to nonlethal doses of methyl parathion on brain regional acetylcholinesterase and muscarinic cholinergic receptors in female rats
Authors: Ma Tangeng , Kramer Robert E. , Baker Rodney C. , Fan Lir‐Wan , Ho Ing K.
Published: December 2002

The in vivo and in vitro effects of methyl parathion, a phosphorothionate insecticide, on cholinergic neurotransmitter systems in the brain of rats were investigated. Three groups of adult female rats received 0, 0.1, or 1.0 mg/kg methyl parathion via dermal exposure for 95 days. Exposure to 0.1 mg/kg methyl parathion produced inhibition of AChE in the caudate‐putamen and thalamic nuclei, whereas 1.0 mg/kg resulted in inhibition of AChE in most brain regions. The same doses of methyl parathion had no effect on [3H]QNB binding to muscarinic receptors in the brain regions examined. The in vitro study demonstrated that methyl parathion causes preferential inhibition of AChE and [3H]QNB binding in specific brain regions. As an inhibitor of AChE, methyl paraoxon was 1,000‐fold more potent than was methyl parathion. Similarly, methyl paraoxon showed brain region‐specific inhibition of the enzyme. Generally, the brain stem was highly sensitive to organophosphate‐induced inhibition of AChE activity and [3H]QNB binding. Because central respiratory neurons gather in the brain stem, preferential effects there and in other brain regions may underlie lethal toxicity of methyl parathion and other organophosphates. © 2002 Wiley‐Liss, Inc.
Protein kinase C activity, translocation, and selective isoform subcellular redistribution in the rat cerebral cortex after in vitro ischemia
Authors: Selvatici Rita , Marino Silvia , Piubello Carmela , Rodi Donata , Beani Lorenzo , Gandini Enrico , Siniscalchi Anna
Published: December 2002

Protein kinase C (PKC) involvement in ischemia‐induced neuronal damage has been investigated in superfused rat cerebral cortex slices submitted to 15 min of oxygen‐glucose deprivation (OGD) and in primary cultures of rat cortical neurons exposed to 100 μM glutamate (GLU) for 10 min. OGD significantly increased the total PKC activity in the slices, mostly translocated in the particulate fraction. After 1 hr of reperfusion, the total PKC activity was reduced and the translocated fraction dropped by 84% with respect to the control. Western blot analysis of OGD samples showed an increase in total β2 and ϵ PKC isoform levels. After reperfusion, the total levels of α, β1, β2 and γ isoforms were significantly reduced, whereas the ϵ isoform remained at an increased level. Endogenous GLU release from OGD slices increased to about 15 times the basal values after 15 min of oxygen‐glucose deprivation, and to 25 and 35 times the basal level in the presence of the PKC inhibitors staurosporine (0.1 μM) and bisindolylmaleimide (1 μM), respectively. Western blot analysis of GLU‐treated cortical neurons showed a significant decrease only in the total level of β2 isoforms. Cell survival was reduced to 31% in GLU‐treated neuronal cultures; PKC inhibitors were not able to modify this effect. These findings demonstrate that the cell response to OGD and GLU involves PKC in a complex way. The net role played by PKC during OGD may be to reduce GLU release and, consequently, neurotoxicity. The isoforms β2 and ϵ are affected the most and may play a significant role in the mechanisms underlying neurotoxicity/neuroprotection. © 2002 Wiley‐Liss, Inc.
Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase‐2 inhibitor APHS can be reversed by a prostanoid
Authors: Carlson Noel G.
Published: December 2002

The neuroprotective properties of two cyclooxygenase‐2 (COX‐2) specific inhibitors, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl]‐methanesulfonamide (NS398) and o‐(acetoxy‐phenyl)hept‐2‐ynyl2 sulfide (APHS) were examined in vitro using a mixed cortical neuronal culture system. Each of these inhibitors conferred a concentration‐dependent neuroprotective effect against an excitotoxic assault induced by NMDA. Neuroprotection was observed when the COX‐2 inhibitor was added before or even 1–3 hours after NMDA, which was coincident with an NMDA‐induced increase of COX‐2 transcripts in neurons. To test whether these COX‐2 inhibitors confer neuroprotection by inhibiting biosynthesis of prostanoids that may contribute toward excitotoxicity, two NMDA‐induced prostanoids, PGE2 and PGF2α, were tested for their ability to reverse the neuroprotective properties of APHS. APHS‐mediated neuroprotection was overcome by the concentration‐dependent (as low as 100 nM) administration of a synthetic analog of PGE2, 17‐phenyl‐trinor‐PGE2 (17‐pt‐E2), which is a relatively specific agonist for the EP1 and EP3 prostaglandin receptors; however, PGF2α had no significant effect on neuroprotection conferred by APHS. In the absence of APHS, neuroprotection was observed with either prostanoid. PGE2 may in some instances contribute toward excitotoxicity, and the inhibition of synthesis of this prostanoid may in part explain the neuroprotective properties of these COX‐2 inhibitors. Published 2002 Wiley‐Liss, Inc.
Upregulation of c‐Kit receptor and stem cell factor in cerebellar inhibitory synapses in response to kainic acid
Authors: Kim D. , Im J.O. , Won Y.J. , Yoon S.Y. , Lee E.J. , Lee J.H. , Hong H.N.
Published: December 2002

