bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T
Authors: Hassan Madiha AH , Ketat Amal F 
Published: April 2005

Abstract
Background
Cardiac hypertrophy is a major risk factor for morbidity and mortality in a number of cardiovascular diseases. Consequently, the signaling pathways that inhibit cardiac hypertrophy are currently receiving much interest. Among them, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase I, has been recognized as a negative regulator of cardiac hypertrophy. The present study investigated the in-vivo effect of sildenafil as a phosphodiestrase-5A (PDE-5A) inhibitor on the hypertrophic response of rat heart to isoproterenol and the relation of this effect to the level of myocardial cGMP and integrity of the constitutive nitric oxide synthase (cNOS) activity.

Results
The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium. Conversely, daily subcutaneous administration of isoproterenol for 10 days caused significant myocardial hypertrophy, cell injury and decline in survival. When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury. Interestingly, sildenafil was accompanied by significant rise in myocardial cGMP level, a parameter which was found in the present study to possess a significant negative correlation with cardiac hypertrophy and leak of cardiac troponin T into serum. At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium. However, in rats given Nω-nitro-L-arginine (L-NNA) as a competitive inhibitor of cNOS, sildenafil failed to show any favorable effect on survival or the myocardial injury parameters used to assess isoproterenol-induced injury.

Conclusion
The present study suggests that increased cardiac cGMP level by sildenafil have a cardioprotective effect probably through acting as a post-receptor negative regulator of cardiac sympathetic responsiveness. Integrity of NOS function was an essential prerequisite for sildenafil's mediated cardioprotection encountered in the present study.
Automated analysis of digital fundus autofluorescence images of geographic atrophy in advanced age-related macular degeneration using confocal scanning laser ophthalmoscopy (cSLO)
Authors: Deckert A , Schmitz-Valckenberg S , Jorzik J , Bindewald A , Holz FG , Mansmann U 
Published: April 2005

Abstract
Background
Fundus autofluorescence (AF) imaging using confocal scanning laser ophthalmoscopy (cSLO) provides an accurate delineation of areas of geographic atrophy (GA).
Automated computer-assisted methods for detecting and removing interfering vessels are needed to support the GA quantification process in longitudinal studies and in reading centres.

Methods
A test tool was implemented that uses region-growing techniques to segment GA areas. An algorithm for illuminating shadows can be used to process low-quality images. Agreement between observers and between three different methods was evaluated by two independent readers in a pilot study. Agreement and objectivity were assessed using the Bland-Altman approach.

Results
The new method (C) identifies vascular structures that interfere with the delineation of GA. Results are comparable to those of two commonly used procedures (A, B), with a mean difference between C and A of -0.67 mm2 (95% CI [-0.99, -0.36]), between B and A of -0.81 mm2, (95% CI [-1.08, -0.53]), and between C and B of 0.15 mm2 (95% CI [-0.12, 0.41]). Objectivity of a method is quantified by the mean difference between observers: A 0.30 mm2 (95% CI [0.02, 0.57]), B -0.11 mm2 (95% CI [-0.28, 0.10]), and C 0.12 mm2 (95% CI [0.02, 0.22]).

Conclusion
The novel procedure is comparable with regard to objectivity and inter-reader agreement to established methods of quantifying GA. It considerably speeds up the lengthy measurement process in AF with well defined GA zones.
Overexpression of β1-chain-containing laminins in capillary basement membranes of human breast cancer and its metastases
Authors: Fujita Manabu , Khazenzon Natalya M , Bose Shikha , Sekiguchi Kiyotoshi , Sasaki Takako , Carter William G , Ljubimov Alexander V , Black Keith L , Ljubimova Julia Y 
Published: April 2005

Abstract
Introduction
Laminins are the major components of vascular and parenchymal basement membranes. We previously documented a switch in the expression of vascular laminins containing the α4 chain from predominantly laminin-9 (α4β2γ1) to predominantly laminin-8 (α4β1γ1) during progression of human brain gliomas to high-grade glioblastoma multiforme. Here, differential expression of laminins was studied in blood vessels and ductal epithelium of the breast.

Method
In the present study the expressions of laminin isoforms α1–α5, β1–β3, γ1, and γ2 were examined during progression of breast cancer. Forty-five clinical samples of breast tissues including normal breast, ductal carcinomas in situ, invasive ductal carcinomas, and their metastases to the brain were compared using Western blot analysis and immunohistochemistry for various chains of laminin, in particular laminin-8 and laminin-9.

