bluuebunny/crossref_metadata_2025 huggingface dataset:
Expressions of VEGF and its receptors in rat corpus luteum during interferon alpha administration in early and pseudopregnancy
Authors: Celik‐Ozenci Ciler , Akkoyunlu Gokhan , Korgun Emin Turkay , Savas Burhan , Demir Ramazan
Published: February 2004

It is accepted that angiogenesis plays an important role in the development of the corpus luteum (CL) and is probably necessary for normal lutein cell function. A number of drugs currently being tested in clinical trials as possible angiogenesis inhibitors were not originally developed with the intention of suppressing tumor angiogenesis. Interferon alpha (IFN‐α) is one of the notable examples of such ‘accidental angiogenesis inhibitors’ and daily administration of IFN‐α is known to suppress tumor growth, tumor vascularization, and down‐regulation of various growth factors. We investigated the effects of IFN‐α treatment on the expression of vascular endothelial growth factor (VEGF), and its receptors KDR and Flt‐1, and CD34 in CL during the first week of pseudopregnancy and pregnancy in hormonally induced rat ovaries by immunohistochemistry and Western blot techniques. Basal body temperatures of the drug‐treated rats, as an indicator of treatment effect, were determined daily and were increased significantly when compared to controls (38.03 ± 0.18 vs. 36.6 ± 0.1°C), respectively. The effect of IFN‐α treatment was minimal when the entire week was evaluated, however, the expression of VEGF decreased at 3rd, 5th, and 7th days of both pregnancy and pseudopregnancy, when compared to the 1st day, whereas there was not a such alteration in the untreated rats regarding these days. The daily subcutaneous administrations of 672.500 U IFN‐α2b had minimal effects on the expressions of VEGF, and its two receptors KDR and Flt‐1 in either pregnant or pseudopregnant corpora lutea utilizing HSCORE. Mol. Reprod. Dev. 67: 414–423, 2004. © 2004 Wiley‐Liss, Inc.
Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) expression during induced luteolysis in the bovine corpus luteum
Authors: Neuvians Tanja P. , Berisha Bajram , Schams Dieter
Published: February 2004

Angiogenic factors, like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), and their receptors, are strongly regulated during the development of bovine corpus luteum (CL). The aim of this study was to investigate real‐time changes of these factors in luteal tissue of cows (n = 4–5 per group) in the mid‐luteal phase (day 8–12) after intramuscular injection of the PGF2α‐analog Cloprostenol. Before (control) and 2, 4, 12, 48, and 64 hr after prostaglandin (PG) injection, CL were collected by transvaginal ovariectomy. RT‐PCR for VEGF, VEGF‐receptor type 1 (VEGF‐R1), VEGF‐R2, acidic FGF (FGF‐1), basic FGF (FGF‐2), and FGF‐receptor (FGF‐R) was performed. Additionally, the protein concentration for VEGF was determined. The mRNA expression of VEGF and its two receptors (VEGF‐R1 and ‐R2) was significantly downregulated during structural luteolysis (after 12 hr). VEGF protein concentration already significantly declined 2 hr after PGF2α. Surprisingly FGF‐1 and FGF‐2 were significantly and maximally upregulated during functional luteolysis (until 12 hr). Furthermore, FGF‐R mRNA was significantly upregulated at 2 hr after PGF2α, when compared with the control group. During structural luteolysis, the expression of FGFs and their receptors was not significantly different from control, except FGF‐2 mRNA, which was downregulated at 64 hr. We conclude that the cessation of VEGF‐support for the CL plays a role during structural luteolysis, whereas FGFs seem to have a major impact on functional luteolysis. The possible role of these growth factors could be a transient counter‐regulation of luteolysis, but also an involvement in preventing inflammatory reactions during luteal regression. Mol. Reprod. Dev. 67: 389–395, 2004. © 2004 Wiley‐Liss, Inc.
Polycystin‐2 associates with the polycystin‐1 homolog, suREJ3, and localizes to the acrosomal region of sea urchin spermatozoa
Authors: Neill Anna T. , Moy Gary W. , Vacquier Victor D.
Published: February 2004

Polycystin‐2, the protein mutated in type 2 autosomal dominant polycystic kidney disease, is an integral transmembrane protein with nonselective cation channel activity. Here we report on the sea urchin sperm homolog of polycystin‐2 (suPC2). Like other polycystin‐2 family members, suPC2 is a six‐pass transmembrane protein containing C‐terminal cytoplasmic EF hand and coiled‐coil domains. The protein localizes exclusively to the plasma membrane over the sperm acrosomal vesicle. This localization coincides with the previously reported localization of the sea urchin PC1 homolog, suREJ3. Co‐immunoprecipitation shows that suPC2 and suREJ3 are associated in the membrane. The location of suPC2 sug‐gests that it may function as a cation channel mediating the sperm acrosome reaction. The low cation selectivity of PC2 channels would explain data indicating that Na+ and Ca2+ may enter sea urchin sperm through the same channel during the acrosome reaction. Mol. Reprod. Dev. 67: 472–477, 2004. © 2004 Wiley‐Liss, Inc.
Bovine sperm capacitation: assessment of phosphodiesterase activity and intracellular alkalinization on capacitation‐associated protein tyrosine phosphorylation
Authors: Galantino‐Homer Hannah L. , Florman Harvey M. , Storey Bayard T. , Dobrinski Ina , Kopf Gregory S.
Published: February 2004

