bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical strain applied to human fibroblasts differentially regulates skeletal myoblast differentiation
Authors: Hicks Michael R. , Cao Thanh V. , Campbell David H. , Standley Paul R.
Published: June 2012

Cyclic short-duration stretches (CSDS) such as those resulting from repetitive motion strain increase the risk of musculoskeletal injury. Myofascial release is a common technique used by clinicians that applies an acyclic long-duration stretch (ALDS) to muscle fascia to repair injury. When subjected to mechanical strain, fibroblasts within muscle fascia secrete IL-6, which has been shown to induce myoblast differentiation, essential for muscle repair. We hypothesize that fibroblasts subjected to ALDS following CSDS induce myoblast differentiation through IL-6. Fibroblast conditioned media and fibroblast-myoblast cocultures were used to test fibroblasts' ability to induce myoblast differentiation. The coculture system applies strain to fibroblasts only but still allows for diffusion of potential differentiation mediators to unstrained myoblasts on coverslips. To determine the role of IL-6, we utilized myoblast unicultures ± IL-6 (0–100 ng/ml) and cocultures ± α-IL-6 (0–200 μg/ml). Untreated uniculture myoblasts served as a negative control. After 96 h, coverslips ( n = 6–21) were microscopically analyzed and quantified by blinded observer for differentiation endpoints: myotubes per square millimeter (>3 nuclei/cell), nuclei/myotube, and fusion efficiency (%nuclei within myotubes). The presence of fibroblasts and fibroblast conditioned media significantly enhanced myotube number ( P < 0.05). However, in coculture, CSDS applied to fibroblasts did not reproduce this effect. ALDS following CSDS increased myotube number by 78% and fusion efficiency by 96% vs. CSDS alone ( P < 0.05). Fibroblasts in coculture increase IL-6 secretion; however, IL-6 secretion did not correlate with enhanced differentiation among strain groups. Exogenous IL-6 in myoblast uniculture failed to induce differentiation. However, α-IL-6 attenuated differentiation in all coculture groups ( P < 0.05). Fibroblasts secrete soluble mediators that have profound effects on several measures of myoblast differentiation. Specific biophysical strain patterns modify these outcomes, and suggest that myofascial release after repetitive strain increases myoblast differentiation and thus may improve muscle repair in vivo. Neutralization of IL-6 in coculture significantly reduced differentiation, suggesting fibroblast-IL-6 is necessary but not sufficient in this process.
Aerosol bolus dispersion in acinar airways—influence of gravity and airway asymmetry
Authors: Ma Baoshun , Darquenne Chantal
Published: June 2012

The aerosol bolus technique can be used to estimate the degree of convective mixing in the lung; however, contributions of different lung compartments to measured dispersion cannot be differentiated unambiguously. To estimate dispersion in the distal lung, we studied the effect of gravity and airway asymmetry on the dispersion of 1 μm-diameter particle boluses in three-dimensional computational models of the lung periphery, ranging from a single alveolar sac to four-generation (g4) structures of bifurcating airways that deformed homogeneously during breathing. Boluses were introduced at the beginning of a 2-s inhalation, immediately followed by a 3-s exhalation. Dispersion was estimated by the half-width of the exhaled bolus. Dispersion was significantly affected by the spatial orientation of the models in normal gravity and was less in zero gravity than in normal gravity. Dispersion was strongly correlated with model volume in both normal and zero gravity. Predicted pulmonary dispersion based on a symmetric g4 acinar model was 391 ml and 238 ml under normal and zero gravity, respectively. These results accounted for a significant amount of dispersion measured experimentally. In zero gravity, predicted dispersion in a highly asymmetric model accounted for ∼20% of that obtained in a symmetric model with comparable volume and number of alveolated branches, whereas normal gravity dispersions were comparable in both models. These results suggest that gravitational sedimentation and not geometrical asymmetry is the dominant factor in aerosol dispersion in the lung periphery.
Fuzzy Soft Multiset Theory
Authors: Alkhazaleh Shawkat , Salleh Abdul Razak
Published: June 2012

