bluuebunny/crossref_metadata_2025 huggingface dataset:
Kidney Injury Molecule-1 Expression in Rat Proximal Tubule after Treatment with Segment-Specific Nephrotoxicants
Authors: Chiusolo Arianna , Defazio Rossella , Zanetti Edoardo , Mongillo Michele , Mori Nadia , Cristofori Patrizia , Trevisan Andrea
Published: March 2010

Dose-response expression of kidney injury molecule-1 (KIM-1) gene in kidney cortex and its correlation with morphology and traditional biomarkers of nephrotoxicity (plasma creatinine and blood urea nitrogen, BUN) or segment-specific marker of proximal tubule injury (kidney glutamine synthetase, GSK) were studied in male rats treated with proximal tubule segment-specific nephrotoxicants. These included hexachloro-1:3-butadiene (HCBD, S3segment-specific), potassium dichromate (chromate, S1-S2segment-specific), and cephaloridine (Cph, S2segment-specific). Rats were treated with a single intraperitoneal (ip) injection of HCBD 25, 50, and 100 mg/kg, subcutaneous (sc) injection of chromate 8, 12.5, and 25 mg/kg; or ip injection of Cph 250, 500, and 1,000 mg/kg. KIM-1 gene showed a dose-dependent up-regulation induced by all segment-specific nephrotoxicants. Interestingly, magnitude of the up-regulation reflected the severity of microscopic tubular changes (degeneration, necrosis, and regeneration). Even low-severity microscopic observations were evidenced by significant gene expression changes. Furthermore, KIM-1 showed significant up-regulation even in the absence of morphological changes. In contrast, traditional and specific markers demonstrated low sensitivity or specificity. In conclusion, this study suggested KIM-1 as a sensitive molecular marker of different levels of tubular injury, and it is likely to represent a potential tool for early screening of nephrotoxicants.
Migraine symptomatology and major depressive disorder
Authors: Ligthart Lannie , Penninx Brenda WJH , Nyholt Dale R , Distel Marijn A , de Geus Eco JC , Willemsen Gonneke , Smit Johannes H , Boomsma Dorret I
Published: March 2010

Introduction and objective: Migraine and major depressive disorder (MDD) frequently co-occur, but it is unclear whether depression is associated with a specific subtype of migraine. The objective of this study was to investigate whether migraine is qualitatively different in MDD patients ( N = 1816) and non-depressed controls ( N = 3428).

Methods: Migraine symptom data were analyzed using multi-group Latent Class Analysis, and a qualitative comparison was made between the symptom profiles of MDD patients and controls, while allowing for differences in migraine prevalence and severity between groups.

Results: In both groups, three migrainous headache classes were identified, which differed primarily in terms of severity. Both mild and severe migrainous headaches were two to three times more prevalent in MDD patients. Migraine symptom profiles showed only minor qualitative differences in the MDD and non-MDD groups: in the severe migrainous headache class, significant differences were observed only in the prevalence of aggravation by physical activity (83% and 91% for the non-MDD and MDD groups, respectively) and aura (42% vs. 53%, respectively).

Conclusion: The similar overall symptom profiles observed in the MDD and non-MDD subjects suggest that a similar disease process may underlie migraine in both groups.
Is it possible to antagonize 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin- induced cleft palate by prenatal administration of folic acid? An experimental study
Authors: Li Cheng-hao , Bing Shi  , Wei He  , Tian Meng
Published: March 2010

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause a high percentage of cleft palate in fetuses when administered during organogenesis in certain strains of mice including C57BL/6J. In this study, folic acid (FA) was tested for antiteratogenic effects on TCDD-induced cleft palate in fetal mice. The pregnant C57BL/6J mice were dosed with 24 µg TCDD/kg and/or 5 mg, 10 mg, 20 mg, 40 mg FA/kg body weight on gestation day (GD) 10. The control group mice received 50 mL sesame oil/kg body weight on GD10. The mice were sacrificed on GD12.5, GD13.5, GD14.5, GD15.5, and GD16.5. The harvested embryos were examined to detect the incidence of cleft palate and the developing palatal shelves on different phases were investigated morphologically and histologically among different groups. Total frequency of clefts was 55.56% in TCDD group and 17.50% (5 mg), 42.85% (10 mg), 42.10% (20 mg), 28.26% (40 mg) in TCDD + FA groups. FA (5 mg) reduced the incidence of the cleft palate from 55.56% to 17.50% (p = 0.005). There were no significant differences between the TCDD group and 10 mg, 20 mg, 40 mg TCDD + FA groups. Based on the these results, the present study suggests that FA can reduce the incidence of 2,3,7,8-TCDD-indued cleft palate in mice.
Transient Basal Ganglia and Thalamic Involvement Following Mycoplasma pneumoniae Infection Associated With Antiganglioside Antibodies
Authors: Fusco Carlo , Bonini Elena , Soncini Giuliana , Frattini Daniele , Giovannini Simona , Giustina Elvio Della
Published: March 2010