Neuronal stimulation was induced in rats by systemic administration of kainic acid (KA) to determine if such stimulation is responsible for changes in the expression patterns of c‐Kit and stem cell factor (SCF) in cerebellar synapses between inhibitory interneurons and Purkinje cells. Using immunocytochemistry and immunoblotting analyses, we demonstrate that c‐Kit receptor tyrosine kinase and its ligand SCF are present on the pre‐ and postsynaptic sides of inhibitory synapses on Purkinje cells. These proteins are upregulated during the first 48 hr after KA treatment, whereas their levels fall below that of the control by 1 week and remain as such thereafter. Expression of both c‐Kit and SCF are significantly elevated in the Purkinje cell layer 24 hr after KA administration, and the Purkinje cell layer exhibits a loss of calbindin D‐28K immunoreactivity. Expression of c‐Kit in basket cell axon terminals is activated until 48 hr after KA treatment, suggesting the transient participation of c‐Kit receptor tyrosine kinase in the maintenance of these axonal terminals. Also during the first 48 hr after KA treatment, SCF levels increase in axonal processes of Purkinje cells, and these SCF‐positive axons correlate with c‐Kit‐positive pinceau structures. The increased expression of c‐Kit and SCF in response to KA‐induced neuronal stimulation may indicate that c‐Kit receptor tyrosine kinase and its ligand SCF function in the inhibitory synapse between cerebellar interneurons and Purkinje cells, and that this role is most pronounced during the first 48 hr after KA treatment. © 2002 Wiley‐Liss, Inc.
Analysis of protein–nucleic acid interactions by photochemical cross‐linking and mass spectrometry
Authors: Steen Hanno , Jensen Ole Nørregaard
Published: December 2002

I.
Introduction
163

II.
Photochemical Cross‐Linking
165

III.
Structural Analysis of Protein–Nucleic Acid Heteroconjugates
165

IV.
Analytical Challenges
168

A. Ionization of Peptide–Oligonucleotide Heteroconjugates
168

   1.  MALDI MS Analysis of Heteroconjugates
168

   2.  Electrospray Ionization (ESI) MS Analysis of Heteroconjugates
170

B. Mass Analysis and Sequencing of Heteroconjugates
170

C. Photochemical Reaction Mechanisms
170

V.
Mass Spectrometric Analysis of Photochemically Cross‐Linked Heteroconjugates
171

A. Analysis of Intact Protein–Oligonucleotide Heteroconjugates by MS
171

B. Mass Analysis of Peptide–Oligonucleotide Heteroconjugates
174

C. Sequence Information by MS
174

   1.  MALDI MS‐Based Sequencing of Peptide–Nucleic Acid Heteroconjugates
174

   2.  Sequence Information by ESI MS/MS
175

   3.  Other Mass Spectrometric Techniques for the Analysis of Protein/Peptide–Oligonucleotide Heteroconjugates
176

VI.
Conclusions and Perspectives
178

Acknowledgments
179

Abbreviations
179

References
179

Photochemical cross‐linking is a commonly used method for studying the molecular details of protein‐nucleic acid interactions. Photochemical cross‐linking aids in defining nucleic acid binding sites of proteins via subsequent identification of cross‐linked protein domains and amino acid residues. Mass spectrometry (MS) has emerged as a sensitive and efficient analytical technique for determination of such cross‐linking sites in proteins. The present review of the field describes a number of MS‐based approaches for the characterization of cross‐linked protein‐nucleic acid complexes and for sequencing of peptide‐nucleic acid heteroconjugates. The combination of photochemical cross‐linking and MS provides a fast screening method to gain insights into the overall structure and formation of protein‐oligonucleotide complexes. Because the analytical methods are continuously refined and protein structural data are rapidly accumulating in databases, we envision that many protein‐nucleic acid assemblies will be initially characterized by combinations of cross‐linking methods, MS, and computational molecular modeling. © 2002 Wiley Periodicals, Inc., Mass Spec Rev 21:163–182, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mas.10024
Naturally and externally pulsed electrospray
Authors: Wei Junfei , Shui Wenqing , Zhou Feng , Lu Yu , Chen Kankai , Xu Guobing , Yang Pengyuan
Published: December 2002