Results
Laminin α4 chain was observed in vascular basement membranes of most studied tissues, with the highest expression in metastases. At the same time, the expression of laminin β2 chain (a constituent of laminin-9) was mostly seen in normal breast and carcinomas in situ but not in invasive carcinomas or metastases. In contrast, laminin β1 chain (a constituent of laminin-8) was typically found in vessel walls of carcinomas and their metastases but not in those of normal breast. The expression of laminin-8 increased in a progression-dependent manner. A similar change was observed from laminin-11 (α5β2γ1) to laminin-10 (α5β1γ1) during breast tumor progression. Additionally, laminin-2 (α2β1γ1) appeared in vascular basement membranes of invasive carcinomas and metastases. Chains of laminin-5 (α3β3γ2) were expressed in the ductal epithelium basement membranes of the breast and diminished with tumor progression.

Conclusion
These results suggest that laminin-2, laminin-8, and laminin-10 are important components of tumor microvessels and may associate with breast tumor progression. Angiogenic switch from laminin-9 and laminin-11 to laminin-8 and laminin-10 first occurs in carcinomas in situ and becomes more pronounced with progression of carcinomas to the invasive stage. Similar to high-grade brain gliomas, the expression of laminin-8 (and laminin-10) in breast cancer tissue may be a predictive factor for tumor neovascularization and invasion.
A Branch-and-Price Algorithm and New Test Problems for Spectrum Auctions
Authors: Günlük Oktay , Ladányi Lászlo , de Vries Sven 
Published: April 2005

When combinatorial bidding is permitted in auctions, such as the proposed FCC Auction #31, the resulting full valuations and winner-determination problem can be computationally challenging. We present a branch-and-price algorithm based on a set-packing formulation originally proposed by Dietrich and Forrest (2002, “A column generation approach for combinatorial auctions,” in Mathematics of the Internet: E-Auction and Markets. The IMA Volumes in Mathematics and Its Applications, Vol. 127, Springer-Verlag, New York, 15–26). This formulation has a variable for every possible combination of winning bids for each bidder. Our algorithm exploits the structure of the XOR-of-OR bidding language used by the FCC. We also present a new methodology to produce realistic test problems based on the round-by-round results of FCC Auction #4. We generate 2,639 test problems, which involve 99 items and are substantially larger than most of the previously used benchmark problems. Because there are no real-life test problems for combinatorial spectrum auctions with the XOR-of-OR language, we used these test problems to observe the computational behavior of our algorithm. Our algorithm can solve all but one test problem within 10 minutes, appears to be very robust, and for difficult instances compares favorably to the natural formulation solved using a commercial optimization package with default settings. Although spectrum auctions are used as the guiding example to describe the merits of branch and price for combinatorial auctions, our approach applies to auctions of multiple goods in other scenarios similarly.
Positive vs. Negative Externalities in Inventory Management: Implications for Supply Chain Design
Authors: Netessine Serguei , Zhang Fuqiang 
Published: April 2005

In this paper we analyze the impact of supply-side externalities existing among downstream retailers on supply chain performance. Namely, multiple retail firms face stochastic demand, purchase the product from the upstream wholesaler, and make stocking decisions that affect all other retailers in the same echelon. Two sources of inefficiencies exist in such a supply chain: One is double marginalization and the other is externalities among retailers. Whereas double marginalization always leads to inventory understocking at the retail echelon, we find that the implications of externalities are more complex, because different externalities can improve or deteriorate supply chain performance, relative to the situation without externalities. We show that the effect of externalities depends critically on whether the stocking decisions of retailers exhibit positive (complementarity) or negative (substitutability) externalities, and whether retailers are managed centrally or competitively. Under complementarity, competing retailers tend to understock the product (compared with the centralized inventory management at the retail level), thus aggravating the double-marginalization effect. This is the opposite of what happens under substitutability, where competing retailers tend to overstock the product, thus compensating for the double-marginalization effect. Hence, we conclude that supply chain coordination between retailers and the wholesaler is most important when there is downstream competition that exhibits complementarity. From the wholesaler's point of view, competition among retailers is preferable over centralization of retailers when externalities are negative, and vice versa when externalities are positive. Moreover, with competition on complements, both retailers and the wholesaler have incentives to coordinate the supply chain.
On the Value of Mix Flexibility and Dual Sourcing in Unreliable Newsvendor Networks
Authors: Tomlin Brian , Wang Yimin 
Published: April 2005

