bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Myopathy, Sideroblastic Anemia, and Lactic Acidosis: An Autosomal Recessive Syndrome in Persian Jews Caused by a Mutation in the PUS1 Gene
Authors: Zeharia Avraham , Fischel-Ghodsian Nathan , Casas Kari , Bykhovskaya Yelena , Tamari Hana , Lev Dorit , Mimouni Marc , Lerman-Sagie Tally
Published: May 2009

We report the seventh case of autosomal recessive inherited mitochondrial myopathy, lactic acidosis, and sideroblastic anemia. The patient, a product of consanguineous Persian Jews, had the association of mental retardation, dysmorphic features, lactic acidosis, myopathy, and sideroblastic anemia. Muscle biopsy demonstrated low activity of complexes 1 and 4 of the respiratory chain. Electron microscopy revealed paracrystalline inclusions in most mitochondria. Southern blot of the mitochondrial DNA did not show any large-scale rearrangements. The patient was found to be homozygous for the 656C→T mutation in the pseudouridine synthase 1 gene ( PUS1). Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia is an oxidative phosphorylation disorder causing sideroblastic anemia, myopathy, and, in some cases, mental retardation that is due to mutations in the nuclear-encoded PUS1 gene. This finding provides additional evidence that mitochondrial ribonucleic acid modification impacts the phenotypic expression of oxidative phosphorylation disorders. ( J Child Neurol 2005;20:449—452).
Seizure Worsening Caused by Decreased Serum Valproate During Meropenem Therapy
Authors: Santucci Margherita , Parmeggiani Antonia , Riva Roberto
Published: May 2009

Serum concentrations of valproate were reduced and seizures were exacerbated by concomitant meropenem therapy in a child with a neurodegenerative disorder and epilepsy. In this patient, a rapid decline of valproate serum concentrations was observed on two occasions with meropenem antibiotic therapy. This event was the most likely cause of observed seizure exacerbation. Meropenem should be used with caution in patients treated with valproate owing to the drastic lowering of serum valproate concentration and the consequent risk of seizure worsening. ( J Child Neurol 2005;20:456—457).
A Child with Transient Neurologic Deficits and Headache Associated with Cerebrospinal Fluid Pleocytosis
Authors: Safier Robert , Alper Gulay
Published: May 2009

We report a case of a 10-year-old girl who had several episodes of severe headache, altered consciousness, and temporary neurologic signs and symptoms within a 2-month period. Cerebrospinal fluid examination showed lymphocytic pleocytosis and increased protein. Extensive microbiologic investigation and neuroimaging studies were negative. Cerebrospinal fluid findings were normalized within a 3-month period, and the patient has not had further episodes through 15 months of follow-up. This combination of symptoms represents a benign, monophasic illness without further progression. The etiology, however, remains unclear. ( J Child Neurol 2005;20:439—441).
Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic Nerve Atrophy (PEHO)-Like Syndrome: What Diagnostic Characteristics Are Defining?
Authors: D'Arrigo Stefano , Grazia Bruzzone Maria , Faravelli Francesca , Riva Daria , Pantaleoni Chiara
Published: May 2009

Progressive encephalopathy with edema, hypsarrhythmia, and optic nerve atrophy (PEHO) syndrome is a rare, apparently autosomal recessive condition in which characteristic dysmorphic features are associated with subcutaneous edema, visual deficit, early arrest of psychomotor development, seizures, and cerebellar atrophy. A condition similar to PEHO syndrome, but without the neuroradiologic or ophthalmologic signs, is known as PEHO-like syndrome. We present the case of a child with PEHO-like syndrome and underline the need for a careful follow-up of these patients to identify signs and symptoms that can have a later onset, such as optic atrophy. ( J Child Neurol 2005;20:454—456.)
Rural Economic Development in the United States
Authors: Johnson Janna
Published: May 2009

The U.S. Department of Agriculture's Business and Industry (B&I) Guaranteed Loan Program guarantees loans made by rural banks to rural businesses. The author evaluates B&I's effectiveness in increasing employment using basic ordinary least squares (OLS) and propensity score matching models. The author finds a robust association between loan reception and increased employment growth. A loan of $1,000 per capita is accompanied by a 3% to 6% increase in employment-per-capita growth and a 3% to 5% decrease in earnings-per-worker growth over the 2 years after the loan, leaving the effect on total county earnings indeterminate. The author concludes that the B&I loan program subsidizes loans associated with increased employment growth, although the jobs created are lower paying than average.
The Influence of Myers-Briggs Type Indicator Profiles on Team Development Processes
Authors: Kuipers Ben S. , Higgs Malcolm J. , Tolkacheva Natalia V. , de Witte Marco C.
Published: May 2009

The Myers-Briggs Type Indicator (MBTI) is one of the most common personality assessments and a frequently used instrument for team development. However, in relation to team development processes, there is little research and literature on the role of personality in general and the usefulness of MBTI in particular. This article starts with a review of the MBTI and explores the relationship between MBTI profiles and team processes using a sample of 1,630 people working in 156 teams in a Swedish industrial organization. The results show that only a small number of MBTI personality profiles have a significant relationship with team processes. Overall, the composition of teams in terms of MBTI profiles does not seem to predict team development very well. Findings suggest that the MBTI may be used as an instrument for personal development and as a vehicle for group members to gain a better understanding of each other.
The Cost-Effectiveness of Direct-to-Consumer Advertising for Prescription Drugs
Authors: Atherly Adam , Rubin Paul H.
Published: May 2009