I.
Introduction
148

 II.
Continuous Electrospray
149

III.
Pulsation in an ESI Process
150

A. High‐Frequency Pulsation
150

B. Low‐Frequency Pulsation
153

IV.
Pulsing in Electrospray or Pulsed Electrospray
155

A. Pulsed in ESI in Low Frequency
155

B. Pulsed in ESI in High Frequency
156

C. Features of a Pulsed ESI
158

 V.
Closing Remarks
161

Acknowledgments
161

References
161

The current studies on pulsation phenomena in electrospray ionization, and pulsed electrospray ionization (ESI) under external electrical control are reviewed. A number of investigations have shown that two types of pulsation processes exist: low‐frequency fluctuation and high‐frequency droplet‐formation. The low‐frequency pulsation is induced by an imbalance between the flow rate of the input sample to the Taylor cone and the feed rate of the output solution to the liquid filament. The high‐frequency pulsation mainly results from the initial droplet formation process, and is modulated by the low‐frequency pulsation. The fundamental and experimental sections of these two pulsations are discussed. Experimental results also show that low and high pulsations can both be controlled electrically to create a pulsed ESI so that high sensitivity and an enhanced S/N ratio can be achieved. However, the co‐ordination of the synchronization between a natural pulsation and a pulsed ESI, as well as its application to mass spectrometer (MS) analysis, demands further research. © 2002 Wiley Periodicals, Inc., Mass Spec Rev 21:148–162, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mas.10026
Urodynamically age‐specific prevalence of urinary incontinence in women with urinary symptoms
Authors: Lin Ho‐Hsiung , Torng Pao‐Ling , Sheu Bor‐Ching , Shau Wen‐Yi , Huang Su‐Cheng
Published: December 2002

Aims:

To determine the age‐specific prevalence rates of different types of urinary incontinence in women with urinary symptoms using urodynamic studies (UDS).

Methods:

One thousand five hundred women with urinary symptoms who underwent UDS in our department from January 1997 through December 1999 were enrolled. A detailed history, physical examination, and data of multi‐channel UDS including uroflowmetry, filling and voiding cystometry, stress urethral pressure profile, and 20‐minute pad test were obtained for each patient. The urodynamic findings of each patient were analyzed and correlated with age in decades.

Results:

Of 1,500 women, 329 were excluded from analysis because they had undergone anti‐incontinence surgery (n=27), had undergone treatment for cervical cancer (n=147), or were being followed‐up after medication (n=155). Of the remaining 1,171 patients, 656 (56%) had genuine stress incontinence (GSI), 68 (5.8%) had detrusor instability (DI), 187 (16%) had mixed GSI/DI, 245 (20.9%) had either voiding or storing dysfunction without concomitant incontinence, and 15 (1.3%) had normal urodynamic findings. The 41–50‐ and 51–60‐year age groups had the highest prevalence rates of urinary incontinence, accounting for 31% and 28% of GSI cases, 35% and 25% of DI cases, and 40% and 27% of mixed GSI/DI cases, respectively. The prevalence of GSI and mixed GSI/DI increased consistently with age, but the prevalence of DI decreased after age 66. Thus, the prevalence rates of GSI, DI, and mixed GSI/DI were 56%, 5.8%, and 16%, respectively, in women with urinary symptoms.

Conclusions:

Female urinary incontinence had a biogenic peak prevalence in the 41–50‐year and 51–60‐year age groups. Neurourol. Urodynam. 22:29–32, 2003. © 2003 Wiley‐Liss, Inc.
Morphometric analysis of the collagen changes induced by subcutaneous injection of interferon‐gamma after bladder outlet obstruction in the rat
Authors: Kim Kwang Myung , Kang Jeongyoon , Jung Jung Yun
Published: December 2002

Aims:

The objective of this study was to examine the effects of interferon‐gamma injection on changes in collagen content, after the creation of partial bladder outlet obstruction in the rats.

Methods:

A total of 50 Sprague‐Dawley female rats were subjected to partial bladder outlet obstruction by using metal rods. The rats were divided into five groups (n = 10 in each group): normal control (N), sham operation (S), bladder outlet obstruction for 4 weeks (BOO), interferon‐gamma injection after sham operation (S + IFN), and interferon‐gamma injection after bladder outlet obstruction (BOO + IFN). Interferon‐gamma was subcutaneously injected (100,000 units per injection, LG chemical Co., Seoul, Korea) daily for 4 weeks in the injection groups, after which all rats were sacrificed.

Results:

The collagen area percentage (collagen/collagen + muscle) in each bladder, calculated through image analysis, was 40.7 ± 1.6% in the N, 38.2 ± 2.0% in the S, 26.6 ± 3.8% in the S + IFN, 19.9 ± 2.5% in the BOO, and 12.4 ± 2.0% in the BOO + IFN group (mean ± standard error). The difference in the collagen area percentage between the N and S groups (P > 0.05) was not significant, but there were significant differences between the N and S + IFN groups (P < 0.05), between the S and S + IFN groups (P < 0.05), and between the BOO and BOO + IFN groups (P < 0.05).

Conclusions:

It appears that interferon‐gamma decreases the collagen content in the obstructed rat bladder. Neurourol. Urodynam. 22:70–76, 2003. © 2003 Wiley‐Liss, Inc.
Video urodynamics using transrectal ultrasonography for lower urinary tract symptoms in women
Authors: Tosaka Akira , Murota‐Kawano Akiko , Ando Masao
Published: December 2002

Aims:

To understand the properties of lower urinary tract disorders in women, we evaluated 60 female patients with lower urinary tract disorders or symptoms of recurrent cystitis by free uroflowmetry and video urodynamics using transrectal ultrasonography (VU‐TRUS).

Methods:

Results of urodynamic studies or symptoms of stress incontinence were used to divide 60 women into 7 normal controls and 53 with voiding dysfunctions.