Mammalian sperm capacitation is the obligatory maturational process leading to the development of the fertilization‐competent state. Heparin is known to be a unique species‐specific inducer of bovine sperm capacitation in vitro and glucose a unique inhibitor of this induction. Heparin‐induced capacitation of bovine sperm has been shown to correlate with protein kinase A (PKA)‐dependent protein tyrosine phosphorylation driven by an increase in intracellular cAMP. This study examines the possible roles of cyclic nucleotide phosphodiesterase (PDE) activity and intracellular alkalinization on bovine sperm capacitation and the protein tyrosine phosphorylation associated with it. Measurement of whole cell PDE kinetics during capacitation reveals neither a substantial change with heparin nor one with glucose: PDE activity is effectively constitutive in maintaining intracellular cAMP levels during capacitation. In contrast to a transient increase in intracellular pH, a sustained increase in medium pH by switching from 5% CO2/95% air incubation to 1% CO2/99% air incubation over 4 hr in the absence of heparin resulted in an increase in protein tyrosine phosphorylation and in the extent of induced acrosome reaction comparable to that observed following heparin‐induced capacitation in 5% CO2. These results suggest that increased bicarbonate‐dependent adenylyl cyclase activity, driven by alkalinization, increases intracellular cAMP and so increases PKA activity mediating protein tyrosine phosphorylation. Quantitative analysis of the lactic acid production rate by bovine sperm glycolysis accounts fully for intracellular acidification sufficient to offset heparin‐induced alkalinization, thus inhibiting capacitation. The mechanism by which heparin uniquely induces intracellular alkalinization in bovine sperm leading to capacitation remains obscure, inviting future investigation. Mol. Reprod. Dev. 67: 487–500, 2004. © 2004 Wiley‐Liss, Inc.
Functionally distinctive testicular cell lines of zebrafish to support male germ cell development
Authors: Kurita Kayoko , Sakai Noriyoshi
Published: February 2004

Here we describe two testicular cell lines of zebrafish with distinct functions to support the development of male germ cells. Twelve cell lines were established by single‐colony isolation from tumor‐like testis‐derived ZtA6 cells, and the features characteristic of Sertoli cells such as phagocytic activity and transcription both of their specific genes, sox9a and Wilms' tumor suppressor WT1, and of the vas gene of germ cells were analyzed in the lines. Six lines exhibited these three characteristics of Sertoli cells. Despite the single‐colony isolation, low levels of vas expression were detected in three lines. Two lines, ZtA6‐2 and ZtA6‐12, showed almost the same characteristics as Sertoli cells, but exhibited distinctive features when male germ cells were cocultured with each line as feeders. The in vitro fertilization by the culture of germ cells with ZtA6‐12 produced more embryos than that with ZtA6‐2. In contrast, ZtA6‐2 gave rise to large clumps of germ cells after a 12‐day culture, while ZtA6‐12 still produced only small clumps. Expression of vas, strongly expressed in spermatogonia and premeiotic spermatocytes, was prolonged in the culture with ZtA6‐2, while it reduced in that with ZtA6‐12. Compared with the previous results obtained on the original ZtA6 cells, these results suggested that the function of the ZtA6‐2 cells was directed to stimulate the proliferation of spermatogonia, and ZtA6‐12 to stimulate the differentiation into sperm. These cell lines will facilitate investigation of Sertoli cell molecules that contribute to the proliferation and differentiation of spermatogonia, and the longer culture time of male germ cells by using these lines successively. Mol. Reprod. Dev. 67: 430–438, 2004. © 2004 Wiley‐Liss, Inc.
Subzero water transport characteristics of boar spermatozoa confirm observed optimal cooling rates
Authors: Devireddy R.V. , Fahrig B. , Godke R.A. , Leibo S.P.
Published: February 2004

Incomplete understanding of the water transport parameters (reference membrane permeability,Lpg, and activation energy,ELp) during freezing in the presence of extracellular ice and cryoprotective agents (CPAs) is one of the main limiting factors in reconciling the difference between the numerically predicted value and the experimentally determined optimal rates of freezing in boar (and in general mammalian) gametes. In the present study, a shape‐independent differential scanning calorimeter (DSC) technique was used to measure the water transport during freezing of boar spermatozoa. Water transport data during freezing of boar sperm cell suspensions were obtained at cooling rates of 5 and 20°C/min in the presence of extracellular ice and 6% (v/v) glycerol. Using previously published values, the boar sperm cell was modeled as a cylinder of length 80.1 μm and a radius of 0.31 μm with an osmotically inactive cell volume,Vb, of 0.6Vo, whereVois the isotonic cell volume. By fitting a model of water transport to the experimentally obtained data, the best‐fit water transport parameters (LpgandELp) were determined. The “combined‐best‐fit” parameters at 5 and 20°C/min for boar spermatozoa in the presence of extracellular ice are:Lpg = 3.6 × 10−15m3/N · s (0.02 μm/min‐atm) andELp = 122.5 kJ/mole (29.3 kcal/mole) (R2= 0.99); and the corresponding parameters in the presence of extracellular ice and glycerol are:Lpg[cpa] = 0.90 × 10−15m3/N · s (0.005 μm/min‐atm) andELp[cpa] = 75.7 kJ/mole (18.1 kcal/mole) (R2 = 0.99). The water transport parameters obtained in the present study are significantly different from previously published parameters for boar and other mammalian spermatozoa obtained at suprazero temperatures and at subzero temperatures in the absence of extracellular ice. The theoretically predicted optimal rates of freezing using the new parameters (∼30°C/min) are in close agreement with previously published but experimentally determined optimal cooling rates. This analysis reconciles a long‐standing difference between theoretically predicted and experimentally determined optimal cooling rates for boar spermatozoa. Mol. Reprod. Dev. 67: 446–457, 2004. © 2004 Wiley‐Liss, Inc.
Polycystins: what polycystic kidney disease tells us about sperm
Authors: Kierszenbaum Abraham L.
Published: February 2004

