bluuebunny/crossref_metadata_2025 huggingface dataset:
Silver-Russell and Beckwith-Wiedemann Syndromes: Opposite (Epi)Mutations in 11p15 Result in Opposite Clinical Pictures
Authors: Eggermann Thomas
Published: April 2009

Progress in the identification of the (epi)genetic basis of imprinting disorders has provided greater insight into the central role of imprinted genes in regular human growth. In addition to the well-known Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes, imprinting disturbances have recently been identified in transient neonatal diabetes mellitus, uniparental disomy (14) syndromes and Silver- Russell syndrome (SRS). Among these diseases, the growth retardation disorder SRS is unique because it is the first human disorder associated with epigenetic mutations that affect two different chromosomes. In addition to maternal uniparental disomy of chromosome 7, hypomethylation of the imprinting control region 1 in 11p15 and maternal duplication of 11p15 have recently been described as major (epi)genetic disturbances in SRS. Interestingly, opposite (epi)- mutations are involved in the overgrowth disease Beckwith-Wiedemann syndrome (BWS). Thus SRS and BWS can be regarded as two genetically and clinically opposite clinical pictures. Although not yet completely understood, SRS and BWS can be used as models to decipher the functional link between the observed (epi)genetic mutations and the clinical features in individuals with disturbed growth. Future studies will clarify the complex basis of human growth and hopefully contribute to better-directed therapies.
Network of European Studies of Genes in Growth (NESTEGG)
Authors: Johnston Linda B. , Ester Wiestske , Caliebe Janina , Molinas Catherine , Wollmann Hartmut , Fryklund Linda , Clark Adrian J. , Ranke Michael B. , Tauber Maithe , Hokken Koelega Anita , Savage Martin O.
Published: April 2009

The network of European studies of genes in growth (NESTEGG) is an international growth genomics project, focusing on the birth size phenotypes of small for gestational age (SGA) and idiopathic short stature. Seven hundred controls and 1,275 cases with their parents have been recruited. Detailed clinical histories and auxological measurements are recorded in a clinical database. Candidate gene studies are being undertaken with the study DNA samples. These genetic data will be used to explore associations with the clinical phenotypes of short stature and SGA birth size, and, in a subset, response to growth hormone (GH) therapy. This article describes the study methodology and reviews the association of the exon 3-deleted genotype of the GH receptor with GH responsiveness in GH-treated children born SGA.
Growth Hormone Receptor Exon 3 Isoforms and Their Implication in Growth Disorders and Treatment
Authors: Jorge Alexander A.L. , Arnhold Ivo J.P.
Published: April 2009

Human recombinant growth hormone (hGH) has been used to treat short stature in several different conditions, but considerable inter-individual variation in short- and long-term growth response exists. Pharmacogenomics can provide important insights into hGH therapy. The GH receptor (GHR) is the first key molecule mediating GH action. In the past 3 years, a common GHR polymorphism reflecting the presence (GHRfl) or absence (GHRd3) of exon 3 has been under intensive investigation regarding its influence on the response to hGH therapy. Studies that evaluated response to GH treatment determined by these two GHR isoforms in children with GH deficiency, girls with Turner syndrome, children born small for gestational age and patients with acromegaly showed that patients carrying the GHRd3 allele demonstrated a greater GH sensitivity than patients homozygous for the GHRfl allele. Other studies presented contradictory data, however, which may be caused by confounding factors such as small sample sizes and differences in experimental design. This GHR exon 3 genotype is the first identified genetic factor found to modulate the individual response to GH therapy. This article reviews the historical aspects and pharmacogenetic studies published to date in relation to this GHR polymorphism. The analyses of present and future validation studies may define the use of this and other polymorphisms in clinical practice, moving from pharmacogenetics to routine application and allowing individualization of hGH doses to optimize final outcome.
Noonan Syndrome, the Ras–MAPK Signalling Pathway and Short Stature
Authors: Binder Gerhard
Published: April 2009

Short stature, with a mean final height almost two standard deviations below the normal mean, is a major feature of Noonan syndrome. The biological basis of the growth failure is not yet clear. The recent detection of mutations in the protein tyrosine phosphatase, non-receptor type 11 gene (PTPN11) in half of all individuals with Noonan syndrome has opened up a new perspective from the endocrine point of view, since the tyrosine phosphatase SHP2 encoded by PTPN11 is implicated in the downregulation of growth hormone (GH) receptor signalling. Current data show decreased insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP-3) levels in those children with Noonan syndrome who carry PTPN11 mutations. GH responsiveness seems to be reduced in the presence of PTPN11 mutations, but, so far, data are too scarce to draw any final conclusions. Children with Noonan or Noonan-related syndromes carrying mutations in components of the Ras–mitogen-activated protein kinase (MAPK) signalling pathway downstream from SHP2 also have short stature, though less frequently in the case of SOS1 mutations. Therefore, apart from the disturbance of GH signalling, there must be other relevant mechanisms that influence longitudinal growth in Noonan syndrome. In a small subgroup of patients with Noonan syndrome and Noonan-related syndromes, tumour risk is increased. This susceptibility is relevant when GH therapy is considered. Progress in the understanding of cell regulation by Ras–MAPK signalling and its interconnection with other pathways will hopefully provide evidence on which therapy might be helpful and which might be nocuous in the care of children with Noonan syndrome.
Oncogene-Induced Cellular Senescence: Causal Factor in the Growth Arrest of Pituitary Microadenomas?
Authors: Mooi Wolter J.
Published: April 2009

