bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of immunohistochemical markers in non‐small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers
Authors: Au NHC , Cheang M , Huntsman DG , Yorida E , Coldman A , Elliott WM , Bebb G , Flint J , English J , Gilks CB , Grimes HL
Published: August 2004

This study has investigated a panel of immunomarkers in non‐small cell lung carcinoma (NSCLC). Unsupervised hierarchical clustering analysis was used to investigate the possibility of identifying different subgroups in NSCLC based on their molecular expression profile rather than morphological features. A tissue microarray consisting of 284 cases of NSCLC was constructed. Immunohistochemistry was used to detect the presence of 18 biomarkers including synaptophysin, chromogranin, bombesin, NSE, GFI1, ASH‐1, p53, p63, p21, p27, E2F‐1, cyclin D1, Bcl‐2, TTF‐1, CEA, HER2/neu, cytokeratin 5/6, and pancytokeratin. Univariate analysis of all 18 markers for prognostic significance was performed. Immunohistochemical scoring data for NSCLC were analysed by unsupervised hierarchical clustering analysis. Kaplan–Meier survival curves were plotted for the different cluster groups of lung tumours identified by this method. Analysis of the three different World Health Organization (WHO) subtypes (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) of NSCLC individually showed that different markers were significant in different subtypes. For example, p53 and p63 were significant for squamous cell carcinoma (p = 0.007 and p = 0.03, respectively), whereas cyclin D1 and HER2/neu were significant prognostic markers for adenocarcinoma (p = 0.025 and p = 0.015, respectively). These markers were not significant prognostic predictors for NSCLC as a group. Hierarchical clustering analysis of NSCLC produced four separate cluster groups, although the vast majority of cases were found in two cluster groups, one dominated by squamous cell carcinoma and the other by adenocarcinoma. The clinical outcomes of cases from the four cluster groups were not significantly different. Prognostic indicators vary between different morphological subtypes of NSCLC. Unsupervised hierarchical clustering analysis, based on an extended immunoprofile, identifies two main cluster groups corresponding to adenocarcinoma and squamous cell carcinoma; cases of large cell carcinomas are assigned to one of these two groups based on their molecular phenotype. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Decreased expression of apical Na+ channels and basolateral Na+, K+‐ATPase in ulcerative colitis
Authors: Greig ER , Boot‐Handford RP , Mani V , Sandle GI
Published: August 2004

Impaired absorption of sodium (Na+) and water is a major factor in the pathogenesis of diarrhoea in ulcerative colitis (UC). Electrogenic Na+ absorption, present mainly in human distal colon and rectum, is defective in UC, but the molecular basis for this is unclear. The effect of UC on the expression of apical Na+ channels (ENaC) and basolateral Na+, K+‐ATPase, the critical determinants of electrogenic Na+ transport, was therefore investigated in this study. Sigmoid colonic and/or proximal rectal mucosal biopsies were obtained from patients with mild to moderate UC, and patients with functional abdominal pain (controls). ENaC subunit expression was studied by immunohistochemistry, western blot analysis, and in situ hybridization, and Na+, K+‐ATPase isoform expression was studied by immunohistochemistry, western blotting, and northern blot analysis. UC was associated with substantial decreases in the expression of the ENaC β‐ and γ‐subunit proteins and mRNAs, whereas the decrease in ENaC α‐subunit protein detected by immunolocalization was less marked. The levels of expression of Na+, K+‐ATPase α1‐ and β1‐isoform proteins were also lower in UC patients than in controls, although there were no differences in Na+, K+‐ATPase α1‐ and β1‐isoform mRNA levels between the two groups. Taken together, these results show that UC results mainly in decreased expression of the apical ENaC β‐ and γ‐subunits, as well as the basolateral Na+, K+‐ATPase α1‐ and β1‐isoforms. In conclusion, these changes provide a basis for the low/negligible levels of electrogenic Na+ absorption seen in the distal colon and rectum of UC patients, which contribute to the pathogenesis of diarrhoea in this disease. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Inverse correlation of secreted frizzled‐related protein 4 and β‐catenin expression in endometrial stromal sarcomas
Authors: Hrzenjak Andelko , Tippl Michaela , Kremser Marie‐Luise , Strohmeier Bettina , Guelly Christian , Neumeister Doris , Lax Sigurd , Moinfar Farid , Tabrizi Ali Dastranj , Isadi‐Moud Narges , Zatloukal Kurt , Denk Helmut
Published: August 2004