In 1999 Molodtsov introduced the concept of soft set theory as a general mathematical tool for dealing with uncertainty. Alkhazaleh et al. in 2011 introduced the definition of a soft multiset as a generalization of Molodtsov′s soft set. In this paper we give the definition of fuzzy soft multiset as a combination of soft multiset and fuzzy set and study its properties and operations. We give examples for these concepts. Basic properties of the operations are also given. An application of this theory in decision‐making problems is shown.
Stability-Indicating RP-TLC/Densitometry Determination of Raloxifene Hydrochloride in Bulk Material and in Tablets
Authors: Shirkhedkar A. A. , Rajput J. K. , Rajput D. K. , Surana S. J.
Published: June 2012

A stability-indicating RP-TLC/Densitometry method for analysis of Raloxifene hydrochloride both in bulk material and in tablets was developed and validated. Densitometric analysis of Raloxifene hydrochloride was carried out at 311 nm on TLC aluminium plates precoated with silica gel 60RP-18 F254S as the stationary phase and methanol : water : ammonia (95 : 05 : 0.1 v/v) as mobile phase. Raloxifene hydrochloride was well resolved at Rf 0.55 ± 0.02. The linear regression analysis data for the calibration plots showed good linear relationship with r2=0.9969±0.0015 with respect to peak area in the concentration range 100–600 ng per band. The mean value ± SD of slope and intercept was found to be 15.05±0.44 and 201.9±29.58 with respect to peak area. The limits of detection and quantification were 9.27 ng and 27.10 ng, respectively. Raloxifene hydrochloride was subjected to acid and alkali hydrolysis, oxidation, dry heat, and photodegradation. The drug underwent degradation under basic and oxidation conditions. This indicates that the drug is susceptible to alkali hydrolysis and oxidation. The proposed developed RP-TLC/Densitometry method can be applied for identification and quantitative determination of Raloxifene hydrochloride in bulk material and tablets.
Integrating Decision Support and Social Networks
Authors: Antunes Francisco , Costa João Paulo
Published: June 2012

We elaborate on the shifting of decision support systems towards social networking, which is based on the concepts of Web 2.0 and Semantic Web technology. As the characteristics of the relevant components are different from traditional decision support systems, we present necessary adaptations when adopting social networks for decision support within an organization. We also present organizational obstacles when adopting/using such systems and clues to overcome them.
Novel Anti-Melanoma Immunotherapies: Disarming Tumor Escape Mechanisms
Authors: Sapoznik Sivan , Hammer Ohad , Ortenberg Rona , Besser Michal J. , Ben-Moshe Tehila , Schachter Jacob , Markel Gal
Published: June 2012

The immune system fights cancer and sometimes temporarily eliminates it or reaches an equilibrium stage of tumor growth. However, continuous immunological pressure also selects poorly immunogenic tumor variants that eventually escape the immune control system. Here, we focus on metastatic melanoma, a highly immunogenic tumor, and on anti-melanoma immunotherapies, which recently, especially following the FDA approval of Ipilimumab, gained interest from drug development companies. We describe new immunomodulatory approaches currently in the development pipeline, focus on the novel CEACAM1 immune checkpoint, and compare its potential to the extensively described targets, CTLA4 and PD1. This paper combines multi-disciplinary approaches and describes anti-melanoma immunotherapies from molecular, medical, and business angles.
Markers of the APC/β-Catenin Signaling Pathway as Potential Treatable, Preneoplastic Biomarkers of Risk for Colorectal Neoplasms
Authors: Ahearn Thomas U. , Shaukat Aasma , Flanders W. Dana , Seabrook March E. , Bostick Roberd M.
Published: June 2012

Background: Malfunctioning of the adenomatous polyposis coli (APC)/β-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/β-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case–control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma.

Methods: We evaluated APC, β-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires.

Results: In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total β-catenin expression (APC/β-catenin score) was 14.3% greater in controls than in cases [P = 0.02; OR, 0.40; 95% confidence interval (CI), 0.14–1.14]. Compared with controls, in cases, APC expression was 3.2% lower, β-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/β-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D3 concentrations ≥ 27 ng/mL].

