bluuebunny/crossref_metadata_2025 huggingface dataset:
A Modification of Minimal Residual Iterative Method to Solve Linear Systems
Authors: Sheng Xingping , Su Youfeng , Chen Guoliang
Published: April 2009

We give a modification of minimal residual iteration (MR), which is 1V‐DSMR to solve the linear system Ax = b. By analyzing, we find the modifiable iteration to be a projection
technique; moreover, the modification of which gives a better (at least the same) reduction of the residual
error than MR. In the end, a numerical example is given to demonstrate the reduction of the residual
error between the 1V‐DSMR and MR.
Severe Keratitis Caused byPseudomonas aeruginosaSuccessfully Treated with Ceftazidime Associated with Acetazolamide
Authors: Hue Benoit , Doat Marc , Renard Gilles , Brandely Marie-Laure , Chast François
Published: April 2009

Purpose. To report a case of microbial keratitis caused by Pseudomonas aeruginosa treated with a combination of acetazolamide and ceftazidime.Methods. Case report.Results. We report the case of a 17-year-old contact lens-wearing female who developed severe keratitis due toPseudomonas aeruginosatemporarily healed with topical fortified antibiotic eye drops. After few days, the patient relapsed, and topical and intravenous ceftazidime were added. Concomitantly, oral administration of acetazolamide was prescribed. This carbonic anhydrase inhibitor was added to the antibiotic regimen in order to decrease the anterior chamber pH, and then, the ceftazidime ionization. By lowering the state of ionization of the antibiotic in the aqueous humor, its concentration was increased. This was confirmed by an improvement of the patient within few days and a rapid eradication of the infection.Conclusion. This is the first reported case of keratitis caused byP. aeruginosasuccessfully treated using acetazolamide as an enhancer of ceftazidime effectiveness.
On the Global Attractivity of a Max‐Type Difference Equation
Authors: Gelişken Ali , Çinar Cengiz
Published: April 2009

We investigate asymptotic behavior and periodic nature of positive solutions of the difference equation , where A > 0 and 0 < α < 1. We prove that every positive solution of this difference equation approaches or is eventually periodic with period 2.
Synthesis and Characterization of Biologically Active 10-Membered Tetraazamacrocyclic Complexes of Cr(III), Mn(III), and Fe(III)
Authors: Singh Dharam Pal , Malik Vandna , Kumar Ramesh
Published: April 2009

A new series of macrocyclic complexes of type [M(TML)X]X2; where M = Cr(III), Mn(III), or Fe(III); TML is tetradentate macrocyclic ligand and X = Cl−1, NO3−1, CH3COO−1 for Cr(III), Fe(III), and X = CH3COO−1 for Mn(III) has been synthesized by template condensation of succinyldihydrazide and glyoxal. The complexes have been formulated as [M(TML)X]X2 due to 1:2 electrolytic natures of these complexes as shown by conductivity measurements. The complexes have been characterized with the help of elemental analyses, molar conductance, electronic, infrared, far infrared spectral studies and magnetic susceptibilities. On the basis of these studies, a five-coordinate distorted square-pyramidal geometry, in which two nitrogens and two carbonyl oxygen atoms are suitably placed for coordination toward the metal ion, has been proposed for all the complexes. The complexes were tested for their in vitro antibacterial activity. Some of the complexes showed remarkable antibacterial activities against some selected bacterial strains. The minimum inhibitory concentration shown by these complexes was compared with minimum inhibitory concentration shown by some standard antibiotics like linezolid and cefaclor.
On Series-Like Iterative Equation with a General Boundary Restriction
Authors: Song Wei , Yang Guo-qiu , Lei Feng-chun
Published: April 2009

By means of Schauder fixed point theorem and Banach contraction principle, we investigate the existence and uniqueness of Lipschitz solutions of the equation"Equation missing". Moreover, we get that the solution"Equation missing" depends continuously on"Equation missing". As a corollary, we investigate the existence and uniqueness of Lipschitz solutions of the series-like iterative equation"Equation missing" with a general boundary restriction, where"Equation missing" is a given Lipschitz function, and"Equation missing" are compact convex subsets of"Equation missing" with nonempty interior.
Origin of the Difference in the Resistivity of As‐Grown Focused‐Ion‐ and Focused‐Electron‐Beam‐Induced Pt Nanodeposits
Authors: De Teresa J. M. , Córdoba R. , Fernández-Pacheco A. , Montero O. , Strichovanec P. , Ibarra M. R.
Published: April 2009

We study the origin of the strong difference in the resistivity of focused‐electron‐ and focused‐Ga‐ion‐beam‐induced deposition (FEBID and FIBID, resp.) of Pt performed in a dual beam equipment using as the precursor gas. We have performed in‐situ and ex‐situ resistance measurements in both types of nanodeposits, finding that the resistivity of Pt by FEBID is typically four orders of magnitude higher than Pt by FIBID. In the case of Pt by FEBID, the current‐versus‐voltage dependence is nonlinear and the resistance‐versus‐temperature behavior is strongly semiconducting, whereas Pt by FIBID shows linear current‐versus‐voltage dependence and only slight temperature dependence. The microstructure, as investigated by high‐resolution transmission electron microscopy, consists in all cases of Pt single crystals with size about 3 nm embedded in an amorphous carbonaceous matrix. Due to the semiconducting character of the carbon matrix, which is the main component of the deposit, we propose that the transport results can be mapped onto those obtained in semiconducting materials with different degrees of doping. The different transport properties of Pt by FEBID and FIBID are attributed to the higher doping level in the case of FIBID, as given by composition measurements obtained with energy‐dispersive X‐ray microanalysis.
Cellular Source and Amount of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor in Tumors Determine Response to Angiogenesis Inhibitors
Authors: Sennino Barbara , Kuhnert Frank , Tabruyn Sebastien P. , Mancuso Michael R. , Hu-Lowe Dana D. , Kuo Calvin J. , McDonald Donald M.
Published: April 2009

Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels. [Cancer Res 2009;69(10):4527–36]
Identification of PDE4D as a Proliferation Promoting Factor in Prostate Cancer Using a Sleeping Beauty Transposon-Based Somatic Mutagenesis Screen
Authors: Rahrmann Eric P. , Collier Lara S. , Knutson Todd P. , Doyal Meghan E. , Kuslak Sheri L. , Green Laura E. , Malinowski Rita L. , Roethe Laura , Akagi Keiko , Waknitz Michelle , Huang Wei , Largaespada David A. , Marker Paul C.
Published: April 2009

Retroviral and transposon-based mutagenesis screens in mice have been useful for identifying candidate cancer genes for some tumor types. However, many of the organs that exhibit the highest cancer rates in humans, including the prostate, have not previously been amenable to these approaches. This study shows for the first time that the Sleeping Beauty transposon system can be used to identify candidate prostate cancer genes in mice. Somatic mobilization of a mutagenic transposon resulted in focal epithelial proliferation and hyperplasia in the prostate. Efficient methods were established to identify transposon insertion sites in these lesions, and analysis of transposon insertions identified candidate prostate cancer genes at common insertion sites, including Pde4d. PDE4D was also overexpressed in human prostate cancer patient samples and cell lines, and changes in PDE4D mRNA isoform expression were observed in human prostate cancers. Furthermore, knockdown of PDE4D reduced the growth and migration of prostate cancer cells in vitro, and knockdown of PDE4D reduced the growth and proliferation rate of prostate cancer xenografts in vivo. These data indicate that PDE4D functions as a proliferation promoting factor in prostate cancer, and the Sleeping Beauty transposon system is a useful tool for identifying candidate prostate cancer genes. [Cancer Res 2009;69(10):4388–97]
Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen
Authors: Dubovsky Jason A. , McNeel Douglas G. , Powers John J. , Gordon John , Sotomayor Eduardo M. , Pinilla-Ibarz Javier A.
Published: April 2009

Purpose: Critical to the success of active immunotherapy against cancer is the identification of immunologically recognized cancer-specific proteins with low tolerogenic potential. Cancer testis antigens (CTA), in particular, fulfill this requirement as a result of their aberrant expression restricted to cancer cells and lack of expression in normal tissues bypassing tolerogenic mechanisms against self. Although CTAs have been extensively studied in solid malignancies, little is known regarding their expression in chronic lymphocytic leukemia (CLL).

Experimental Design: Using a two-pronged approach we evaluated the immunogenicity of 29 CTAs in 22 patients with CLL and correlated these results to reverse transcriptase PCR data from CLL cell lines and patient cells.

Results: We identified IgG-specific antibodies for one antigen, NXF2, and confirmed this response by ELISA and Western blot. We found that treatment of CLL with 5-aza-2′-deoxycytidine can induce expression of NXF2 that lasted for several weeks after treatment. Treatment also increased levels of MHC and costimulatory molecules (CD80, CD86, and CD40) necessary for antigen presentation. In addition, we identified other promising antigens that may have potential immunotherapeutic application.

Conclusions: Our findings suggest that NXF2 could be further pursued as an immunotherapeutic target in CLL, and that treatment with demethylating agents could be exploited to specifically modulate CTA expression and effective antigen presentation in malignant B cells.
Ratio of 17HSD1 to 17HSD2 Protein Expression Predicts the Outcome of Tamoxifen Treatment in Postmenopausal Breast Cancer Patients
Authors: Jansson Agneta , Delander Lovisa , Gunnarsson Cecilia , Fornander Tommy , Skoog Lambert , Nordenskjöld Bo , Stål Olle
Published: April 2009

Purpose: Estrogens have great significance in the development of breast cancer. After menopause, most estrogen biosynthesis is done in peripheral tissue, and the main enzymes involved in balancing the amount of estrone against estradiol are 17β-hydroxysteroid dehydrogenases (17HSD). The aim of this study was to investigate the prognostic and tamoxifen predictive values of 17HSD1 and 17HSD2 expression.

Experimental Design: Tumors from low-risk breast cancer patients randomized to adjuvant tamoxifen therapy or no adjuvant treatment were analyzed with immunohistochemistry to investigate protein expression of 17HSD1 and 17HSD2 in 912 cases. All patients had lymph node-negative breast cancer and were postmenopausal at the time of diagnosis.