Results:

In normal controls, VU‐TRUS showed that the mean posterior urethrovesical angle and anteroposterior diameter of the proximal urethra at maximum flow was 151.4 degrees and 4.9 mm, respectively. In patients with voiding dysfunction, VU‐TRUS during voiding revealed various urethral abnormalities, including 16 detrusor sphincter dyssynergia, 4 detrusor bladder neck dyssynergia, and 13 insufficient opening of the entire urethra. VU‐TRUS also showed pelvic floor abnormalities, including 24 urethral hypermobilities (group 1) and 11 cystoceles (group 2). Eighteen patients had neither urethral hypermobility nor cystocele (group 3). Major pressure‐flow abnormalities in the 53 patients with voiding dysfunctions were weak detrusor (72%) and/or bladder outlet obstruction (25%). There were no significant differences in the distribution of the pressure‐flow abnormalities among the three groups. However, the mean values of abdominal pressure at maximum flow of group 1 (20.9 cm H2O) and group 2 (17.9 cm H2O) were significantly higher than that of group 3 (6.3 cm H2O; each P < 0.05). The mean values of residual urine volume of group 2 (60.8 mL) and group 3 (77.6 mL) were significantly higher than that of group 1 (23.5 mL; each P < 0.05).

Conclusions:

The symptoms of women with lower urinary tract disorders were frequently accompanied by urethral and/or pelvic floor abnormalities during voiding that were clearly detected by VU‐TRUS. VU‐TRUS is useful for objective evaluation of female lower urinary tract symptoms. Neurourol. Urodynam. 22:33–39, 2003. © 2003 Wiley‐Liss, Inc.
Polynomial particular solutions for certain partial differential operators
Authors: Golberg M. A. , Muleshkov A. S. , Chen C. S. , Cheng A. H.‐D.
Published: December 2002

In this article, we consider a variant of the Dual Reciprocity Method (DRM) for solving boundary value problems based on approximating source terms by polynomials other than the traditional basis functions. The use of pseudo‐spectral approximations and symbolic methods enables us to obtain highly accurate results without solving the often ill‐conditioned equations that occur when radial basis function approximations are used. When the given partial differential equation is either Poisson's equation or an inhomogeneous Helmholtz‐type equation, we are able to obtain either closed form particular solutions or efficient recursive algorithms. Using the particular solutions, we convert the inhomogeneous equations to homogeneous. The resulting homogeneous equations are then amenable to solution by boundary‐type methods such as the Boundary Element Method (BEM) or the Method of Fundamental Solutions (MFS). Using the MFS, we provide numerical solutions to a variety of boundary value problems in R2 and R3. Using this approach, we can achieve high accuracy with a modest number of interpolation and collocation points. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 19: 112–133, 2003
Uniform approximation of singularly perturbed reaction‐diffusion problems by the finite element method on a Shishkin mesh
Authors: Xenophontos Christos , Fulton Scott R.
Published: December 2002

We consider the numerical approximation of singularly perturbed reaction‐diffusion problems over two‐dimensional domains with smooth boundary. Using the h version of the finite element method over appropriately designed piecewise uniform (Shishkin) meshes, we are able to uniformly approximate the solution at a quasi‐optimal rate. The results of numerical computations showing agreement with the analysis are also presented. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 19: 89–111, 2003
The upwind finite difference fractional steps methods for two‐phase compressible flow in porous media
Authors: Yuan Yirang
Published: December 2002

The upwind finite difference fractional steps methods are put forward for the two‐phase compressible displacement problem. Some techniques, such as calculus of variations, multiplicative commutation rule of difference operators, decomposition of high‐order difference operators, and prior estimates, are adopted. Optimal order estimates in L2 norm are derived to determine the error in the approximate solution. This method has already been applied to the numerical simulation of seawater intrusion and migration‐accumulation of oil resources. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 19: 67–88, 2003
An explicit third‐order numerical method for size‐structured population equations
Authors: Kostova Tanya
Published: December 2002

A numerical method incorporating a combination of a difference scheme and several uniform and nonuniform quadrature rules is presented. The method is designed to solve size‐structured population equations with linear growth rate and nonlinear fertility and mortality rates. A detailed analysis of the global discretization error is carried out. Examples with known exact solutions have been solved numerically using the proposed method. The computations show that the global error is of third order as predicted by the theory. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 19: 1–21, 2003
Adaptive numerical solution of thick plates using first‐order shear deformation theory. Part I: Error estimates
Authors: Ludwig M. J. , Shaw Simon , Whiteman J. R.
Published: December 2002

A posteriori error estimation employing both a residual based estimator and a recovery based estimator is discussed. Interest is focused upon the application to Reissner‐Mindlin type thick plates modeled using first‐order shear deformation theory, and our investigation is limited to uniform meshes of bilinear quadrilateral elements. Numerical results for selected test problems are presented for the resulting error estimators and discussed. © 2002 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 19: 44–66, 2003
Prenatal sonographic diagnosis of the 49,XXXXY syndrome
Authors: Schluth Caroline , Doray Bérénice , Girard‐Lemaire Françoise , Kohler Monique , Langer Bruno , Gasser Bernard , Lindner Véronique , Flori Elisabeth
Published: December 2002