Pituitary microadenomas are exceedingly common in the general population, and only a very few progress to a size of more than a few millimetres. The early and total, or near- total, growth arrest preventing the outgrowth of these adenomas calls to mind the phenomenon of oncogene- induced cellular senescence (OIS), a growth arrest response brought about by oncogenic signalling. In the past, OIS has been demonstrated in a variety of benign neoplastic lesions, in animal models as well as in man. OIS results from the activation of powerful antiproliferative signalling networks, and presumably acts as a protective response preventing the outgrowth of early neoplastic lesions that are driven by a single or a very few oncogenic lesions. A few recent studies on pituitary tumorigenesis in Rb+/– mice, as well as some preliminary observations in human pituitary adenomas, lend support to the idea that OIS is also an important mediator of growth arrest in these occult pituitary tumours. If so, the fact that over 99.9% of pituitary adenomas never produce clinical problems of mass effect attests to the efficacy of this response.
Pituitary Tumour-Transforming Gene (PTTG) and Pituitary Senescence
Authors: Chesnokova Vera , Melmed Shlomo
Published: April 2009

Pituitary tumours account for 15% of intracranial neoplasms and are benign monoclonal neoplasms that may be clinically silent or secrete hormones, including prolactin, growth hormone, adrenocorticotrophic hormone or, rarely, thyroid-stimulating hormone or gonadotrophins. These adenomas account for clinical infertility, growth disorders and hypercortisolism or metabolic dysfunctions associated with hypopituitarism. We explored the role of disordered pituitary cell proliferation control in the pathogenesis of these invariably benign adenomas, studying the mechanisms underlying pituitary aneuploidy, premature proliferative arrest (senescence), markers of cell proliferation and tumorigenesis in single, double or triply mutant transgenic mice with mutations of Rb, Pttg and/or p21. Our results provide further insights into the role of cell-cycle control and growth constraints on experimental and human pituitary tumours, which underlie their failure to progress to malignancy. These results improve our understanding of pituitary syndromes associated with infertility, growth disorders, hypercortisolism or adrenal, thyroid and gonadal failure due to abrogated pituitary function.
Differential Gene Expression in Models of Pituitary Prolactin-Producing Tumoral Cells
Authors: Giacomini Damiana , Haedo Mariana , Gerez Juan , Druker Jimena , Páez-Pereda Marcelo , Labeur Marta , Stalla Günter K. , Arzt Eduardo
Published: April 2009

Although several genes and signalling pathways have been identified as important effectors in the development of pituitary tumours, our understanding of pituitary tumorigenesis remains incomplete and is the focus of much current research. Use of the mRNA differential display technique in prolactinomas from D2-receptor knockout mice and in stable GH3 cell line clones with enhanced tumorigenicity in vivo has led to the identification of two genes that are involved in the pathogenic process – BMP-4 and RSUME. Bone morphogenetic protein-4 (BMP-4) has been found to have a crucial role in prolactinoma development and also in signalling crosstalk with oestrogens. In contrast, BMP-4 has an inhibitory role in corticotrophinomas. RSUME (RWD-containing sumoylation enhancer) was identified from a transformed lactosomatotrophic cell line that had increased tumorigenic and angiogenic potential. Expression of RSUME was induced under hypoxic conditions and it has a potential role during vascularization. The differential expression and action of BMP-4 in prolactinomas and corticotrophinomas highlights the importance of studying a gene with contrasting actions in two cell lineages of the same organ in order to understand the pituitary transformation process. Both BMP-4 and RSUME may be interesting targets for inhibiting steps involved in pituitary tumorigenesis.
Genetics, Gene Expression and Bioinformatics of the Pituitary Gland
Authors: Davis Shannon W. , Potok Mary Anne , Brinkmeier Michelle L. , Carninci Piero , Lyons Robert H. , MacDonald James W. , Fleming Michelle T. , Mortensen Amanda H. , Egashira Noboru , Ghosh Debashis , Steel Karen P. , Osamura Robert Y. , Hayashizaki Yoshihide , Camper Sally A.
Published: April 2009

Genetic cases of congenital pituitary hormone deficiency are common and many are caused by transcription factor defects. Mouse models with orthologous mutations are invaluable for uncovering the molecular mechanisms that lead to problems in organ development and typical patient characteristics. We are using mutant mice defective in the transcription factors PROP1 and POU1F1 for gene expression profiling to identify target genes for these critical transcription factors and candidates for cases of pituitary hormone deficiency of unknown aetiology. These studies reveal critical roles for Wnt signalling pathways, including the TCF/LEF transcription factors and interacting proteins of the groucho family, bone morphogenetic protein antagonists and targets of notch signalling. Current studies are investigating the roles of novel homeobox genes and pathways that regulate the transition from proliferation to differentiation, cell adhesion and cell migration. Pituitary adenomas are a common human health problem, yet most cases are sporadic, necessitating alternative approaches to traditional Mendelian genetic studies. Mouse models of adenoma formation offer the opportunity for gene expression profiling during progressive stages of hyperplasia, adenoma and tumorigenesis. This approach holds promise for the identification of relevant pathways and candidate genes as risk factors for adenoma formation, understanding mechanisms of progression, and identifying drug targets and clinically relevant biomarkers.
Genetic, Molecular and Clinical Features of Familial Isolated Pituitary Adenomas
Authors: Daly Adrian F. , Tichomirowa Maria A. , Beckers Albert
Published: April 2009