In this paper we use published information to analyze the economic value of Direct to Consumer Advertising (DTCA). The reviewed research finds that DTCA leads to increased demand for the advertised drug and that the effect of the drug tends to be class-wide rather than product specific. There is weak evidence that DTCA may increase compliance and improve clinical outcomes. However, there is little research on the effect of DTCA on inappropriate prescribing or on the characteristics of patients who respond to treatment. On net, if the advertised drugs are cost effective on average and the patients using the drugs in response to the advertisement are similar to other users, DTCA is likely cost effective. Overall, the literature to date is consistent with the idea that DTCA is beneficial, but further research is needed before definitive conclusions can be drawn.
Community-Associated Methicillin-Resistant Staphylococcus aureus Skin and Soft-Tissue Infection in HIV-Infected Patients
Authors: Trinh T. Tony , Short William R. , Mermel Leonard A.
Published: May 2009

Background. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as the most common cause of skin and soft tissue infections (SSTIs). Methods. Retrospective chart review of 43 adult HIV-infected patients with CA-MRSA SSTI was conducted. Results. Antibiotic susceptibility was as follows: vancomycin (100%), rifampin (100%), gentamicin (97.7%), tetracycline (96.5%), trimethoprim-sulfamethoxazole (95.2%), clindamycin (89.5%), levofloxacin (66.7%), and erythromycin (6.9%). At SSTI presentation, 58.5% of patients had CD4 counts greater than 200 cells/uL, 82.9% had a viral load (VL) below 100 000 log copies/mL, 6 of whom had undetectable VL. All 43 patients received empiric antibiotic therapy. Additionally, 34 patients underwent incision and drainage (I&D). For the 37 patients with follow-up data available at 4 weeks, 30 of the infections were resolved/resolving and 7 had no improvement or worsened. Conclusion. A majority of our patients with CA-MRSA SSTI did not have immunological/virological markers consistent with severe HIV/AIDS disease at time of presentation.
IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells
Authors: Shi Ping , Lai Raymond , Lin Quan , Iqbal Abid S. , Young Leah C. , Kwak Larry W. , Ford Richard J. , Amin Hesham M.
Published: May 2009

Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase plays important roles in the pathogenesis of several malignancies. Although it promotes the growth of stimulated hematopoietic cells, a direct role of IGF-IR in malignant lymphoma has not been identified. Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+ ALCL) is a unique type of T-cell lymphoma. Approximately 85% of ALK+ ALCL cases harbor the translocation t(2;5)(p23;q35), which generates the chimeric oncogene NPM-ALK. In the present study, we explored a possible role of IGF-IR in ALK+ ALCL. Our results demonstrate that IGF-IR and IGF-I are widely expressed in ALK+ ALCL cell lines and primary tumors. Importantly, we identified novel reciprocal functional interactions between IGF-IR and NPM-ALK. Antagonism of IGF-IR decreased the viability, induced apoptosis and cell-cycle arrest, and decreased proliferation and colony formation of ALK+ ALCL cell lines. These effects could be explained by alterations of cell survival regulatory proteins downstream of IGF-IR signaling. Our findings improve current understanding of the biology of IGF-IR and NPM-ALK and have significant therapeutic implications as they identify IGF-IR signaling as a potential therapeutic target in ALK+ ALCL and possibly other types of malignant lymphoma.
Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M
Authors: Singh Thiyam Ramsing , Bakker Sietske T. , Agarwal Sheba , Jansen Michael , Grassman Elke , Godthelp Barbara C. , Ali Abdullah Mahmood , Du Chang-hu , Rooimans Martin A. , Fan Qiang , Wahengbam Kebola , Steltenpool Jurgen , Andreassen Paul R. , Williams David A. , Joenje Hans , de Winter Johan P. , Meetei Amom Ruhikanta
Published: May 2009

FANCM is a component of the Fanconi anemia (FA) core complex and one FA patient (EUFA867) with biallelic mutations in FANCM has been described. Strikingly, we found that EUFA867 also carries biallelic mutations in FANCA. After correcting the FANCA defect in EUFA867 lymphoblasts, a “clean” FA-M cell line was generated. These cells were hypersensitive to mitomycin C, but unlike cells defective in other core complex members, FANCM−/− cells were proficient in monoubiquitinating FANCD2 and were sensitive to the topoisomerase inhibitor camptothecin, a feature shared only with the FA subtype D1 and N. In addition, FANCM−/− cells were sensitive to UV light. FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM−/− cells, whereas a FANCM ATPase mutant did not. Because both mutants restored the formation of FANCD2 foci, we conclude that FANCM functions in an FA core complex–dependent and –independent manner.
Statistical identification of gene association by CID in application of constructing ER regulatory network
Authors: Liu Li-Yu D , Chen Chien-Yu , Chen Mei-Ju M , Tsai Ming-Shian , Lee Cho-Han S , Phang Tzu L , Chang Li-Yun , Kuo Wen-Hung , Hwa Hsiao-Lin , Lien Huang-Chun , Jung Shih-Ming , Lin Yi-Shing , Chang King-Jen , Hsieh Fon-Jou
Published: May 2009

Background

A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating in silico inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs) (X) and their downstream genes (Y) based on clinical data. More specifically, we use estrogen receptor α (ERα) as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A).