Experimental evidence indicates that the membrane‐associated proteins polycystin‐1 and polycystin‐2 operate as a receptor‐calcium channel complex that regulates signaling pathways essential for modulation of renal tubulogenesis. Polycystic kidney disease is characterized by defective renal tubular structure and results from mutations in either PKD1 or PKD2 genes. Recent data suggest that polycystin‐1 and polycystin‐2 might localize to primary cilium in principal cells of renal collecting tubules and are thought to act as mechanosensors of fluid flow and contents. Ciliary bending by fluid flow or mechanical stimulation induce Ca2+ release from intracellular stores, presumably to modulate ion influx in response to tubular fluid flow. Polycystins are also emerging as playing a significant role in sperm development and function. Drosophila polycystin‐2 is associated with the head and tail of mature sperm. Targeted disruption of the PKD2 homolog results in nearly complete male sterility without disrupting spermatogenesis. Mutant sperm are motile but are unable to reach the female storage organs (seminal receptacles and spermathecae). The sea urchin polycystin‐1‐equivalent suPC2 colocalizes with the polycystin‐1 homolog REJ3 to the plasma membrane over the acrosomal vesicle. This localization site suggests that the suPC2‐REJ3 complex may function as a cation channel mediating acrosome reaction when sperm contact the jelly layer surrounding the egg at fertilization. Future studies leading to the identification of specific ligands for polycystins, including the signaling pathways, might define the puzzling relationship between renal tubular morphogenesis and sperm development and function. Mol. Reprod. Dev. 67: 385–388, 2004. © 2004 Wiley‐Liss, Inc.
Newborn screening for fragile X syndrome
Authors: Bailey Donald B.
Published: February 2004

Newborn screening for fragile X syndrome (FXS) is technically possible, and in the relatively near future accurate and inexpensive screening technologies are likely to be available. When that happens, will America's public health system adopt newborn screening for fragile X syndrome? This article addresses this issue by first placing screening for FXS in the context of the history and current status of newborn screening policy and practice. Lack of a proven medical treatment may stand as a barrier to newborn screening, but strong arguments can be made that early intervention provides important services for identified newborns and their families. Furthermore, other arguments could be used to justify newborn screening, including informed reproductive risk, medically necessary information, and consumer demand. Fragile X syndrome is offered as a prototype for many of the issues that will face society as more genetic disorders are discovered and new technologies for screening are developed. MRDD Research Reviews 2004;10:3–10. © 2004 Wiley‐Liss, Inc.
Attention and language in fragile X
Authors: Cornish Kim , Sudhalter Vicki , Turk Jeremy
Published: February 2004

Fragile X syndrome (FXS) is a well‐recognized cause of mental retardation and developmental delay in males. Alongside the well‐documented clinical characteristics of the condition, recent advances in technology and methodology have begun to define FXS at a number of different levels: genetic, brain structure and function, cognition, and behavior. This article suggests that the FXS phenotype is not merely a juxtaposition of spared and impaired functions but rather may be characterized by an inhibitory control deficit that interferes with the individual's ability to modulate output causing perseverative responding across various skill areas. It is further suggested that an inability to modulate arousal may be at least one cause for the inhibitory control deficit that typifies the FXS phenotype. The approach to understanding atypical development outlined here holds exciting promise for future research in FXS and other developmental disorders. MRDD Research Reviews 2004;10:11–16. © 2004 Wiley‐Liss, Inc.
The neuroanatomy and neuroendocrinology of fragile X syndrome
Authors: Hessl David , Rivera Susan M. , Reiss Allan L.
Published: February 2004

Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene–brain–behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic–pituitary–adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population. MRDD Research Reviews 2004;10:17–24. © 2004 Wiley‐Liss, Inc.
Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS)
Authors: Hagerman Paul J. , Hagerman Randi J.
Published: February 2004