A case of acute and reversible bilateral basal ganglia with thalami involvement associated with serological evidence of Mycoplasma pneumoniae infection is reported. Increased titers of immunoglobulin M antibodies against GM1 ganglioside components were found during an acute phase of neurological illness. Brain magnetic resonance imaging (MRI) showed bilateral involvement of the basal ganglia and thalamus, which disappeared 1 month later. The child recovered fully after corticosteroid and immunoglobulin therapy, and antiganglioside antibodies returned to within the normal range. The authors speculate on the diagnostic hypothesis regarding selective basal ganglia and thalamic involvement and the relationship with anti-GM1 ganglioside immunoglobulin M antibodies.
Finite Element Formulation for Ferroelectric Hysteresis of Piezoelectric Materials
Authors: Kaltenbacher M. , Kaltenbacher B. , Hegewald T. , Lerch R.
Published: March 2010

For the numerical simulation of non-linear piezoelectric material behavior, we use a constitutive relation that is based on a decomposition of the physical quantities dielectric displacement and mechanical strain into a reversible and an irreversible part. Therein, we set the irreversible part of the dielectric displacement equal to the irreversible electric polarization and express the irreversible mechanical strain by a polynomial ansatz of the irreversible electric polarization. The reversible parts of mechanical strain and dielectric displacement are further described by the linear piezoelectric constitutive law. We apply a Preisach hysteresis operator to compute the irreversible polarization from the history of the driving electric field. Furthermore, the entries of the piezoelectric modulus tensor are assumed to be functions of the electric polarization. To efficiently solve the non-linear system of partial differential equations, we have developed a quasi-Newton scheme and use the finite element (FE) method for the numerical solution. This FE scheme has been applied to numerically calculate the dynamic behavior of a piezoelectric disc and a stack actuator. The obtained results compare well to measured data.
Quasi-Experimental Design, Constituency, and Advancing Women’s Interests: Reexamining the Influence of Gender on Substantive Representation
Authors: MacDonald Jason A. , O'Brien Erin E.
Published: March 2010

Research investigating whether female legislators provide more effective substantive representation on women’s issues than their male colleagues faces a significant methodological hurdle. Models used to estimate the effect of gender on representation inevitably omit constituency variables that affect the character of legislators’ decisions and are also correlated with gender, potentially biasing the estimates of the effect of gender. Employing a quasi-experimental research design as an alternative strategy, the authors remove this hurdle and estimate the influence of gender on representation free from this potential bias. The authors find that gender does affect representation and observe critical mass effects.
Relationship Between Psychological Distress and Endogenous Anticoagulants in Patients With a Previous Venous Thromboembolic Event
Authors: Krummenacher René , Lukas Paul S. , Demarmels Biasiutti Franziska , Begré Stefan , Znoj Hansjörg , von Känel Roland
Published: March 2010

Background: Psychological distress, particularly anxiety and depression, has been associated with a prothrombotic state. However, the relationship between psychosocial factors and endogenous anticoagulants protein S (PS) and protein C (PC) has not previously been investigated. We explored the association between psychological distress, PS, and PC in patients with an objectively diagnosed venous thromboembolic event (VTE). Methods: We investigated 126 consecutively enrolled patients ≥3 months after VTE (ie, deep venous thrombosis and/or pulmonary embolism) and ≥1 month of discontinuation of oral anticoagulants. Approximately 10 days before blood collection for thrombophilia workup, anxiety and depression scores were assessed using the Hospital Anxiety and Depression scale (HADS). Protein C and S were determined by routine laboratory assays. Results: After controlling for demographic and medical factors, PC, as measured by the PC-activated partial thromboplastin time (aPTT) method and the PC-chromatin substrate method, was positively associated with psychological distress (sum of anxiety plus depression symptoms; P ≤ .027), anxiety (P ≤ .055), and depression (P ≤ .031), explaining between 3% and 6% of the variance. Total PS antigen showed a direct relationship with psychological distress (P = .025) and depression (P = .005), explaining 5% and 7% of respective variances. Free PS showed a positive association with depression (P = .046), explaining 3% of the variance. Anxiety showed no independent association with either PS measure. Conclusions: Psychological distress is independently associated with enhanced endogenous anticoagulant potential. This might reflect a counterregulatory mechanism to outweigh the previously observed hypercoagulability in individuals under chronic stress and with elevated symptoms of anxiety and depression.
Palliative care for people severely affected by multiple sclerosis: evaluation of a novel palliative care service
Authors: Edmonds Polly , Hart Sam , Wei Gao  , Vivat Bella , Burman Rachel , Silber Eli , Higginson Irene J
Published: March 2010