Results

The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC), Student's t-test (STT), coefficient of determination (CoD), and mutual information (MI). When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y) against a discrete variable (X), it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays.

Conclusion

CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the association predicted by CID are applicable to the construction of transcriptional regulatory networks. This study shows how information from different data sources and learning algorithms can be integrated to investigate whether relevant regulatory mechanisms identified in cell models can also be partially re-identified in clinical samples of breast cancers.

Availability

the implementation of CID in R codes can be freely downloaded from http://homepage.ntu.edu.tw/~lyliu/BC/.
Improving Gene-finding in Chlamydomonas reinhardtii:GreenGenie2
Authors: Kwan Alan L , Li Linya , Kulp David C , Dutcher Susan K , Stormo Gary D
Published: May 2009

Background

The availability of whole-genome sequences allows for the identification of the entire set of protein coding genes as well as their regulatory regions. This can be accomplished using multiple complementary methods that include ESTs, homology searches and ab initio gene predictions. Previously, the Genie gene-finding algorithm was trained on a small set of Chlamydomonas genes and shown to improve the accuracy of gene prediction in this species compared to other available programs. To improve ab initio gene finding in Chlamydomonas, we assemble a new training set consisting of over 2,300 cDNAs by assembling over 167,000 Chlamydomonas EST entries in GenBank using the EST assembly tool PASA.

Results

The prediction accuracy of our cDNA-trained gene-finder, GreenGenie2, attains 83% sensitivity and 83% specificity for exons on short-sequence predictions. We predict about 12,000 genes in the version v3 Chlamydomonas genome assembly, most of which (78%) are either identical to or significantly overlap the published catalog of Chlamydomonas genes [1]. 22% of the published catalog is absent from the GreenGenie2 predictions; there is also a fraction (23%) of GreenGenie2 predictions that are absent from the published gene catalog. Randomly chosen gene models were tested by RT-PCR and most support the GreenGenie2 predictions.

Conclusion

These data suggest that training with EST assemblies is highly effective and that GreenGenie2 is a valuable, complementary tool for predicting genes in Chlamydomonas reinhardtii.
Water deficit alters differentially metabolic pathways affecting important flavor and quality traits in grape berries of Cabernet Sauvignon and Chardonnay
Authors: Deluc Laurent G , Quilici David R , Decendit Alain , Grimplet Jérôme , Wheatley Matthew D , Schlauch Karen A , Mérillon Jean-Michel , Cushman John C , Cramer Grant R
Published: May 2009

Background

Water deficit has significant effects on grape berry composition resulting in improved wine quality by the enhancement of color, flavors, or aromas. While some pathways or enzymes affected by water deficit have been identified, little is known about the global effects of water deficit on grape berry metabolism.

Results

The effects of long-term, seasonal water deficit on berries of Cabernet Sauvignon, a red-wine grape, and Chardonnay, a white-wine grape were analyzed by integrated transcript and metabolite profiling. Over the course of berry development, the steady-state transcript abundance of approximately 6,000 Unigenes differed significantly between the cultivars and the irrigation treatments. Water deficit most affected the phenylpropanoid, ABA, isoprenoid, carotenoid, amino acid and fatty acid metabolic pathways. Targeted metabolites were profiled to confirm putative changes in specific metabolic pathways. Water deficit activated the expression of numerous transcripts associated with glutamate and proline biosynthesis and some committed steps of the phenylpropanoid pathway that increased anthocyanin concentrations in Cabernet Sauvignon. In Chardonnay, water deficit activated parts of the phenylpropanoid, energy, carotenoid and isoprenoid metabolic pathways that contribute to increased concentrations of antheraxanthin, flavonols and aroma volatiles. Water deficit affected the ABA metabolic pathway in both cultivars. Berry ABA concentrations were highly correlated with 9-cis-epoxycarotenoid dioxygenase (NCED1) transcript abundance, whereas the mRNA expression of otherNCEDgenes and ABA catabolic and glycosylation processes were largely unaffected. Water deficit nearly doubled ABA concentrations within berries of Cabernet Sauvignon, whereas it decreased ABA in Chardonnay at véraison and shortly thereafter.

Conclusion

The metabolic responses of grapes to water deficit varied with the cultivar and fruit pigmentation. Chardonnay berries, which lack any significant anthocyanin content, exhibited increased photoprotection mechanisms under water deficit conditions. Water deficit increased ABA, proline, sugar and anthocyanin concentrations in Cabernet Sauvignon, but not Chardonnay berries, consistent with the hypothesis that ABA enhanced accumulation of these compounds. Water deficit increased the transcript abundance of lipoxygenase and hydroperoxide lyase in fatty metabolism, a pathway known to affect berry and wine aromas. These changes in metabolism have important impacts on berry flavor and quality characteristics. Several of these metabolites are known to contribute to increased human-health benefits.
Evaluation of the passage of Lactobacillus gasseri K7 and bifidobacteria from the stomach to intestines using a single reactor model
Authors: Ritter Philipp , Kohler Christian , von Ah Ueli
Published: May 2009

Background

Probiotic bacteria are thought to play an important role in the digestive system and therefore have to survive the passage from stomach to intestines. Recently, a novel approach to simulate the passage from stomach to intestines in a single bioreactor was developed. The advantage of this automated one reactor system was the ability to test the influence of acid, bile salts and pancreatin.