Conclusions: These preliminary data suggest that the combined expression of APC and β-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms.

Impact: Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 21(6); 969–79. ©2012 AACR.
MEDI0639: A Novel Therapeutic Antibody Targeting Dll4 Modulates Endothelial Cell Function and Angiogenesis In Vivo
Authors: Jenkins David W. , Ross Sarah , Veldman-Jones Margaret , Foltz Ian N. , Clavette Brandon C. , Manchulenko Kathy , Eberlein Cath , Kendrew Jane , Petteruti Philip , Cho Song , Damschroder Melissa , Peng Li , Baker Dawn , Smith Neil R. , Weir Hazel M. , Blakey David C. , Bedian Vahe , Barry Simon T.
Published: June 2012

The Notch signaling pathway has been implicated in cell fate determination and differentiation in many tissues. Accumulating evidence points toward a pivotal role in blood vessel formation, and the importance of the Delta-like ligand (Dll) 4-Notch1 ligand–receptor interaction has been shown in both physiological and tumor angiogenesis. Disruption of this interaction leads to a reduction in tumor growth as a result of an increase in nonfunctional vasculature leading to poor perfusion of the tumor. MEDI0639 is an investigational human therapeutic antibody that targets Dll4 to inhibit the interaction between Dll4 and Notch1. The antibody cross-reacts to cynomolgus monkey but not mouse species orthologues. In vitro MEDI0639 inhibits the binding of Notch1 to Dll4, interacting via a novel epitope that has not been previously described. Binding to this epitope translates into MEDI0639 reversing Notch1-mediated suppression of human umbilical vein endothelial cell growth in vitro. MEDI0639 administration resulted in stimulation of tubule formation in a three-dimensional (3D) endothelial cell outgrowth assay, a phenotype driven by disruption of the Dll4-Notch signaling axis. In contrast, in a two-dimensional endothelial cell–fibroblast coculture model, MEDI0639 is a potent inhibitor of tubule formation. In vivo, MEDI0639 shows activity in a human endothelial cell angiogenesis assay promoting human vessel formation and reducing the number of vessels with smooth muscle actin-positive mural cells coverage. Collectively, the data show that MEDI0639 is a potent modulator of Dll4-Notch signaling pathway. Mol Cancer Ther; 11(8); 1650–60. ©2012 AACR.
GSK-3 Promotes Cell Survival, Growth, and PAX3 Levels in Human Melanoma Cells
Authors: Kubic Jennifer D. , Mascarenhas Joseph B. , Iizuka Takumi , Wolfgeher Don , Lang Deborah
Published: June 2012

GSK-3 is a serine/threonine kinase involved in a diverse range of cellular processes. GSK-3 exists in two isoforms, GSK-3α and GSK-3β, which possess some functional redundancy but also play distinct roles depending on developmental and cellular context. In this article, we found that GSK-3 actively promoted cell growth and survival in melanoma cells, and blocking this activity with small-molecule inhibitor SB216763 or gene-specific siRNA decreased proliferation, increased apoptosis, and altered cellular morphology. These alterations coincided with loss of PAX3, a transcription factor implicated in proliferation, survival, and migration of developing melanoblasts. We further found that PAX3 directly interacted with and was phosphorylated in vitro on a number of residues by GSK-3β. In melanoma cells, direct inhibition of PAX3 lead to cellular changes that paralleled the response to GSK-3 inhibition. Maintenance of PAX3 expression protected melanoma cells from the anti-tumor effects of SB216763. These data support a model wherein GSK-3 regulates proliferation and morphology of melanoma through phosphorylation and increased levels of PAX3. Mol Cancer Res; 10(8); 1065–76. ©2012 AACR.
A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas
Authors: Cheng Yingduan , Liang Pei , Geng Hua , Wang Zhaohui , Li Lili , Cheng Suk Hang , Ying Jianming , Su Xianwei , Ng Ka Man , Ng Margaret H.L. , Mok Tony S.K. , Chan Anthony T.C. , Tao Qian
Published: June 2012