Pituitary adenomas occur in a familial setting in about 5% of all cases, and over half of these are due to multiple endocrine neoplasia type 1 (MEN1) and Carney’s complex (CNC). Non-MEN1/CNC familial pituitary tumours of all tumour phenotypes, known as familial isolated pituitary adenomas (FIPA), were first described in the late 1990s. Clinical features of FIPA differ from those of sporadic pituitary adenomas, as patients with FIPA have a younger age at diagnosis and larger tumours. About 15% of patients with FIPA have mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. This article describes the clinical features of FIPA, the tumour pathologies found in this setting and the genetic/molecular data that have recently been reported in FIPA.
Recent Clinical and Pathophysiological Advances in Non-Functioning Pituitary Adenomas
Authors: Korbonits Márta , Carlsen Eivind
Published: April 2009

Pituitary adenomas are being recognized and diagnosed with increasing frequency. One of the most common forms of pituitary lesion is the clinically non-functioning pituitary adenoma (NFPA), which is often diagnosed incidentally. The vast majority of pituitary adenomas are sporadic, but familial adenomas can occur in the multiple pituitary adenoma type 1 syndrome, in Carney complex or in familial isolated pituitary adenoma. Distinguishing NFPA from prolactinomas can occasionally cause a differential diagnostic problem due to the ‘stalk effect’. NFPA often show hormone synthesis on tissue immunostaining without causing clinical symptoms. Most often these are silent gonadotroph adenomas, with silent corticotroph or somatotroph adenomas occurring less frequently. It is unclear why these silent adenomas do not release hormones at a clinically recognizable level, although it is probable that there is a continuum between fully functional and completely silent adenomas. Another intriguing feature of NFPAs is the lack of clinical response to somatostatin analogues, despite the presence of somatostatin receptors and an often good response in the in vitro setting. Temozolomide has been successfully used for the treatment of a few aggressive pituitary adenomas, and the response to this drug could be influenced by the expression of the DNA repair enzyme O-6-methylguanine DNA methyltransferase. The early diagnosis, prediction of long-term outcome and treatment of NFPAs remain a challenge for endocrinologists.
The MEN1 Gene and Pituitary Tumours
Authors: Agarwal Sunita K. , Ozawa Atsushi , Mateo Carmen M. , Marx Stephen J.
Published: April 2009

Sporadic multiple endocrine neoplasia type 1 (MEN1) is defined as the occurrence of tumours in two of three main endocrine tissue types: parathyroid, pituitary and pancreaticoduodenal. A prolactinoma variant or Burin variant of MEN1 was found to occur in three large kindreds, with more prolactinomas and fewer gastrinomas than typical MEN1. MEN1 tumours differ from common tumours by showing features from the MEN1 gene (e.g. larger pituitary tumours). They also show various expressions of tumour multiplicity; however, pituitary tumour in MEN1 is usually solitary. Diagnosis in MEN1 carriers during childhood is not directed at cancers but at benign morbid tumours. Morbid prolactinoma occurred at the age of 5 years in one MEN1 individual; hence, this is the earliest age at which to recommend tumour surveillance in carriers. The MEN1 gene shows biallelic inactivation in 30% of some types of common variety endocrine tumours (e.g. parathyroid adenoma, gastrinoma, insulinoma and bronchial carcinoid), but in only 1–5% of common pituitary tumours. Heterozygous knockout of MEN1 in mice provides a robust model of MEN1 and has been found to support further research on anti-angiogenesis therapy for pituitary tumours. The rarity of MEN1 mutations in some MEN1-like states aids the identification of other mutated genes, such as AIP, HRPT2 and p27Kip1. We present recent clinical and basic findings about the MEN1 gene, particularly concerning hereditary vs. common variety pituitary tumours.
The Decline of Pharmaceutical Psychiatry and the Increasing Role of Psychological Medicine
Authors: Fava Giovanni A.
Published: April 2009

The increasing influence of the pharmaceutical industry on psychiatric research and practice is leading to an intellectual and clinical crisis. A narrow concept of science attempts to apply oversimplified neurobiological models to the understanding and treatment of mental disorders, and relegates psychiatrists to a marginal role. This paper reviews some emerging trends of renewal that may be subsumed under the rubric of psychological medicine: use of a multidisciplinary approach, emphasis on psychotherapeutic strategies leading to self-management, reliance on repeated assessments, integration of different treatment modalities and independence from the pharmaceutical industry. The concept of psychological medicine, defined as the clinical application of the psychosomatic approach, may provide room for innovative paths in psychiatric research and treatment.
Conflicts of Interest and Disclosure in the American Psychiatric Association’s Clinical Practice Guidelines
Authors: Cosgrove Lisa , Bursztajn Harold J. , Krimsky Sheldon , Anaya Maria , Walker Justin
Published: April 2009

Background: Clinical practice guidelines (CPG) are developed, endorsed, and disseminated through professional medical organizations such as the American Psychiatric Association (APA) as the standard of care for health care providers. Because of their influence, it is critical that CPG are based on objective data, unprejudiced by stakeholder groups, and that any financial associations between authors of CPG and the pharmaceutical industry are made transparent. The present study examined the degree and type of financial ties to the pharmaceutical industry held by authors of 3 major CPG. Methods: By using multimodal screening techniques, we investigated the financial relationships to the pharmaceutical companies of 20 work group members who authored the guidelines for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Results: Eighteen CPG authors (90%) had at least 1 financial tie to the pharmaceutical industry. All of the CPG authors who had industry relationships had financial relationships with companies whose products were specifically considered or included in the guideline they authored. The leading categories of financial interest held by CPG authors were research funding (77.7%), consultancies (72.2%), members of corporate boards (44.4%), and collaborators in industry-funded studies (44.4%). Conclusions: Ninety percent of the authors of 3 major CPG in psychiatry had financial ties to companies that manufacture drugs which were explicitly or implicitly identified in the guidelines as recommended therapies for the respective mental illnesses. None of the financial associations of the authors were disclosed in the CPG.
Gonadotropin-Releasing Hormone Agonist Reduces Aromatase Cytochrome P450 and Cyclooxygenase-2 in Ovarian Endometrioma and Eutopic Endometrium of Patients with Endometriosis
Authors: Kim Young Ah , Kim Mi Ran , Lee Jae Hoon , Kim Ji Yeon , Hwang Kyung Joo , Kim Han Seong , Lee Eung Soo
Published: April 2009