Lactobacillus gasseri K7 is a strain isolated from infant faeces with properties making the strain interesting for cheese production. In this study, a single reactor system was used to evaluate the survival of L. gasseri K7 and selected bifidobacteria from our collection through the stomach-intestine passage.

Results

Initial screening for acid resistance in acidified culture media showed a low tolerance of Bifidobacterium dentium for this condition indicating low survival in the passage. Similar results were achieved with B. longum subsp. infantis whereas B. animalis subsp. lactis had a high survival.

These initial results were confirmed in the bioreactor model of the stomach-intestine passage. B. animalis subsp. lactis had the highest survival rate (10%) attaining approximately 5 × 106 cfu ml-1 compared to the other tested bifidobacteria strains which were reduced by a factor of up to 106. Lactobacillus gasseri K7 was less resistant than B. animalis subsp. lactis but survived at cell concentrations approximately 1000 times higher than other bifidobacteria.

Conclusion

In this study, we were able to show that L. gasseri K7 had a high survival rate in the stomach-intestine passage. By comparing the results with a previous study in piglets we could confirm the reliability of our simulation. Of the tested bifidobacteria strains, only B. animalis subsp. lactis showed acceptable survival for a successful passage in the simulation system.
A case-control study on the combined effects of p53 and p73 polymorphisms on head and neck cancer risk in an Italian population
Authors: Gallì Paola , Cadoni Gabriella , Volante Mariangela , De Feo Emma , Amore Rosarita , Giorgio Arianna , Arzani Dario , Paludetti Gaetano , Ricciardi Gualtiero , Boccia Stefania
Published: May 2009

Background

The purpose of this study is to analyze the combined effects of selectedp53 andp73 polymorphisms and their interaction with lifestyle habits on squamous cell carcinoma of the head and neck (SCCHN) risk and progression in an Italian population.

Methods

Two hundred and eighty-three cases and 295 hospital controls were genotyped forp53 polymorphisms on exon 4 (Arg72Pro), intron 3 and 6, andp73 G4C14-to-A4T14. Their association with SCCHN was estimated using a logistic regression analysis, while a multinomial logistic regression approach was applied to calculate the effect of the selected polymorphisms on SCCHN different sites (oral cavity, oropharynx, hypopharynx and larynx). We performed an haplotype analysis of thep53 polymorphisms, and a gene-gene interaction analysis for the combined effects ofp73 G4C14-to-A4T14 andp53 polymorphisms.

Results

We found a significant increased risk of SCCHN among individuals with combinedp73 exon 2 G4A andp53 intron 3 variant alleles (OR = 2.22, 95% CI: 1.08–4.56), and a protective effect for those carrying thep53 exon 4-p53 intron 6 diplotype combination (OR = 0.67; 95% CI: 0.47–0.92). From the gene-environment interaction analysis we found that individuals aged < 45 years carryingp73 exon 2 G4A variant allele have a 12.85-increased risk of SCCHN (95% CI: 2.10–78.74) compared with persons of the same age with the homozygous wild type genotype. Improved survival rate was observed amongp53 intron 6 variant allele carriers (Hazard Ratio = 0.51 (95% CI: 0.23–1.16).

Conclusion

Our study provides for the first time evidence that individuals carryingp53 exon 4 andp53 intron 6 variant alleles are significantly protected against SCCHN, and also shows that an additional risk is conferred by the combination ofp73 exon 2 G4C14-to-A4T14 andp53 intron 3 variant allele. Larger studies are required to confirm these findings.
NR2B Receptor Blockade Inhibits Pain-Related Sensitization of Amygdala Neurons
Authors: Ji Guangchen , Horváth Csilla , Neugebauer Volker
Published: May 2009

Pain-related sensitization and synaptic plasticity in the central nucleus of the amygdala (CeA) depend on the endogenous activation of NMDA receptors and phosphorylation of the NR1 subunit through a PKA-dependent mechanism. Functional NMDA receptors are heteromeric assemblies of NR1 with NR2A-D or NR3A, B subunits. NMDA receptors composed of NR1 and NR2B subunits have been implicated in neuroplasticity and are present in the CeA. Here we used a selective NR2B antagonist (Ro-256981) to determine the contribution of NR2B-containing NMDA receptors to pain-related sensitization of CeA neurons. Extracellular single-unit recordings were made from CeA neurons in anesthetized adult male rats before and during the development of an acute arthritis. Arthritis was induced in one knee joint by intraarticular injections of kaolin and carrageenan. Brief (15 s) mechanical stimuli of innocuous (100–500 g/30 mm2) and noxious (1000–2000 g/30 mm2) intensity were applied to the knee and other parts of the body. In agreement with our previous studies, all CeA neurons developed increased background and evoked activity after arthritis induction. Ro-256981 (1, 10 and 100 μM; 15 min each) was administered into the CeA by microdialysis 5–6 h postinduction of arthritis. Ro-256981 concentration-dependently decreased evoked responses, but not background activity. This pattern of effect is different from that of an NMDA receptor antagonist (AP5) in our previous studies. AP5 (100 μM – 5 mM) inhibited background activity and evoked responses. The differential effects of AP5 and Ro-256981 may suggest that NMDA receptors containing the NR2B subunit are important but not sole contributors to pain-related changes of CeA neurons.
Hydrodebridement of wounds: effectiveness in reducing wound bacterial contamination and potential for air bacterial contamination
Authors: Bowling Frank L , Stickings Daryl S , Edwards‐Jones Valerie , Armstrong David G , Boulton Andrew JM
Published: May 2009

Background

The purpose of this study was to assess the level of air contamination with bacteria after surgical hydrodebridement and to determine the effectiveness of hydro surgery on bacterial reduction of a simulated infected wound.