Epigenetic disruption of tumor suppressor genes is frequently involved in tumorigenesis. We identified a novel 19q13 KRAB domain-containing zinc finger protein, ZNF545/ZFP82, broadly expressed in normal tissues but downregulated in multiple tumor cell lines. The ZNF545 promoter contains a CpG island, which is frequently methylated in cell lines. The transcriptional silencing of ZNF545 could be reversed by pharmacologic or genetic demethylation, indicating direct epigenetic silencing. ZNF545 was also frequently methylated in multiple primary tumors of nasopharyngeal, esophageal, lung, gastric, colon, and breast, but rarely in normal epithelial tissues and paired normal tissues. ZNF545 is located in the nucleus and mainly sequestered in nucleoli, functioning as a repressor. ZNF545 is able to repress NF-κB and AP-1 signaling pathways, whereas ectopic expression of ZNF545 in silenced tumor cells significantly inhibited their growth and induced apoptosis. Functional studies showed that ZNF545 was involved in ribosome biogenesis through inhibiting the activity of rDNA promoter and decreasing cellular protein translation efficiency. Thus, we identified ZNF545 as a novel tumor suppressor inducing tumor cell apoptosis, repressing ribosome biogenesis and target gene transcription. The tumor-specific methylation of ZNF545 could be an epigenetic biomarker for cancer diagnosis. Mol Cancer Res; 10(7); 925–36. ©2012 AACR.
Dietary Methyl Donor Depletion Protects Against Intestinal Tumorigenesis in Apc
Min/+ Mice
Authors: Kadaveru Krishna , Protiva Petr , Greenspan Emily J. , Kim Young-In , Rosenberg Daniel W.
Published: June 2012

Despite recent population data, the influence of dietary folate supplementation on colon cancer risk remains controversial. This study examines the effects of folate deficiency, in combination with choline, methionine, and vitamin B12 depletion, on intestinal tumorigenesis in ApcMin/+ mice. Methyl donor sufficient (MDS) and deficient (MDD) diets were started at five or 10 weeks of age and tumors evaluated at 16 weeks. MDD suppressed intestinal tumor formation in ApcMin/+ mice (∼80%) when started at five weeks of age. The protective effect was lost when MDD was initiated at 10 weeks of age, indicating an important time dependency on cancer suppression. Concomitant with cancer protection, MDD restricted body weight gain. Therefore, a second study was conducted in which MDS was given ad libitum or pair-fed with MDD. Although small intestinal tumors were reduced 54% in pair-fed MDS mice, MDD caused a further reduction (96%). In colon, although MDD did not affect tumor numbers, tumor size was reduced. Gene expression profiling of normal-appearing colonic mucosa after 11 weeks on MDD identified a total of 493 significantly downregulated genes relative to the MDS group. Pathway analysis placed many of these genes within general categories of inflammatory signaling and cell-cycle regulation, consistent with recently published human data obtained during folate depletion. Further studies are warranted to investigate the complex interplay of methyl donor status and cancer protection in high-risk populations. Cancer Prev Res; 5(7); 911–20. ©2012 AACR.
Apples to Origins: Identifying Brain Tumor Stem Cell Genes by Comparing Transcriptomes of Normal and Cancer Stem Cells
Authors: Wortham Matthew , Yan Hai
Published: June 2012

The mechanisms whereby medulloblastoma stem cells coordinate tumor propagation are poorly understood. Using microarray analysis, Corno and colleagues draw parallels and distinctions between medulloblastoma stem cells from the Ptch+/− mouse and normal neural stem cells, identifying Ebf3 as a cancer stem cell–specific transcript critical for tumor growth. Cancer Discov; 2(6); 492–4. ©2012 AACR.