Multiple sclerosis results in both physical and psychological disability but some patients have needs that are not adequately met by existing services. Our objective was to explore whether a new palliative care service improved outcomes for people severely affected by multiple sclerosis. A delayed intervention randomized controlled trial was undertaken with multiple sclerosis patients deemed by staff to have palliative care needs. The intervention was a multiprofessional palliative care team assessment and follow-up. The intervention group was offered the team immediately (fast track, FI); the control group continued best standard care and then offered the team after 3 months (standard intervention, SI). The main outcome measures were: patient reported issues using the Palliative Care Outcome Scale and Multiple Sclerosis Impact Scale at 12 weeks and caregiver burden using the Zarit Burden Inventory. Sixty-nine people were referred to the service; 52 consented or were eligible to be randomized (26 to the FI and 26 to the SI groups). At 12 weeks people in the FI group had an improvement (mean change —1.0) in the total score of 5 key symptoms whereas there was deterioration in the SI group (mean change 1.1, F = 4.75, p = 0.035). There was no difference in the change in general Palliative Care Outcome Scale or Multiple Sclerosis Impact Scale scores. There was an improvement in caregiver burden in the FI group and a deterioration in the SI group ( F = 7.60, p = 0.013). Involvement with the palliative care service appeared to positively affect some key symptoms and reduced informal caregiver burden.
Induction welding and heat treatment of steel pipes: Evolution of crystallographic texture detrimental to toughness
Authors: Yan P. , Guüngör Ö. E. , Thibaux P. , Bhadeshia H. K. D. H.
Published: March 2010

Steel welding using induction heating to produce pipelines is found to have lower toughness at the weld junction than the base material, even after a heat treatment which reaustenitises the weld zone. Detailed crystallographic characterisation indicates that the poor toughness is due to the crystallographically coarse grains present after welding; the coarse scale is not visible using just optical microscopy. The post-weld heat treatment does not improve the situation at the weld junction, because the detrimental crystallographic characteristics are reproduced on cooling.
Analysis of martensite transformation behaviour in welded joint using low transformation temperature welding wire
Authors: Yamamoto J. , Hiraoka K. , Mochizuki M.
Published: March 2010

Low transformation temperature welding (LTTW) wire has been found to improve the fatigue strength in welded joints. In the present study, the temperature dependence of the mechanical properties in a dual phase microstructure of austenite and martensite was estimated using the properties of full austenite and full martensite in numerical analyses. A welding method effective for residual stress reduction and fatigue strength improvement was shown by applying a calculation method under transformation superplasticity and transformation induced plasticity in high strength steel welded joints. With this method, the influence of the welding pass sequence on the residual stress distribution and fatigue strength was examined in a boxing fillet welded joint using LTTW. The transformation tensile residual stress in the weld toe was decreased by sectioned welding, and the fatigue limit by sectioned welding with LTTW improved in comparison with the fatigue limit of a joint welded with conventional wire in the same process.
Genetic algorithm for optimisation of A-TIG welding process for modified 9Cr–1Mo steel
Authors: Vasudevan M. , Arunkumar V. , Chandrasekhar N. , Maduraimuthu V.
Published: March 2010

It is essential to set up the activated tungsten inert gas (A-TIG) welding process parameters to produce the desired weld bead geometry and heat affected zone (HAZ) width in modified 9Cr–1Mo steel weld joints. Therefore, it becomes necessary to develop a tool for optimisation of A-TIG welding process. Genetic algorithm (GA) based model has been developed to determine the optimum process parameters. In this methodology, first independent ANN models correlating depth of penetration, weld bead width and HAZ width with current, voltage and torch speed respectively were developed. Then, GA code was developed in which the objective function was evaluated using the ANN models. There was good agreement between the target and actual values of bead geometry and HAZ width obtained using the GA optimised process parameters. Thus, a methodology using GA has been developed for optimising the A-TIG process parameters for modified 9Cr–1Mo steel.
Developing predictive tools for friction stir weld quality assessment
Authors: Singh K. V. , Hamilton C. , Dymek S.
Published: March 2010

This research programme explores predictive tools that assess friction stir weld quality in aluminium alloys through dynamic characterisation. The study focuses on the correlations between dynamic interrogations measures of friction stir welded panels with the weld energy, as welded mechanical properties and the microstructure. 7136-T76 aluminium extrusions were joined at unique weld energies, and to characterise and identify the friction stir welds through non-destructive techniques, theoretical modelling and lab scale dynamic testing were conducted to establish the correlation between the weld energy and the associated spectral characteristics of the beam (natural frequencies/mode shapes). In this non-destructive evaluation study, the modal parameters were measured and were correlated with the friction stir weld microstructure and the physical parameters of the welded components, such as axial and flexural rigidities. The viability of weld parameter identification and weld quality assessment of friction stir welding beams using dynamic interrogation techniques is demonstrated.
Model for grain evolution during friction stir welding of aluminium alloys
Authors: Robson J. D. , Campbell L.
Published: March 2010