Endometrial stromal sarcomas are rare uterine tumours. Whereas the histology and immunohistochemistry of these tumours are well documented, almost nothing is known about the molecular mechanisms involved in their pathogenesis. To characterize the genes altered in these malignancies, a genome‐wide cDNA library was generated by suppression subtractive hybridization and a set of differentially expressed clones was isolated. These were then used to produce custom‐spotted cDNA arrays. Genes deregulated in endometrial stromal sarcomas were identified by cDNA array hybridization and were confirmed by quantitative real‐time PCR analyses and in situ hybridization. Following cDNA array analysis, more than 300 genes deregulated in endometrial stromal sarcoma were selected and sequenced. Among the most significantly deregulated genes were those of secreted frizzled‐related proteins (SFRPs), in particular secreted frizzled‐related protein 4 (SFRP4). SFRPs are putative modulators of the Wnt‐signalling pathway and play a role in different cellular events including cell proliferation. Compared with normal endometrium, the expression of SFRP4 was decreased in both low‐grade endometrial stromal sarcoma (ESS; n = 10) and undifferentiated endometrial sarcoma (UES; n = 4), being lower in the latter more aggressive form. These results were verified on paraffin wax‐embedded tissue by quantitative real‐time PCR analysis and in situ hybridization. Furthermore, the expression of β‐catenin, an important component of the Wnt‐signalling pathway, was regulated in an opposite manner to SFRP4, being particularly increased in undifferentiated sarcomas. The activation of the Wnt‐signalling pathway was additionally supported by the immunohistochemical demonstration that β‐catenin was translocated to the nucleus in UES. SFRP4 may therefore be a putative tumour suppressor involved in deregulation of the Wnt pathway and in the pathogenesis of ESS and UES. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Angiopoietins in tumours: the angiogenic switch
Authors: Tait Catherine R , Jones Pamela F
Published: August 2004

On first view, the literature pertaining to the expression of the angiopoietins in tumours is confusing and does not readily offer a consensus pattern. Apparently conflicting publications report increased, decreased or unchanged expression levels of both angiopoietin‐1 (Ang‐1) and angiopoietin‐2 (Ang‐2) in a wide range of tumours. However, closer scrutiny of the literature, taking into account relative increases or decreases of each factor, reveals a consensus pattern, seen in almost all instances of expression profiling of the angiopoietins in tumours. What becomes apparent is that although absolute levels of either angiopoietin may increase or decrease, the ratio of Ang‐1:Ang‐2 shifts in favour of Ang‐2. Given that Ang‐2 is a destabilization factor, rendering vasculature in a more plastic state amenable to sprouting (under the influence of vascular endothelial growth factor, VEGF) or regression, this analysis suggests that tumours shift the angiogenic balance towards a pro‐angiogenic state through altering the balance between the angiopoietins. This in turn implicates Ang‐2 as a candidate for the angiogenic switch and also as an important potential therapeutic target. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Increased CCL27–CCR10 expression in allergic contact dermatitis: implications for local skin memory
Authors: Moed Heleen , Boorsma Dick M , Tensen Cornelis P , Flier Jacoba , Jonker Maureen J , Stoof Tom J , von Blomberg B Mary E , Bruynzeel Derk P , Scheper Rik J , Rustemeyer Thomas , Gibbs Susan
Published: August 2004

Allergic contact dermatitis (ACD) is a T‐cell‐mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. While it is becoming clear which chemokines and receptors determine the development of ACD, the mechanisms involved in the retention of T cells in the skin after resolution of inflammation are still unknown. Unravelling these mechanisms will help us to understand local skin memory as observed in retest reactivity and flare‐up reactions. This study was designed to evaluate the role of chemokine–chemokine receptor interactions in local T‐cell retention. The results show that expression of the CCR10 targeting ligand CCL27 is not only increased during inflammation, but also remains increased several weeks after clinical responsiveness to patch testing. In parallel with increased CCL27 expression, an increased number of infiltrating cells could still be detected in skin that, clinically, had returned to normal 21 days after patch testing. These persisting cells were characterized as CD4+ cells expressing CCR10, while no CD8+ CCR10+ cells could be detected. The presence of these cells is most likely an allergen‐mediated effect, as increased levels of CCL27 and CCR10 could not be detected 21 days after initiating an irritant contact dermatitis reaction. In contrast to CCL27, increased expression of CXCL9, CXCL10, and CXCL11 could only be observed during the clinically inflammatory phase of ACD. In conclusion, local CCL27‐mediated retention of CCR10+ CD4+ T cells in sites previously challenged by ACD could be responsible for phenomena such as local skin memory observed in retest reactions and flare‐up reactions in which the presence of persisting T cells results in an accelerated inflammatory response upon renewed allergen challenge. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Self‐organization of striped pattern of refractive indices in photopolymer film
Authors: Uematsu Takafumi , Watanabe Akira , Yamaguchi Yukio
Published: August 2004

We report on a self‐organized striped pattern of refractive indices in a photopolymer film. Silicon oxide (SiO2) particles (1.3‐μm diameter) were dispersed on a cover glass above a monomer mixture (bifunctional methacrylate monomer, cyanoethylmethacrylate, and 2,4,6‐trimethylbenzoyldiphenylphosphine oxide), and the sample was uniformly irradiated from a tube light source. The self‐organized striped pattern was observed inside a 0.45‐mm thickness photopolymer film. In contrast, no pattern was observed in a 0.45‐mm thickness sample photopolymerized without particles on a cover glass. The results suggest that the SiO2 particles acted as “lenses” and produced a light distribution reflecting the shape of the light source used during the irradiation. The photopolymerization extended in depth according to the light distribution, and then the striped pattern was generated inside a medium. The photopolymer film with the striped pattern has an angular dependence in the transmittance as a result of the microstructure and can be applied to a flexible optical transmission filter. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 3351–3358, 2004
Sequence‐based prediction of pathological mutations
Authors: Ferrer‐Costa C. , Orozco M. , de la Cruz X.
Published: August 2004

