bluuebunny/crossref_metadata_2025 huggingface dataset:
The improved survival of hematopoietic cells cultured with a fusion protein of insulin-like growth factor II (IGF-II) and interleukin 3 (IL-3) is associated with increases in Bcl-xL and phosphatidylinositol-3 kinase activity
Authors: DiFalco Marcos R , Ali Suhad , Congote Luis Fernando
Published: March 2003

We compared the antiapoptotic activity of a recombinant chimera of insulin-like growth factor II (IGF-II) and interleukin (IL)-3 with the corresponding equimolar mixture of the individual components based on changes in several factors associated with survival in the CD34+ human hematopoietic cell line TF-1. Propidium iodide-stained cells analyzed by fluorescein-activated cell sorter indicated that the chimera was more effective than the corresponding equimolar mixture in decreasing the amounts of apoptotic cells and increasing the proportion of cells in the S-phase of the cell cycle. The chimera was more effective in increasing the antiapoptotic protein BclxL and produced a significant increase in signal transducer and activator of transcription-5 posphorylation and in phosphatidylinositol-3 kinase (PI-3K) activity. The PI-3K inhibitor LY294002 specifically inhibited cell survival in the presence of the chimera, suggesting a key role of this enzyme in the potentiation of survival caused by the linkage of IGF and IL-3. This potentiation of survival and its preferential inhibition by LY294002 were also observed in a nontransformed, primary culture of human umbilical cord endothelial cells.
Inhibition of actin polymerization by peroxynitrite modulates neutrophil functional responses
Authors: Clements Mark K , Siemsen Daniel W , Swain Steve D , Hanson Angela J , Nelson-Overton Laura K , Rohn Troy T , Quinn Mark T
Published: March 2003

Peroxynitrite, a potent oxidant generated in inflammatory tissues, can nitrate tyrosine residues on a variety of proteins. Based on previous studies suggesting that actin might be a potential target for peroxynitrite-mediated nitration in neutrophils, we investigated the effects of peroxynitrite on actin function. We show here that peroxynitrite and the peroxynitrite generator (SIN-1) modified actin in a concentration-dependent manner, resulting in an inhibition of globular-actin polymerization and filamentous-actin depolymerization in vitro. The effects of peroxynitrite were inhibited by the pyrrolopyrimidine antioxidant PNU-101033E, which has been shown previously to specifically block peroxynitrite-mediated tyrosine nitration. Furthermore, spectrophotometric and immunoblot analysis of peroxynitrite-treated actin demonstrated a concentration-dependent increase in nitrotyrosine, which was also blocked by PNU-101033E. Activation of neutrophils in the presence of a nitric oxide donor (S-nitroso-N-acetylpenicillamine) resulted in nitration of exogenously added actin. Nitrated actin was also found in peroxynitrite-treated neutrophils, suggesting that actin may be an important intracellular target during inflammation. To investigate this issue, we analyzed the effect of peroxynitrite treatment on a number of actin-dependent neutrophil processes. Indeed, neutrophil actin polymerization, migration, phagocytosis, and respiratory burst activity were all inhibited by SIN-1 treatment in a concentration-dependent manner. Therefore, the ability of peroxynitrite to inhibit actin dynamics has a significant effect on actin-dependent, cellular processes in phagocytic cells and may modulate their host defense function.
Alerting and tuning the immune response by extracellular nucleotides
Authors: la Sala Andrea , Ferrari Davide , Di Virgilio Francesco , Idzko Marco , Norgauer Johannes , Girolomoni Giampiero
Published: March 2003

The interplay between pro- and anti-inflammatory mechanisms during inflammatory and immune responses is critical for avoiding excessive tissue damage. Extracellular nucleotides (e.g., adenosine 5′-triphosphate) may represent constitutive signals that can alert the immune system of abnormal cell death. Relatively high doses of nucleotides induce rapid release of proinflammatory mediators and favor pathogen killing. However, recent findings on antigen presenting cells, particularly dendritic cells, revealed a more complex role for these molecules. Chronic exposure to low-dose nucleotides can redirect cellular responses to prototypic activation stimuli, leading to suppressed inflammation and immune deviation.
Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia
Authors: Kawaguchi Hiroshi , Kobayashi Masao , Nakamura Kazuhiro , Konishi Nakao , Miyagawa Shin-ichiro , Sato Takashi , Toyoda Hidemi , Komada Yoshihiro , Kojima Seiji , Todoroki Yukiko , Ueda Kazuhiro , Katoh Osamu
Published: March 2003

We examined the expression of granule constituent genes in myeloid progenitor cells during proliferation and differentiation in patients with severe congenital neutropenia (SCN). The heterozygous mutation of the neutrophil elastase gene was identified in two of four patients. The CD34+/granulocyte-colony stimulating factor receptor (G-CSFR)+ cells of SCN patients showed defective responsiveness to G-CSF in serum-deprived culture. The CD34+/G-CSFR+ cells expressed low levels of the granule constituent mRNAs. The transcription levels of primary granule enzyme genes in CD34+/G-CSFR+ cells were gradually enhanced and then decreased when cells were induced toward myeloid lineage with G-CSF in normal subjects. However, the primary up-regulation and the following down-regulation of these enzyme transcriptions were not clearly observed in SCN patients. No differences in expressions of the lactoferrin gene were seen between normal subjects and patients with SCN. We hypothesize that the abnormal regulation of the transcription in primary granule constituents might involve the defective proliferation and differentiation of myeloid cells in patients with SCN.
OX52 is the rat homologue of CD6: evidence for an effector function in the regulation of CD5 phosphorylation
Authors: Castro Mónica A A , Nunes Raquel J , Oliveira Marta I , Tavares Paula A , Simões Carla , Parnes Jane R , Moreira Alexandra , Carmo Alexandre M
Published: March 2003