Aims: To investigate whether the GnRH agonist may reduce aromatase P450 and COX-2 in the eutopic endometrium of patients with endometriosis and ovarian endometrioma. Materials and Methods: Endometrial specimens and ovarian endometrioma were obtained from 15 women with endometriosis undergoing laparoscopic surgery. The stromal cells of the eutopic endometrium and ovarian endometroma were cultured in the presence of the GnRH agonist (leuprolide acetate 0, 1, 5 and 10 μM) for 24 h. To investigate the effects of the GnRH agonist on the eutopic endometrium in vivo, biopsy samples of the endometrium (n = 5) among the patients who underwent laparoscopy were obtained after GnRH agonist therapy. The protein production of aromatase cytochrome P450 and COX-2 was examined by Western blot. Results: Proteins of aromatase P450 and COX-2 were reduced in the eutopic endometrium of patients with endometriosis treated with the GnRH agonist for 3 months. The stromal cells in the culture of endometrial explants and ovarian endometrioma which were treated with the GnRH agonist reduced the aromatase P450 and COX-2. Conclusion: The GnRH agonist reduced aromatase P450 and COX-2 by direct action on the eutopic endometrium of patients with endometriosis and ovarian endometrioma.
Effects of E2 and E1 Glycosylation on Specific Membrane Fusion in Rubella Virus Strain JR23
Authors: Wu Bing , Liu Xiaoli , Wang Zhiyu
Published: April 2009

Objectives: To explore the effects of glycosylation in glycoprotein on membrane fusion in rubella virus strain JR23. Methods: The N-linked glycosylation sites in glycoproteins were mutated individually or in combination. Total expression and cell surface expression efficiencies of mutant proteins were assayed with Western blot and FACS. The fusion functions were assayed with Giemsa staining and reporter gene method. Binding activity of mutant proteins was detected with hemadsorption assays. Results: We observed that total expression levels of all the mutant proteins in cells were unchanged, but the cell surface expression efficiencies of all the mutant proteins except E2 S131V were lower than wild-type protein. When effects of reduced cell surface expression were eliminated, mutant proteins N53G, S73I, S131V and T78A had lower fusion activities than wild-type protein, and binding abilities of E2 S73I and E1 T78A decreased slightly. But in all the combined mutants, no cell fusion was detected, and only a minor hemadsorption was observed in N53G-S131V, N53G-T78A and N53G-T211A. Conclusions: Glycosylation of glycoproteins were involved in cell surface expression synergistically. Glycosylation on E2 N53, N71, N129 and E1 N76 altered the specific membrane fusion, whereas no effects were detected on E1 N177 and N209 individually.
Correlation between nNOS Expression and Erectile Dysfunction in Experimental Diabetes Mellitus Rats of Different Ages
Authors: Hu Jin-Jia , Gu Hong-Yu , Ding Wen-Long , Yuan Shu-juan , Zhong Mei-Fang , Liu Li
Published: April 2009

Objective: To assess the correlation between neuronal nitric oxide synthase (nNOS) expression in the brain, lumbosacral spinal cord, sympathetic trunk, prostate and penis, and erectile dysfunction (ED) associated with diabetes mellitus (DM). Methods: DM was induced in adult male Sprague-Dawley rats by injecting streptozotocin. After 1, 2, 3 and 4 months, apomorphine was injected to test the penile reflex. The animals were then sacrificed, and the corpora cavernosa were isolated for a diastolic function test. In addition, the cortex of the brain, lumbosacral spinal cord, thoracic and lumbar sympathetic trunk, and root of the penis and prostate of each animal were subjected to a nNOS catalytic activity assay. Results: The times of penile reflex decreased gradually with the prolongation of DM. Acetylcholine-induced corpus cavernosum relaxation also markedly decreased in DM rats. On the other hand, in DM rats nNOS expression was elevated in the temporal cortex, hippocampus and hypothalamus, but was reduced in the spinal cord, sympathetic trunk and prostate. Statistics showed that nNOS expression in the brain correlated negatively with penis reflex and corpus cavernosum relaxation, while nNOS expression in the spinal cord, sympathetic trunk, penis and prostate had a positive correlation with penis reflex and corpus cavernosum relaxation. Conclusion: The expression of nNOS in the central and peripheral nervous systems correlated with diabetic ED and was a cause of diabetic ED.
Rapid Detection of Porcine Reproductive and Respiratory Syndrome Virus by Reverse Transcription Loop-Mediated Isothermal Amplification
Authors: Qin Chen , Jian Li , Xue-En Fang , Wei Xiong
Published: April 2009