We connect the mix-flexibility and dual-sourcing literatures by studying unreliable supply chains that produce multiple products. We consider a firm that can invest in product-dedicated resources and totally flexible resources. Product demands are uncertain at the time of resource investment, and the products can differ in their contribution margins. Resource investments can fail, and the firm may choose to invest in multiple resources for a given product to mitigate such failures. In comparing a single-source dedicated strategy with a single-source flexible strategy, we refine the common intuition that a flexible strategy is strictly preferred to a dedicated strategy when the dedicated resources are costlier than the flexible resource. We prove that this intuition is correct if the firm is risk neutral or if the resource investments are perfectly reliable. The intuition can be wrong, however, if both of these conditions fail to hold, because there is a resource-aggregation disadvantage to the flexible strategy that can dominate the demand pooling and contribution-margin benefits of the flexible strategy when resource investments are unreliable and the firm is risk averse. We investigate the influence that resource attributes, firm attributes, and product-portfolio attributes have on the attractiveness of various supply-chain structures that differ in their levels of mix flexibility and diversification, and we investigate the influence these attributes have on the optimal resource investments within a given supply-chain structure. Our results indicate that the appropriate levels of diversification and flexibility are very sensitive to the resource costs and reliabilities, the firm's downside risk tolerance, the number of products, the product demand correlations and the spread in product contribution margins.
Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment
Authors: van Santbrink Evert J P , Hohmann Femke P , Eijkemans Marinus J C , Laven Joop S E , Fauser Bart C J M 
Published: April 2005

Objective: To assess whether the addition of metformin to gonadotrophin ovulation induction in insulin-resistant, normogonadotrophic, anovulatory women alters ovarian responsiveness to exogenous FSH.
Design: Placebo-controlled double-blind assessment in an academic hospital.
Results: After a progestagen withdrawal bleeding, patients were randomised for either metformin (n = 11) or placebo (n = 9) treatment. In cases of absent ovulation, exogenous FSH was subsequently administered to induce ovulation. Only during metformin treatment did body mass index and androgen (androstenedione and testosterone) levels decrease, whereas FSH and LH levels increased significantly. In the metformin group, a single patient ovulated before the initiation of exogenous FSH. Significantly more monofollicular cycles and lower preovulatory oestradiol concentrations were observed in women receiving FSH with metformin compared with FSH alone.
Conclusions: Metformin co-treatment in a group of insulin-resistant, normogonadotrophic, anovulatory patients resulted in normalization of the endocrine profile and facilitated monofollicular development during the FSH induction of ovulation.
Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement
Authors: Maghnie Mohamad , Aimaretti Gianluca , Bellone Simonetta , Bona Gianni , Bellone Jaele , Baldelli Roberto , de Sanctis Carlo , Gargantini Luigi , Gastaldi Roberto , Ghizzoni Lucia , Secco Andrea , Tinelli Carmine , Ghigo Ezio 
Published: April 2005

Objective: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 μg/l based on a cohort of subjects with a mean age of 45 years.
Design and methods: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic–pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8±2.3 years, range 17–25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2±4.4 years, range 15.1–30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals.
Results: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8±2.0 μg/l, range 0.1–6.1 μg/l) compared with the 39 controls (18.5±15.5 μg/l, range 6.1–84.0 μg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 μg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 μg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of −1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I ≤ − 2.0 SDS showed a sensitivity of 62%.
Conclusion: Our data show that the cut-off value of the peak GH response to ITT of less than 3 μg/l or 5 μg/l and of IGF-I of less than −2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic–pituitary abnormalities.
The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5
Authors: Hofland Leo J , van der Hoek Joost , Feelders Richard , van Aken Maarten O , van Koetsveld Peter M , Waaijers Marlijn , Sprij-Mooij Diana , Bruns Christian , Weckbecker Gisbert , de Herder Wouter W , Beckers Albert , Lamberts Steven W J 
Published: April 2005