The MRC OX52 monoclonal antibody is a marker of rat T lymphocytes. We have cloned by polymerasechain reaction the rat homologue of CD6, and fluorescein-activated cell sorter analysis and immunoprecipitations using OX52 in COS7 cells transfected with rat CD6 cDNA showed that CD6 is the cell-surface molecule recognized by OX52. Immunoprecipitation analysis showed that CD6 coprecipitated with CD5, which in turn, was coprecipitated equivalently with CD2, CD6, and the T cell receptor (TCR), but the fraction of CD5 associated with CD6 was highly phosphorylated in kinase assays, in marked contrast with the low level of phosphorylation of CD5 associated with TCR or CD2. Examination of protein kinases associating with these antigens showed that paradoxically, CD2 coprecipitated the highest amount of Lck and Fyn. CD6 also associated with Lck, Fyn, and ZAP-70, although at lower levels but additionally coprecipitated the Tec family kinase Itk, which is absent from CD2, CD5, and TCR complexes. Lck together with Itk was the best combination of kinases, effectively phosphorylating synthetic peptides corresponding to a cytoplasmic sequence of CD5. Overall, our results suggest that CD6 has an important role in the regulation of CD5 tyrosine phosphorylation, probably as a result of its unique feature of associating with kinases of different families.
Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP
Authors: Klegeris Andis , McGeer Patrick L
Published: March 2003

To explore whether the proinflammatory products of the 5-lipoxygenase (5-LOX) pathway are involved in microglia-mediated toxicity toward neuronal cells, we evaluated the effects of 5-LOX inhibitors using an in vitro assay system where human neuronal SH-SY5Y cells are exposed to toxic secretions from THP-1 monocytic cells or human microglia. The specific 5-LOX inhibitors, REV 5901, zileuton, and 5-hydroxyeicosatetraenoic acid lactone; the nonselective LOX inhibitors, phenidone and dapsone; the dual 5-LOX/cyclooxygenase inhibitor, tepoxalin; and the selective inhibitor of the 5-LOX-activating protein (FLAP), MK-886, inhibited such toxicity. The toxicity was enhanced by the 5-LOX product leukotriene (LT)D4 and reduced by the selective cysteinyl LT receptor (CysLT1) antagonist MK-571. The mRNAs for 5-LOX and FLAP were detected in THP-1 cells and human microglia but not in SH-SY5Y cells. The data suggest that inhibition of proinflammatory LT production by 5-LOX inhibition could selectively reduce toxicity of microglial cells and thus be beneficial in neuroinflammatory diseases.
Autoimmune sensorineural hearing loss: is it still a clinical diagnosis?
Authors: Mathews J. , Rao S. , Kumar B. N.
Published: March 2003

Inner ear involvement with sensorineural hearing loss (SNHL) has been reported in many autoimmune disorders including ulcerative colitis. The pathogenetic mechanism of hearing loss in ulcerative colitis is thought to be immune mediated. Diagnostic tests are being developed to identify inner ear autoantibodies, that may be the cause of such hearing loss. The only test that is currently available for clinical use is the Otoblot test. This, however, tests only for antibodies against bovine heat shock protein 70 which is only one of the many cross-reacting proteins against the inner ear in suspected immune-mediated hearing loss. The clinical response to steroid therapy is thus the mainstay in the diagnosis of immune-mediated hearing loss. This paper presents a series of patients with clinically suspected autoimmune hearing loss. Diagnostic assays for this condition are discussed along with a review of the recent advances in the pathogenesis and laboratory diagnosis of immune-mediated sensorineural hearing loss.
Is This Woman Perimenopausal?
Authors: Bastian Lori A. , Smith Crystal M. , Nanda Kavita
Published: March 2003

Context

Perimenopause is a time of transition for women at midlife. Women want to know whether they are starting this change and physicians need to know the accuracy of a clinical examination in identifying perimenopausal women.These women should be counseled about alleviating climacteric symptoms, using contraception, and preventing diseases such as osteoporosis.

Objective

To systematically review the accuracy of self-assessment, symptoms, signs, and laboratory tests in diagnosing women in perimenopause.

Data Sources

English-language articles that presented data relevant to diagnosis of perimenopause were identified in a MEDLINE search from 1966 to 2001. References of these articles and other publications also were reviewed.

Study Selection

Cross-sectional or longitudinal studies of women aged 40 years or older that used the definition of perimenopause as 3 to 11 months of amenorrhea or irregular periods, included a premenopausal control group, and reported a clinical examination finding. Of 1246 articles identified, 16 studies were included in the analysis.

Data Extraction

Two authors independently reviewed articles for quality (L.A.B. and C.M.S.). Discrepancies were resolved by a third author (K.N.).

Data Synthesis

The prior probability of perimenopause is directly related to a woman's age. After considering age, the following yielded the greatest positive likelihood ratios (LRs+): self assessment of going through the transition (LR+ range, 1.53-2.13), symptoms of hot flashes (LR+ range, 2.15-4.06), night sweats (LR+ 1.90; 95% confidence interval [CI], 1.63-2.21), vaginal dryness (LR+ range, 1.48-3.79), high follicle-stimulating hormone levels (LR+ 3.06; 95% CI, 2.06-4.54), and low inhibin B levels (LR+ 2.05; 95% CI, 0.96-4.39). Self-assessment of perimenopausal status had the smallest negative LR (range, 0.18-0.36).