A simple model for recrystallisation and grain growth in the nugget of friction stir welds has been developed on the basis that the dominant recrystallisation mechanism is geometric dynamic recrystallisation. In combination with a process model capable of predicting the strain, strain rate and temperature history of any region within the weld, the current model can predict the grain size after friction stir welding. The model has been tested against experimental data in the literature for a friction stir welding in AA2524 and found to give a reasonable prediction of the final nugget grain size without arbitrary fitting. The model has then been used to predict the influence of dispersoid particles and the effect of cooling rate behind the tool on the grain size evolution in the nugget.
Safety and efficacy of rituximab in patients with hepatitis C virus–related mixed cryoglobulinemia and severe liver disease
Authors: Petrarca Antonio , Rigacci Luigi , Caini Patrizio , Colagrande Stefano , Romagnoli Paolo , Vizzutti Francesco , Arena Umberto , Giannini Carlo , Monti Monica , Montalto Paolo , Matucci-Cerinic Marco , Bosi Alberto , Laffi Giacomo , Zignego Anna Linda
Published: March 2010

The effectiveness of rituximab in hepatitis C virus (HCV)–related mixed cryoglobulinemia (MC) has been shown. However, the risk of an increase in viral replication limits its use in cirrhosis, a condition frequently observed in patients with MC. In this prospective study, 19 HCV-positive patients with MC and advanced liver disease, who were excluded from antiviral therapy, were treated with rituximab and followed for 6 months. MC symptoms included purpura, arthralgias, weakness, sensory-motor polyneuropathy, nephropathy, and leg ulcers. Liver cirrhosis was observed in 15 of 19 patients, with ascitic decompensation in 6 cases. A consistent improvement in MC syndrome was evident at the end-of-treatment (EOT) and end-of-follow-up (EOF-U). Variable modifications in both mean viral titers and alanine aminotransferase values were observed at admission, EOT, third month of follow-up, and EOF-U (2.62 × 106, 4.28 × 106, 4.82 × 106, and 2.02 × 106 IU/mL and 63.6, 49.1, 56.6, and 51.4 IU/L, respectively). Improvement in liver protidosynthetic activity and ascites degree was observed at EOT and EOF-U, especially in more advanced cases. This study shows the effectiveness and safety of rituximab in MC syndrome with advanced liver disease. Moreover, the depletion of CD20+ B cells was also followed by cirrhosis syndrome improvement despite the possibility of transient increases of viremia titers.
Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids
Authors: Kohli Divyanshoo R. , Li Yunfang , Khasabov Sergey G. , Gupta Pankaj , Kehl Lois J. , Ericson Marna E. , Nguyen Julia , Gupta Vinita , Hebbel Robert P. , Simone Donald A. , Gupta Kalpna
Published: March 2010

Sickle cell disease causes severe pain. We examined pain-related behaviors, correlative neurochemical changes, and analgesic effects of morphine and cannabinoids in transgenic mice expressing human sickle hemoglobin (HbS). Paw withdrawal threshold and withdrawal latency (to mechanical and thermal stimuli, respectively) and grip force were lower in homozygous and hemizygous Berkley mice (BERK and hBERK1, respectively) compared with control mice expressing human hemoglobin A (HbA-BERK), indicating deep/musculoskeletal and cutaneous hyperalgesia. Peripheral nerves and blood vessels were structurally altered in BERK and hBERK1 skin, with decreased expression of μ opioid receptor and increased calcitonin gene-related peptide and substance P immunoreactivity. Activators of neuropathic and inflammatory pain (p38 mitogen-activated protein kinase, STAT3, and mitogen-activated protein kinase/extracellular signal-regulated kinase) showed increased phosphorylation, with accompanying increase in COX-2, interleukin-6, and Toll-like receptor 4 in the spinal cord of hBERK1 compared with HbA-BERK. These neurochemical changes in the periphery and spinal cord may contribute to hyperalgesia in mice expressing HbS. In BERK and hBERK1, hyperalgesia was markedly attenuated by morphine and cannabinoid receptor agonist CP 55940. We show that mice expressing HbS exhibit characteristics of pain observed in sickle cell disease patients, and neurochemical changes suggestive of nociceptor and glial activation. Importantly, cannabinoids attenuate pain in mice expressing HbS.
Library of molecular associations: curating the complex molecular basis of liver diseases
Authors: Buchkremer Stefan , Hendel Jasmin , Krupp Markus , Weinmann Arndt , Schlamp Kai , Maass Thorsten , Staib Frank , Galle Peter R , Teufel Andreas
Published: March 2010

Background

Systems biology approaches offer novel insights into the development of chronic liver diseases. Current genomic databases supporting systems biology analyses are mostly based on microarray data. Although these data often cover genome wide expression, the validity of single microarray experiments remains questionable. However, for systems biology approaches addressing the interactions of molecular networks comprehensive but also highly validated data are necessary.