Methods

Four porcine samples were scored then infected with a broth culture containing a variety of organisms and incubated at 37°C for 24 hours. The infected samples were then debrided with the hydro surgery tool (Versajet, Smith and Nephew, Largo, Florida, USA). Samples were taken for microbiology, histology and scanning electron microscopy pre‐infection, post infection and post debridement. Air bacterial contamination was evaluated before, during and after debridement by using active and passive methods; for active sampling the SAS‐Super 90 air sampler was used, for passive sampling settle plates were located at set distances around the clinic room.

Results

There was no statistically significant reduction in bacterial contamination of the porcine samples post hydrodebridement. Analysis of the passive sampling showed a significant (p < 0.001) increase in microbial counts post hydrodebridement. Levels ranging from 950 colony forming units per meter cubed (CFUs/m3) to 16780 CFUs/m3 were observed with active sampling of the air whilst using hydro surgery equipment compared with a basal count of 582 CFUs/m3. During removal of the wound dressing, a significant increase was observed relative to basal counts (p < 0.05). Microbial load of the air samples was still significantly raised 1 hour post‐therapy.

Conclusion

The results suggest a significant increase in bacterial air contamination both by active sampling and passive sampling. We believe that action might be taken to mitigate fallout in the settings in which this technique is used.
Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis
Authors: Akhavani Mohammed A , Madden Leigh , Buysschaert Ian , Sivakumar Branavan , Kang Norbert , Paleolog Ewa M
Published: May 2009

Introduction

Rheumatoid arthritis (RA) is characterised by invasion of cartilage, bone and tendon by inflamed synovium. Previous studies in our laboratory have shown that hypoxia is a feature of RA synovitis. In the present study, we investigated the consequences of hypoxia on angiogenesis and synovial fibroblast migration in RA.

Methods

Synovial tissue was harvested from RA patients, and synovial membrane cells were cultured under conditions either of hypoxia (1% oxygen) or normoxia (21% oxygen). Protein levels of matrix metalloproteinases (MMPs) and angiogenic factors were measured, while RNA was extracted for PCR quantification of MMPs/tissue inhibitors of MMP (TIMPs) and angiogenic factors. Migration of RA synovial fibroblasts through collagen, and the effect of RA synovial cell supernatants in an in vitro angiogenesis assay, were utilised to determine the functional relevance of changes in mRNA/protein.

Results

We observed upregulation under hypoxic conditions of MMPs responsible for collagen breakdown, specifically collagenase MMP-8, and the gelatinases MMP-2 and MMP-9, at both mRNA and protein levels. Increased MT1-MMP mRNA was also observed, but no effect on TIMP-1 or TIMP-2 was detected. RA fibroblast migration across collagen was significantly increased under hypoxic conditions, and was dependent on MMP activity. Furthermore, expression of angiogenic stimuli, such as vascular endothelial growth factor (VEGF), and VEGF/placental growth factor heterodimer, was also increased. Crucially, we show for the first time that hypoxia increased the angiogenic drive of RA cells, as demonstrated by enhanced blood vessel formation in an in vitro angiogenesis assay.

Conclusions

Hypoxia may be responsible for rendering RA synovial lining proangiogenic and proinvasive, thus leading to the debilitating features characteristic of RA.
The Excitatory Peptide Kisspeptin Restores the Luteinizing Hormone Surge and Modulates Amino Acid Neurotransmission in the Medial Preoptic Area of Middle-Aged Rats
Authors: Neal-Perry Genevieve , Lebesgue Diane , Lederman Matthew , Shu Jun , Zeevalk Gail D. , Etgen Anne M.
Published: May 2009

Reproductive success depends on a robust and appropriately timed preovulatory LH surge. The LH surge, in turn, requires ovarian steroid modulation of GnRH neuron activation by the neuropeptide kisspeptin and glutamate and γ-aminobutyric acid (GABA) neurotransmission in the medial preoptic area (mPOA). Middle-aged females exhibit reduced excitation of GnRH neurons and attenuated LH surges under estrogen-positive feedback conditions, in part, due to increased GABA and decreased glutamate neurotransmission in the mPOA. This study tested the hypothesis that altered kisspeptin regulation by ovarian steroids plays a role in age-related LH surge dysfunction. We demonstrate that middle-aged rats exhibiting delayed and attenuated LH surges have reduced levels of Kiss1 mRNA in the anterior hypothalamus under estrogen-positive feedback conditions. Kisspeptin application directly into the mPOA rescues total LH release and the LH surge amplitude in middle-aged rats and increases glutamate and decreases GABA release to levels seen in the mPOA of young females. Moreover, the N-methyl-d-aspartate receptor antagonist MK801 blocks kisspeptin reinstatement of the LH surge. These observations suggest that age-related LH surge dysfunction results, in part, from reduced kisspeptin drive under estrogen-positive feedback conditions and that kisspeptin regulates GnRH/LH release, in part, through modulation of mPOA glutamate and GABA release.
Three-Dimensional Ovarian Organ Culture as a Tool to Study Normal Ovarian Surface Epithelial Wound Repair
Authors: Jackson Kevin S. , Inoue Kari , Davis David A. , Hilliard Tyvette S. , Burdette Joanna E.
Published: May 2009