Conclusions

No one symptom or test is accurate enough by itself to rule in or rule out perimenopause. Clinicians should diagnose perimenopause based on menstrual history and age without relying on laboratory test results.
A new patient with Lowry–Wood syndrome with mild phenotype
Authors: Brunetti‐Pierri Nicola , De Brasi Daniele , Ikegawa Shiro , Camera Giovanni , Andria Generoso , Sebastio Gianfranco
Published: March 2003

Lowry–Wood syndrome (LWS) is a rare condition characterized by multiple epiphyseal dysplasia (MED), microcephaly, and congenital nystagmus. A variable degree of mental retardation can also be present. It is probably inherited as an autosomal recessive trait. We report a new case of MED and microcephaly, without other additional features, suggesting a mild form of LWS. Molecular analysis of the cartilage oligomeric matrix protein (COMP) gene was performed and failed to find mutations. © 2003 Wiley‐Liss, Inc.
Direct Liquid‐Phase Sulfonation of Methane to Methanesulfonic Acid by SO3 in the Presence of a Metal Peroxide
Authors: Mukhopadhyay Sudip , Bell Alexis T.
Published: March 2003

Activation of methane by metal peroxides: Calcium peroxide serves as an effective radical initiator in the liquid‐phase sulfonation of methane to methansulfonic acid (MSA) by SO3 [Eq. (1)]. Under the best reaction conditions a 91 % conversion of SO3 to MSA was achieved.
Adhesion between poly(ethylene terephthalate) silk and chlorohydrin rubber for aerial film
Authors: Song Yuexian , Zheng Yuansuo , Wang Youdao
Published: March 2003

The surface adhesion activation of poly(ethylene terephthalate) silk (PET silk) was accomplished through dipping in a reaction product of a water‐soluble modified epoxide resin (SJR‐2) and a precondensed resorcinol‐formaldehyde (SJR‐1), and by partial curing of the dip. Then, the adhesion activated sample was coated with a single resorcinol‐formaldehyde latex (RFL) dip prepared from SJR‐1. The effects of heat treatment conditions and formulation of impregnation solution as well as RFL prepared with water‐soluble SJR‐1 resin on the adhesion between PET silk and chlorohydrin rubber for aerial film were studied. High adhesion between PET silk and chlorohydrin rubber was obtained by using optimized RFL formulation and heat treatment condition, and the high levels of adhesion were maintained after oil impregnating test, dynamic fatigue and storage stability test. The PET silk possessed good adhesion to natural rubber (NR), chloroprene rubber (CR), hydrogenated nitrile rubber (HNBR), acrylonitrile‐butadiene and rubber (NBR), and chlorohydrin rubber (CHR). RFL filled with diffused carbon black improved the fatigue endurance and oil resistance of adhesion. The adhesion activator is nontoxic. This method of adhesion activation and RFL preparation for adhesion treatment of poly(ethylene terephthalate) silk is a practical technique with excellent technological, economical, and safety effects. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 2097–2099, 2003
Quantitative evaluation of cotton‐bound glyoxal in the presence of glycols
Authors: Schramm C. , Rinderer B.
Published: March 2003

Cotton fabric is modified chemically to convey crease resistance to the cellulosic material by means of an appropriate crosslinking agent. For this purpose glyoxal was tested as a nonformaldehyde durable press agent. The cotton‐bound glyoxal can be quantified by means of isocratic HPLC, whereby the glyoxal‐treated fabric is hydrolyzed by a NaOH solution. During this pretreatment glyoxal is extracted from the cellulosic sample and converted into glycolate by an internal Cannizzaro reaction. The addition of glycols such as ethylene glycol or diethylene glycol into the formulation results in a remarkable decrease of the amount of glyoxal that is detected. This phenomenon can be explained by the fact that the glycol reacts with the glyoxal, thus hampering the internal Cannizzaro reaction. The acidic hydrolysis and the alkaline hydrolysis provide the same results, thus indicating that the alkaline treatment removes all the cotton‐bound glyoxal. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 1870–1875, 2003
Identification and characterization of a peptide mimetic that may detect a species of disease‐associated anticardiolipin antibodies in patients with the antiphospholipid syndrome
Authors: Visvanathan Sudha , Scott Jamie K. , Hwang Kwan‐Ki , Banares Michelle , Grossman Jennifer M. , Merrill Joan T. , FitzGerald John , Chukwuocha Reginald U. , Tsao Betty P. , Hahn Bevra H. , Chen Pojen P.
Published: March 2003

Objective

To test the feasibility of applying a mimetic (specific for a patient‐derived prothrombotic anticardiolipin antibody [aCL]) to study the homologous, disease‐associated aCL in patients with antiphospholipid syndrome (APS).

Methods

We used the CL15 monoclonal aCL to screen 17 phage‐display peptide libraries. Peptides (corresponding to recurrent peptide sequences) and their derivatives were synthesized and analyzed for binding to CL15 and for their abilities to inhibit CL15 from binding to cardiolipin. A peptide was chosen and used to study CL15‐like IgG aCL in plasma samples from patients with APS, patients with systemic lupus erythematosus (SLE) but without APS, and normal healthy donors.