Results: Low 17HSD1 expression was associated with significant benefit from tamoxifen treatment among patients with estrogen receptor (ER)-positive tumors (P < 0.001). For patients with a 17HSD1 score not exceeding that of 17HSD2, tamoxifen increased the rate of distant recurrence-free survival (hazard ratio, 0.37; 95% confidence interval, 0.23-0.60) and breast cancer-specific survival (hazard ratio, 0.30; 95% confidence interval, 0.16-0.54), whereas no apparent effect was observed when the 17HSD1 score was higher than that of 17HSD2. The interaction was significant for both distant recurrence-free survival (P = 0.036) and breast cancer-specific survival (P = 0.014). In the cohort of systemically untreated patients, no prognostic importance was observed.

Conclusions: This is the first report that clearly distinguishes between the prognostic and predictive importance of 17HSD1 and 17HSD2 in ER-positive breast cancer treated with or without tamoxifen. Our data suggest that the 17HSD1/17HSD2 ratio might be useful as a predictive factor for tamoxifen treatment in ER-positive breast cancer patients.
γH2AX Expression in Tumors Exposed to Cisplatin and Fractionated Irradiation
Authors: Bañuelos C. Adriana , Banáth Judit P. , Kim Joo-Young , Aquino-Parsons Christina , Olive Peggy L.
Published: April 2009

Purpose: Is retention of γH2AX foci useful as a biomarker for predicting the response of xenograft tumors to cisplatin with X-ray? Is a similar approach feasible using biopsies from patients with cervical cancer?

Experimental Design: Mice bearing SiHa, WiDr, or HCT116 xenograft tumors were exposed to cisplatin and/or three daily doses of 2 Gy. Tumors were excised 24 h after treatment and single cells were analyzed for clonogenic fraction and retention of γH2AX foci. Tumor biopsies were examined using 47 paraffin-embedded sections from untreated tumors and 24 sections from 8 patients undergoing radiochemotherapy for advanced cancer of the cervix.

Results: Residual γH2AX measured 24 h after cisplatin injection accurately predicted surviving fraction in SiHa and WiDr xenografts. When a clinically equivalent protocol using cisplatin and fractionated irradiation was employed, the fraction of xenograft cells lacking γH2AX ranked survival accurately but underestimated tumor cell kill. Residual γH2AX foci were detected in clinical samples; on average, only 25% of tumor nuclei exhibited one or more γH2AX foci before treatment and 74% after the start of treatment.

Conclusion: γH2AX can provide useful information on the response of human tumors to the combination of cisplatin and radiation, but prediction becomes less accurate as more time elapses between treatment and tumor biopsy. Use of residual γH2AX as a biomarker for response is feasible when cell survival exceeds ∼20%, but heterogeneity in endogenous and treatment-induced γH2AX must be considered.
A Combination of Micronutrients Is Beneficial in Reducing the Incidence of Prostate Cancer and Increasing Survival in theLadyTransgenic Model
Authors: Venkateswaran Vasundara , Klotz Laurence H. , Ramani Meera , Sugar Linda M. , Jacob Latha E. , Nam Robert K. , Fleshner Neil E.
Published: April 2009

We have previously shown that administration of a combination of micronutrients (selenium, vitamin E, and lycopene) inhibits prostate cancer (PCa) development in the Lady transgenic model. In the present study, we examine timing of initiation of micronutrients, and the effect of micronutrient combinations, on PCa development in Lady transgenic model.

Transgenic males were randomized to either a control diet; control diet supplemented with human equivalent doses of vitamin E, selenium, and lycopene (E+S+L); or control diet supplemented with vitamin E and selenium (E+S). In separate experiments, the combination of E+S+L was initiated at varying time points (4, 8, 20, and 36 weeks of age).

A combination of E+S+L resulted in a significant reduction in PCa and liver metastasis when intervention was commenced within 8 weeks of age (P < 0.0001). Immunohistochemical analysis revealed a strong correlation between disease-free state with up-regulation of the prognostic marker p27Kip1 (P < 0.0001) and decreased expression of proliferating cell nuclear antigen and significantly increased apoptotic index (P < 0.0001). On the contrary, a combination of E+S was not effectual in preventing PCa, with a high proportion (84.6%) of animals developing PCa and a small proportion (11.5%) developing high-grade PIN.

Early commencement of micronutrients (E+S+L) is beneficial in reducing PCa. Lycopene is an essential component of the combination and effective (when used with E+S) for PCa prevention. These observations provide support for their chemopreventive effect and some clues about their mechanism of action. These key findings will be complementary to the outcome from the Selenium and Vitamin E Chemoprevention Trial.
Nonsteroidal Anti-Inflammatory Drug Use and Endometrial Cancer Risk in the NIH-AARP Diet and Health Study
Authors: Danforth Kim N. , Gierach Gretchen L. , Brinton Louise A. , Hollenbeck Albert R. , Katki Hormuzd A. , Leitzmann Michael F. , Schatzkin Arthur , Lacey James V.
Published: April 2009