Carriers of fragile X mental retardation 1 (FMR1) premutation alleles (55 to 200 CGG repeats) are generally spared the more serious neurodevelopmental problems associated with the full‐mutation carriers (>200 repeats) of fragile X syndrome. However, some adult male premutation carriers (55–200 repeats) develop a neurological syndrome involving intention tremor, ataxia, dementia, parkinsonism, and autonomic dysfunction. In excess of one‐third of male premutation carriers over 50 years of age develop the fragile X‐associated tremor/ataxia syndrome (FXTAS). FXTAS also represents a new form of inclusion disease, with eosinophilic intranuclear inclusions found throughout the brain in both neurons and astrocytes. Because FXTAS appears to be relatively specific to male premutation carriers, who are known to possess elevated levels of FMR1 mRNA, the neuropathology may arise as a consequence of a toxic gain‐of‐function of the mRNA itself, although this proposal requires additional direct testing. One of the critical needs at present is a better estimate for the prevalence of this disorder, because FXTAS is likely to be underdiagnosed in the adult movement disorders clinics. MRDD Research Reviews 2004;10:25–30. © 2004 Wiley‐Liss, Inc.
Phenotypic variation and FMRP levels in fragile X
Authors: Loesch Danuta Z. , Huggins Richard M. , Hagerman Randi J.
Published: February 2004

Data on the relationships between cognitive and physical phenotypes, and a deficit of fragile X mental retardation 1 (FMR1) gene‐specific protein product, FMRP, are presented and discussed in context with earlier findings. The previously unpublished results obtained, using standard procedures of regression and correlations, showed highly significant associations in males between FMRP levels and the Wechsler summary and subtest scores and in females between these levels and the full‐scale intelligence quotient (FSIQ), verbal and performance IQ, and some Wechsler subtest scores. The published results based on data from 144 extended families with fragile X, recruited from Australia and the United States within a collaborative NIH‐supported project, were obtained using robust modification of maximum likelihood in pedigrees. The results indicated that processing speed, short‐term memory, and the ability to control attention, especially in the context of regulating goal‐directed behavior, may be primarily affected by the FMRP depletion. The effect of this depletion on physical phenotype was also demonstrated, especially on body and head height and extensibility of finger joints. It is recommended that further studies should rely on more accurate measures of FMRP levels, and use of larger samples, to overcome extensive variability in the data. MRDD Research Reviews 2004;10:31–41. © 2004 Wiley‐Liss, Inc.
Psychopharmacology in fragile X syndrome—Present and future
Authors: Berry‐Kravis Elizabeth , Potanos Kristina
Published: February 2004

In addition to cognitive disability, fragile X syndrome (FXS) is associated with behavioral problems that are often functionally limiting. There are few controlled trials to guide treatment; however, available information does suggest that medications can be quite helpful for a number of categories of behavioral disturbance in FXS. Specifically, stimulants appear to be quite useful for management of distractibility, hyperactivity, and impulsive behavior; antidepressants help with anxiety, obsessive‐compulsive behaviors and mood dysregulation; and antipsychotics can reduce aggression. These medications are supportive and help minimize dysfunctional behaviors and maximize functioning. As more is learned about the neural functions of FMRP, medications in the future will be expected to target specific synaptic mechanisms dysregulated in FXS brain and thus ameliorate the cognitive deficit with resultant behavioral improvements. This article summarizes knowledge about effectiveness and approaches to management of currently available psychopharmacology for behavior in FXS and discusses early leads to future treatments for cognition. MRDD Research Reviews 2004;10:42–48. © 2004 Wiley‐Liss, Inc.
Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome
Authors: Beckel‐Mitchener Andrea , Greenough William T.
Published: February 2004

Fragile X syndrome (FXS) is characterized by a pattern of morphological, functional, and molecular characteristics with, in at least some cases, apparent relationships among phenotypic features at different levels. Gross morphology differences in the sizes of some human brain regions are accompanied by fine structural alterations in the shapes and in the numbers of dendritic spines in both humans and the knockout mouse model. The excess number of spines, their immature appearance, and the impaired withdrawal of inappropriately oriented dendrites in FXS or the mouse model suggest impairment of neuronal maturation, including dendritic and spine pruning. It is not clear how these differences arise, although regionally or globally impaired translation of the mRNAs that interact with the Fmr1 protein product, FMRP, in the vicinity of the synapse, including genes involved in synapse development and plasticity and dendritic retraction, is certainly plausible. FMRP binds mRNA and may be involved in both transport and translation of the mRNAs it binds. The mRNAs it binds belong to multiple functional classes, apparently indicating that FMRP may impact multiple cellular processes. In one example, the glucocorticoid receptor, whose mRNA binds FMRP, regulates the stress‐sensitive glucocorticosteroids. Both human FXS and the mouse model exhibit a protracted elevation in glucocorticosteroids after stress. Possible relationships of other genes to morphological and functional characteristics of FXS are also discussed. MRDD Research Reviews 2004;10:53–59. © 2004 Wiley‐Liss, Inc.
RNA interference: A new mechanism by which FMRP acts in the normal brain? What can Drosophila teach us?
Authors: Siomi Haruhiko , Ishizuka Akira , Siomi Mikiko C.
Published: February 2004