Results

Library screening with CL15 yielded 4 recurrent peptide sequences. Analyses of peptides showed that peptide CL154C reacted with antibody CL15 and inhibited binding of CL15 to cardiolipin, indicating that peptide CL154C may be a peptide mimetic for the CL15 aCL. Initial studies with plasma samples revealed that CL154C‐reactive IgG was present (positivity defined as the mean + 3 SD optical density of the 25 normal controls) in 15 of 21 APS patients and 1 of 12 SLE patients.

Conclusion

These findings suggest that it is feasible to develop a specific enzyme‐linked immunosorbent assay for each immunologically and functionally distinct disease‐associated aCL. Additional testing of CL154C with a larger number of APS patients and SLE patients, as well as identification of peptide mimetics for each distinct aCL, will reveal the diagnostic potential of CL154C and other mimetics in identifying patients with aCL who are at risk of developing life‐threatening thrombosis.
Incorporating user search behavior into relevance feedback
Authors: Ruthven Ian , Lalmas Mounia , van Rijsbergen Keith
Published: March 2003

In this paper, we present five user experiments on incorporating behavioral information into the relevance feedback process. In particular, we concentrate on ranking terms for query expansion and selecting new terms to add to the user's query. Our experiments are an attempt to widen the evidence used for relevance feedback from simply the relevant documents to include information on how users are searching. We show that this information can lead to more successful relevance feedback techniques. We also show that the presentation of relevance feedback to the user is important in the success of relevance feedback.
Requirements for a cocitation similarity measure, with special reference to Pearson's correlation coefficient
Authors: Ahlgren Per , Jarneving Bo , Rousseau Ronald
Published: March 2003

Author cocitation analysis (ACA), a special type of cocitation analysis, was introduced by White and Griffith in 1981. This technique is used to analyze the intellectual structure of a given scientific field. In 1990, McCain published a technical overview that has been largely adopted as a standard. Here, McCain notes that Pearson's correlation coefficient (Pearson's r) is often used as a similarity measure in ACA and presents some advantages of its use. The present article criticizes the use of Pearson's r in ACA and sets forth two natural requirements that a similarity measure applied in ACA should satisfy. It is shown that Pearson's r does not satisfy these requirements. Real and hypothetical data are used in order to obtain counterexamples to both requirements. It is concluded that Pearson's r is probably not an optimal choice of a similarity measure in ACA. Still, further empirical research is needed to show if, and in that case to what extent, the use of similarity measures in ACA that fulfill these requirements would lead to objectively better results in full‐scale studies. Further, problems related to incomplete cocitation matrices are discussed.
Pharmacokinetics of intravenous chlorzoxazone in rats with dehydration and rehydration: effects of food intakes
Authors: Kim Yu C. , Kim Yoon G. , Kim Eun J. , Cho Min K. , Kim Sang G. , Lee Myung G.
Published: March 2003

The following results were obtained recently from our laboratories; in rats with 72‐h water deprivation (rats with dehydration), the hepatic cytochrome P450 2E1 (CYP2E1) was three‐fold induced with an increase in the mRNA. Rehydration of 48‐h water‐deprived rats for the next 24 h with free access of food (rats with rehydration) restored CYP2E1 level to that of control. However, rehydration of 48‐h water‐deprived rats for the next 24 h with limited food supply (20% of control) failed to restore the CYP2E1 level to that of control. Hence, the CYP2E1 changes in rats with dehydration and rehydration resulted from differences in food intakes but not from dehydration or rehydration per'se. Chlorzoxazone (CZX) is metabolized to 6‐hydroxychlorzoxazone (OH‐CZX) mainly by CYP2E1 in rats. Therefore, the pharmacokinetics of CZX and OH‐CZX were compared after intravenous administration of CZX, 25 mg/kg, to control rats and rats with dehydration and rehydration with free access of food. In rats with dehydration, the amount of 24‐h urinary excretion of free OH‐CZX plus its glucuronide conjugates (Ae OH−CZX, 0–24 h, expressed in terms of intravenous dose of CZX) was significantly greater (45.6 compared with 35.6%) and area under the plasma concentration–time curve from time zero to time infinity (AUC) of CZX was significantly smaller (2190 compared with 3200 µg min/ml) than those in control rats. The above data indicated that the formation of OH‐CZX increased significantly in rats with dehydration due to 3‐fold induction of CYP2E1. In rats with rehydration with free access of food, the Ae OH−CZX, 0–24 h (39.0 compared with 35.6%) and AUC of CZX (2870 compared with 3200 µg min/ml) were restored (comparable) to control levels since the expression of CYP2E1 in rats with dehydration returned to control level by rehydration. The above data indicate that CZX could be used as a chemical probe to assess the activity of CYP2E1 in rats with dehydration and rehydration. Copyright © 2003 John Wiley & Sons, Ltd.
Specific congenital heart defects in RSH/Smith‐Lemli‐Opitz syndrome: Postulated involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia
Authors: Digilio Maria Cristina , Marino Bruno , Giannotti Aldo , Dallapiccola Bruno , Opitz John M.
Published: March 2003

BACKGROUND

RSH/Smith‐Lemli‐Opitz syndrome is an autosomal recessive syndrome due to an inborn error of cholesterol metabolism and is characterized by developmental delay, facial anomalies, hypospadias, congenital heart defect (CHD), postaxial polydactyly, and 2–3 toe syndactyly. CHD is found in half of the propositi, and a specific association with atrioventricular canal defect (AVCD) and anomalous pulmonary venous return has been demonstrated.