Chronic inflammation may play an etiologic role in endometrial cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce inflammatory activity by inhibiting the proinflammatory cyclooxygenase enzymes and, therefore, may decrease cancer risk. However, few studies have examined the association between NSAID use and endometrial cancer. We conducted a prospective study among 72,524 women in the NIH-AARP Diet and Health Study. Women completed a questionnaire in 1996–1997 on lifestyle and health-related factors, including type and frequency of NSAID use within the past year, and were followed through 2003 by linkages to cancer registries and vital status databases. During 488,261 person-years of follow-up, there were 732 incident endometrial cancers. NSAID use, compared with nonuse of NSAIDs, was not significantly associated with endometrial cancer risk [relative risk (RR), 0.90; 95% confidence interval (95% CI), 0.74–1.09]. Null associations were also observed by type of NSAID use [aspirin only: RR, 0.88; 95% CI, 0.70–1.11; nonaspirin NSAID (NA-NSAID) only: RR, 1.01; 95% CI, 0.79–1.29; both aspirin and NA-NSAIDs: RR, 0.85; 95% CI, 0.68–1.06]. Generally, results were not statistically significant by frequency of use for aspirin or NA-NSAIDs. Results did not change when women with a history of heart disease, hypertension, or diabetes were excluded to minimize the potential for confounding by indication. Overall, our data do not support an association between aspirin or NA-NSAID use and endometrial cancer risk.
The Growth Hormone Cascade and Its Role in Mammalian Growth
Authors: Rosenfeld Ron G. , Hwa Vivian
Published: April 2009

The myriad actions of growth hormone (GH) are still incompletely understood, despite decades of research. Although it is a major regulator of post-natal growth in mammals, much of its effects on skeletal growth are recognized to be mediated indirectly, through the stimulation of production of insulin-like growth factor (IGF)-I, as well as some of the major serum carrier proteins for IGF-I and -II, such as IGF-binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). The regulation of IGF-I production by GH appears to be mediated entirely by signalling through the Janus kinase (JAK) 2 pathway, via the phosphorylation of the transcription factor, signal transducer and activator of transcription (STAT) 5b. GH also signals, however, through additional pathways that are likely to be critical to the metabolic actions of GH.
Genes of Importance in the Hormonal Regulation of Growth Plate Cartilage
Authors: Chagin Andrei S. , Sävendahl Lars
Published: April 2009

Longitudinal bone growth occurs in the growth plate through a process in which resting zone chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization. Bone growth is controlled by a multitude of genes encoding for hormones and growth factors acting systemically and/or locally in the growth plate. From studies of individuals with a mutated aromatase gene and a male patient with defective oestrogen receptor (ER) α, it has become clear that the action of oestrogen is indispensable for normal pubertal growth and growth plate fusion. As new aromatase inhibitors and specific modulators of ERs are developed, these could offer more specific ways to modulate longitudinal growth and growth plate fusion. It is difficult to extrapolate data obtained in experimental animals, as clear species differences exist, emphasizing the need for new models that will allow studies in human growth plate cartilage.
The Future of Research into Growth Hormone Responsiveness
Authors: Rosenfeld Ron G.
Published: April 2009

Decades of experience with growth hormone (GH) therapy have indicated considerable variability in responsiveness to therapy, even within single diagnostic categories, such as GH deficiency, Turner syndrome, intrauterine growth retardation and idiopathic short stature. It is likely that the major explanation for such variability lies in the genetic composition of the patient, including mutations of genes participating in the GH-insulin growth factor I cascade and genetic polymorphisms. Future studies of pharmacogenomic and pharmacoproteomic markers may allow us to better predict and categorize responsiveness to therapy.
G-Protein and Signalling in Pituitary Tumours
Authors: Lania Andrea , Spada Anna
Published: April 2009

The genesis of pituitary tumours is still under debate. Although these neoplasias are monoclonal in origin, mutations of GNAS1, the gene encoding the α subunit of the stimulatory G-protein, Gs, are the only mutational changes unequivocally associated with growth hormone (GH)-secreting adenomas. However, despite the growth advantage that this oncogene has been demonstrated to confer in vitro, patients carrying this mutation have a similar clinical and biochemical phenotype to those who do not carry it. This discrepancy is due to the occurrence of events able to counteract the biological effect of the mutation. Consistent with a potential role of the cyclic adenosine monophosphate pathway in the proliferation of somatotrophs, germline mutations of the gene encoding the type 1α regulatory subunit of protein kinase A (PRKAR1A) have been found in patients with the Carney complex, a syndrome including GH-secreting adenomas, whereas alterations in the expression levels of this subunit are frequently observed in sporadic adenomas.
The Effect of Angiotensin II on the Number of Macula Densa Cells through the AT1 Receptor
Authors: Razga Zsolt , Nyengaard Jens Randel
Published: April 2009

The present study was performed to obtain information about a possible correlation between the activity of the renin-angiotensin system and the stereological features of the macula densa (MD). In normal kidneys, the numbers of angiotensin II AT1 receptors were estimated in MD cells and in the neighboring tubular cells. The total volumes of MD, MD cells, neighboring tubular cells, and the total number of MD cells, were measured in normal and candesartan-treated rats (15 mg/kg/day over 21 days). In the normal kidneys, the relative number of AT1 receptors in MD cells [mean = 0.17 (CV = 0.23)] was significantly (p = 0.03) lower than that in normal tubular cells [0.25 (0.21)]. A significant difference (p < 0.01) was observed in the total volume between MD cells [515 μm3 (0.14)] and normal tubular cells [984 μm3 (0.19)]. Candesartan treatment significantly elevated (p < 0.01) the total volume of the MD, whereas the total number of MD cells was increased [from 14.2 (0.11) to 19.5 (0.11)]. The results demonstrated that the transdifferentiation from normal tubular cells to MD cells can be controlled by pharmacological means. The structural features of MD controlled by the renin-angiotensin system may be one of the important factors governing the sensitivity of tubuloglomerular feedback.
Fifty Years with the Hamilton Scales for Anxiety and Depression
Authors: Bech P.
Published: April 2009