The fragment of the membrane protein M gene with high conservation and specificity of porcine reproductive and respiratory syndrome virus (PRRSV) was chosen to be the target region, according to which six special primers were designed successfully. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) was applied to detect the PRRSV by incubation at 65° for only 45 min with the ladder-like pattern of bands from 182 bp on the agarose gel, and the product specificity was confirmed by RsaI. The result of RT-LAMP could also be visualized directly with the naked eye by adding the intercalating dye Picogreen®. The RT-LAMP was identified to detect only the PRRSV in all viruses tested, which demonstrated the high specificity. By using various sample dilutions as templates, the sensitivity of RT-LAMP was found to be 100-fold higher than that of RT-PCR and could be comparable to the fluorescence quantitative RT-PCR. A comparison was obtained by the RT-LAMP and PCR assays using 20 clinical samples. Finally, a rapid, convenient and reliable PRRSV detection system was developed using the RT-LAMP.
6,7-Dihydroxy-3,4-Dihydroisoquinoline: A Novel Inhibitor of Nuclear Factor-κB and in vitro Invasion in Murine Mammary Cancer Cells
Authors: Alvarez Francisco N. , Carlson Louise M. , Lindner Inna , Lee Kelvin P.
Published: April 2009

Background: The inhibition of nuclear factor (NF)-κB with nontoxic agents is a promising possible treatment approach that may inhibit tumor cell proliferation, counteract the prosurvival pathways that mediate resistance to cytotoxic therapy, and prevent tumor cell metastasis. Methods: An initial structure-activity relationship study of the NF-κB inhibitory activity of acetophenone-type compounds using electrophoretic mobility shift assay and Western blot analysis is presented. An in vitro cell invasion assay using DA3 cells, a murine breast cancer cell line, was conducted to model antimetastatic activity. Results: The carbonyl moiety is found to be the functional group responsible for inhibition of NF-κB, and a novel, more effective agent, 6,7-dihydroxy-3,4-dihydroisoquinoline, is postulated and confirmed. The compounds are characterized as active in the inhibition of both the canonical and noncanonical NF-κB signaling pathways. Lastly, 6,7-dihydroxy-3,4-dihydroisoquinoline is discovered to inhibit in vitro invasion in DA3 cells. Conclusion: 6,7-Dihydroxy-3,4-dihydroisoquionoline and its derivatives are presented as potential prototypes for a novel series of nontoxic antimetastatic agents that can be used in conjunction with current cancer therapeutic techniques.
Heat-Shock Protein 70-Overexpressing Gastric Epithelial Cells Are Resistant to Indomethacin-Induced Apoptosis
Authors: Hirata Ikuhiro , Naito Yuji , Handa Osamu , Hayashi Natsuko , Mizushima Katsura , Adachi Satoko , Omatsu Tatsushi , Okayama Tetsuya , Kishimoto Etsuko , Ichikawa Hiroshi , Takagi Tomohisa , Kokura Satoshi , Otaka Michiro , Yoshikawa Toshikazu
Published: April 2009

Background/Aims: Protecting intestinal mucosa from nonsteroidal anti-inflammatory drugs is still an unsolved problem. It has been revealed that apoptosis in epithelial cells as a result of mitochondrial injury is an important pathogenesis in indomethacin-induced gastric mucosal injury. In this study, we revealed the effect of overexpressed heat-shock protein 70 (HSP70) in indomethacin-induced apoptosis and oxidative stress. Methods: HSP70-overexpressing rat gastric mucosal cells (7018-RGM-1 cells) and control cells (pBK-CMV-12 cells) were used and treated with 0–500 μM of indomethacin for 24 h. Cell viability and cytotoxity were measured by a WST-8 assay and a lactate dehydrogenase release assay, respectively. Apoptosis was observed by fluorescence microscopy staining with Hoechst 33342 and propidium iodide. The expression of Bcl-2 family proteins, activation of caspase-3, and 4-hydroxy-2-nonenal (4-HNE)-modified proteins were assessed by Western blot analysis. Results: Indomethacin caused apoptosis of gastric epithelial cells. The 7018-RGM-1 cells survived significantly after indomethacin treatment compared to the control cells. The increase in pro-apoptotic Bad proteins, the decrease in anti-apoptotic Bcl-2 proteins, and caspase activation were all suppressed in the 7018-RGM-1 cells. A lower level of indomethacin-induced 4-HNE-modification was detected in the 7018-RGM-1 cells than in the control cells. Conclusion: Overexpressed HSP70 may potentiate resistance to apoptosis and oxidative stress in indomethacin-induced gastric epithelial cell injury.
The Effects of Helicobacter pylori Eradication on Body Mass Index and Dyspeptic Symptoms
Authors: Suto Hiroyuki , Yamazaki Yukinao , Yoshida Ikumi , Yamakawa Akiyo , Ohtani Masahiro , Ito Yoshiyuki , Kuriyama Masaru , Kato Takuji , Azuma Takeshi
Published: April 2009

Background and Aim: The relationship between Helicobacter pylori infection and body mass index (BMI) and dyspeptic symptoms is controversial. We investigated the changes in BMI and dyspeptic symptoms after H. pylori eradication among stages of atrophic gastritis classified according to the serum pepsinogen (PG) I/II ratio. Methods: One hundred and sixty-three H. pylori-positive patients underwent eradication therapy for H. pylori. Serum PG I and II concentrations were measured before treatment, and the PG I/II ratio was classified into three groups: PG I/II ratio <2.0, PG I/II ratio ≥2.0 and <4.0, and PG I/II ratio ≥4.0 were considered to be low, middle, and high, respectively. Their BMI and abdominal symptoms were checked before, 1 and 5 years after treatment, and these changes were investigated among the three groups. Results: The mean BMI changes 1 year after treatment in the low PG I/II ratio group were significantly higher than those in other groups. Most abdominal symptoms in the high PG I/II ratio group were most severe before eradication but improved significantly after eradication. Conclusions: The effects of H. pylori eradication on BMI and dyspeptic symptoms may be different according to the serum PG I/II ratio before eradication.
Minimizing Misdiagnosis: Psychometric Criteria for Possible or Probable Memory Impairment
Authors: Brooks Brian L. , Iverson Grant L. , Feldman Howard H. , Holdnack James A.
Published: April 2009