Results

We have therefore generated the first comprehensive database for published molecular associations in human liver diseases. It is based on PubMed published abstracts and aimed to close the gap between genome wide coverage of low validity from microarray data and individual highly validated data from PubMed. After an initial text mining process, the extracted abstracts were all manually validated to confirm content and potential genetic associations and may therefore be highly trusted. All data were stored in a publicly available database, Library of Molecular Associations http://www.medicalgenomics.org/databases/loma/news, currently holding approximately 1260 confirmed molecular associations for chronic liver diseases such as HCC, CCC, liver fibrosis, NASH/fatty liver disease, AIH, PBC, and PSC. We furthermore transformed these data into a powerful resource for molecular liver research by connecting them to multiple biomedical information resources.

Conclusion

Together, this database is the first available database providing a comprehensive view and analysis options for published molecular associations on multiple liver diseases.
Handling ethical, legal and social issues in birth cohort studies involving genetic research: responses from studies in six countries
Authors: Ries Nola M , LeGrandeur Jane , Caulfield Timothy
Published: March 2010

Background

Research involving minors has been the subject of much ethical debate. The growing number of longitudinal, pediatric studies that involve genetic research present even more complex challenges to ensure appropriate protection of children and families as research participants. Long-term studies with a genetic component involve collection, retention and use of biological samples and personal information over many years. Cohort studies may be established to study specific conditions (e.g. autism, asthma) or may have a broad aim to research a range of factors that influence the health and development of children. Studies are increasingly intended to serve as research platforms by providing access to data and biological samples to researchers over many years.

This study examines how six birth cohort studies in North America and Europe that involve genetic research handle key ethical, legal and social (ELS) issues: recruitment, especially parental authority to include a child in research; initial parental consent and subsequent assent and/or consent from the maturing child; withdrawal; confidentiality and sample/data protection; handling sensitive information; and disclosure of results.

Methods

Semi-structured telephone interviews were carried out in 2008/09 with investigators involved in six birth cohort studies in Canada, Denmark, England, France, the Netherlands and the United States. Interviewees self-identified as being knowledgeable about ELS aspects of the study. Interviews were conducted in English.

Results

The studies vary in breadth of initial consent, but none adopt a blanket consent for future use of samples/data. Ethics review of new studies is a common requirement. Studies that follow children past early childhood recognise a need to seek assent/consent as the child matures. All studies limit access to identifiable data and advise participants of the right to withdraw. The clearest differences among studies concern handling of sensitive information and return of results. In all studies, signs of child abuse require reports to authorities, but this disclosure duty is not always stated in consent materials. Studies vary in whether they will return to participants results of routine tests/measures, but none inform participants about findings with unknown clinical significance.

Conclusions

Analysis of how cohort studies in various jurisdictions handle key ELS issues provides informative data for comparison and contrast. Consideration of these and other examples and further scholarly exploration of ELS issues provides insight on how best to address these aspects in ways that respect the well-being of participants, especially children who become research subjects at the start of their lives.
Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer
Authors: Lee Chien-Hsing , Hung Hsing-Wen , Hung Pei-Hsin , Shieh Yi-Shing
Published: March 2010

Background

Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells.

Results

We used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer.

Conclusions

EGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.
Cysteine 95 and other residues influence the regulatory effects of Histidine 69 mutations on Human Immunodeficiency Virus Type 1 protease autoprocessing
Authors: Huang Liangqun , Hall Alyssa , Chen Chaoping
Published: March 2010

Background

Regulated autoprocessing of HIV Gag-Pol precursor is required for the production of mature and fully active protease. We previously reported that H69E mutation in a pseudo wild type protease sequence significantly (>20-fold) impedes protease maturation in an in vitro autoprocessing assay and in transfected mammalian cells.

Results

Interestingly, H69E mutation in the context of a laboratory adapted NL4-3 protease showed only moderate inhibition (~4-fold) on protease maturation. There are six point mutations (Q7K, L33I, N37S, L63I, C67A, and C95A) between the NL4-3 and the pseudo wild type proteases suggesting that the H69E effect is influenced by other residues. Mutagenesis analyses identified C95 as the primary determinant that dampened the inhibitory effect of H69E. L63 and C67 also demonstrated rescue effect to a less extent. However, the rescue was completely abolished when H69 was replaced by aspartic acid in the NL4-3 backbone. Charge substitutions of surface residues (E21, D30, E34, E35, and F99) to neutral or positively charged amino acids failed to restore protease autoprocessing in the context of H69E mutation.