Ovarian cancers are primarily derived from a single layer of epithelial cells surrounding the ovary, the ovarian surface epithelium (OSE). Ovarian surface proliferation is associated with ovulation and has been suggested to play a role in ovarian surface transformation and cancer progression. Aspects of ovarian surface repair after ovulation include proliferation, migration, and surface regeneration. To study ovarian surface repair, an organ culture system was developed that supports the proliferation, encapsulation, and repair of an artificially wounded surface. Wounded mouse ovaries embedded into an alginate hydrogel matrix have normal OSE cells as demonstrated by expression of cytokeratin 8, vimentin, N-cadherin, and a lack of E-cadherin. Normal OSE cells began proliferating and migrating around wounded surfaces after 1 d of culture. Organ cultures were propagated in medium supplemented with BSA and fetal bovine serum to determine optimal growth conditions. BSA cultured organs had OSE that proliferated significantly more than controls until d 4, whereas fetal bovine serum cultured organs had significantly more surface area encapsulated by OSE. Overall, a three-dimensional ovarian organ culture supports the growth of normal OSE in response to artificial wounding and provides a novel system for investigating wound repair as it relates to the possible role of ovulation and ovarian cancer.
Theca-Specific Estrogen Receptor-α Knockout Mice Lose Fertility Prematurely
Authors: Lee Sungeun , Kang Dong-Wook , Hudgins-Spivey Susan , Krust Andree , Lee Eun-Young , Koo Youngbum , Cheon Yongpil , Gye Myung Chan , Chambon Pierre , Ko CheMyong
Published: May 2009

Estrogen receptor-α (Esr1) mediates estrogen action in regulating at all levels of the hypothalamic-pituitary-ovarian axis. Whereas the importance of Esr1 in hypothalamus and pituitary has been demonstrated by loss of fertility in the neuron- and pituitary-specific Esr1 knockout mice, whether Esr1 plays a critical role in the ovary remains to be determined. In the ovary, Esr1 is mainly expressed in the theca/interstitial cells and germinal epithelium and thus is believed to mediate estrogen action in these cells. In this study, we assessed the importance of Esr1 in the ovarian theca cells in regulating female reproduction. The Cre-LoxP approach was used to selectively delete the Esr1 gene in the theca cells, and the reproductive consequence of the deletion was measured. Adolescent theca-specific Esr1 knockout (thEsr1KO) mice (<4 months of age) are fertile and cycling. However, they begin to display an erratic pattern of estrous cycles and become infertile before they reach the age of 6 months. The ovaries of thEsr1KOmice (≥4 months) have fewer corpora lutea but more antral follicles than the age-matching wild-type mice. The numbers of 17-hydroxylase-expressing cells are largely increased in the interstitium of the thEsr1KO mouse ovary. Interestingly, whereas basal levels of serum testosterone and FSH were mildly elevated, LH level was either markedly lower or undetectable in the thEsr1KO mice. When superstimulated by exogenous gonadotropins, thEsr1KO mice released significantly fewer oocytes that wild-type littermates and developed multiple hemorrhagic cysts. Taken together, this study demonstrates that theca Esr1 plays a critical role in regulating female reproduction.
Growth Differentiation Factor 9 Enhances Activin A-Induced Inhibin B Production in Human Granulosa Cells
Authors: Shi Feng-Tao , Cheung Anthony P. , Leung Peter C. K.
Published: May 2009

Activin A or growth differentiation factor 9 (GDF9) alone can increase βB-mRNA level in human granulosa-lutein cells from women undergoing in vitro fertilization, but their potential interactions and related cell signaling pathways involved are unknown. We therefore compared inhibin subunit and inhibin levels and activation of activin receptors (ACVRs) and Smad signaling pathway in these human granulosa-lutein cells with and without GDF9 and/or activin A treatment. Inhibin subunit (α, βA, βB), ACVR, and Smad2/3/4/7 mRNA levels, inhibin A and B production, and Smad phosphorylation were assessed by real-time RT-PCR, ELISA, and immunoblotting, respectively. Data were analyzed by ANOVA followed by Tukey’s test. Activin A (1–50 ng/ml) or GDF9 (1–200 ng/ml) alone had only little stimulatory effects on α- and βA-mRNA levels. In contrast, GDF9 could stimulate βB-subunit levels but to a lesser degree than the dose- and time-dependent effects of activin A. Compared with untreated cells, GDF9 pretreatment for 24 h significantly enhanced activin A-induced βB-mRNA levels, inhibin B secretion, and Smad2/3 phosphorylation (effects attenuated by bone morphogenetic protein receptor 2 extracellular domain, a GDF9 antagonist); and induced ACVR2B/1B and Smad2/3 but reduced Smad7 (an inhibitory Smad) mRNA levels. We report here for the first time that GDF9 enhances cell response to activin A by modulating key components of the activin signaling pathway in regulating inhibin subunits and hence inhibin B production in human granulosa-lutein cells.
Regulation of Oxytocin Receptor Responsiveness by G Protein-Coupled Receptor Kinase 6 in Human Myometrial Smooth Muscle
Authors: Willets Jonathon M. , Brighton Paul J. , Mistry Rajendra , Morris Gavin E. , Konje Justin C. , Challiss R. A. John
Published: May 2009