The 49,XXXXY syndrome is a rare sex chromosome anomaly with an approximate incidence of 1 in 85 000 male live births. The diagnosis is usually ascertained postnatally by the association of mental retardation, variable growth deficiency, Down syndrome‐like facial dysmorphy, hypogenitalism and other malformations, especially involving the heart and skeleton. Prenatal diagnosis of the pentasomy 49,XXXXY is generally fortuitous and sonographic features have rarely been described in the literature. We report here on two cases of 49,XXXXY syndrome diagnosed prenatally because of sonographic abnormalities. In the first, amniocentesis was performed at 26 weeks' gestation for polyhydramnios, unilateral clubfoot and micropenis. In the second, a karyotype was carried out on chorionic villi at 13 weeks' gestation for cystic hygroma. These observations and the six previously reported cases demonstrate that cystic hygroma in first or second trimester of pregnancy may be associated with sex chromosome aneuploidy other than Turner syndrome. Moreover, they emphasize the importance of detailed sonographic examination in the second trimester, as small penis and abnormal posturing of the lower extremities are very suggestive of the 49,XXXXY syndrome. Copyright © 2002 John Wiley & Sons, Ltd.
Prenatal diagnosis and treatment of fetal long QT syndrome: a case report
Authors: Chang Ing‐Kuang , Shyu Ming‐Kwang , Lee Chien‐Nan , Kau Miau‐Ling , Ko Yu‐Hsueh , Chow Song‐Nan , Hsieh Fon‐Jou
Published: December 2002

We report a case of a fetus presenting with bradycardia, intermittent atrioventricular (AV) block, ventricular tachycardia (VT) and the signs of fetal congestive heart failure (ascites and scrotal hydrocele) during mid‐gestation. Prenatal treatment with β‐adrenergic blocker (propranolol) and digitalis glycosides was prescribed because of suspicion of long QT syndrome occurring with fetal congestive heart failure. The male baby was born at 39 weeks of gestation and showed a prolonged QT interval (QTc = 492 ms) and frequent variable AV block or alternating left and right bundle branch block, depending on the atrial rate. Prenatal administration of lidocaine failed to correct the fetal VT. Conversely, propranolol decreased the attack frequency of fetal VT. Postnatal administration of the K+ channel opener (nicorandil) successfully shortened the QT interval and improved the outcome. Copyright © 2002 John Wiley & Sons, Ltd.
Preference assessment of prenatal diagnosis for Down syndrome: is 35 years a rational cutoff?
Authors: Grobman W. A. , Dooley S. L. , Welshman E. E. , Pergament E. , Calhoun E. A.
Published: December 2002

Objective

To compare the perceptions of miscarriage and birth of a child with Down syndrome among pregnant women and to evaluate the implications of these preferences for the traditional 35‐year old maternal age risk boundary.

Methods

An interviewer‐administered survey was given to 186 pregnant women receiving antepartum care at a university hospital. Preferences, as reflected by utilities, for birth of a child with Down syndrome and pregnancy miscarriage, stratified by patient characteristics, were assessed.

Results

The utility for the birth of a child with Down syndrome decreased (p < 0.001) as clinical severity increased from mild (0.78) to severe (0.65). Miscarriage of a pregnancy had a mean utility of0.76 ± 0.31. Women who desired prenatal diagnosis had a utility value for miscarriage (0.79 ± 0.28) that was significantly higher than for the birth of a child with Down syndrome of unknown severity (0.73 ± 0.27). In multivariable logistic regression, desire for prenatal diagnosis was the only factor associated with a preference of miscarriage over birth of an affected child (odds ratio 2.26, 95% confidence interval 1.03, 4.96).

Conclusion

Women who desire prenatal diagnosis do not perceive the birth of a child with Down syndrome and a pregnancy miscarriage to be equivalent health states. This finding calls into question the rationale of the 35‐year‐old maternal age criterion and suggests that actual patient preferences should be better incorporated into the decision to offer definitive prenatal diagnosis. Copyright © 2002 John Wiley & Sons, Ltd.
Uptake of prenatal screening for chromosomal anomalies: impact of test results in a previous pregnancy
Authors: Spencer Kevin
Published: December 2002

Aim

To assess whether the uptake of prenatal screening for trisomy 21 in a subsequent pregnancy is influenced by being classified in the ‘increased risk’ or ‘not at increased risk’ group in the first pregnancy.

Setting

District General Hospital Maternity Unit.

Methods

Amongst a group of women attending for maternity care at this hospital, the maternity records were examined to find women having at least two pregnancies. Any prenatal screening record for each pregnancy was retrieved from the prenatal screening database.

Prenatal screening for trisomy 21 was by a combination of maternal serum α‐fetoprotein (AFP) and free β‐human chorionic gonadotrophin (β‐hCG) in the second trimester and by maternal serum free β‐hCG and pregnancy‐associated plasma protein‐A (PAPP‐A) and fetal nuchal translucency (NT) thickness in the first trimester.

Women were stratified according to their trisomy 21 risk into an ‘increased risk’ group (1: <250 in the second trimester and 1: <300 in the first trimester) or ‘not at increased risk’ group based on their first pregnancy. In a second pregnancy, the records were examined to see if the mother accepted prenatal screening in the second pregnancy. The rate of acceptance of screening in a subsequent pregnancy, depending on whether ‘at increased risk’ or ‘not at increased risk’ in the first pregnancy, was examined using chi square tests.