Commentary on Corno et al., p. 554.
Impaired Bone Formation with a High-Protein Diet in Rats with Adriamycin-Induced Nephrotic Syndrome
Authors: Lim A Young , Kim Su Yeon , Lee In Seok , Choue Ryowon
Published: June 2012

Background/Aim: The purpose of the study was to investigate the effects of a high-protein (HP) diet on bone metabolism in rats with adriamycin (ADR)-induced nephrotic syndrome. Methods: Nephrotic syndrome was established by weekly injections of ADR (2 mg/kg, i.p.) for 6 weeks. After a final injection, we confirmed that nephrotic syndrome had developed. Then, the rats were divided into two groups for the dietary treatments, namely the HP diet (30% of calories from protein) and the low-protein (LP) diet (7% of calories from protein), and were fed an isocaloric diet for the following 5 weeks. Results: Urinary protein and phosphate excretion were significantly greater in the HP diet group than in the LP diet group (p < 0.05). Serum parathyroid hormone and osteocalcin levels were significantly higher and lower, respectively, in the HP diet group (p < 0.05). Femur weight, femur mass index and femur calcium contents were significantly lower in the HP diet group than in the LP diet group (p < 0.05). Bone mineral density was significantly lower in the HP diet group than in the LP diet group (p < 0.05); however, bone mineral content did not differ between the two groups. Conclusion: We confirmed that an HP diet negatively affects bone mineral metabolism and bone density in ADR-induced nephrotic syndrome rats.
Caspase-3-Independent Internucleosomal DNA Fragmentation in Ischemic Acute Kidney Injury
Authors: Yoshida Taiko , Shimizu Akira , Masuda Yukinari , Mii Akiko , Fujita Emiko , Yoshizaki Kaoru , Higo Seiichiro , Kanzaki Go , Kajimoto Yusuke , Takano Hideki , Fukuda Yuh
Published: June 2012

Background/Aims: Renal tubular cell death in ischemia-reperfusion does not follow the classical apoptosis or necrosis phenotype. We characterized the morphological and biochemical features of injured tubular epithelial cells in ischemic acute kidney injury (AKI). Methods: Ischemic AKI was induced in rats by 60 min of ischemia followed by 24 h of reperfusion. Light and electron microscopic TUNEL (LM-TUNEL and EM-TUNEL), gel electrophoresis of extracted DNA, and caspase-3 involvement were examined during the development of death. Results: Damaged tubular epithelial cells with condensed and LM-TUNEL-positive (+) nuclei were prominent at 12 and 18 h after reperfusion with DNA ‘ladder’ pattern on gel electrophoresis. EM-TUNEL+ cells were characterized by nuclei with condensed and clumping chromatin, whereas the cytoplasm showed irreversible necrosis. The protein levels and activity of caspase-3 did not increase in kidneys after reperfusion. In addition, caspase inhibitor (ZVAD-fmk) failed to inhibit DNA fragmentation and prevent tubular epithelial cell death in ischemic AKI. Conclusion: Caspase-3-independent internucleosomal DNA fragmentation occurs in injured tubular epithelial cells undergoing irreversible necrosis in ischemic AKI. The manner of this cell death may be identical to the cell death termed apoptotic necrosis, aponecrosis, or necrapoptosis. Ischemia-reperfusion injury activates caspase-3-independent endonuclease, which in turn induces irreversible damage of tubular epithelial cells, and may contribute to the initiation and development of AKI.
Expression of the Sodium/Calcium/Potassium Exchanger, NCKX4, in Ameloblasts
Authors: Hu Ping , Lacruz Rodrigo S. , Smith Charles E. , Smith Susan M. , Kurtz Ira , Paine Michael L.
Published: June 2012