Oxytocin plays an important role in the progression, timing, and modulation of uterine contraction during labor and is widely used as an uterotonic agent. We investigated the mechanisms regulating oxytocin receptor (OTR) signaling in human primary myometrial smooth muscle cells and the ULTR cell-line. Oxytocin produced concentration-dependent increases in both total [3H]inositol phosphate accumulation and intracellular Ca2+ concentration ([Ca2+]i); however, responses were greater and more reproducible in the ULTR cell line. Assessment of phospholipase C activity in single cells revealed that the OTR desensitizes rapidly (within 5 min) in the presence of oxytocin (100 nm). To characterize OTR desensitization further, cells were stimulated with a maximally effective concentration of oxytocin (100 nm, 30 sec) followed by a variable washout period and a second identical application of oxytocin. This brief exposure to oxytocin caused a marked decrease (>70%) in OTR responsiveness to rechallenge and was fully reversed by increasing the time period between agonist challenges. To assess involvement of G protein-coupled receptor kinases (GRKs) in OTR desensitization, cells were transfected with small interfering RNAs to cause specific ≥75% knockdown of GRKs 2, 3, 5, or 6. In both primary myometrial and ULTR cells, knockdown of GRK6 largely prevented oxytocin-induced OTR desensitization; in contrast, selective depletion of GRKs 2, 3, or 5 was without effect. These data indicate that GRK6 recruitment is a cardinal effector of OTR responsiveness and provide mechanistic insight into the likely in vivo regulation of OTR signaling in uterine smooth muscle.
Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver
Authors: Okabe Mayuko , Tsukahara Yuko , Tanaka Minoru , Suzuki Kaori , Saito Shigeru , Kamiya Yoshiko , Tsujimura Tohru , Nakamura Koji , Miyajima Atsushi
Published: May 2009

Hepatic oval cells are considered to be facultative hepatic stem cells(HSCs) that differentiate into hepatocytes and cholangiocytes in severely injured liver. Hepatic oval cells have also been implicated in tumorigenesis. However, their nature and origin remain elusive. To isolate and characterize mouse oval cells, we searched for cell surface molecules expressed on oval cells and analyzed their nature at the single-cell level by flow cytometric analysis and in the in vitro colony formation assay. We demonstrate that epithelial cell adhesion molecule (EpCAM) is expressed in both mouse normal cholangiocytes and oval cells, whereas its related protein, TROP2, is expressed exclusively in oval cells, establishing TROP2 as a novel marker to distinguish oval cells from normal cholangiocytes. EpCAM+ cells isolated from injured liver proliferate to form colonies in vitro, and the clonally expanded cells differentiate into hepatocytes and cholangiocytes,suggesting that the oval cell fraction contains potential HSCs. Interestingly,such cells with HSC characteristics exist among EpCAM+ cells of normal liver. Intriguingly, comparison of the colony formation of EpCAM+ cells in normal and injured liver reveals little difference in the number of potential HSCs, strongly suggesting that most proliferating mouse oval cells represent transit-amplifying cells rather than HSCs.
The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation
Authors: Moniot Brigitte , Declosmenil Faustine , Barrionuevo Francisco , Scherer Gerd , Aritake Kosuke , Malki Safia , Marzi Laetitia , Cohen-Solal Anne , Georg Ina , Klattig Jürgen , Englert Christoph , Kim Yuna , Capel Blanche , Eguchi Naomi , Urade Yoshihiro , Boizet-Bonhoure Brigitte , Poulat Francis
Published: May 2009

Activation by the Y-encoded testis determining factor SRY and maintenance of expression of the Sox9 gene encoding the central transcription factor of Sertoli cell differentiation are key events in the mammalian sexual differentiation program. In the mouse XY gonad, SOX9 upregulates Fgf9, which initiates a Sox9/Fgf9 feedforward loop,and Sox9 expression is stimulated by the prostaglandin D2 (PGD2)producing lipocalin prostaglandin D synthase (L-PGDS, or PTDGS) enzyme, which accelerates commitment to the male pathway. In an attempt to decipher the genetic relationships between Sox9 and the L-Pgds/PGD2 pathway during mouse testicular organogenesis,we found that ablation of Sox9 at the onset or during the time window of expression in embryonic Sertoli cells abolished L-Pgdstranscription. By contrast, L-Pgds-/- XY embryonic gonads displayed a reduced level of Sox9 transcript and aberrant SOX9 protein subcellular localization. In this study, we demonstrated genetically that the L-Pgds/PGD2 pathway acts as a second amplification loop of Sox9 expression. Moreover, examination of Fgf9-/- and L-Pgds-/- XY embryonic gonads demonstrated that the two Sox9 gene activity amplifying pathways work independently. These data suggest that, once activated and maintained by SOX9, production of testicular L-PGDS leads to the accumulation of PGD2, which in turn activates Sox9 transcription and nuclear translocation of SOX9. This mechanism participates together with FGF9 as an amplification system of Sox9 gene expression and activity during mammalian testicular organogenesis.
Privacy Protection and Technology Diffusion: The Case of Electronic Medical Records
Authors: Miller Amalia R. , Tucker Catherine
Published: May 2009