Results

In the second trimester study, 4601 women were identified with two pregnancies during the study period. Of these, 4559 women had prenatal screening in a subsequent pregnancy. Initially, 273 women were identified in the high‐risk group, and of these 252 (92.3%) elected to have prenatal screening in a subsequent pregnancy. This compared with 4307 of 4328 (99.5%) women in the low‐risk group.

In the first trimester study, 1077 women were identified with two pregnancies during the study period. Of these, 1072 had prenatal screening in a subsequent pregnancy. Initially, 60 women were identified in the high‐risk group, and of these 56 (93.3%) elected to have prenatal screening in a subsequent pregnancy. This compared with 1016 of 1017 (99.9%) in the low‐risk group.

Statistically, there was no difference between the rate of declining prenatal screening in a second pregnancy amongst those in the high‐risk group in a first pregnancy or those in the low‐risk group (p = 0.429 for second trimester screening and p = 0.794 for first trimester screening). Similarly, no difference could be demonstrated between rates when screening in the first or second trimester (p = 0.961) for those in the high‐risk group.

Conclusion

Despite the understandable anxiety associated with being identified in the high‐risk group (as a false positive finding) in a previous pregnancy, this did not seem to deter women from accepting prenatal screening in a subsequent pregnancy. Copyright © 2002 John Wiley & Sons, Ltd.
Misclassification of current benzodiazepine exposure by use of a single baseline measurement and its effects upon studies of injuries
Authors: Ray Wayne A. , Thapa Purushottam B. , Gideon Patricia
Published: December 2002

Purpose

Measurement of drug exposure is a major methodologic challenge for pharmacoepidemiologic studies of acute effects of medications taken intermittently. If the effect is plausible only during periods of active drug use, daily (or even more frequent) exposure measurement is optimal. Benzodiazepines, episodically used hypnotics and anxiolytics, impair psychomotor function and some epidemiologic studies have reported users have increased risk of unintentional injuries. However, several prospective cohort studies of this question defined benzodiazepine exposure status from a single baseline measurement, and these have not consistently reported increased risk. We used data from an historical cohort study to demonstrate the extent of misclassification potentially induced by this practice.

Methods

The cohort consisted of 2510 Tennessee nursing home residents 65 years of age or older identified in a prior study of antidepressants and falls. Both baseline users (any in 7 days preceding start of follow‐up) and current use (use on a given day of follow‐up) of benzodiazepines were determined from facility medication administration records, which record information on drugs given to the resident each day. Falls were ascertained from nursing home incident reports and medical records. The effect of benzodiazepine exposure for each ascertaiment method was estimated from incidence rate ratios adjusted for multiple fall risk factors by Poisson regression.

Results

The 666 baseline benzodiazepine users had current use on 44.6% (95%CI, 40.2–49.2%) of follow‐up person‐days; baseline non‐users had current use for 3.7% of days (2.8–4.7%). Misclassification increased with length of follow‐up and with quintile of fall risk. The adjusted fall incidence rate ratios for the baseline user and current use definitions were 1.02 (95%CI, 0.95–1.10) and 1.44 (1.33–1.56), respectively.

Conclusion

These findings strongly suggest that to avoid potentially serious misclassification, studies of the acute effects of benzodiazepines and other drugs taken intermittently need to track exposure on a day‐by‐day basis. Copyright © 2002 John Wiley & Sons, Ltd.
Frequency of use of acetaminophen, nonsteroidal anti‐inflammatory drugs, and aspirin in US women
Authors: Curhan Gary C. , Bullock Andrea J. , Hankinson Susan E. , Willett Walter C. , Speizer Frank E. , Stampfer Meir J.
Published: December 2002

Purpose

To determine the frequency of use of the three main classes of over‐the‐counter analgesics: acetaminophen, nonsteroidal anti‐inflammatory drugs, and aspirin in two large US female cohorts.

Methods

We conducted a cross‐sectional study of the frequency of analgesic use and the characteristics of users in female participants in the Nurses Health Study I (n = 86 985) and the Nurses Health Study II (n = 93 002) who were between the ages of 33 and 77 years. Information on frequency of current analgesic use was assessed by mailed questionnaire.

Results

All three classes of analgesics were used frequently. For example, acetaminophen was used ≥ 1 day/week by more than 20% of women. NSAIDs were used ≥ 1 day/week by 42% of women aged 51 years or younger, and aspirin was used ≥ 6 days/week by 25% women over age 51 years. The frequency of use of the individual analgesics varied by age (p < 0.001). In addition, women in the highest category of use of any of the analgesics tended to have a higher body mass index, were more likely to have hypertension and diabetes, and were more likely to be current smokers.

Conclusions

Analgesic use is very common among US women. Physicians should be cognizant of the frequency of use of the various over‐the‐counter analgesics in their female patient population. Copyright © 2002 John Wiley & Sons, Ltd.
A survey of physician efficacy requirements to plan clinical trials
Authors: Oremus Mark , Collet Jean‐Paul , Corcos Jacques , Shapiro Stanley H.
Published: December 2002

Purpose

Eliciting physician efficacy requirements for utilizing medical treatments can be a useful means of helping plan a clinical trial. Efficacy requirements were studied for female stress urinary incontinence, where an experimental treatment (collagen injection) was compared to the standard therapy (surgery).