METHODS

We report on an additional patient with RSH/SLOS presenting with complete AVCD and anomalous pulmonary venous return, and discuss the possible relationship of the Sonic Hedgehog (SHH) pathway as causative factor of these CHDs and those in heterotaxia patients with postaxial polydactyly syndromes.

RESULTS

Anatomic similarities between heterotaxia and CHDs of several syndromes with postaxial polydactyly have been noted previously, considering the frequent association of AVCD with common atrium in these conditions. It is known that both CHDs of heterotaxia and postaxial polydactyly can be related to abnormalities of the SHH pathway. Cholesterol has a critical role in the formation of normally active hedgehog proteins. It could be hypothesized that specific types of CHDs in RSH/SLOS can be caused by modifications of the SHH protein related to the defect of cholesterol biosynthesis.

CONCLUSIONS

The specific association of AVCD and anomalous pulmonary venous return in patients with RSH/SLOS and the finding of AVCD ± common atrium in several syndromes with polydactyly leads to the hypothesis that heterotaxia due to SHH anomalies could be involved in a large spectrum of conditions. Perturbations in different components of the SHH pathway could lead to several developmental errors presenting with partially overlapping clinical manifestations. Birth Defects Research (Part A) 67149–153, 2003. © 2003 Wiley‐Liss, Inc.
Guidelines for case classification for the national birth defects prevention study
Authors: Rasmussen Sonja A. , Olney Richard S. , Holmes Lewis B. , Lin Angela E. , Keppler‐Noreuil Kim M. , Moore Cynthia A.
Published: March 2003

Background

Previous studies have suggested that etiologic heterogeneity may complicate epidemiologic analyses designed to identify risk factors for birth defects. Case classification uses knowledge of embryologic and pathogenetic mechanisms to make case groups more homogeneous and is important to the success of birth defects studies.

METHODS

The goal of the National Birth Defects Prevention Study (NBDPS), an ongoing multi‐site case–control study, is to identify environmental and genetic risk factors for birth defects. Information on environmental risk factors is collected through an hour‐long maternal interview, and DNA is collected from the infant and both parents for evaluation of genetic risk factors. Clinical data on infants are reviewed by clinical geneticists to ensure they meet the detailed case definitions developed specifically for the study. To standardize the methods of case classification for the study, an algorithm has been developed to guide NBDPS clinical geneticists in this process.

RESULTS

Methods for case classification into isolated, multiple, and syndrome categories are described. Defects considered minor for the purposes of case classification are defined. Differences in the approach to case classification for studies of specific defects and of specific exposures are noted.

CONCLUSIONS

The case classification schema developed for the NBDPS may be of value to other clinicians working on epidemiologic studies of birth defects etiology. Consideration of these guidelines will lead to more comparable case groups, an important element of careful studies aimed at identifying risk factors for birth defects. Birth Defects Research (Part A) 67:193–201, 2003. © 2003 Wiley‐Liss, Inc.
Population‐based study of l‐transposition of the great arteries: Possible associations with environmental factors
Authors: Kuehl Karen S. , Loffredo Christopher A.
Published: March 2003

BACKGROUND

L transposition of the great arteries (l‐tga) is an uncommon congenital cardiovascular malformation that occurs from abnormal looping of the primitive cardiac tube. Little is known about risk factors for the development of l‐tga.

METHODS

This study is a case–control study of 36 cases of l‐tga compared to 3,495 population‐based live born infant controls in the Baltimore Washington Infant Study (1981–1989 births). Extensive personal and occupational exposure data from parental interviews were available for all subjects. A geographic information system was used to identify potential environmental exposures, for example, hazardous waste sites prioritized for cleanup (National Priority List sites). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using exact parameter estimates from logistic regression.

RESULTS

Most infants with l‐tga had multiple cardiovascular anomalies, with single ventricle in 47%. Over 75% of all cases of l‐tga occur in two regions of contiguous cases. Within these regions, the case control OR of l‐tga are 13.4 (95%CI, 4.7–37.8) Both areas are characterized by release of toxic chemicals into air and by hazardous waste sites. Parental exposures to hair dye, smoking and laboratory chemicals are also associated with case status.

CONCLUSIONS

L‐tga, a congenital cardiovascular malformation due to very early abnormalities in embryogenesis, is associated strongly with residency in two small regions of Maryland and District of Columbia (DC), and with other parental personal or occupational exposures. Additional research is needed to identify the components of spatial and other associations that constitute etiologic risk factors. Birth Defects Research (Part A) 67162–167, 2003. © 2003 Wiley‐Liss, Inc.
Exposure‐disease continuum for 2‐chloro‐2′‐deoxyadenosine, a prototype ocular teratogen. 3. Intervention with PK11195
Authors: Charlap Jeffrey H. , Donahue Ronald J. , Knudsen Thomas B.
Published: March 2003

BACKGROUND

Treatment of pregnant mice with 2‐chloro‐2′‐deoxyadenosine (2CdA) on Day 8 of gestation induces microphthalmia through a mechanism linked to the p53 tumor suppressor pathway. The present study defines the response of Day 8 mouse embryos through time with respect to pharmacologic intervention with PK11195, a ligand of the mitochondrial peripheral benzodiazepine receptor (Bzrp).