From the moment Max Hamilton started his psychiatric education, he considered psychometrics to be a scientific discipline on a par with biochemistry or pharmacology in clinical research. His clinimetric skills were in operation in the 1950s when randomised clinical trials were established as the method for the evaluation of the clinical effects of psychotropic drugs. Inspired by Eysenck, Hamilton took the long route around factor analysis in order to qualify his scales for anxiety (HAM-A) and depression (HAM-D) as scientific tools. From the moment when, 50 years ago, Hamilton published his first placebo-controlled trial with an experimental anti-anxiety drug, he realized the dialectic problem in using the total score on HAM-A as a sufficient statistic for the measurement of outcome. This dialectic problem has been investigated for more than 50 years with different types of factor analyses without success. Using modern psychometric methods, the solution to this problem is a simple matter of reallocating the Hamilton scale items according to the scientific hypothesis under examination. Hamilton’s original intention, to measure the global burden of the symptoms experienced by the patients with affective disorders, is in agreement with the DSM-IV and ICD-10 classification systems. Scale reliability and obtainment of valid information from patients and their relatives were the most important clinimetric innovations to be developed by Hamilton. Max Hamilton therefore belongs to the very exclusive family of eminent physicians celebrated by this journal with a tribute.
Quality of Life Measurement in Antidepressant Trials
Authors: De Fruyt Jürgen , Demyttenaere Koen
Published: April 2009

Background: Quality of life (QoL) measurement in medicine has gone a long way. It has gained popularity as a more humanitarian outcome measurement. In this paper, a review is given of its historical backgrounds with a special focus on the use of QoL assessment in psychiatry. Different theoretical concepts are discussed. A closer look is taken at the use of QoL measurements in antidepressant trials. Methods: An analysis was performed on the use of QoL measurement in recent antidepressant trials of duloxetine and escitalopram. Results: QoL measurement was found to have abandoned its initial purposes, and to have been used without any theoretical framework. Conclusions: Although frequently used in antidepressant trials, the analysis and reporting of results is virtually non-existent. It remains unclear if QoL measurement, as currently used, gives any information that is not already captured by more formal depression rating scales. The question then remains whether QoL measurement in antidepressant trials has any added value and, if so, whether this is just a story of missed opportunities.
Mechanisms of M3 Muscarinic Receptor Regulation by Wash-Resistant Xanomeline Binding
Authors: Noetzel Meredith J. , Grant Marianne K.O. , El-Fakahany Esam E.
Published: April 2009

Background/Aims: Xanomeline has been shown to bind in a unique manner at M1 and M3 muscarinic receptors, with interactions at both the orthosteric site and an allosteric site. We have previously shown that brief exposure of Chinese hamster ovary cells that express the M3 receptor to xanomeline followed by removal of free agonist results in a delayed decrease in radioligand binding and receptor response to agonists. In the current study, we were interested in determining the mechanisms of this effect. Methods: Cells were treated with carbachol, pilocarpine or xanomeline for 1 h followed by washing and either used immediately or after waiting for 23 h. Control groups included cells that were not exposed to agonists and cells that were treated with agonists for 24 h. Radioligand binding and functional assays were conducted to determine the effects of agonist treatments. Results: The above treatment protocol with xanomeline resulted in similar effects of the binding of [3H]NMS and [3H]QNB. When receptor function is blocked using a variety of methods, the long-term effects of xanomeline binding were absent. Conclusion: Our data indicate that xanomeline wash-resistant binding at the receptor allosteric site leads to receptor downregulation and that receptor activation is necessary for these effects.
Schneckenbecken Dysplasia in Fetus: Report of Four Cases
Authors: Lahmar-Boufaroua Ahlem , Yacoubi Mohamed Tahar , Belaid Leila , Delezoide Anne Lize
Published: April 2009

Several different types of lethal short-limbed skeletal dysplasia with platyspondylia have been recognized with a different mode of inheritance. Schneckenbecken dysplasia, a very rare lethal osteochondrodysplasia, is included in these entities, with an autosomal recessive mode of inheritance. We describe 4 new Tunisian cases with clinical, radiographic and histopathological features. The fetuses were of consanguineous parents. Prenatal diagnostics of short limbs were carried out on ultrasounds at 20, 22, 23 and 28 weeks of gestation. The radiographic findings were typical, showing especially the small ilia with medial snail-like projection. The chondro-osseous histology of the 4 cases was compatible with the diagnostics demonstrating cartilage anomalies characterized by hypercellularity, hypervascularisation and chondrocytes with central large round nucleus. Schneckenbecken dysplasia should be considered when the phenotype of dwarfism and snail feature of iliac bone associated with histological finding are presented. Frozen fetal samples should be taken in order to look for candidate genes.
Increased Uptake and Improved Intracellular Survival of a Teicoplanin-Resistant Mutant of Methicillin-Resistant Staphylococcus aureus in Non-Professional Phagocytes
Authors: Renzoni Adriana , Huggler Elzbieta , Kelley William L. , Lew Daniel , Vaudaux Pierre
Published: April 2009