Conclusions

Taken together, we suggest that residue 69 along with other amino acids such as C95 plus L63 and C67 to a less extent modulate precursor structures for the regulation of protease autoprocessing in the infected cell.
Accuracy of DXA in estimating body composition changes in elite athletes using a four compartment model as the reference method
Authors: Santos Diana A , Silva Analiza M , Matias Catarina N , Fields David A , Heymsfield Steven B , Sardinha Luís B
Published: March 2010

Background

Dual-energy x-ray absorptiometry (DXA) provides an affordable and practical assessment of multiple whole body and regional body composition. However, little information is available on the assessment of changes in body composition in top-level athletes using DXA. The present study aimed to assess the accuracy of DXA in tracking body composition changes (relative fat mass [%FM], absolute fat mass [FM], and fat-free mass [FFM]) of elite male judo athletes from a period of weight stability to prior to a competition, compared to a four compartment model (4C model), as the criterion method.

Methods

A total of 27 elite male judo athletes (age, 22.2 ± 2.8 yrs) athletes were evaluated. Measures of body volume by air displacement plethysmography, bone mineral content assessed by DXA, and total-body water assessed by deuterium dilution were used in a 4C model. Statistical analyses included examination of the coefficient of determinant (r2), standard error of estimation (SEE), slope, intercept, and agreement between models.

Results

At a group level analysis, changes in %FM, FM, and FFM estimates by DXA were not significantly different from those by the 4C model. Though the regression between DXA and the 4C model did not differ from the line of identity DXA %FM, FM, and FFM changes only explained 29%, 36%, and 38% of the 4C reference values, respectively. Individual results showed that the 95% limits of agreement were -3.7 to 5.3 for %FM, -2.6 to 3.7 for FM, and -3.7 to 2.7 for FFM. The relation between the difference and the mean of the methods indicated a significant trend for %FM and FM changes with DXA overestimating at the lower ends and underestimating at the upper ends of FM changes.

Conclusions

Our data indicate that both at group and individual levels DXA did not present an expected accuracy in tracking changes in adiposity in elite male judo athletes.
Distinguishing between hot-spots and melting-pots of genetic diversity using haplotype connectivity
Authors: Nguyen Binh , Spillner Andreas , Emerson Brent C , Moulton Vincent
Published: March 2010

We introduce a method to help identify how the genetic diversity of a species within a geographic region might have arisen. This problem appears, for example, in the context of identifying refugia in phylogeography, and in the conservation of biodiversity where it is a factor in nature reserve selection. Complementing current methods for measuring genetic diversity, we analyze pairwise distances between the haplotypes of a species found in a geographic region and derive a quantity, called haplotype connectivity, that aims to capture how divergent the haplotypes are relative to one another. We propose using haplotype connectivity to indicate whether, for geographic regions that harbor a highly diverse collection of haplotypes, diversity evolved inside a region over a long period of time (a "hot-spot") or is the result of a more recent mixture (a "melting-pot"). We describe how the haplotype connectivity for a collection of haplotypes can be computed efficiently and briefly discuss some related optimization problems that arise in this context. We illustrate the applicability of our method using two previously published data sets of a species of beetle from the genus Brachyderes and a species of tree from the genus Pinus.
Simultaneous determination of three major bioactive saponins of Panax notoginseng using liquid chromatography-tandem mass spectrometry and a pharmacokinetic study
Authors: Chen Wei , Dang Yunjie , Zhu Chunyan
Published: March 2010

Background

Panax notoginseng saponins (PNS), the main active components of Radix Notoginseng, has been used for treating atherosclerosis, cerebral infarction, and cerebral ischemia. Ginsenosides Rg1, ginsenoside Rb1, and notoginsenoside R1 are the main contributors of biological activities, determination of these three saponins is very important for the in vivo evaluation of PNS. The present study aims to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ginsenosides Rg1, ginsenoside Rb1, and notoginsenoside R1. The use of this method was exemplified in pharmacokinetic study of beagle dog plasma after oral administration of PNS.

Methods

Liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was combined with solid-phase extraction (SPE). This setup was used to determine simultaneously the three major PNS (ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1) in beagle dog plasma. Tandem mass spectrometry was performed using electrospray ionization in the positive ion mode.

Results

The lower limits of quantification were 0.5 ng/mL for notoginsenoside R1, 0.82 ng/mL for ginsenoside Rg1, and 1.10 ng/mL for ginsenoside Rb1. The calibration curves for the three saponins were linear over the concentration ranges 2.64-264 ng/mL (r2 = 0.9967, P = 0.003), 3.6-360 ng/mL (r2 = 0.9941, P = 0.004), and 18.7-1870 ng/mL (r2 = 0.9912, P = 0.004) for notoginsenoside R1, ginsenoside Rg1, and ginsenoside Rb1, respectively. Within these concentration ranges, the relative standard deviation (RSD) of intra- and interday assays for the three PNS from beagle dog plasma samples were less than 12%.