The development of methods to assess the impact of amino acid mutations on human health has become an important goal in biomedical research, due to the growing number of nonsynonymous SNPs identified. Within this context, computational methods constitute a valuable tool, because they can easily process large amounts of mutations and give useful, almost cost‐free, information on their pathological character. In this paper we present a computational approach to the prediction of disease‐associated amino acid mutations, using only sequence‐based information (amino acid properties, evolutionary information, secondary structure and accessibility predictions, and database annotations) and neural networks, as a model building tool. Mutations are predicted to be either pathological or neutral. Our results show that the method has a good overall success rate, 83%, that can reach 95% when trained for specific proteins. The methodology is fast and flexible enough to provide good estimates of the pathological character of large sets of nonsynonymous SNPs, but can also be easily adapted to give more precise predictions for proteins of special biomedical interest. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Molecular recognition of aldehydes by aldehyde dehydrogenase and mechanism of nucleophile activation
Authors: Wymore Troy , Hempel John , Cho Samuel S. , MacKerell Alexander D. , Nicholas Hugh B. , Deerfield David W.
Published: August 2004

Experimental structural data on the state of substrates bound to class 3 Aldehyde Dehydrogenases (ALDH3A1) is currently unknown. We have utilized molecular mechanics (MM) simulations, in conjunction with new force field parameters for aldehydes, to study the atomic details of benzaldehyde binding to ALDH3A1. Our results indicate that while the nucleophilic Cys243 must be in the neutral state to form what are commonly called near‐attack conformers (NACs), these structures do not correlate with increased complexation energy calculated with the MM‐Generalized Born Molecular Volume (GBMV) method. The negatively charged Cys243 (thiolate form) of ALDH3A1 also binds benzaldehyde in a stable conformation but in this complex the sulfur of Cys243 is oriented away from benzaldehyde yet yields the most favorable MM‐GBMV complexation energy. The identity of the general base, Glu209 or Glu333, in ALDHs remains uncertain. The MM simulations reveal structural and possible functional roles for both Glu209 and Glu333. Structures from the MM simulations that would support either glutamate residue as the general base were further examined with Hybrid Quantum Mechanical (QM)/MM simulations. These simulations show that, with the PM3/OPLS potential, Glu209 must go through a step‐wise mechanism to activate Cys243 through an intervening water molecule while Glu333 can go through a more favorable concerted mechanism for the same activation process. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Genetic polymorphisms among human cytomegalovirus (HCMV) wild‐type strains
Authors: Pignatelli Sara , Monte Paola Dal , Rossini Giada , Landini Maria Paola
Published: August 2004

Human cytomegalovirus (HCMV) clinical isolates display genetic polymorphisms in multiple genes. Some authors have suggested that those polymorphisms may be implicated in HCMV‐induced immunopathogenesis, as well as in strain‐specific behaviours, such as tissue‐tropism and ability to establish persistent or latent infections. This review summarises the features of the main clustered HCMV polymorphic open reading frames and also briefly cites other variable loci within the viral genome. The implications of gene polymorphisms are discussed in terms of potentially advantageous higher fitness obtained by the strain, but also taking into account that the published data are often speculative. The last section of this review summarises and critically analyses the main literature reports about the linkage of strain specific genotypes with clinical manifestations of HCMV disease in different patient populations affected by severe cytomegalovirus infections, namely immunocompromised subjects and congenitally infected newborns. Copyright © 2004 John Wiley & Sons, Ltd.
A study of science teaching self‐efficacy and outcome expectancy beliefs of teachers in India
Authors: Desouza Josephine M. Shireen , Boone William J. , Yilmaz Ozgul
Published: August 2004

Elementary and middle school teachers in urban schools in India provided responses to the science efficacy instrument (STEBI‐A). These responses were evaluated using Rasch analysis and parametric tests. Rasch fit statistics and person‐item maps were evaluated. It was found that the instrument worked well for the two groups of teachers, but the differential item functioning analysis found that the teachers utilized several items in the scale differently. Parametric tests suggested that self‐efficacy and outcome expectancy measures correlated highly for middle school teachers, for those that did not have a science degree and a written science curriculum. Significant predictors of self‐efficacy are—minutes per week science is taught, educational level, number of days in the school year, holding of a science degree, and the presence of a science curriculum. From all of the analyses we conclude that teaching experience is important, but not necessarily enough to increase teachers' outcome expectancy beliefs. The results of this study should benefit educators and policy makers with respect to teacher education in India and around the world. © 2004 Wiley Periodicals, Inc. Sci Ed 88:837–854, 2004
Reflective scientific sense‐making dialogue in two languages: The science in the dialogue and the dialogue in the science
Authors: Ash Doris
Published: August 2004