Background/Aims: Endogenous development of glycopeptide-intermediate resistance is linked to multiple genetic and phenotypic changes in clinical and laboratory isolates of Staphylococcus aureus. This study evaluated endocytic uptake and intracellular survival of a teicoplanin-resistant derivative of S. aureus in a human epithelial cell line, and compared these to the isogenic teicoplanin-susceptible parent or a spontaneously derived, susceptible revertant. Methods: Endocytic uptake of teicoplanin-resistant and teicoplanin-susceptible strains by human embryonic kidney 293 cells was estimated by a lysostaphin protection assay. Differential intracellular survival of all S. aureus strains from 2 to 24 h was evaluated by colony-forming unit counts of Triton X-100-lysed 293 cells, following lysostaphin inactivation. Results: Endocytic uptake of the teicoplanin-resistant strain increased by approximately 4-fold over its teicoplanin-susceptible counterparts. Furthermore, the teicoplanin-resistant strain showed an 11-fold increase in intracellular colony-forming unit counts from 2 to 24 h, compared to its teicoplanin-susceptible counterparts that showed marginal (<2-fold) changes during the same time period. Infected host cells showed no significant viability loss at 24 h, as assessed by Trypan blue dye exclusion. Conclusions: Intracellular location might confer a significant fitness benefit to glycopeptide-intermediate isolates of methicillin-resistant S. aureus and further protect them from cell wall-active antibiotics whose intracellular activity is limited.
Association between Aldosterone Synthase CYP11B2 Polymorphism and Essential Hypertension in Chinese: A Meta-Analysis
Authors: Cheng Xiaoshu , Xu Gaosi
Published: April 2009

A thymidine-to-cytosine substitution in the –344 promoter region of the aldosterone synthase gene (CYP11B2) has been associated with essential hypertension in some but not all studies conducted in Chinese. We performed a meta-analysis to evaluate the association of the –344C/T polymorphism with essential hypertension in Chinese. A total of 7,472 individuals (4,259 unselected hypertensive patients and 3,213 normotensive controls) from 9 case-control studies were included in the present investigation. Significant associations between the risk of hypertension and the CC genotype and C allele frequencies were found in a total of 19 studies. Our findings support the notion that the CYP11B2 –344C/T polymorphism is associated with essential hypertension. In addition, C allele frequency was found to be lower in southern Chinese controls than in their northern counterparts, and the higher TT genotype homozygous frequency in the southern Chinese supports the hypothesis that the northern Chinese are of southern origin.
Levodopa: Past, Present, and Future
Authors: Hauser Robert A.
Published: April 2009

Levodopa has been the mainstay of treatment for Parkinson’s disease (PD) for more than 40 years. During this time, researchers have strived to optimize levodopa formulations to minimize side effects, enhance central nervous system (CNS) bioavailability, and achieve stable therapeutic plasma levels. Current strategies include concomitant treatment with inhibitors of dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) to prolong the peripheral levodopa half-life and increase CNS bioavailability. Levodopa combined with DDC inhibition is the current standard method of delivering levodopa for symptomatic treatment of PD. Recent research suggests that continuous dopaminergic stimulation that more closely approximates physiological stimulation may delay or prevent the development of motor fluctuations (‘wearing off’) and dyskinesias. Strategies currently being used to achieve more continuous dopaminergic stimulation include the combination of an oral levodopa/DDC inhibitor with a COMT inhibitor and the enteral infusion of a levodopa gel formulation. Attempts are underway to develop oral and transdermal very long-acting levodopa preparations.
Inhibition Effects of KRDS, a Peptide Derived from Lactotransferrin, on Platelet Function and Arterial Thrombus Formation in Dogs
Authors: Wu Guoxin , Ruan Changgeng , Drouet Ludovic , Caen Jacques
Published: April 2009

KRDS (Lys-Arg-Asp-Ser), a tetrapeptide from human lactotransferrin, was tested for its effects in vitro on dog platelet function and in vivo on femoral arterial thrombus formation in dogs. KRDS inhibited ADP (8 μM)-induced platelet aggregation (IC50: 350 μM) and arachidonic acid (2 mM)-induced thromboxane B2 generation (IC50: 175 μM). In addition, the thrombin (0.2 U/ml)-induced serotonin release was inhibited by KRDS (IC50: 525 μM) and the expression of alpha-granule membrane protein (GMP-140) was also inhibited (IC50: 350 μM). The results show that KRDS is an inhibitor for platelet aggregation and secretion to which the inhibition is more potent. Meanwhile, in the experiment of arterial thrombosis in dogs, KRDS (5 μM/kg) and 125I-SZ-51 (a monoclonal antibody against GMP-140) were injected before operation and immediately after the thrombus formation, respectively. In the KRDS group, the weight of removed thrombi was reduced to 50% of that in controls and the radioactivity per mg of labeled thrombi to 33.3% while in blood the radioactivity increased 2 times that in controls at the 4th hour after the injection of 125I-SZ-51. The radioactivity ratio between removed thrombi and blood was only 16% of that in controls. These results indicate that KRDS can inhibit thrombus formation in vivo and is a promising antithrombotic agent.
Intraduodenal Absorption in the Rabbit of a Novel Heparin Salt
Authors: Andriuoli G. , Caramazza I. , Galimberti G. , Zoppetti G. , Benedini F. , Sala A. , Del Soldato P.
Published: April 2009