Background/Aims: Memory impairment can be easily misdiagnosed in older adults because obtaining some low scores is common. The objective of the present study is to present new psychometric criteria for determining ‘possible’ and ‘probable’ memory impairment. Methods: We propose criteria based on an analysis of performance from 450 healthy older adults (55–87 years old) on 3 measures from the WMS-III: Logical Memory, Word List, and Visual Reproduction. These measures yield 8 age-adjusted scores for learning, recall, and recognition. The proposed criteria for memory impairment are based on the prevalence of low scores when simultaneously examining all 8 scores and are stratified by current intelligence, estimated premorbid intelligence, and education. The criteria are subsequently validated on 100 healthy older adults and 34 patients with ‘possible’ or ‘probable’ Alzheimer’s Disease (AD). Results: Tables with cutoffs and false-positive rates are presented for clinical use. In the validation cohort there were no misclassifications in AD patients. Conclusion: This study presents steps in the development of proposed psychometric criteria that, in conjunction with clinical judgment, could minimize the misdiagnosis of memory impairment. It is important to reduce misdiagnosis in order to (a) optimize patient care, (b) provide an accurate foundation for identifying biological and neurological markers, and (c) successfully develop disease-modifying treatments. Further validation in a sample of older adults with lesser degrees of cognitive impairment is needed.
Downregulation of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Oral Squamous Cell Carcinoma: Correlation with Tumor Progression and Poor Prognosis
Authors: Shinozuka Keiji , Uzawa Katsuhiro , Fushimi Kazuaki , Yamano Yukio , Shiiba Masashi , Bukawa Hiroki , Yokoe Hidetaka , Tanzawa Hideki
Published: April 2009

Objective: To identify genes associated with therapeutic targets of oral squamous cell carcinoma (OSCC), we compared gene expression profiles in OSCC-derived cell lines with human normal oral keratinocytes. Methods: We analyzed the gene expression profiles of OSCCs using Affymetrix GeneChip analysis. The identified genes were analyzed by an Ingenuity Pathway Analysis tool to identify networks of interacting genes. A candidate gene was further evaluated for the expression status of the mRNA and protein in OSCC-derived cell lines and primary OSCCs. Results: The microarray data identified 188 genes downregulated in OSCC-derived cell lines, and the genetic pathways associated with expression changes were generated. Among the genes mapped to the network with the highest significance, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was analyzed further. CEACAM1 mRNA and protein were frequently downregulated in OSCC-derived cell lines compared with human normal oral keratinocytes. Immunohistochemical analysis showed that primary OSCCs were significantly decreased in CEACAM1. Moreover, CEACAM1 expression was correlated with the TNM staging. We also found that CEACAM1-negative expression was significant both for disease-free (p = 0.036) and overall survival (p = 0.032). Conclusion: Repression of CEACAM1 could contribute to cancer progression and may indicate a poor prognosis for patients with OSCC.
Circulating and Disseminated Tumor Cells in the Clinical Management of Breast Cancer Patients: Unanswered Questions
Authors: Amadori A. , Rossi E. , Zamarchi R. , Carli P. , Pastorelli D. , Jirillo A.
Published: April 2009

Breast cancer is the most common cancer in women. Although survival rates have improved with the use of new therapeutic agents, many issues remain unresolved and new predictive and prognostic factors are needed in clinical practice. Several studies have suggested a prognostic and predictive role for circulating and disseminated tumor cells in metastatic disease and adjuvant treatment. Because of recent technological advances, oncologists have gained a new perspective on this disease. Circulating tumor cells could be both a new tumor marker as well as a tool to gain novel insight into the natural history of this neoplastic disease.
Assessment of Right Ventricular Function Using Tissue Doppler Imaging in Infants with Pulmonary Hypertension
Authors: Patel Neil , Mills John F. , Cheung Michael M.H.
Published: April 2009

Background: In infants with pulmonary hypertension (PHT), right ventricular (RV) function may be altered and contribute to disease severity. Tissue Doppler imaging (TDI) is a new echocardiographic modality which directly measures myocardial velocities and may allow quantitative assessment of systolic and diastolic ventricular function in infants. Objective: To measure and compare RV myocardial velocities in infants with PHT and in normal control infants, using TDI. Methods: This was a prospective case-control study. Twenty-eight control infants and 15 infants with PHT, of whom 11 had congenital diaphragmatic hernia (CDH), were recruited. TDI was used to obtain systolic and diastolic myocardial velocities in the RV and interventricular septum in all infants. Results: There were significant reductions in systolic isovolumic contraction velocity (IVV; 5.3 vs. 6.6 cm/s) and systolic ejection velocity (S; 6.6 vs. 9.2 cm/s) in the PHT group compared to the control group. Early diastolic myocardial velocity, E’, was also significantly reduced in the RV in the PHT infants compared to controls (–4.3 vs. 8.6 cm/s). The same significant reductions in systolic and early diastolic TDI velocities were observed in the subgroup of CDH infants alone. Conclusions: TDI permits non-invasive assessment of RV myocardial velocities in infants. Reduced systolic and diastolic velocities in PHT may represent impaired systolic contraction and early diastolic relaxation. Therapies which target inotropic and lusitropic function may be appropriate in infants with PHT and RV dysfunction. The load-dependency of TDI measures in infants and the effects of specific therapies on RV function in PHT require further investigation.
Anti-Hepatitis B Virus Activity and Mechanisms of Recombinant Human Serum Albumin-Interferon-α-2b Fusion Protein in vitro and in vivo
Authors: Bingfa Xu , Qinglin Fan , Hui Huang , Canjun Wang , Wei Wei , Lihua Song
Published: April 2009