In this paper I focus on the transition from everyday to scientific ways of reasoning, and on the intertwined roles of meaning‐making dialogue and science content as they contribute to scientific literacy. I refer to views of science, and how scientific understanding is advanced dialogically, by Hurd (Science Education, 1998, 82, 402–416), Brown (The Journal of Learning Sciences, 1992, 2(2), 141–178), Bruner (Acts of Meaning, Cambridge, MA: Harvard University Press, 1990), Roth (In J. Brophy (Ed.), Social Constructivist Teaching: Affordances and Constraints (Advances in Research on Teaching Series, Vol. 9), New York: Elsevier/JAI, 2003), and Wells (Dialogic Inquiry: Towards a Sociocultural Practice and Theory of Education, New York: Cambridge University Press, 1999). I argue that family collaborative dialogues in nonschool settings can be the foundations for scientific ways of thinking. I focus on the particular reflective family dialogues at the Monterey Bay Aquarium, when family members remembered and synthesized essential biological themes, centering on adaptation, from one visit to the next, in both Spanish and English. My approach is informed by sociocultural theory, with emphasis on the negotiations of meaning in the zone of proximal development (Vygotsky, 1978), as learners engage in joint productive activity (Tharp & Gallimore, Rousing Minds to Life: Teaching, Learning and Schooling in Social Context, New York: Cambridge University Press, 1988). Over the past decades, researchers have discovered that observing social activity, conversation, and meaning‐making in informal settings (Crowley & Callanan, 1997; Guberman, 2002; Rogoff, 2001; Vasquez, Pease‐Alvarez, & Shannon, Pushing Boundaries: Language and Culture in a Mexicano Community, New York: Cambridge University Press, 1994) has much to teach us regarding learning in general. To date there has been little research with Spanish‐speaking families in informal learning settings and virtually none that integrates the home with both formal and informal learning. © 2004 Wiley Periodicals, Inc. Sci Ed 88:855–884, 2004
The persistence of personal and social themes in context: Long‐ and short‐term studies of students' scientific ideas
Authors: Helldén Gustav F. , Solomon Joan
Published: August 2004

In this paper we will examine the persistence of “misconceptions.” We used data from a longitudinal study of personal ideas in 24 students' thinking about ecological processes. The results show students often speaking about personal experiences dating from an early age, to which they had also referred in similar interviews conducted years before. These data are compared with results from a different study of middle school physics students' thinking about energy and steam engines. After the new learning had been “successfull” completed and assessed, old ideas returned. These findings are used to set up a theoretical basis for understanding the longitudinal results. Findings from memory studies are shown to explicate the long‐term effects of the passage of time and prompts for the recall of scientific concepts. © 2004 Wiley Periodicals, Inc. Sci Ed 88:885–900, 2004
Altered emotional behaviors and the expression of 5‐HT1A and M1 muscarinic receptors in μ‐opioid receptor knockout mice
Authors: Yoo Ji‐Hoon , Lee Seok‐Yong , Loh Horace H. , Ho Ing K. , Jang Choon‐Gon
Published: August 2004

Anxiety and depression alterations have been reported in μ‐opioid receptor knockout mice after exon 2 disruption. However, emotional behaviors, such as novelty and emergence responses have not been reported in μ‐opioid receptor knockout mice due to the disruptions of exon 2 and 3. Here, we report that μ‐opioid receptor knockout mice, with deletion of exon 2 and 3, display significant emotional behavior changes; they showed less anxiety in the elevated plus maze and emergence tests, reduced response to novel stimuli in the novelty test, and less depressive‐like behavior in the forced‐swim test. Analysis of the compensatory mechanism in μ‐opioid receptor knockout mice revealed that the M1 mRNA levels were reduced in the cortex, caudate putamen, nucleus accumbens, and hippocampus, and that M1 receptor levels were reduced in the nucleus accumbens, CA1, and the dentate gyrus of the hippocampus, versus the wild‐type. However, 5‐HT1A receptor levels were significantly elevated in the cerebral cortex and in the hypothalamus of μ‐opioid receptor knockout mice versus the wild‐type. These aberrant emotional behavioral phenotypes are possibly related to M1 and 5‐HT1A receptor alterations in the μ‐opioid receptor knockout mice. Overall, our study suggests that μ‐opioid receptor may play a role in the modification of emotional responses to novelty, anxiety, and depression. Synapse 54:72–82, 2004. © 2004 Wiley‐Liss, Inc.
Senescent phenotype achieved in vitro is indistinguishable, with the exception of Bcl‐2 content, from that attained during the in vivo aging process
Authors: Königsberg Mina , López‐Diazguerrero Norma E. , Aguilar María C. , Ventura José L. , Gutiérrez‐Ruiz María C. , Zentella Alejandro
Published: August 2004

Senescent phenotype can be attained by diverse agents, thus suggesting that there might be molecular differences between the senescence achieved in vivo and the senescence‐like state attained in vitro under culture conditions. In this study we compare the senescent phenotype reached by cells derived from young animals when cultured in vitro with the one associated with the in vivo aging process. Several in vitro senescence parameters, including MTT reduction, proliferation rate, DNA synthesis, SA‐β‐gal staining, and both in vivo and in vitro Bcl‐2 content, were determined. Alterations in DNA electrophoretic mobility were evaluated to test differences in bulk chromatin structure. Our results indicate that although it is possible to achieve a senescent phenotype with cells derived from young animals aged in culture, this phenotype differs from the one observed in older animals, due to lack of in vivo damage inducers to which cells are being exposed during natural aging.
GABAB receptors on central terminals of C‐afferents mediate intersegmental Aδ‐afferent evoked hypoalgesia
Authors: Jones Toni L. , Sweitzer Sarah M. , Peters Michael C. , Wilson Steven P. , Yeomans David C.
Published: August 2004