METHODS

Pregnant CD‐1 mice dosed with 2CdA with or without PK11195 on gestation Day 8 provided fetuses for teratologic evaluation on Day 14 and Day 17; HPLC measured pyridine nucleotides (NADH/NAD+) at 1.5 hr, RT‐PCR measured mitochondrial 16S rRNA abundance at 3.0 hr, and p53 protein induction was assessed with immunostaining at 4.5 hr postexposure.

RESULTS

The mean incidences of malformed fetuses were significantly higher in the 7.5 mg/kg 2CdA treatment group (50.2% malformed) vs. the 2CdA + 4.0 mg/kg PK11195 co‐treatment group (4.4% malformed). Malformed fetuses displayed a range of ocular defects that included microphthalmia and keratolenticular dysgenesis (Peters anomaly). No malformations were observed in the control or PK11195 alone groups. PK11195 also protected litters from increased resorption rates and fetal weight reduction. It did not rescue early effects on NADH balance (1.5 hr) or 16S rRNA expression (3.0 hr); however, the p53 response (4.5 hr) was downgraded in 2CdA + PK11195 embryos vs. 2CdA alone. By delaying the administration of PK11195 in 1.5 hr intervals it was determined that the window for protection closed between 4.5 to 6.0 hr after 2CdA.

CONCLUSIONS

The capacity of PK11195 to suppress the pathogenesis of microphthalmia implies a critical role for mitochondrial peripheral benzodiazepine receptors in the p53‐dependent mode of action of 2CdA on ocular development. Birth Defects Research (Part A) 67:108–115, 2003. © 2003 Wiley‐Liss, Inc.
T‐box genes and cardiac development
Authors: Ryan Kenneth , Chin Alvin J.
Published: March 2003

Background

T‐box genes play roles in vertebrate gastrulation and in later organogenesis. Their existence in all metazoans examined so far indicates that this is an evolutionarily ancient gene family. Drosophila melanogaster has eight T‐box genes, whereas Caenorhabditis elegans has 22. Mammals appear to have at least 18 T‐box genes, comprising five subfamilies.

Methods

A full range of cytological, developmental, molecular and genetic methodologies have recently been applied to the study of T‐box genes.

Results

Over the last 5 years, mutations in TBX1 and TBX5 have been implicated in two human disorders with haplo‐insufficient cardiovascular phenotypes, DiGeorge/velocardiofacial syndrome and Holt‐Oram (“heart‐hand”) syndrome. Interestingly, the number of T‐box gene family members discovered to have cardiac or pharyngeal arch expression domains during vertebrate embryonic development has steadily grown. In addition, various Tbx5 loss‐of‐function models in organisms as distant as the mouse and zebrafish do indeed phenocopy Holt‐Oram syndrome. Finally, the intriguing discovery earlier this year that a T‐box gene is expressed in a subset of cardioblasts in D. melanogaster suggests that members of this gene family may have fundamental, conserved roles in cardiovascular pattern formation.

Conclusions

These developments prompted us to review the current understanding of the contribution of T‐box genes to cardiovascular morphogenesis. Birth Defects Research (Part C) 69:25–37, 2003. © 2003 Wiley‐Liss, Inc.
Neural crest and cardiovascular development: A 20‐year perspective
Authors: Hutson Mary Redmond , Kirby Margaret L.
Published: March 2003

Background

Twenty years ago this year was the first publication describing a region of neural crest cells necessary for normal cardiovascular development. Ablation of this region in chick resulted in persistent truncus arteriosus, mispatterning of the great vessels, outflow malalignments, and hypoplasia or aplasia of the pharyngeal glands.

Methods

We begin with a historical perspective and then review the progress that has been made in the ensuing 20 years in determining the direct and indirect contributions of the neural crest cells, now termed cardiac neural crest cells, in cardiovascular and pharyngeal arch development. Many of the molecular pathways that are now known to influence the specification, migration, patterning and final targeting of the cardiac neural crest cells are also reviewed.

Results

Although much knowledge has been gained by using many genetic manipulations to understand the cardiac neural crest cells' role in cardiovascular development, most models fail to explain the phenotypes seen in syndromic and non‐syndromic human congenital heart defects, such as the DiGeorge syndrome.

Conclusions

We propose that the cardiac neural crest exists as part of a larger cardiocraniofacial morphogenetic field and describe several human syndromes that result from abnormal development of this field. Birth Defects Research (Part C) 69:2–13, 2003. © 2003 Wiley‐Liss, Inc.
Development of the cardiac pacemaking and conduction system
Authors: Gourdie Robert G. , Harris Brett S. , Bond Jaqueline , Justus Charles , Hewett Kenneth W. , O'Brien Terrence X. , Thompson Robert P. , Sedmera David
Published: March 2003

The heartbeat is initiated and coordinated by a heterogeneous set of tissues, collectively referred to as the pacemaking and conduction system (PCS). While the structural and physiological properties of these specialized tissues has been studied for more than a century, distinct new insights have emerged in recent years. The tools of molecular biology and the lessons of modern embryology are beginning to uncover the mechanisms governing induction, patterning and developmental integration of the PCS. In particular, significant advances have been made in understanding the developmental biology of the fast conduction network in the ventricles – the His‐Purkinje system. Although this progress has largely been made by using animal models such as the chick and mouse, the insights gained may help explain cardiac disease in humans, as well as lead to new treatment strategies. Birth Defects Research (Part C) 69:46–57, 2003. © 2003 Wiley‐Liss, Inc.
A Combined Invariant Test for a Null Variance Ratio
Authors: El‐Bassiouni M.Y. , Halawa A.M.
Published: March 2003