Fragile X syndrome is the most common heritable form of mental retardation caused by loss‐of‐function mutations in the FMR1 gene. The FMR1 gene encodes an RNA‐binding protein that associates with translating ribosomes and acts as a negative translational regulator. Recent work in Drosophila melanogaster has shown that the fly homolog of FMR1 (dFMR1) plays an important role in regulating neuronal morphology, which may underlie the observed deficits in behaviors of dFMR1 mutant flies. Biochemical analysis has revealed that dFMR1 forms a complex that includes ribosomal proteins and, surprisingly, Argonaute2 (AGO2), an essential component of the RNA‐induced silencing complex (RISC) that mediates RNA interference (RNAi) in Drosophila. dFMR1 also associates with Dicer, another essential processing enzyme of the RNAi pathway. Moreover, both a micro‐RNA (miRNA) and short interfering RNAs (siRNAs) can coimmunoprecipitate with dFMR1. Together these findings suggest that dFMR1 functions in an RNAi‐related apparatus to regulate the expression of its target genes at the level of translation. These findings raise the possibility that Fragile X syndrome may be the result of a protein synthesis abnormality caused by a defect in an RNAi‐related apparatus. Because the core mechanisms of complex behaviors such as learning and memory and circadian rhythms appear to be conserved, studies of Fragile X syndrome using Drosophila as a model provide an economy‐of‐scale for identifying biological processes that likely underlie the abnormal morphology of dendritic spines and behavioral disturbances observed in Fragile X patients. MRDD Research Reviews 2004;10:68–74. © 2004 Wiley‐Liss, Inc.
Prospects for gene therapy in the fragile X syndrome
Authors: Rattazzi Mario C. , LaFauci Giuseppe , Brown W. Ted
Published: February 2004

“If politics is the art of the possible, research is the art of the soluble. Both are immensely practical‐minded affairs.” P. B. Medawar.

Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater challenges and diverse vectors and brain delivery approaches are under investigation. We argue that in the case of the fragile X syndrome the approach most likely to have a chance of being effective should consist of a small, diffusible vector derived from the adeno‐associated virus, carrying an FMR1 cDNA comprising the 5′ promoter region and the 3′ untranslated region of the gene, delivered to the entire brain by osmotic blood–brain barrier disruption. The approach can be tested in Fmr1 knockout mice, although changes in their neurobehavioral abnormalities may be difficult to evaluate. A defect in the expression of GABA(A) receptors in these mice—if shown to be a direct consequence of the Fmr1 defect—promises to be a more readily assessable marker of restored FMRp function on gene transfer. MRDD Research Reviews 2004;10:75–81. © 2004 Wiley‐Liss, Inc.
Novel RF coil geometry for lower extremity imaging
Authors: Brown Ryan , Mareyam Azma , Reid Eric , Wang Yi
Published: February 2004

A receive‐only phased‐array coil was designed to image the lower extremities. The array consists of four volume coils placed on two cylindrical formers. The coil array has the ability to image both legs simultaneously over a 40 cm longitudinal field of view (FOV). Experiments using phantoms show an increase in signal‐to‐noise ratio (SNR) in regions of interest through the center of the coil by an average factor of 2.8 over the body coil and 1.5 over the GE 4‐channel torso array. In vivo data acquired from 10 subjects show that the X array provided similar SNR improvement in spin‐echo images and more vascular details in angiographic images compared to the torso array. Magn Reson Med 51:635–639, 2004. © 2004 Wiley‐Liss, Inc.
Linear combination of multiecho data: Short T2 component selection
Authors: Jones Craig K. , Xiang Qing‐San , Whittall Kenneth P. , MacKay Alex L.
Published: February 2004

The myelin sheath, which is wrapped around the axons in the brain, can be affected by many diseases, resulting in cognitive and physical disability. Other work showed water in the myelin sheath has a T2 ≈ 15 ms. The current standard technique to estimate the fraction of myelin water in vivo is to collect multiecho data and fit the decay curves using a nonnegative least‐squares (NNLS) algorithm. A new algorithm was developed to calculate optimized coefficients which were used to linearly combine multiecho data to estimate the myelin water signal. A set of simulations showed the new technique was accurate over a broad range of myelin water signal. The myelin water fraction from brain regions in scans from five volunteers, estimated by the linear combination method, agreed with the myelin water fraction estimated by the standard technique. The strength of the new technique is that the linear combination does not assume an underlying T2 model and is 20,000 times faster than NNLS. Magn Reson Med 51:495–502, 2004. © 2004 Wiley‐Liss, Inc.
Experimental method to eliminate frequency modulation sidebands in localized in vivo 1H MR spectra acquired without water suppression
Authors: Dong Zhengchao , Dreher Wolfgang , Leibfritz Dieter
Published: February 2004

An experimental method is described to eliminate frequency modulation sidebands in localized in vivo proton MR spectra acquired without water suppression. Based on the fact that the phases of the sideband artifact signals are coherent with the phases of the gradient pulses, the proposed method measures and combines signals with sequences using opposite gradients to cancel the sidebands. Factors effecting the results of the cancellation are investigated. Optimized cancellation is achieved by trimming the refocusing gradients, optimizing the spoiler gradients, or replacing the spoiler gradients with a 16‐step RF phase cycling. The performance of the method is demonstrated by phantom and in vivo experiments on the healthy rat brain. Magn Reson Med 51:602–606, 2004. © 2004 Wiley‐Liss, Inc.
Novel NMR approach to assessing gene transfection: 4‐fluoro‐2‐nitrophenyl‐β‐D‐galactopyranoside as a prototype reporter molecule for β‐galactosidase
Authors: Cui Weina , Otten Pieter , Li Yingming , Koeneman Kenneth S. , Yu Jianxin , Mason Ralph P.
Published: February 2004