The current study tested the hypothesis that repetitive activation of sciatic Aδ‐afferents evokes a saphenous C‐afferent hypoalgesia mediated by pre‐synaptic GABAB receptors. Tonic activation of sciatic Aδ‐afferents was produced by cutaneous application of dimethyl sulfoxide (DMSO) followed by repetitive thermal activation of Aδ‐afferents on the dorsolateral hind paw. The tonic activation of sciatic Aδ‐afferents produced hypoalgesia in saphenous C‐afferents. Intrathecal administration of the GABAB receptor antagonist, saclofen, attenuated saphenous hypoalgesia demonstrating at least partial mediation by central GABAB receptors. To determine if this central GABAB receptor activation occurs at pre‐synaptic primary afferent terminals or postsynaptic spinal cord neurons, the dorsal hind paws of mice were infected with a recombinant herpes simplex virus type 1 (HSV‐1) designed to selectively knock down expression of the GABAB1a receptor subunit (PAGB1a) in primary afferents or a control virus encoding the E. coli lacZ gene (PZ). Four weeks after infection, GABAB receptor immunoreactivity in the superficial dorsal horns ipsilateral to PAGB1a application was reduced and hypoalgesia in saphenous C‐afferents was attenuated when compared to PZ‐infected mice. These findings indicate an intersegmental, sciatic Aδ‐afferent‐evoked hypoalgesic effect on saphenous C‐afferent responses that is mediated by pre‐synaptic GABAB receptors on the terminals of those C‐afferents.
Neurotrophic factors and the pathophysiology of schizophrenic psychoses
Authors: Durany Nuria , Thome Johannes
Published: August 2004

The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14 million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders.
Phospholipase Cγ2 contributes to stable thrombus formation on VWF
Authors: Rathore Vipul , Wang Demin , Newman Debra K. , Newman Peter J.
Published: August 2004

Though phospholipase C PLCγ2 is known to play an important role in platelet activation by collagen and fibrinogen, its importance in GPIb‐mediated platelet activation is less well understood. To better understand the role of PLCγ2 in GPIb‐mediated adhesion and thrombus formation, we examined the ability of wild‐type and PLCγ2‐ deficient murine platelets to spread on immobilized von Willebrand factor (VWF) under static conditions, and to attach to and form thrombi on VWF under conditions of arterial shear. While absence of PLCγ2 had only a minimal effect on platelet adhesion to immobilized VWF, its absence impaired spreading and profoundly affected thrombus growth and stability on VWF.
Spatial feeding patterns of herring (Clupea harengus L.), sprat (Sprattus sprattus L.), and the three-spined stickleback (Gasterosteus aculeatus L.) in the Gulf of Finland, Baltic Sea
Authors: Peltonen Heikki , Vinni Mika , Lappalainen Antti , Pönni Jukka
Published: August 2004

The pelagic-fish fauna in the Gulf of Finland, Baltic Sea was sampled by trawling and hydroacoustics in September 2002. Spatial and size/age-dependent patterns in the diets of herring (Clupea harengus), sprat (Sprattus sprattus), and the three-spined stickleback (Gasterosteus aculeatus) were explored. At night the fish concentrated at thermocline depth but at dawn they scattered over a larger depth range. All three fish species fed on mesozooplankton but nektobenthos, for example, was scarce. In the eastern Gulf of Finland, where there is a strong freshwater inflow, the cladoceran Bosmina longispina was the dominant prey item, but it was also abundant in the diets of young-of-the-year (total length <10 cm) clupeids in the western Gulf of Finland. In these more saline western areas, calanoid copepods, especially Eurytemora affinis, were the most important prey for large (≥10 cm) clupeids. The large clupeids in particular, also fed on Temora longicornis. The diet of three-spined stickleback overlapped with that of the clupeids. However, Cercopagis pengoi, a recent arrival to the area, was much more abundant in the diet of stickleback than in the diet of clupeids.
Prenatal intravenous cocaine and the heart rate‐orienting response: a dose–response study
Authors: Foltz Tara L. , Snow Diane M. , Strupp Barbara J. , Booze Rosemarie M. , Mactutus Charles F.
Published: August 2004