Conclusions

This LC/MS/MS method in combination with SPE is useful in the pharmacokinetic study of PNS, such as the simultaneous determination of saponins in beagle dog plasma after oral administration.
Thyroid function in children with growth hormone (GH) deficiency during the initial phase of GH replacement therapy - clinical implications
Authors: Smyczynska Joanna , Hilczer Maciej , Stawerska Renata , Lewinski Andrzej
Published: March 2010

Background

Normal thyroid hormone secretion or appropriate L-thyroxine (L-T4) substitution is necessary for the optimal effect of the growth hormone (GH) administration on growth rate. The decrease of free thyroxine (FT4) levels at recombinant human GH (rhGH) therapy onset has been reported in several studies. The aim of the present study was to evaluate the effect of rhGH administration on thyrotropin (TSH) and FT4serum concentrations in children with GH deficiency (GHD) during the 1st year of therapy, as well as to assess potential indications to thyroid hormone supplementation in them.

Patients and methods

The analysis involved data of 75 children (59 boys, 16 girls) with disorders of GH secretion (GHD, neurosecretory dysfunction - NSD) and partial GH inactivity (inactGH), who were treated with rhGH for - at least - one year. In all the children, body height and height velocity (HV) were assessed before and after 1 year of therapy, while TSH, FT4, IGF-I and IGFBP-3 before treatment and after 3-6 months and 1 year of treatment. In the patients, who revealed hypothyroidism (HypoT), an appropriate L-T4substitution was introduced immediately. The incidence of HypoT, occurring during the initial phase of rhGH therapy, was assessed, as well as its influence on the therapy effectiveness.

Results

Before rhGH substitution, there were no significant differences in either auxological indices or TSH and FT4secretion, or IGF-I concentration and its bioavailability among the groups of patients. During the initial 3-6 months of rhGH administration, a significant decrease of FT4serum concentration, together with a significant increase of IGF-I SDS and IGF-I/IGFBP-3 molar ratio was observed in all the studied groups. In 17 children, HypoT was diagnosed and L-T4substitution was administered. Despite similar IGF-I secretion increase, the improvement of HV presented significantly lower in children with HypoT than in those who remained euthyroid all the time.

Conclusions

The incidence of HypoT during the initial phase of GH treatment in children with GHD and the negative effect of even transient thyroid hormone deficiency on the growth rate should be taken into account.
"Idiopathic" mental retardation and new chromosomal abnormalities
Authors: Galasso Cinzia , Lo-Castro Adriana , El-Malhany Nadia , Curatolo Paolo
Published: March 2010

Mental retardation is a heterogeneous condition, affecting 1-3% of general population. In the last few years, several emerging clinical entities have been described, due to the advent of newest genetic techniques, such as array Comparative Genomic Hybridization. The detection of cryptic microdeletion/microduplication abnormalities has allowed genotype-phenotype correlations, delineating recognizable syndromic conditions that are herein reviewed. With the aim to provide to Paediatricians a combined clinical and genetic approach to the child with cognitive impairment, a practical diagnostic algorithm is also illustrated. The use of microarray platforms has further reduced the percentage of "idiopathic" forms of mental retardation, previously accounted for about half of total cases. We discussed the putative pathways at the basis of remaining "pure idiopathic" forms of mental retardation, highlighting possible environmental and epigenetic mechanisms as causes of altered cognition.
Interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis
Authors: Page Charlotte E , Smale Shaun , Carty Sara M , Amos Nicholas , Lauder Sarah N , Goodfellow Rhian M , Richards Peter J , Jones Simon A , Topley Nicholas , Williams Anwen S
Published: March 2010

Introduction

The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis.

Methods

We studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)).

Results

IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA.

Conclusions

Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis.
Local vertical seismic profiling (VSP) elastic reverse-time migration and migration resolution: Salt-flank imaging with transmitted P-to-S waves
Authors: Xiao Xiang , Leaney W. Scott
Published: March 2010