Methods

A self‐administered questionnaire was sent to 223 North American urologists, gynecologists, and urogynecologists. An interviewer also administered a similar questionnaire to 20 other clinician‐specialists.

Results

The response rate for the self‐administered questionnaire was 48.4% (108/223). All 20 clinician‐specialists who were approached for an interview consented. On average, respondents to the self‐administered questionnaire indicated they would consider using collagen as the first line treatment if the absolute reduction in efficacy of collagen versus surgery was no larger than 23%. The corresponding result for the interview‐questionnaire was 22%. Efficacy was measured as patient satisfaction with treatment. In the opinion of the physicians, surgery would remain the standard therapy if the reduction was greater than 34% (self‐administered questionnaire), or 37% (interviewer‐administered questionnaire).

Conclusions

The elicitation of physician efficacy requirements provides an idea of the treatment effect that would be needed for a clinical trial to have an impact on medical practice. These requirements can be used to calculate a relevant sample size. Copyright © 2002 John Wiley & Sons, Ltd.
Adverse events in users of sertraline: results from an observational study in psychiatric practice in The Netherlands
Authors: Meijer Welmoed E. E. , Heerdink Eibert R. , van Eijk Jacques ThM. , Leufkens Hubert G. M.
Published: December 2002

Purpose

To evaluate the safety profile of sertraline versus other Selective Serotonin Reuptake Inhibitors (SSRIs) directly following the introduction of sertraline to the Dutch market.

Methods

In a prospective follow‐up study, 109 psychiatrists included patients with a new episode of treatment with sertraline and an equal number of patients starting treatment with other SSRIs. All Adverse Events (AEs) during follow‐up were recorded by the psychiatrists for the duration of SSRI treatment until discontinuation or until at least 12 months.

Results

A total of 1251 patients were included in the study of which 659 used sertraline and 592 used other SSRIs (paroxetine, fluoxetine or fluvoxamine). The most frequently reported events in sertraline users and users of other SSRIs were nausea (160 (24.3%) sertraline patients versus 160 (27.0%) patients using other SSRIs), headache (127 (19.3%) sertraline patients versus 101 (17.1%) patients using other SSRIs), diarrhoea (94 (14.0%) sertraline patients versus 40 patients using other SSRIs (6.8%, p<0.05)), sweating (88 (13.4%) sertraline patients versus 69 (11.7%) patients using other SSRIs) and dizziness (75 (11.4%) sertraline patients versus 70 (11.8%) patients using other SSRIs). A total of 121 patients reported 134 different unlabelled AEs of which 10 were reported by more than 1% of the population.

Conclusions

In this study we found that almost three out of four patients reported an adverse event. When comparing with other SSRIs and the literature, we found a similar distribution of the most frequently reported adverse events in patients using sertraline. However, in this observational study we found over 100 different unlabelled adverse events. Copyright © 2002 John Wiley & Sons, Ltd.
Spontaneous reporting of adverse drug reactions by nurses
Authors: Bäckström M. , Mjörndal T. , Dahlqvist R.
Published: December 2002

Background

An Erratum has been published for this article in Pharmacoepidemiology and Drug Safety 12(2) 2003, 157–159.

Spontaneous reporting of adverse drug reactions (ADRs) remains one of the most effective methods to detect new and serious drug reactions. However, it is well known that there is a high degree of under‐reporting.

Objective

This study was carried out as an attempt to improve and increase the reporting of ADRs by investigating the utility of nurses reporting in addition to physicians, as usual.

Methods

During a 12‐month study period, nurses working at two departments of geriatric medicine in northern Sweden received special instruction regarding drugs and ADRs, ADR reporting and special aspects of ADRs in elderly people. The reports from the nurses were scrutinized concerning the seriousness of the reaction, reported drugs and type of reaction (type A or B). All nurses working at the two departments (117) were eligible to report but in practice only those attending the teaching sessions did so. A comparison with historical reporting and with reporting from other geriatric departments in Sweden was also carried out. At the end of the study all participating nurses received a questionnaire aimed at investigating their attitudes towards ADR reporting.

Results

After the 12‐month study period 18 ADR reports involving 22 reactions had been received. Seven of these were assessed as serious reactions. All of the reactions were of type A. In comparison, during the corresponding time period from the study clinics during the preceding year, only two reports were registered. During the study period only 15 reports were registered from the other 50 geriatric departments in Sweden.

Conclusion

Even though the total number of ADR reports was small, our data indicate a substantial increase in the reporting rate. This indicates that instructed and interested nurses could play an important role in detecting and reporting suspected ADRs. Copyright © 2002 John Wiley & Sons, Ltd.
An approximate Bayesian risk‐analysis for the gastro‐intestinal safety of ibuprofen
Authors: Wang Jixian , Donnan Peter T. , MacDonald Thomas M.
Published: December 2002

Purpose

Although several studies on ibuprofen and its gastro‐intestinal (GI) risk have been reported, the dose–response relationship was not clear due to the lack of information regarding high‐dose exposure. Analysis using Bayesian methods is appropriate whenever data are sparse, although such methods are not easily implemented.