Aims:To evaluate the anti-hepatitis B virus (anti-HBV) effects and mechanisms of recombinant human serum albumin-interferon-α-2b fusion protein (rHSA-IFNα-2b) in vitro and in vivo. Methods: The inhibiting effects on HBV replication were examined in the HepG2 2.2.15 cell line and in ducks, and the expressions of signal transducers and transactivator 1 (STAT1), IFN-stimulated gene factor 3 (ISGF3) and 2′,5′-oligoadenylate synthetase 1 (OAS1) were investigated by the reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Results: In vitro,at concentrations from 0.075 to 1.2 nmol/l, rHSA-IFNα-2b inhibited the releases of extracellular hepatitis B surface antigen, hepatitis B e antigen and HBV DNA in a dose-dependent manner; rHSA- IFNα-2b also increased the levels of STAT1, ISGF3 and OAS1. In vivo, rHSA-IFNα-2b reduced the levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin and duck hepatitis B virus (DHBV) DNA in the sera of DHBV-infected ducks. Conclusions:We provide the first evidence that rHSA-IFNα-2b significantly inhibits HBV replication in HepG2 2.2.15 cells and in ducks, and that the antiviral effect of rHSA-IFNα-2b in vivo is more potent than that of IFNα-2b. The anti-HBV mechanism probably operates by triggering the JAK-STAT signaling pathway and increasing the expression of OAS1.
Necrotizing Enterocolitis – 150 Years of Fruitless Search for the Cause
Authors: Obladen Michael
Published: April 2009

Necrotizing enterocolitis (NEC) is not a new disease but one that has been reported since special care units began to house preterm infants. It was observed in foundling hospitals in Paris [Billard, 1828] and Vienna [Bednar, 1850] and, as it occurred in clusters, was regarded as a nosocomial infection in the infant hospitals of Zurich [Willi, 1944] and Berlin [Ylppö, 1931]. Clinical and patho-anatomic characterization was achieved by Schmidt and Quaiser in 1952. The unproven hypothesis of mesenteric hypoperfusion as a major etiological factor arose from animal models and analogous perforating disorders in term infants. Despite similarities between NEC and clostridial infections, few studies employed anaerobic culture techniques. The pathogenesis remains unclear and its distinction from related disorders uncertain. It is unlikely that strategies to prevent NEC will be successful unless the disease is better understood.
Liver Enzymes Cannot Be Used to Predict Liver Damage after Global Hypoxia-Ischemia in a Neonatal Pig Model
Authors: Karlsson Mathias , Satas Saulius , Stone Janet , Porter Helen , Thoresen Marianne
Published: April 2009

Background: The term newborn pig is an established model for studying both brain and organ pathology after hypoxia-ischemia (HI). Serial liver enzyme activity is often used to predict liver injury but little is known about the relation between consecutive values of different liver enzymes and histologically verified liver injury. Objective: To determine whether plasma values of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) differed between newborn pigs with liver injures and pigs with normal livers after a severe global HI insult. Methods: Nineteen ≤36-hour-old pigs underwent a 45-min global HI insult followed by 72-hour survival. Four histological sections from standardized areas within each liver were examined. Areas under the curve (AUC) for the enzymes were calculated and compared between pigs with pathological changes in the liver (n = 12) and pigs with normal liver histology (n = 7). Results: No differences in AUC for the enzyme values were seen between the groups. However, in pigs with liver injuries a transient significant increase in LDH at the end of the HI insult (928 U/l (567–1,031)) was seen compared to the baseline value (679 U/l (548–866), p = 0.010). Significantly more liver injury was seen in animals with the umbilical vein catheter (UVC) tip inserted into the liver (p = 0.040) compared to animals with the UVC tip located outside the liver. Conclusions: In newborn pigs subjected to global HI, only LDH increases alongside pathological changes in the liver. Normal values of ALT and AST do not exclude hepatic injury.
Periventricular Echodensity Measured with the Integrated Backscatter System: From a Qualitative Assessment to a Quantitative Approach
Authors: Yoshizawa Yukihiro , Watanabe Masayuki , Ohki Yasushi , Tokuyama Kenichi , Mayuzumi Hiroo , Takahashi Yukiko , Morikawa Akihiro
Published: April 2009