The intraduodenal absorption of a new low-molecular-weight heparin (LMWH) diamine salt (ITF 1331) was compared with the parent compound ITF 1060 and with sodium LMWH, in anaesthetized rabbits. The administration of either salt, but not of sodium LMWH, resulted in a dose-related increase in plasma anti-Xa activity. In this respect ITF 1331 was slightly superior to ITF 1060, and in acute-toxicity studies the counterion itself (ITF 258) was less toxic than that in ITF 1060 (counterion No. 4). These data confirm that a tertiary diamine within the counterion is an important structural requirement for the bioavailability of heparin by the intraduodenal route, and suggest that ITF 1331 may represent an important advance in the search for an oral heparin.
Warfarin-Induced Skin Necrosis in 2 Patients with Protein S Deficiency: Successful Reinstatement of Warfarin Therapy
Authors: Anderson David R. , Brill-Edwards Patrick , Walker Irwin
Published: April 2009

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.
Platelet-Induced Thrombin Generation Time: A New Sensitive Global Assay for Platelet Function and Coagulation
Authors: Basic-Micic M. , Roman C. , Herpel U. , Kling E. , Scholz B. , Breddin H.K.
Published: April 2009

A new sensitive test – platelet-induced thrombin generation time (PITT) – is described, in which the formation of thrombin in partially anticoagulated platelet-rich plasma (PRP) leads to aggregation immediately followed by coagulation of PRP. 0.6 ml PRP are rotated in a disk-shaped cuvette within the light beam of a photometer. In PITT, platelets stick to the cuvette wall and, mediated by a large PRP/surface/air interface at the cuvette wall, are activated and participate in thrombin formation which leads to aggregation and clotting. The times from onset of rotation until aggregation (Ta) and until coagulation (Tc) of the PRP samples are recorded. PITT was very sensitive and detected low concentrations of unfractionated heparin (0.01 IU/ml) in vitro. PITT parameters were significantly prolonged ex vivo 2 h after oral administration of acetylsalicylic acid (0.5 g) and after single subcutaneous injections of heparin (5,000 IU). Patients receiving phenprocoumon prophylaxis had markedly prolonged Ta and Tc values (longer than 20 min, n = 23). Patients with recent thrombotic episodes had markedly shorter values than healthy volunteers. PITT may become a very sensitive global test to detect mild hemorrhagic disorders, to monitor the effects of antithrombotic drugs and to detect patients with a risk of vascular occlusions.
Ultrastructural Aspects of Female Aging Wistar Rat Epithelium Tongue: A HRSEM and TEM Study
Authors: Lopes Marilia Gabriela de Oliveira , Watanabe Ii-sei , Soares Luís Eduardo Silva , da Silva Newton Soares , da Silva Marcelo Cavenaghi Pereira
Published: April 2009

Background: There is general consensus that the effects of intrinsic aging on the oral mucosa are relatively small, though potentially important to understanding the pathologies present in the aged animals. Objective: In this paper, the development of dorsal surface of rat tongue was examined using transmission electron microscopy (TEM) and high-resolution scanning electron microscopy (HRSEM) in order to understand the age-related structural and ultrastructural changes experimentally. Methods: In this study, we used female rats 75 and 720 days old (adult and aging). Tissues of rat tongue were prepared and the specimens submitted to HRSEM and TEM techniques. Results: The analysis of HRSEM and TEM demonstrated that the same characteristic keratinous epithelium was found in aging animals, however with some modifications. Conclusion: We agree that there are obvious changes in the oral mucosa with aging and these modifications can be observed starting from the ultrastructural aspects.
Cryptococcal Pleuritis Containing a High Level of Adenosine Deaminase in a Patient with AIDS: A Case Report
Authors: Yoshino Yusuke , Kitazawa Takatoshi , Tatsuno Keita , Ota Yasuo , Koike Kazuhiko
Published: April 2009

Cryptococcal infection is the 4th most common opportunistic infection in patients with acquired immune deficiency syndrome (AIDS). Although pleural effusion alone is an unusual presentation, we present a case of cryptococcal pleuritis in an AIDS patient which was initially difficult to discriminate from tuberculous pleuritis because of the high level of pleural adenosine deaminase (ADA). Cryptococcus neoformans was detected in the culture of the pleural effusion after the initiation of antituberculous treatment. High levels of ADA in the pleural fluid can be observed in patients with cryptococcal pleuritis, and longer incubation of pleural fluid should be performed in all patients who present with pleuritis associated with a high ADA level as the only significant finding.
The Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) Study: Baseline Characteristics of the Population
Authors: Bousser M.G. , Amarenco P. , Chamorro A. , Fisher M. , Ford I. , Fox K. , Hennerici M. , Mattle H.P. , Rothwell P.M.
Published: April 2009