Gene therapy holds great promise for the treatment of diverse diseases. However, widespread implementation is hindered by difficulties in assessing the success of transfection in terms of spatial extent, gene expression, and longevity of expression. The development of noninvasive reporter techniques based on appropriate molecules and imaging modalities may help to assay gene expression. 4‐Fluoro‐2‐nitrophenyl‐β‐D‐galactopyranoside (PFONPG) is a novel prototype NMR‐sensitive molecule, which is highly responsive to the action of β‐galactosidase (β‐gal), the product of the lacZ gene. The molecule is stable in solution and with respect to wild‐type cells, but the enzyme causes very rapid liberation of the aglycone, accompanied by color formation and a 19F NMR chemical shift of 5–10 ppm, depending on pH. Since the product is pH‐sensitive, this opens the possibility for direct pH determinations at the site of enzyme activity. Molecular and 19F NMR characteristics of PFONPG in solution, blood, and prostate tumor cells are presented. This prototype molecule facilitates a novel approach for assaying gene activity in vivo. Magn Reson Med 51:616–620, 2004. © 2004 Wiley‐Liss, Inc.
Maximum likelihood estimation of signal amplitude and noise variance from MR data
Authors: Sijbers J. , den Dekker A.J.
Published: February 2004

In MRI, the raw data, which are acquired in spatial frequency space, are intrinsically complex valued and corrupted by Gaussian‐distributed noise. After applying an inverse Fourier transform, the data remain complex valued and Gaussian distributed. If the signal amplitude is to be estimated, one has two options. It can be estimated directly from the complex valued data set, or one can first perform a magnitude operation on this data set, which changes the distribution of the data from Gaussian to Rician, and estimate the signal amplitude from the obtained magnitude image. Similarly, the noise variance can be estimated from both the complex and magnitude data sets. This article addresses the question whether it is better to use complex valued data or magnitude data for the estimation of these parameters using the maximum likelihood method. As a performance criterion, the mean‐squared error (MSE) is used. Magn Reson Med 51:586–594, 2004. © 2004 Wiley‐Liss, Inc.
Time‐resolved 3D contrast‐enhanced MRA of an extended FOV using continuous table motion
Authors: Madhuranthakam Ananth J. , Kruger David G. , Riederer Stephen J. , Glockner James F. , Hu Houchun H.
Published: February 2004

A method is presented for acquiring 3D time‐resolved MR images of an extended (>100 cm) longitudinal field of view (FOV), as used for peripheral MR angiographic runoff studies. Previous techniques for long‐FOV peripheral MRA have generally provided a single image (i.e., with no time resolution). The technique presented here generates a time series of 3D images of the FOV that lies within the homogeneous volume of the magnet. This is achieved by differential sampling of 3D k‐space during continuous motion of the patient table. Each point in the object is interrogated in five consecutive 3D image sets generated at 2.5‐s intervals. The method was tested experimentally in eight human subjects, and the leading edge of the bolus was observed in real time and maintained within the imaging FOV. The data revealed differential bolus velocities along the vasculature of the legs. Magn Reson Med 51:568–576, 2004. © 2004 Wiley‐Liss, Inc.
MR properties of excised neural tissue following experimentally induced inflammation
Authors: Stanisz Greg J. , Webb Stephanie , Munro Catherine A. , Pun Teresa , Midha Rajiv
Published: February 2004

Changes in the MR parameters of inflamed neural tissue were measured in vitro. Tumor necrosis factor‐alpha (TNF‐α) was injected into rat sciatic nerves to induce inflammation with negligible axonal loss and demyelination. The MR parameters, such as T1/T2 relaxation and magnetization transfer (MT), were measured 2 days after TNF‐α injection and were found to be substantially different from those of normal nerves. The average T1/T2 relaxation times increased, whereas the MT ratio (MTR) and the quantitative MT parameter M0B (which describes the semisolid pool of protons) decreased. The MR parameters correlated very well with the extracellular volume fraction (EM) of neural tissue evaluated by quantitative histopathology. The multicomponent T2 relaxation was shown to provide the best quantitative assessment of changes in neural tissue microstructure, and allowed us to distinguish between the processes of inflammation and demyelination. In comparison, the MT measurements were less successful due to competing contributions of demyelination and pH‐sensitive changes in the MT effect. Magn Reson Med 51:473–479, 2004. © 2004 Wiley‐Liss, Inc.
Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI
Authors: Morawski Anne M. , Winter Patrick M. , Crowder Kathryn C. , Caruthers Shelton D. , Fuhrhop Ralph W. , Scott Michael J. , Robertson J. David , Abendschein Dana R. , Lanza Gregory M. , Wickline Samuel A.
Published: February 2004