Attentional dysfunction is a persistent behavioral abnormality that is emerging as one of the cardinal features in the investigations of the teratogenic effects of cocaine in humans and rodents. The present study sought to extend this work by using a dose–response design with an alternate strain of rat. Virgin Long–Evans female rats, implanted with an IV access port prior to breeding were administered saline, 0.5, 1.0, or 3.0 mg/kg of cocaine HCl from gestational day (GD) GD8–21 (1× per day‐GD8–14, 2× per day‐GD15–21). Cocaine had no significant effect on maternal or litter parameters. At 14–15 days of age, 1 male and 1 female from each litter were tested to evaluate the heart rate orienting response (HR‐OR). Following 20 min for acclimation, pups were presented an olfactory stimulus for 20 s per trial, across four trials, and with an intertrial interval of 2 min. The initial baseline HR was not significantly different across the treatment groups, although cocaine did alter the stability of the QRS complex duration. The magnitude of the HR‐OR averaged across trials increased as a linear function of dosage of cocaine. A more complex (quadratic) interaction between cocaine dose and sex of the offspring was also noted. When examined across trials, the controls failed to display any significant within‐session variation in the HR‐OR; in contrast all of the prenatal cocaine treated groups displayed either sensitization (low and high dose) or habituation of the response (middle dose). Analysis of the peak HR‐OR confirmed that the controls were indeed displaying the response on at least one trial of the session, albeit not consistently on any specific trial. The more vigorous HR‐OR of the prenatal cocaine groups, relative to vehicle controls, most likely reflects an alteration in development of the neural basis of response; as previously shown, the most vigorous response to the olfactory stimulus is seen early (12 days of age) and progressively decreases across the preweaning period. In sum, prenatal exposure to cocaine, at least when administered by the IV route, provides reproducible alterations in attentional processes, as indexed by the noradrenergically‐mediated HR‐OR. The documentation of a linear dose–response function suggests that there is likely no threshold for the drug‐induced alteration. Moreover, the sex of the animal also appears to play some role in the nature of the expression of the altered HR‐OR.
Juvenile 5HT1B receptor knockout mice exhibit reduced pharmacological sensitivity to 5HT1A receptor activation
Authors: El‐Khodor Bassem F. , Dimmler Miriam Hernandez , Amara Djamel Ait , Hofer Myron , Hen Rene , Brunner Dani
Published: August 2004

Serotonin is an important modulator of anxiety and thus drugs that act on this system have frequently been shown to be either anxiogenic or anxiolytic. In addition serotonin has important trophic functions during early development and disruption of serotonin homeostasis is likely to have long‐lasting repercussions in the adult. In the present study we examined the contribution of two serotonin receptor subtypes (5HT1A and 5HT1B) to the pathophysiology of anxiety during development. For this, we have studied homozygous knockout mice lacking the 5HT1B receptor and examined the effect of pharmacological manipulations of 5HT1A and 5HT1B receptors on locomotor activity and emission of ultrasonic vocalization (USV) in 7–8 days old mice. As shown before, drug naïve 5HT1B knockout pups showed reduced USV and were hyperactive, in comparison to wild type controls. The administration of RU24969 (a 5HT1A/1B agonist) showed a dose‐dependent decrease in USV in the wild type and a biphasic effect in the mutants and resulted in dose‐dependent increase in activity in the wild type and, to a lesser extent, in the knockouts. The selective 5HT1A agonist, 8OH‐DPAT, dose‐dependently blocked vocalization in both genotypes and also increased locomotion. To differentially activate 5HT1B receptors we first blocked 5HT1A receptors with WAY100315 and then treated with RU24969. At a high testing temperature, pretreatment with WAY100315 resulted in an anxiogenic effect in wild type pups but not in the knockouts. In agreement with our findings that 5HT1B knockout mice were in general less sensitive to 5HT1A activation, 5HT1A receptor binding was reduced in the knockouts in comparison to controls. Finally, treatment with diazepam dose‐dependently decreased USVs in both group with the knockouts showing enhanced sensitivity to this drug. Our results show that important adaptations to a disturbance of serotonin homeostasis occur during the first week of life within the serotonergic system. The observed decreased in sensitivity of 5HT1B knockout mice to 5HT1A and increased to GABAA manipulations are discussed within the context of serotonergic plasticity during development and the implication for clinical treatment of anxiety in genetically predisposed individuals.
Cocaine‐induced inhibition of process outgrowth in locus coeruleus neurons: role of gestational exposure period and offspring sex
Authors: Snow Diane M. , Carman Heidi M. , Smith Jeffrey D. , Booze Rosemarie M. , Welch Marian A. , Mactutus Charles F.
Published: August 2004

Cocaine use during pregnancy is associated with neurobehavioral problems in school‐aged children that implicate alterations in attentional processes, potentially due to impairments in the noradrenergic system. We analyzed locus coeruleus (LC) neurite outgrowth characteristics following the administration of a physiologically relevant dose of cocaine (3.0 mg/kg) issued during critical phases of gestation (gestational day (GD)8–14, GD15–21, GD8–21). Results showed that cocaine inhibits LC neurite outgrowth and development, as evidenced by a decrease in total neurite length, a decrease in neurite length per cell, and a decrease in the percentage of cells with neurites. Morphological differences between cultures treated with and without cocaine were also evident. Further, the specific gestational exposure period effects were also dependent upon sex of the fetus. Finally, a discriminant function anaylsis suggested that the pattern and magnitude of alterations that defined the GD8–14 exposure were significantly different from that of the GD15–21 or GD8–21 exposures. Collectively, these data demonstrate a direct, disruptive effect of cocaine on noradrenergic neurons and may provide a neurobiological basis for changes in attentional function seen in offspring exposed to cocaine in utero.
Peripheral and central neurochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in humans and nonhuman primates: assessing bioeffect and mechanisms of action
Authors: Anderson George M.
Published: August 2004