This paper investigates the properties of a test that combines the Wald and LMPI (locally most powerful invariant) tests of variance components in unbalanced mixed models. The combined test statistic is easily computed and its null distribution may be approximated by a central F distribution with the degrees of freedom of the numerator adjusted in accordance with the degree of imbalance of the design. Numerical methods are used to show that the approximation is accurate over a wide range of conditions and that the efficiency of the combined test, relative to the power envelope, is satisfactorily high overall.
Extracellular domains of the neurokinin‐1 receptor: Structural characterization and interactions with substance P
Authors: Ulfers Amy L. , Piserchio Andrea , Mierke Dale F.
Published: March 2003

The technical difficulties associated with the structure determination of membrane proteins have limited the structural information available for the ligand binding to G‐protein coupled receptors (GPCRs). Here, we describe a reductionist approach to GPCR structure determination in which the extracellular domains of the receptor are examined by high‐resolution NMR in the presence of a membrane mimetic. The resulting structural features are then incorporated into a molecular model of the receptor, utilizing the x‐ray structure of rhodopsin to generate the topological orientation of the transmembrane helices. The results of our study of the neurokinin‐1 receptor (NK‐1R) and its interactions with substance P (SP) are detailed here. The structure of the N‐terminus, NK‐1R(1–39), and of the third extracellular loop, NK‐1R(264–290), in the presence of dodecylphosphocholine micelles is described. Our findings provide a structural basis for the interpretation of the results from other methods including mutagenesis, fluorescence, and photoaffinity labeling experiments, resulting in an experimentally based, high‐resolution model of SP binding to NK‐1R. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 339–349, 2002
Glycine receptors: Lessons on topology and structural effects of the lipid bilayer
Authors: Cascio Michael
Published: March 2003

The members of the superfamily of nicotinicoid receptors, sometimes referred to as the ligand‐gated ion channel superfamily (LGICS), are essential mediators in the propagation of electrical signals between cells at neuronal and neuromuscular synapses. Given the significant sequence and proposed topological similarities between family members, the structural architecture of any one of these neuroreceptors is believed to be archetypic for the family of ligand‐gated channels. We have focused our biophysical studies on the glycine receptor (GlyR) since homomeric expression of just the α1 chain of the receptor is sufficient to reconstitute native‐like activity when expressed in heterologous cells, and we have successfully overexpressed and purified relatively large quantities of this receptor. Our CD data suggests that the historical four transmembrane helix topology model for nicotinicoid receptors may be erroneous. Proteolytic studies as well as chemical modification studies coupled with mass spectroscopy (MS) have provided additional evidence that this model may be inappropriate. While we suggest a novel topological model for the superfamily of nicotinicoid receptors, the absence of high resolution data for the transmembrane regions of these ion channels precludes further refinement of this model. In addition, we observe structural changes in the recombinant α1 GlyR as a function of bilayer composition, suggesting that these receptors may be dynamically modulated by cellular control over the properties of the plasma membrane. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 359–368, 2002
Innovative magnetic resonance imaging diagnostic agents based on paramagnetic Gd(III) complexes
Authors: Aime Silvio , Dastrù Walter , Crich Simonetta Geninatti , Gianolio Eliana , Mainero Valentina
Published: March 2003

Gd(III) complexes are under intense scrutiny as contrast agents for magnetic resonance imaging (MRI). They act by enhancing tissutal proton relaxation rates. Much has already been done in order to get an in‐depth understanding of the relationships between structure, dynamics, and contrastographic ability of these paramagnetic complexes. Their potential in the assessment of flow, perfusion, and capillary permeability has already been established. The next challenges are in the field of molecular imaging applications, which would allow the attainment of early diagnosis based on the recognition of specific reporters of the onset of the pathological state. To this end, Gd(III) complexes have to be endowed with improved targeting capabilities by conjugating suitable recognition synthons on their surfaces. Small peptides are candidates of choice for the attainment of this goal. Moreover, the intrinsic low sensitivity of the NMR techniques implies the need to deliver large amounts of contrast agents to the target in order to get its visualization in the resulting images. Highly efficient delivery systems have been identified, which bring a great promise for the development of innovative diagnostic agents based on Gd(III) complexes. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 419‐428, 2002
Pressure treatment of tailspike aggregates rapidly produces on‐pathway folding intermediates
Authors: Lefebvre Brian G. , Robinson Anne Skaja
Published: March 2003

Protein folding and aggregation are in direct competition in living systems, yet measuring the two pathways simultaneously has rarely been accomplished. In order to identify the mechanism of high‐pressure dissociation of aggregates, we compared the simultaneous on‐ and off‐pathway behavior following dilution of freshly denatured P22 tailspike protein. Tailspike assembly at 100 μg/mL was monitored at four temperatures using a combination of size‐exclusion chromatography and native polyacrylamide gel electrophoresis (PAGE) and folding and aggregation rates and yields were determined. As temperature increased, the yield of native trimeric tailspike decreased from 26.1 ± 1.3 μg/mL at 20°C to 0 μg/mL at 37°C. Pressure treatment dissociated 60% of the trapped aggregates created at 37°C and yielded 19.8 ± 1.1 μg/mL of native trimer following depressurization and incubation at 20°C. The rate of refolding of “freshly denatured” tailspike was compared to that following pressure treatment. The trimer formation rate increased by a factor of roughly five, and the aggregate rate decreased by a factor of three, following pressure treatment. Circular dichroism and high‐pressure intrinsic tryptophan fluorescence measurements support the model that a structured intermediate is formed in a rapid manner under high pressure from a pressure‐sensitive aggregate population. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng 82: 595–604, 2003.
Applying a Thermodynamic Model to the Non‐Stoichiometric Precipitation of Barium Sulfate
Authors: Vicum L. , Mazzotti M. , Baldyga J.
Published: March 2003