Background: The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study is an international double-blind, randomized controlled trial designed to investigate the superiority of the specific TP receptor antagonist terutroban (30 mg/day) over aspirin (100 mg/day), in reducing cerebrovascular and cardiovascular events in patients with a recent history of ischemic stroke or transient ischemic attack. Here we describe the baseline characteristics of the population. Methods and Results: Parameters recorded at baseline included vital signs, risk factors, medical history, and concomitant treatments, as well as stroke subtype, stroke-associated disability on the modified Rankin scale, and scores on scales for cognitive function and dependency. Eight hundred and two centers in 46 countries recruited a total of 19,119 patients between February 2006 and April 2008. The population is evenly distributed and is not dominated by any one country or region. The mean ± SD age was 67.2 ± 7.9 years, 63% were male, and 83% Caucasian; 83% had hypertension, and about half the population smoked or had quit smoking. Ninety percent of the qualifying events were ischemic stroke, 67% of which were classified as atherothrombotic or likely atherothrombotic (pure or coexisting with another cause). Modified Rankin scale scores showed slight or no disability in 83% of the population, while the scores on the Mini-Mental State Examination, Isaacs’ Set Test, Zazzo’s Cancellation Test, and the instrumental activities of daily living scale showed a good level of cognitive function and autonomy. Conclusions: The PERFORM study population is homogeneous in terms of demographic and disease characteristics. With 19,119 patients, the PERFORM study is powered to test the superiority of terutroban over aspirin in the secondary prevention of cerebrovascular and cardiovascular events in patients with a recent history of ischemic stroke or transient ischemic attack.
Platelet Adhesivity to Subendothelium Is Influenced by Polymorphonuclear Leukocytes: Studies with Aspirin and Salicylate
Authors: Hernández Rosa , Alemany Mónica , Bozzo Jordi , Buchanan Michael R. , Ordinas Antonio , Bastida Eva
Published: April 2009

Interactions between blood platelets and polymorphonuclear leukocytes (PMN) influence cell reactivity. We have examined the effects of inhibiting platelet and PMN cyclooxygenase and lipoxygenase pathways, by treatment with aspirin (ASA) and salicylate (SAL) on platelet-vessel wall interaction studied under flow conditions by means of an annular chamber perfusion system. We have also measured the levels of cyclooxygenase-derived metabolites during perfusion. Perfusates were prepared with untreated and ASA- or SAL-treated PMN or platelets. Our results demonstrated that blockage of the lipoxygenase pathway in PMN significantly increased platelet thrombus formation and favored the production of thromboxane B2 (T×B2) during perfusion, whereas inhibition of cyclooxygenase pathway in PMN had no effect either on platelet deposition or on T×B2 levels. In contrast, blockage of platelet cyclooxygenase, which caused almost total inhibition of T×B2, enhanced platelet adhesion and did not modify platelet thrombus formation. These results suggest that under dynamic conditions cooperative metabolic mechanisms between platelets and PMN directly influence platelet interaction with vascular subendothelium.
Comparative Plasma Disposition and Anticoagulant Activities of Racemic Phenprocoumon and Its Metabolites in Rats
Authors: de Vries Jan Xaver , Simon Michael , Völker Uwe , Walter-Sack Ingeborg , Weber Ellen , Stegmeier K.
Published: April 2009

The anticoagulant phenprocoumon (PH) and its metabolites 6-hydroxy-, 7-hydroxy- and 4′hydroxy-phenprocoumon (6-OH-PH, 7-OH-PH and 4′-OH-PH, respectively) were separately administrated intravenously as racemates to rats in order to measure the potential effects of the major metabolites of PH on coagulation. Plasma samples were assayed for total concentrations of the administered compounds and the corresponding prothrombin times; kinetic parameters and anticoagulant activities were estimated using a pharmacodynamic model based on the rate of synthesis of clotting factors. The relative potencies were in the order PH > 4′-OH-PH > 6-OH-PH > 7-OH-PH the latter showing no activity. Patients on PH therapy showed lower plasma concentrations of metabolites than of PH; in humans the metabolites of PH will not contribute significantly to the overall anticoagulant activity of the drug.
Concentrations of Phenprocoumon in Serum and Serum Water Determined by High-Performance Liquid Chromatography in Patients on Oral Anticoagulant Therapy
Authors: Petersen D. , Barthels Monika , Schumann G. , Büttner J.
Published: April 2009

Two convenient high-performance liquid chromatography procedures are proposed for the determination of phenprocoumon (Marcumar®) in serum (S-PPC) and its unbound fraction in serum water (SW-PPC). S-PPC and SW-PPC were determined in samples from 53 patients undergoing oral anticoagulant therapy who were within the therapeutic interval of the thrombotest. S-PPC concentrations ranged from 0.6 to 5.0 mg/l, SW-PPC from 1.4 to 21.1 μg/l. A linear correlation (r = 0.714) was found between S-PPC and SW-PPC concentrations in the patient samples, the mean free fraction being 0.30%. S-PPC and SW-PPC concentrations were intraindividually stable during therapy. A linear correlation (r = 0.710) was observed between S-PPC concentrations and dosage.
Cathepsin G Inactivates Human Protein S in vitro
Authors: Turkington P.T.
Published: April 2009

Human polymorphonuclear leukocyte cathepsin G was used in vitro to digest human protein S. While clotting assays indicated that the proteinase induced a rapid decrease in activity, polyacrylamide gel electrophoresis-sodium dodecyl sulphate indicated the removal of a peptide of low molecular mass product protein S (des 1-40). The loss in activity was the result of cathepsin G cleaving position Phe40-Tyr41 and removing the calcium-binding region. Calcium ions almost totally protected the cofactor from the action of cathepsin G in vitro.