Before molecular imaging with MRI can be applied clinically, certain problems, such as the potential sparseness of molecular epitopes on targeted cell surfaces, and the relative weakness of conventional targeted MR contrast agents, must be overcome. Accordingly, the conditions for diagnostic conspicuity that apply to any paramagnetic MRI contrast agent with known intrinsic relaxivity were examined in this study. A highly potent paramagnetic liquid perfluorocarbon nanoparticle contrast agent (∼250 nm diameter, >90000 Gd3+/particle) was imaged at 1.5 T and used to successfully predict a range of sparse concentrations in experimental phantoms with the use of standard MR signal models. Additionally, we cultured and targeted the smooth muscle cell (SMC) monolayers that express “tissue factor,” a glycoprotein of crucial significance to hemostasis and response to vascular injury, by conjugating an anti‐tissue factor antibody fragment to the nanoparticles to effect specific binding. Quantification of the signal from cell monolayers imaged at 1.5 T demonstrated, as predicted via modeling, that only picomolar concentrations of paramagnetic perfluorocarbon nanoparticles were required for the detection and quantification of tissue factor at clinical field strengths. Thus, for targeted paramagnetic agents carrying high payloads of gadolinium, it is possible to quantify molecular epitopes present in picomolar concentrations in single cells with routine MRI. Magn Reson Med 51:480–486, 2004. © 2004 Wiley‐Liss, Inc.
Cerebral perfusion assessment by bolus tracking using hyperpolarized 13C
Authors: Johansson E. , Månsson S. , Wirestam R. , Svensson J. , Petersson J.S. , Golman K. , Ståhlberg F.
Published: February 2004

Cerebral perfusion was assessed with 13C MRI in a rat model after intravenous injections of the 13C‐labeled compound bis‐1,1‐(hydroxymethyl)‐1‐13C‐cyclopropane‐D8 in aqueous solutions hyperpolarized by dynamic nuclear polarization (DNP). Since the tracer acted as a direct signal source, several of the problems associated with techniques based on traditional dynamic susceptibility contrast (DSC) MRI contrast agents were avoided. Maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were calculated. The MTT was determined to be 2.8 ± 0.8 sec. However, arterial partial‐volume effects in the animal model prevented accurate absolute quantification of CBF and CBV. It was demonstrated that depolarization of the hyperpolarized 13C tracer via relaxation and the imaging sequence had little influence on CBF assessment when the time resolution of the imaging sequence was short compared to the MTT. However, CBV and MTT were increasingly underestimated as MTT or the depolarization rate increased if depolarization was not taken into account. With a modified bolus‐tracking theory depolarization could be compensated for, assuming that the depolarization rate was known. Three separate compensation methods were investigated experimentally and by numerical simulations. Magn Reson Med 51:464–472, 2004. © 2004 Wiley‐Liss, Inc.
Finite calculus formulation for incompressible solids using linear triangles and tetrahedra
Authors: Oñate Eugenio , Rojek Jerzy , Taylor Robert L. , Zienkiewicz Olgierd C.
Published: February 2004

Many finite elements exhibit the so‐called ‘volumetric locking’ in the analysis of incompressible or quasi‐incompressible problems.In this paper, a new approach is taken to overcome this undesirable effect. The starting point is a new setting of the governing differential equations using a finite calculus (FIC) formulation. The basis of the FIC method is the satisfaction of the standard equations for balance of momentum (equilibrium of forces) and mass conservation in a domain of finite size and retaining higher order terms in the Taylor expansions used to express the different terms of the differential equations over the balance domain. The modified differential equations contain additional terms which introduce the necessary stability in the equations to overcome the volumetric locking problem. The FIC approach has been successfully used for deriving stabilized finite element and meshless methods for a wide range of advective–diffusive and fluid flow problems. The same ideas are applied in this paper to derive a stabilized formulation for static and dynamic finite element analysis of incompressible solids using linear triangles and tetrahedra. Examples of application of the new stabilized formulation to linear static problems as well as to the semi‐implicit and explicit 2D and 3D non‐linear transient dynamic analysis of an impact problem and a bulk forming process are presented. Copyright © 2004 John Wiley & Sons, Ltd.
Patch recovery based on complementary energy
Authors: Ubertini F.
Published: February 2004

In this paper a new stress recovery procedure is presented. The formulation is very simple and based on improving stresses by enforcing compatibility over local patches of elements. This is obtained by minimizing the complementary energy, properly defined for the patch thought as a separate system, among an assumed set of equilibrated stress fields. The resultant implementation is simple, cost effective and numerically stable. Several numerical tests evidence an excellent performance which promises a wide applicability of the new procedure. Copyright © 2004 John Wiley & Sons, Ltd.
Modulation of BDNF expression by electrical stimulation in hindlimb muscles of rats
Authors: Park Byung Rim , Hwang Ji Hyo , Kim Min Sun , Lee Moon Young , Rhee Jeong Kyun , Lee Seong Ho
Published: February 2004