Background: The degree of periventricular white matter echodensity in preterm infants has been utilized as a sign of the early ultrasonographic appearance of periventricular leukomalacia, and this has been called periventricular echodensity (PVE). Objectives: The aim of this study was to quantitatively measure PVE utilizing a new method which is called calibrated integrated backscatter (calibrated IB). Methods: Eighty-eight preterm infants (extremely low birth weight infants, n = 17; very low birth weight infants, n = 26; low birth weight infants, n = 45) without any CNS abnormality were enrolled. IB is the returned sound pressure against supersonic waves sent from an ultrasonographic machine. The IB of the choroid plexus and periventricular white matter in the subrolandic area were measured on a parasagittal cerebral image. The degree of PVE was defined by subtracting the IB of the choroid plexus from that of the periventricular white matter in the subrolandic area (calibrated IB of PVE). Results: The intraobserver and interobserver correlations were both excellent (between 0.87 and 0.98 as correlation coefficients). There was a trend for the calibrated IB of PVE to decrease in accordance with time after birth, with a significant difference in very low birth weight and low birth weight infants. Conclusions: The objectively measured brightness of PVE was comparable to that of the choroid plexus irrespective of the size of the infants. Measurement of the calibrated IB of PVE might be a reliable method to assess PVE.
Skin Care in the NICU Patient: Effects of Wipes versus Cloth and Water on Stratum Corneum Integrity
Authors: Visscher Marty , Odio Mauricio , Taylor Teresa , White Tamina , Sargent Shelly , Sluder Linda , Smith Louise , Flower Teresa , Mason Beth , Rider Maureen , Huebner Amy , Bondurant Pattie
Published: April 2009

Background: NICU patients are at risk of skin breakdown due to prematurity, irritant exposure, medical status and stress. There is a need to minimize damage, facilitate skin development and reduce infection risk, but the literature on the effects of skin care practices in NICU patients is limited. Objectives: To test the hypothesis that baby diaper wipes with emollient cleansers and a soft cloth would minimize skin compromise relative to cloth and water. Methods: In 130 NICU infants (gestational age 23–41 weeks, at enrollment 30–51 weeks), measurements of skin condition, i.e., skin erythema, skin rash, transepidermal water loss (TEWL) and surface acidity (pH), within the diaper and at diaper and chest control sites were determined daily for 5–14 days using standardized methods. Treatments were randomly assigned based on gestational age and starting skin irritation score: wipe A, wipe B, and the current cloth and water NICU standard of care. Results: Perineal erythema and TEWL were significantly lower for wipes A and B than cloth and water beginning at day 5 for erythema (scores of 1.11 ± 0.05, 1.2 ± 0.05, and 1.4 ± 0.06, respectively) and day 7 for TEWL (28.2 ± 1.6, 28.8 ± 1.6, and 35.2 ± 1.6 g/m2/h, respectively). Wipe B produced a significantly lower skin pH (day 5, 5.47 ± 0.03) than wipe A (5.71 ± 0.03) and cloth and water (5.67 ± 0.04). The starting skin condition, stool total, age and time on current standard impacted the outcomes. Conclusions: Both wipes are appropriate for use on medically stable NICU patients, including both full and preterm infants, and provide more normalized skin condition and barrier function versus the cloth and water standard. Wipe B may facilitate acid mantle development and assist in colonization, infection control and barrier repair. Neonatal skin continues to change for up to 8 weeks postnatally, presumably as it adapts to the dry extra-uterine environment.
Incidence of Overactive Bladder after Vaginal Hysterectomy and Associated Repairs for Pelvic Organ Prolapse
Authors: Diez-Itza I. , Aizpitarte I. , Becerro A. , Sarasqueta C.
Published: April 2009

Objective: The aim of this study was to determine the incidence of overactive bladder (OAB) after vaginal hysterectomy for pelvic organ prolapse (POP) and analyze the associated risk factors. Study Design: This was a retrospective cohort study of 217 patients who underwent primary POP vaginal surgery between the years 2000 and 2004 in Donostia Hospital and who did not report OAB before surgery. A personal interview was undertaken after surgery for the diagnosis of OAB, taking into account the ICS 2002 definition. Descriptive statistical analyses and multivariate logistic regression were performed to determine the factors associated with the development of OAB after POP surgery. Results: De novo OAB was diagnosed in 43 (19.8%) patients. The median time at onset of OAB symptoms after surgery was 3 months. Urge urinary incontinence was present in 28 patients (12.9%). Those women operated on also for stress urinary incontinence were at an increased risk for de novo OAB. Conclusion: Nearly 20% of women operated on for POP develop OAB soon after surgery. Those operated on for POP and stress urinary incontinence are more at risk.
Association between Changes in Obesity Parameters and Incidence of Chronic Kidney Disease in Japanese Individuals
Authors: Ishizaka Yuko , Ishizaka Nobukazu , Tani Mizuki , Toda Akiko , Toda Ei-Ichi , Koike Kazuhiko , Nagai Ryozo , Yamakado Minoru
Published: April 2009

Obesity increases the risk for chronic kidney disease (CKD). By analyzing data on individuals who underwent general health screening in two consecutive years, we investigated whether changes in body mass index (BMI) or waist circumference (WC) were associated with the appearance or disappearance of the CKD components; micro-/macroalbuminuria (≥30 mg urinary albumin per gram creatinine) and a low estimated glomerular filtration rate (eGFR; <60 ml/min/1.73 m2). Logistic regression analysis showed that in men with micro-/macroalbuminuria at the first visit, a BMI reduction of ≥0.42 or a WC reduction of ≥3.0 cm over the 1-year period resulted in a significantly reduced incident of micro-/macroalbuminuria at the second visit. On the other hand, a BMI gain of ≥0.33 over 1 year in men without micro-/macroalbuminuria and a low eGFR at the fist visit significantly increased the incident of micro-/macroalbuminuria and a low eGFR, respectively, at the second visit. These findings indicate that lowering the obesity indexes in men with micro-/macroalbuminuria reduced the incidence of this condition at the 1-year follow-up and that, on the contrary, an increase in BMI in men without micro-/macroalbuminuria and a low eGFR at the first examination increased the risk of these conditions during the 1-year follow-up period.