This paper quantifies the effect of state privacy regulation on the diffusion of electronic medical records (EMRs). EMRs allow medical providers to store and exchange patient information using computers rather than paper records. Hospitals may be more likely to adopt EMRs if they can reassure patients that their confidentiality is legally protected. Alternatively, privacy protection may inhibit adoption if hospitals cannot benefit from easily exchanging patient information. We find that state privacy regulation restricting hospital release of health information reduces aggregate EMR adoption by hospitals by more than 24%. We present evidence that suggests that this is due to the suppression of network externalities.
Truthful Bundle/Multiunit Double Auctions
Authors: Chu Leon Yang
Published: May 2009

We address the mechanism design problem for a market with multiple buyers and sellers. Each buyer demands some bundle(s) of various commodities, and each seller supplies multiple units of one commodity. To design truthful double-auction mechanisms, we propose a novel “padding” method that intentionally creates imbalances between the supply availability and demand requirement by introducing a phantom buyer with unlimited budget. To the best of our knowledge, this “padding” method leads to a class of mechanisms that are the first strategy-proof, individually rational, budget-balanced, and asymptotically efficient mechanisms for the specified exchange environment. Furthermore, these mechanisms dominate known truthful bundle/single-unit mechanisms with higher efficiency, lower buying prices, and higher selling prices.
Designing Multimodal Freight Transport Networks: A Heuristic Approach and Applications
Authors: Yamada Tadashi , Russ Bona Frazila , Castro Jun , Taniguchi Eiichi
Published: May 2009

Designing multimodal freight transport networks can facilitate the economic development of regions and countries as well as help to reduce negative environmental impacts. It is therefore crucial that such be undertaken in areas where more priority is given on road-based freight transport systems. This paper proposes a model for strategic transport planning, particularly in freight terminal development and interregional freight transport network design. The model determines a suitable set of actions from a number of possible actions, such as improving the existing infrastructure or establishing new roads, railways, sea links, and freight terminals. Modelling is undertaken within the framework of bilevel programming, where a multimodal multiclass user traffic assignment technique is incorporated within the lower-level problem, whilst the upper-level problem determines the best combination of actions such that the freight-related benefit-cost ratio is maximised. The upper-level problem involves combinatorial optimisation, and a heuristic approach based on genetic local search is applied as a solution technique. Empirical results of the model as applied to an actual large-sized interregional intermodal freight transport network show that genetic local search could provide better performance as compared to other genetic algorithm-based, as well as tabu search-based, heuristics. The model is successfully applied to transport network planning in the Philippines, where the development of a freight transport network is necessary to increase the utilisation of other modes rather than road-based vehicles.
Optimizing the Door Assignment in LTL-Terminals
Authors: Chmielewski Annette , Naujoks Boris , Janas Michael , Clausen Uwe
Published: May 2009

In less-than-truckload (LTL) terminals, arriving trucks have to be assigned to inbound doors and to suitable time slots for unloading. Simultaneously, waiting trucks have to be allocated to outbound doors. During a couple of hours, shipments from all incoming trucks are unloaded, sorted according to their relation, transported to the right outbound door, and loaded on the outgoing truck. (The term “relation” is an equivalent for destination; it originates from the German logistics vocabulary that uses the term to specify a certain transport offered between a source and a sink.) The first and the most important optimization aim is to minimize the total distance when transshipping units, because this leads to reduction in operational costs, which are usually very high. The second, and minor, aim is to minimize the waiting time for each truck. Usually the operator of an LTL transshipment building works with subcontractors when collecting and delivering goods. Therefore, no penalties have to be paid by the operators in case waiting times are too long. The logistical optimization task is modeled as a time-discrete, multicommodity flow problem with side constraints. Based on the applicable model, a decomposition approach and a modified column-generation approach are developed. In parallel, an evolutionary algorithm (EA) was implemented to tackle the problem at hand. Both algorithms—from the field of discrete mathematics, as well as from the field of computational intelligence—are applied to 10 test scenarios. A comparison of the solution process, as well as a comparison of the solution quality, concludes the work.
Social phobia and sexual problems: A comparison of social phobic, sexually dysfunctional and normal individuals
Authors: Munoz Valentina , Stravynski Ariel
Published: May 2009

Objectives. This study sought to test the putative link between social phobia and sexual functioning.

Methods. Three groups consisting of 106 social phobic, 164 sexually dysfunctional and 111 normal participants were assessed in terms of sexual functioning, social anxiety, social functioning and general psychopathology.

Results. Although social phobic men were less sexually active than normal men, they were as sexually satisfied. Social phobic women were alike their normal counterparts in all respects.

Conclusions. Overall, social phobic individuals were not more prone to report sexual problems than normal individuals despite reporting the severest levels of social anxiety. Theoretically, our results are best understood as supporting an interpersonal conception of social phobia and a related socio‐cultural perspective regarding sexual roles.