It is clear that selective serotonin reuptake inhibitors (SSRIs) act powerfully to inhibit serotonin (5‐hydroxytryptamine, 5‐HT) uptake centrally and peripherally. However, there are a number of critical unanswered questions concerning the effects of the drugs in adults and children. The influence of age and duration of treatment on the extent of uptake inhibition and on the enhancement of central serotonergic functioning are unclear. In addition, the relationship of these factors and effects to the therapeutic and adverse effects of the SSRIs remain to be clarified. The general clinical utility of platelet 5‐HT measurement is reviewed and studies assessing central and peripheral uptake blockade in infants and children and non‐human primates are discussed. Recent investigations of central neurochemical effects of the SSRIs in primates assessed through measurement of 5‐HT and related compounds in cisternal cerebrospinal fluid (CSF) of the rhesus monkey are presented. In summary, the studies described have found that: human fetal exposure to SSRIs has substantial effects on 5‐HT transport in utero; exposure to SSRIs through breastmilk of mothers treated for postpartum depression usually has negligible effects on 5‐HT uptake; prescribed SSRIs appear to exert similar effects on 5‐HT transporter blockade in children and adults; and rapid and sustained increases are seen in monkey cisternal CSF levels of 5‐HT upon initiation of SSRI administration. The implications of the observations in terms of behavioral effects, clinical practice, and underlying mechanisms of action of the SSRIs are discussed.
Targeting serotonin and norepinephrine receptors in stress urinary incontinence
Authors: Thor K.B
Published: August 2004

Stress urinary incontinence (SUI) in women is prevalent, and there are no globally developed or widely approved drugs for the disease. One strategy for improving urinary continence is to augment the function of the urethral rhabdosphincter through neuropharmacology. The present review describes the innervation of the urethra, and the role of the central nervous system in controlling nerve activity. Targeting serotonin and norepinephrine (or noradrenaline) receptors in Onuf's nucleus is shown to augment the function of the urethral rhabdosphincter by increasing pudendal nerve efferent activity. It is proposed that the ability of serotonin and norepinephrine to enhance the effects of glutamate (the primary excitatory neurotransmitter for pudendal sphincter motor neurons) while having no direct effects of their own, allow facilitation of rhabdosphincter activity during urine storage while allowing complete relaxation during micturition. Duloxetine, a potent and balanced dual serotonin (5‐HT)‐norepinephrine reuptake inhibitor (SNRI), potentiates these physiological effects of endogenous serotonin and norepinephrine (by inhibiting the reuptake of these neurotransmitters in the pre‐synaptic element) and thereby enhances the central nervous system's natural continence control mechanisms.
Stress urinary incontinence in the gynecological practice
Authors: Contreras Ortiz O
Published: August 2004

This review discusses the prevalence, risk factors, the impact on the quality of life and healthcare‐seeking behavior of women suffering from urinary incontinence (UI) and stress urinary incontinence (SUI) in particular. UI is a common problem, affecting women in all age groups, and has devastating effects on their social, professional and family life. UI may be manifest as stress urinary continence (SUI), i.e. ‘the complaint of involuntary leakage on effort or exertion, or on sneezing or coughing’. SUI is the most common form of UI, reported by approximately 50% of the incontinent women. Alternatively, patients may suffer from urge urinary incontinence (UUI), characterized by the ‘complaint of involuntary leakage accompanied or immediately preceded by urgency’. This is reported by 10–20% of incontinent women. Patients having symptoms of both disorders may be afflicted by mixed urine incontinence (MUI), being reported by 30–40% of incontinent women. This complaint was recently included in the definitions as: ‘Involuntary leakage associated with urgency and also with exertion, effort, sneezing or coughing’. Urodynamic studies show that the prevalence of SUI is underestimated when based on symptoms alone, as many patients with mixed symptoms have pure SUI during urodynamics. Although the etiology of SUI is still poorly understood, among the main risk factors are age, pregnancy, childbirth and obesity. Unfortunately, the majority of the patients suffering UI postpones looking for medical help for years, or may even never consult a physician regarding their problem, despite the considerable negative impact on their quality of life. Feelings of shame and embarrassment play an important role in this, in combination with the common belief that UI is a normal and inevitable consequence of the aging process. Clearly, there is still a long way to go in making patients and society aware of the fact that UI is a disorder, which can and should be treated. Consequently, patients must be encouraged to report their problem, while health care providers should raise the issue on routine exams in risk groups.
Clinical practice guidelines on the initial assessment and treatment of urinary incontinence in women: a US focused review
Authors: Viktrup Lars , Summers Kent H , Dennett Susan L
Published: August 2004

Objective: To identify clinical practice guidelines from prominent US organizations for the initial management of urinary incontinence (UI) in women and compare them with recommendations from the International Consultation on Incontinence (ICI). The challenge of implementing guidelines in the US was also identified. Methods: The medical literature was reviewed to identify relevant practice guidelines on the initial management of UI in community‐dwelling women according to specific inclusion and exclusion criteria. Guidelines were compared with the ICI international gold standard relating to patient identification, initial therapy, and recommendation for specialist referral. Literature on programs to implement guidelines into clinical practice was reviewed. Results: There is general agreement on how females with UI should be initially managed based on guidelines, monographs, and technical bulletins from prominent US organizations. Though these recommendations are more than 5 years old, they are fairly similar to the latest guidelines developed by the ICI in 2001. Minor discrepancies are mainly related to the lack of updating US guidelines based on most recent knowledge. Implementing existing guidelines into clinical practice presents a challenge. Conclusion: No evidence‐based practice guidelines from prominent US organizations on the initial management of UI in women exist that are less than 5 years old, but the latest versions are in alignment with recent ICI/WHO guidelines. Although optimization of UI management may be the goal of guidances, the debate remains over whether these recommendations are actually effective in modifying practice. Simplifying and updating guidelines regularly may enhance adaptation in the initial management of UI in women.
Duloxetine: a new approach for treating stress urinary incontinence
Authors: Moore Kate
Published: August 2004