Methods

A retrospective cohort study to assess this dose–response relationship was carried out using a record linkage database. A Bayesian risk‐analysis was conducted using the Bayesian bootstrap approximation. Risks of GI events at different dose levels were compared using the posterior distributions and the number of events predicted to occur in the future was estimated. Risk factors such as age, gender and co‐morbidity were adjusted for in the analysis. This approximation was compared with the full Bayesian approach using the usual but more computer‐intensive tool of Markov Chain Monte Carlo simulation.

Results

There were 1, 5 and 10 complicated GI events during exposure to high, medium and low dose ibuprofen with 0.2, 1.8 and 7.0 thousand person‐years (PY) exposure, respectively. After adjusting for other risk factors the relative risks of high versus low and medium versus low doses were 6.3 (95% CI = 0.21, 24.17) and 2.5 (95% CI = 0.71, 5.85), respectively. Using the approximate Bayesian method prediction of the number of events in a population of females aged 50–59 with no previous medical problems with 1000 PY drug exposure showed that the estimated probability of having more than five events was 0.048 for the medium‐dose group and 0.14 for the high‐dose group.

Conclusions

High dose ibuprofen appears to have a considerably greater risk of having a larger number of adverse GI events than a medium dose. The approximate Bayesian bootstrap method was demonstrated to be a robust and easily implemented alternative to the full Bayesian approach to risk analysis whenever data are sparse. Copyright © 2002 John Wiley & Sons, Ltd.
Use of ICD‐9 coding as a proxy for stage of disease in lung cancer
Authors: Thomas Simu K. , Brooks Sandra E. , Daniel Mullins C. , Baquet Claudia R. , Merchant Sanjay
Published: December 2002

Objective

To determine the validity of using ICD‐9‐CM codes indicating metastases as a proxy to classify lung cancer patients by stage of disease.

Research Design

This retrospective database analysis used diagnosis codes to classify subjects to either localized or advanced‐stage disease and then compared this classification to the tumor registry staging, which was considered as the ‘gold standard.’

Subjects and Measures

Study subjects included all lung cancer patients treated at our academic institution during 1996–1997, who were also members of a large insurance company. Data were derived from inpatient cancer‐related claims linked with our institution's tumor registry data. Advanced‐stage disease (stages II to IV) was defined by claims indicating lymph node involvement or metastases (ICD‐9 codes 196–199.1). The tumor registry stagings of the disease for these patients were clustered into two groupings, stages 0–I (localized) and stages II–IV (advanced).

Results

Tumor registry entries were identified for 66/77 (85.7%) patients. A total of 19 out of 22 local disease patients (sensitivity of 86.4%) and 30 out of 44 advanced disease patients (sensitivity of 68.2%) were classified correctly by ICD‐9 code. A total of 19 out of 33 patients with local disease codes (PPV of 57.6%) and 30 out of 33 patients with advanced disease codes (PPV = 90.9%) were properly identified.

Conclusions

For a population of lung cancer patients in an academic institution who were under a private insurance plan, the ICD‐9 coding was associated with a sensitivity and positive predictive values that were consistent with previously reported estimates using Medicare–SEER data. The use of such data to classify patients to disease stages should be executed with caution as under‐reporting might exist. Continued attention to discharge abstracting will be needed to improve the validity of this technique. Copyright © 2002 John Wiley & Sons, Ltd.
Characteristics of diarrhoea in 10 008 users of lansoprazole in daily practice: which co‐factors contribute?
Authors: Claessens Angela A. M. C. , Heerdink Eibert R. , van Eijk Jacques Th. M. , Lamers Cornelis B. H. W. , Leufkens Hubert G. M.
Published: December 2002

Purpose

Diarrhoea is one of the most frequently reported adverse events during proton pump inhibitor use in any setting. Because of the limited available information, this study was set up with the aim of assessing the incidence and characteristics of diarrhoea and to investigate possible associated co‐factors in proton pump inhibitor users in daily practice.

Methods

Data were used from a prospective, observational study in which 10 008 lansprazole users were followed over time (1994–1998). The study was designed according to the SAMM guidelines. A nested case–control design was used to compare proton pump inhibitor users reporting diarrhoea with those reporting no diarrhoea.

Results

The frequency of diarrhoea was 3.7% and the incidence density 10.7 per 1000 patient months of proton pump inhibitor use. The diarrhoea was most commonly loose and occurred on average 4.4 times per day. The analysis of co‐factors revealed that patients with concomitant use of oral antibiotics and patients reporting neurological and/or dermatological adverse events, were at risk of developing diarrhoea during proton pomp inhibitor use.

Conclusions

In conclusion, diarrhoea was as frequently reported in our study as in clinical trials and observational data of lansoprazole users. We found the concomitant use of oral antibiotics and the reporting of certain other adverse events to be associated with the reporting of diarrhoea during lansoprazole use. Although a relationship with the proton pump inhibitor intake seemed very plausible, we recommend that use of concomitant medicines as a cause of diarrhoea must be taken into consideration in lansoprazole users. Copyright © 2002 John Wiley & Sons, Ltd.