Objective: Currently, there is no effective medical treatment for patients with pituitary-dependent Cushing’s disease. A novel somatostatin (SS) analogue, named SOM230, with high binding affinity to SS receptor subtypes sst1, sst2, sst3 and sst5 was recently introduced. We compared the in vitro effects of the sst2-preferring SS analogue octreotide (OCT) and the multi-ligand SOM230 on ACTH release by human and mouse corticotroph tumour cells.
Methods: By quantitative RT-PCR the sst subtype expression level was determined in human corticotroph adenomas. In vitro, the inhibitory effect of OCT and SOM230 on ACTH release by dispersed human corticotroph adenoma cells and mouse AtT20 corticotroph adenoma cells was determined. In addition, the influence of dexamethasone on the responsiveness to OCT and SOM230 was studied.
Results: Corticotroph adenomas expressed predominantly sst5 mRNA (six out of six adenomas), whereas sst2 mRNA expression was detected at significantly lower levels. In a 72 h incubation with 10 nmol/l SOM230, ACTH release was inhibited in three out of five cultures (range −30 to −40%). Ten nmol/l OCT slightly inhibited ACTH release in only one of five cultures (− 28%). In AtT20 cells, expressing sst2, sst3 and sst5, SOM230 inhibited ACTH secretion with high potency (IC50 0.2 nmol/l). Dexamethasone (10 nmol/l) pre-treatment did not influence the sensitivity of the cells to the inhibitory effect of SOM230, suggesting that sst5 is relatively resistant to negative control by glucocorticoids.
Conclusions: The selective expression of sst5 receptors in corticotroph adenomas and the preferential inhibition of ACTH release by human corticotroph adenoma cells by SOM230 in vitro, suggest that SOM230 may have potential in the treatment of patients with pituitary-dependent Cushing’s disease.
The clinical, metabolic and endocrine features and the quality of life in adults with childhood-onset craniopharyngioma compared with adult-onset craniopharyngioma
Authors: Kendall-Taylor Pat , Jönsson Peter J , Abs Roger , Erfurth Eva Marie , Koltowska-Häggström Maria , Price David Anthony , Verhelst Johan 
Published: April 2005

Background: Craniopharyngioma is a parasellar tumour that, although benign, tends to behave aggressively. It can occur at any age but most commonly presents in childhood or adolescence.
Objectives: To investigate the frequency and severity of problems associated with craniopharyngioma, using the large international database (KIMS) for adult patients with GH deficiency (GHD), and to assess the differences between the adult onset (AO, aged 18 or above) disease and adults with childhood onset (CO) craniopharyngioma.
Design: Inclusion criteria were: an established diagnosis of craniopharyngioma, severe GHD and no recent GH treatment. These criteria were fulfilled by 393 (184 female, 209 male) patients; 241 had AO (mean age 28.7±8.7 years) and 152 had CO disease (age 42.0±12.3 years). Disease history, clinical features and anthropometric data were recorded at the time of enrolment in the database, and body composition, serum IGF-I, serum lipids and quality of life (QoL) were assessed.
Results: Peak age at onset of craniopharyngioma was 15–20 years. Ninety percent of patients had been treated surgically. CO patients were shorter than AO patients and had much lower IGF-I standard deviation scores (SDS). The majority had hypopituitarism and over 60% had diabetes insipidus. Body mass index (BMI) was higher in AO males (30.2±5.5) than in CO males (28.5±7.5); waist circumference was also greater. Obesity was more common in AO patients (51.8% vs 39.1%). Body composition did not differ between groups. Cholesterol and triglycerides were higher in AO than in CO patients, but high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol did not differ. Quality of life, assessed by Quality of Life-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) and the Nottingham Health Profile, was markedly reduced in all groups with no significant differences between them; the QoL-AGHDA score correlated with age at onset of both craniopharyngioma and GHD, and also with BMI in AO patients.
Conclusions: These data emphasise the generally poor state of health of patients treated for craniopharyngioma, with respect to endocrine and metabolic function, and also the markedly reduced quality of life. In addition to GHD, most patients have evidence of hypothalamic damage with associated obesity, diabetes insipidus and hypopituitarism. Adults with CO craniopharyngioma were shorter, had lower IGF-I, lower BMI, less obesity and slightly lower blood lipid levels than patients with AO craniopharyngioma.
Early manifestation of calcinosis cutis in pseudohypoparathyroidism type Ia associated with a novel mutation in the GNAS gene
Authors: Riepe Felix G , Ahrens Wiebke , Krone Nils , Fölster-Holst Regina , Brasch Jochen , Sippell Wolfgang G , Hiort Olaf , Partsch Carl-Joachim 
Published: April 2005

Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy.
Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright’s hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found.
Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gsα) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T > G in exon 5, leading to the amino acid substitution Ile-106 → Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient’s parents, both of whom showed normal Gsα protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely.
Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.