To evaluate the effects of electrical stimulation of the sciatic nerve on brain‐derived neurotrophic factor (BDNF) expression in the soleus and medial gastrocnemius muscles, we investigated temporal changes in BDNF protein and mRNA expression following electrical stimulation, and the optimal electrical stimulus paradigm for increasing BDNF expression in rats. The sciatic nerve was electrically stimulated with three different paradigms: 1 ms/40 Hz/30 min, 1 ms/40 Hz/40 Hz/5 min and 1 ms/1 Hz/30 min. Levels of BDNF protein and mRNA increased gradually over time after electrical stimulation in both muscles. Of the three stimulus paradigms, electrical stimulation at 1 ms/40 Hz/30 min produced the highest levels of BDNF protein and mRNA in both muscles, whereas stimulation at 1 ms/40 Hz/5 min produced the lowest expression levels. These results suggest that electrical stimulation could enhance neuronal plasticity by increasing BDNF production and paradigms of the stimulus can modulate the level of BDNF production.
GABA receptor‐mediated epileptiform discharges in the rat cortical slices in magnesium‐free aCSF
Authors: Lee Jae‐Kwang , Park En‐Jin , Koh Hae‐Young , Lee Chang‐Joong
Published: February 2004

This study examined the role of the GABAergic system in generating epileptiform discharges in rat cortical slices in Mg2+‐free aCSF by comparing two age groups using a whole cell patch recording. The discharges consisted of recurring slow bursts in the neonatal slices, whereas fast initial depolarization with after‐discharges on the top of the gradual repolarization was mainly observed in the young slices. APV, an NMDA receptor antagonist, suppressed the slow bursts in the neonatal slices, and blocked late afterdischarges, leaving the fast depolarization discharges unaltered in the young slices. Interestingly, BMI, a GABAA receptor antagonist, reduced the frequency and amplitude of the discharges in the neonatal slices, while increasing in the young slices. The reversal potential of the slow bursts was shifted with a chloride ion gradient change across the membrane in the neonatal slices, but not in the young slices. These results demonstrated that the GABAA receptor activation during the neonatal period causes depolarization leading to epileptiform discharges under Mg2+‐free conditions.
Does whisker stimulation induce c‐Fos expression in the rat ipsilateral deafferented cerebral cortex?
Authors: Jung Hyuk‐Sang , Lee Hyun‐Sam , Shin Jung‐Won , Lee Doo‐Jae , Won Ran , Sohn Nak‐Won
Published: February 2004

Recent study has shown that whisker stimulation of intact whiskers causes c‐Fos expression in contralateral barrel layers. However, as few reports have investigated what kind of effect whisker stimuli has on c‐Fos expression in the ipsilateral cerebral cortex, we researched the effect of such whisker stimuli. One side of the whisker pad was deafferented on adult rats, so that the deafferented barrel no longer received direct external stimuli and only one side of the barrel‐whisker system remained. Whiskers on the intact side were then stimulated and the effects of these stimuli on the ipsilateral deafferented barrel cortex were investigated by observing levels of c‐Fos expression, which is known as an excellent marker for functionally excited neurons. Whisker stimulation caused significantly increased c‐Fos expression on the layers II/III, IV of the ipsilateral deafferented cerebral cortex (P < 0.05, P < 0.01). In conclusion, whisker stimulation caused c‐Fos expression not only in the contralateral cerebral cortex, but also in the ipsilateral cerebral cortex.
Expression of COX‐2, mPGE‐synthase1, MDR‐1 (P‐gp), and Bcl‐xL: a molecular pathway of H pylori‐related gastric carcinogenesis
Authors: Nardone Gerardo , Rocco Alba , Vaira Dino , Staibano Stefania , Budillon Alfredo , Tatangelo Fabiana , Sciulli Maria G. , Perna Federico , Salvatore Gaetano , Di Benedetto Maria , De Rosa Gaetano , Patrignani Paola
Published: February 2004

Helicobacter pylori up‐regulates cyclo‐oxygenase‐2 (COX‐2) expression, which in turn is involved in tumourigenesis. Recently, a causal link between COX‐2 and multidrug resistance 1 (MDR‐1) gene expression, implicated in cancer chemoresistance, has been demonstrated. Thus, the expression of COX‐2 and the downstream enzyme involved in PGE2 biosynthesis, microsomal PGE‐synthase1 (mPGES1), was correlated with P‐gp, the product of MDR‐1, and the anti‐apoptotic protein, Bcl‐xL, in gastric biopsies from patients with H pylori infection and in patients with gastric cancer. In a retrospective analysis of endoscopic and pathology files, 40 H pylori‐negative patients (Hp−), 50 H pylori‐positive patients who responded to eradication therapy (Hp+R), 84 H pylori‐positive patients who did not respond to eradication therapy (Hp+NR), and 30 patients with gastric cancer (18 intestinal and 12 diffuse types) were selected. COX‐2, mPGES1, P‐gp, and Bcl‐xL were detected by immunohistochemistry. COX‐2, mPGES1, P‐gp, and Bcl‐xL expression was undetectable in gastric mucosa from Hp− patients. By contrast, COX‐2 and mPGES1 expression was detected in 42% and 44% of Hp+R patients, respectively, and in up to 66% (range 63–66%) of Hp+NR patients (p < 0.05). The expression of COX‐2 and mPGES1 correlated significantly (p < 0.0001) with that of P‐gp and Bcl‐xL. High levels of COX‐2, mPGES1, P‐gp, and Bcl‐xL expression were found in intestinal‐type gastric cancer samples. In conclusion, H pylori‐dependent induction of COX‐2 and mPGES1 is associated with enhanced production of P‐gp and Bcl‐xL that may contribute to gastric tumourigenesis and resistance to therapy. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.