To avoid the defocusing effects of propagating waves through salt and overburden with an inaccurate overburden velocity model, we introduce a vertical seismic profiling (VSP) local elastic reverse-time-migration (RTM) method for salt-flank imaging by transmitted P-to-S waves. This method back-projects the transmitted PS waves using a local velocity model around the well until they are in phase with the back-projected PP waves at the salt boundaries. The merits of this method are that it does not require the complex overburden and salt-body velocities and it automatically accounts for source-side statics. In addition, the method accounts for kinematic and dynamic effects, including anisotropy, absorption, and all other unknown rock effects outside of this lo-cal subsalt velocity model. Numerical tests on an elastic salt model and offset 2D VSP data in the Gulf of Mexico, using a finite-difference time-domain staggered-grid RTM scheme, partly demonstrate the effectiveness of this method over interferometry PS-PP transmission migration and local acoustic RTM. Our method separates elastic wavefields to vector P- and S-wave velocity components at the trial image point and achieves better resolution than local acoustic RTM and interferometric transmission migration. The analytical formulas of migration resolution for local acoustic and elastic RTM show that the migration illumination is limited by data frequency and receiver aperture, and the spatial resolution is lower than standard poststack and prestack migration. This new method can image salt flanks as well as subsalt reflectors.
Finite-element simulations of Stoneley guided-wave reflection and scattering at the tips of fluid-filled fractures
Authors: Frehner Marcel , Schmalholz Stefan M.
Published: March 2010

The reflection and scattering of Stoneley guided waves at the tip of a crack filled with a viscous fluid was studied numerically in two dimensions using the finite-element method. The rock surrounding the crack is fully elastic and the fluid filling the crack is elastic in its bulk deformation behavior and viscous in its shear deformation behavior. The crack geometry, especially the crack tip, is resolved in detail by the unstructured finite-element mesh. At the tip of the crack, the Stoneley guided wave is reflected. The amplitude ratio between reflected and incident Stoneley guided wave is calculated from numerical simulations, which provide values ranging between 43% and close to 100% depending on the type of fluid filling the crack (water, oil or hydrocarbon gas), the crack geometry (elliptical or rectangular), and the presence of asmall gas cap at the cracktip. The interference of incident and reflected Stoneley guided waves leads to a node (zero amplitude) at the tip of the crack. At other positions along the crack, this interference increases the amplitude. However, the exponential decay away from the crack makes the Stoneley guided wave difficult to detect at a relatively short distance away from the crack. The part of the Stoneley guided wave that is not reflected is scattered at the crack tip and emitted into the surrounding elastic rock as body waves. For fully saturated cracks, the radiation pattern of these elastic body waves points in every direction from the crack tip. The emitted elastic body waves can allow the detection of Stoneley guided wave-related resonant signals at distances away from the crack where the amplitude of the Stoneley guided wave itself is too small to be detected.
Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer
Authors: Graesslin Olivier , Abdulkarim Bassam S. , Coutant Charles , Huguet Florence , Gabos Zsolt , Hsu Limin , Marpeau Olivier , Uzan Serge , Pusztai Lajos , Strom Eric A. , Hortobagyi Gabriel N. , Rouzier Roman , Ibrahim Nuhad K.
Published: March 2010

Purpose

Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials.

Patients and Methods

Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada).

Results

Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities.

Conclusion

We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.
Safety, Pharmacokinetics, and Preliminary Clinical Activity of Inotuzumab Ozogamicin, a Novel Immunoconjugate for the Treatment of B-Cell Non-Hodgkin's Lymphoma: Results of a Phase I Study
Authors: Advani Anjali , Coiffier Bertrand , Czuczman Myron S. , Dreyling Martin , Foran James , Gine Eva , Gisselbrecht Christian , Ketterer Nicolas , Nasta Sunita , Rohatiner Ama , Schmidt-Wolf Ingo G.H. , Schuler Martin , Sierra Jorge , Smith Mitchell R. , Verhoef Gregor , Winter Jane N. , Boni Joseph , Vandendries Erik , Shapiro Mark , Fayad Luis
Published: March 2010

Purpose

Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. This was a phase I study to determine the maximum-tolerated dose (MTD), safety, and preliminary efficacy of inotuzumab ozogamicin in an expanded MTD cohort of patients with relapsed or refractory CD22+ B-cell non-Hodgkin's lymphoma (NHL).

Patients and Methods

Inotuzumab ozogamicin was administered intravenously as a single agent once every 3 or 4 weeks at doses ranging from 0.4 to 2.4 mg/m2. Outcomes included MTD, safety, pharmacokinetics, response, progression-free survival (PFS), and overall survival.

Results

Seventy-nine patients were enrolled. The MTD was determined to be 1.8 mg/m2. Common adverse events at the MTD were thrombocytopenia (90%), asthenia (67%), and nausea and neutropenia (51% each). The objective response rate at the end of treatment was 39% for the 79 enrolled patients, 68% for all patients with follicular NHL treated at the MTD, and 15% for all patients with diffuse large B-cell lymphoma treated at the MTD. Median PFS was 317 days (approximately 10.4 months) and 49 days for patients with follicular NHL and diffuse large B-cell lymphoma, respectively.

Conclusion

Inotuzumab ozogamicin has demonstrated efficacy against CD22+ B-cell NHL, with reversible thrombocytopenia as the main toxicity.