Thermodynamic models for aqueous Ba2+‐SO42–‐Na+‐Cl–‐solutions are compared in their accuracy to predict ion activities in saturated and supersaturated solutions. The Pitzer and the Bromley model are employed, taking into account ion pair formation of barium sulfate. Such models are then used to describe particle nucleation and growth, and finally they are imbedded in a mechanistic mixing‐precipitation model for a single feed semibatch process. The effect of the key operating parameters on the mean particle size is analyzed through simulations. The results are compared with previous experimental data, thus highlighting the significance of a proper choice of the thermodynamic model.
Barium Sulphate Agglomeration in a Pipe – An Experimental Study and CFD Modeling
Authors: Bałdyga J. , Jasińska M. , Orciuch W.
Published: March 2003

Agglomeration effects, observed during precipitation of barium sulphate in the unpremixed feed two‐dimensional tubular precipitator, are studied experimentally and interpreted theoretically. Effects of process parameters on precipitation–agglomeration phenomena are predicted using a CFD based model that describes micromixing (the multiple‐time‐scale turbulent mixer model is used) and precipitation (including nucleation, growth and agglomeration of crystals). Agglomeration rate is defined as a product of the collision frequency and the probability of agglomeration.
Dynamic Compartmental Models of Uniformly‐Mixed and Inhomogeneously‐Mixed Gibbsite Crystallizers
Authors: Li T.S. , Livk I. , Lane G. , Ilievski D.
Published: March 2003

The use of simple compartmentalized population balance (PB) models was investigated for describing the crystal size distributions (CSD) of two different laboratory batch gibbsite crystallizers, one uniformly‐mixed and the other inhomogeneously‐mixed with respect to particulate phase. The compartments were selected on the basis of the shear rate and solids concentration distribution maps generated by the computational fluid dynamics (CFD). In the inhomogeneously‐mixed case, the CSD predicted by the compartmental model was highly sensitive to the relationship between the agglomeration kernel and shear rate used to describe the local agglomeration rate. This observation is consistent with recent findings reported in the literature that to correctly account for the agglomeration process in crystallizers its kinetic formulation should be based on the local rather than the volume‐averaged properties.
Two dimensional heat conduction in graded materials using conformal mapping
Authors: Shaw Richard P. , Manolis George D.
Published: March 2003

Heat conduction through non‐homogeneous materials has numerous applications, since many of the man‐made materials that are used in various disciplines such as aerospace, construction, electronics, etc., are composites with carefully manufactured properties that yield desirable thermal characteristics. To that end, fundamental solutions for the heterogeneous heat conduction problem in two dimensions are derived in this work by employing a conformal mapping technique. These functions, besides being useful in their own right, can also be used within the context of integral equation formulations for the solution of boundary‐value problems. Finally, numerical examples for a material described by a family of radially symmetric conductivity are given as an illustration of the proposed method. Copyright © 2003 John Wiley & Sons, Ltd.
On computation of response of a rotor in deformed configuration using three‐dimensional finite elements
Authors: Nandi A.
Published: March 2003

The governing differential equations for a rotor are derived in a rotating reference, which rotates about the centre‐line of the bearings with a speed equal to the shaft spin speed. The same equations of motion are once solved in the original configuration and once in the deformed configuration. It is observed that, though the analysis is based on small displacement elasticity, the difference in the above solutions is not negligible. It is shown that this can be attributed to the moment resultant caused by the centrifugal force in the deformed configuration. Copyright © 2003 John Wiley & Sons, Ltd.
Exact controllability for the magnetohydrodynamic equations
Authors: Barbu Viorel , Havârneanu Teodor , Popa Cătălin , Sritharan S. S.
Published: March 2003

We study the local exact controllability of the steady state solutions of the magnetohydrodynamic equations. The main result of the paper asserts that the steady state solutions of these equations are locally controllable if they are smooth enough. We reduce the local exact controllability of the steady state solutions of the magnetohydrodynamic equations to the global exact controllability of the null solution of the linearized magnetohydrodynamic system via a fixed‐point argument. The treatment of the reduced problem relies on two Carleman‐type inequalities for the backward adjoint system. © 2003 Wiley Periodicals, Inc.
Electrical characterization of linear and non‐linear random networks and mixtures
Authors: Bianco B. , Giordano S.
Published: March 2003

A material composed of a mixture of distinct homogeneous media can be considered as a homogeneous one at a sufficiently large observation scale. The problem of mixture characterization has been exactly solved in case of linear random mixtures, that is, materials for which the various components are isotropic, linear and mixed together as an ensemble of particles having random shapes and positions. In the present work the authors briefly review the linear theory and then consider mixtures of non‐linear media. In particular they give formulas for obtaining their constitutive equations for current density, electrical displacement, and magnetic induction. These relations have been derived by means of heuristic considerations on random networks and they have been verified with simulations obtaining a high degree of accuracy. Copyright © 2003 John Wiley & Sons, Ltd.