Duloxetine is a potent and balanced dual serotonin and norepinephrine reuptake inhibitor (SNRI) that enhances urethral rhabdosphincter activity and bladder capacity in a cat irritated bladder model. Whether this is beneficial in women suffering from stress urinary incontinence (SUI) has been investigated in one phase 2 and three phase 3 placebo‐controlled clinical trials with very comparable inclusion and exclusion criteria and outcome variables. In addition, one phase 3 study was performed in women with SUI awaiting incontinence surgery. These trials involved investigational centers in 5 continents: North America, Europe, Australia, South America and Africa. Duloxetine 80 mg per day (40 mg twice daily) decreased the frequency of incontinence episode frequency (IEF) and improved incontinence‐related quality of life (I‐QOL) independent of baseline incontinence severity and also in patients awaiting surgery. In the trial in patients awaiting surgery, onset of action was closely monitored and all patients who responded to duloxetine did so within 1–2 weeks. The decrease in IEF and improvement in I‐QOL were not due to more frequent voiding, as the mean time between voids increased. Nausea was the most common treatment emergent adverse event. This was mostly experienced early after the start of duloxetine (usually within the first few days) and was usually mild or moderate and non‐progressive in severity. The majority of patients reporting nausea continued treatment with duloxetine and in most of these patients the nausea resolved within 1 to 4 weeks. It can, therefore, be concluded that duloxetine 40 mg twice daily is a new and promising pharmacological treatment approach for women with SUI.
Heterotopic pregnancy after in vitro fertilization–embryo transfer
Authors: Chin H.‐Y. , Chen F.‐P. , Wang C.‐J. , Shui L.‐T. , Liu Y.‐H. , Soong Y.‐K.
Published: August 2004

Objective: A ruptured cornual pregnancy is a rare and challenging problem. We present two cases of cornual pregnancies after in vitro fertilization and embryo transfer (IVF‐ET) treated by cornual resection, with an excellent perinatal outcome for the intrauterine pregnancy in both cases. A literature review of cornual pregnancy after IVF‐ET is also included. Case reports: Two women had undergone IVF‐ET because of tubal problems. Emergent laparotomy was performed because of internal bleeding at 12 weeks of gestation in one case and 17 weeks in the other, and in both cases, ruptured cornual pregnancies were found. Cornual resection and primary repair were performed. The women were discharged on the 6th and 7th postoperative day, respectively, and they underwent an elective cesarean delivery at 37 weeks of pregnancy. They were delivered of healthy babies, one weighing 2700 g and the other 2310 g. Conclusion: These cases illustrate that good perinatal outcomes can be achieved by surgical intervention in heterotopic pregnancies, even in the event of a ruptured cornu.
Computerized cardiotocography in the management of intrauterine growth restriction associated with Doppler velocimetry alterations
Authors: Anceschi M.M. , Ruozi‐Berretta A. , Piazze J.J. , Cosmi E. , Cerekja A. , Meloni P. , Cosmi E.V.
Published: August 2004

Objective: To verify the reliability of computerized cardiotocography (cCTG) in the prediction of the oxygen metabolism status of fetuses with growth restriction and Doppler velocimetry alterations. Methods: From 24 third‐trimester cesarean section performed because of intrauterine growth restriction (IUGR) and Doppler velocimetry alterations, there were 11 cases of fetal heart rate alterations (Dawes–Redman criteria were not satisfied) and 13 cases of reactive cCTG. Fetal lung maturity was detected by amniocentesis and blood samples for umbilical blood gas analysis (UBGA) were collected before the first neonatal breath from the umbilical artery in a double‐clamped segment of the cord. Results: Umbilical cord gas analysis showed arterial cord blood pH to be 7.20 or less in 11 newborns (45.8%), 7.10 or less in 6 (25%), and 7.00 or less in 3 (12.5%). Linear regression analysis showed short‐term variation (STV) in the fetal heart rate to be significantly correlated with umbilical artery pH (r=0.49; P=0.01) and pCO2 (r=−0.50; P=0.01). There were no significant correlations between cCTG and the other UBGA parameters considered. Receiver operator curves permitted to calculate the STV values at which pathological neonatal UBGA values can be expected (pH<7.00 and pCO2>80 mmHg). A short‐term variation less than 4.5 ms was found to predict acidemia with a sensitivity of 100% and a specificity of 70% (positive predictive value, 33%; negative predictive value, 100%), and hypercarbia with a sensitivity of 100% and a specificity of 77.8% (positive predictive value, 55.6%; negative predictive value, 100%). Conclusion: In view of the results of this study, 4.5 ms for STV may be a threshold below which timing of delivery should be decided in cases of fetal growth restriction.