Transcellular calcium transport is an essential activity in mineralized tissue formation, including dental hard tissues. In many organ systems, this activity is regulated by membrane-bound sodium/calcium (Na+/Ca2+) exchangers, which include the NCX and NCKX [sodium/calcium-potassium (Na+/Ca2+-K+) exchanger] proteins. During enamel maturation, when crystals expand in thickness, Ca2+ requirements vastly increase but exactly how Ca2+ traffics through ameloblasts remains uncertain. Previous studies have shown that several NCX proteins are expressed in ameloblasts, although no significant shifts in expression were observed during maturation which pointed to the possible identification of other Ca2+ membrane transporters. NCKX proteins are encoded by members of the solute carrier gene family, Slc24a, which include 6 different proteins (NCKX1–6). NCKX are bidirectional electrogenic transporters regulating Ca2+ transport in and out of cells dependent on the transmembrane ion gradient. In this study we show that all NCKX mRNAs are expressed in dental tissues. Real-time PCR indicates that of all the members of the NCKX group, NCKX4 is the most highly expressed gene transcript during the late stages of amelogenesis. In situ hybridization and immunolocalization analyses clearly establish that in the enamel organ, NCKX4 is expressed primarily by ameloblasts during the maturation stage. Further, during the mid-late maturation stages of amelogenesis, the expression of NCKX4 in ameloblasts is most prominent at the apical poles and at the lateral membranes proximal to the apical ends. These data suggest that NCKX4 might be an important regulator of Ca2+ transport during amelogenesis.
Corpus Callosum Atrophy – A Simple Predictor of Multiple Sclerosis Progression: A Longitudinal 9-Year Study
Authors: Vaneckova M. , Kalincik T. , Krasensky J. , Horakova D. , Havrdova E. , Hrebikova T. , Seidl Z.
Published: June 2012

Aim: To determine whether corpus callosum atrophy predicts future clinical deterioration in multiple sclerosis. Methods: In 39 multiple sclerosis patients the area of corpus callosum in the sagittal plane, T2 and T1 lesion volumes, brain parenchymal fraction and brain atrophy were determined at baseline and 1 year after treatment initiation. Non-parametric and multiple regression models were built to identify the most reliable predictors of disability and of its changes over 9 years. Results: Corpus callosum atrophy during the first year of treatment was the best predictor of disability (r = –0.56) and of its increase at 9 years (r = 0.65). Corpus callosum atrophy of at least 2% predicted increase in disability with 93% sensitivity and 73% specificity (odds ratio = 35). Conclusion: Corpus callosum atrophy is a simple and accurate predictor of future disability accumulation and is feasible for routine clinical practice.
Mortality Statistics for Multiple Sclerosis and Amyotrophic Lateral Sclerosis in Sweden
Authors: Boström Inger , Riise Trond , Landtblom Anne-Marie
Published: June 2012

Background: Multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are chronic neurologic diseases for which distinct explanations of the pathogenesis are lacking. Two large Swedish register studies have rather unexpectedly detected a correlation between MS and ALS. The aim of this study was to investigate if an association between ALS and MS could be demonstrated as has been shown earlier. Material and Methods: Data on mortality from ALS and MS, 1990–2010, were collected from the Swedish National Statistics Office. In all there were 5,696 deaths due to ALS and 3,941 deaths due to MS. Age- and sex-adjusted mortality rates were calculated. Results: There was no correlation between the mortality rates of ALS and MS in the 21 counties of Sweden for the period 1990–2010 (Spearman’s rho = –0.052; p = 0.822; n = 21). The national mean mortality rate for ALS throughout the period of 1990–2010 was 2.98 per 100,000 person-years (95% CI 2.87–3.08). For MS the national mean mortality rate was 2.04 per 100,000 person-years (95% CI 1.95–2.12). Conclusion: This study did not confirm the previously shown association between MS and ALS in Sweden.
Effect of Postnatal Intermittent Hypoxia on Growth and Cardiovascular Regulation of Rat Pups
Authors: Pozo M.E. , Cave A. , Köroğlu Ö.A. , Litvin D.G. , Martin R.J. , Di Fiore J. , Kc P.
Published: June 2012

Background: Intermittent hypoxic episodes are common among preterm infants, although longer term consequences on growth pattern and cardiovascular regulation are unclear. Furthermore, the effects of intermittent hypoxia (IH) may depend on the pattern of hypoxia-reoxygenation. Objectives: We tested the hypothesis that a clustered versus dispersed pattern of repetitive IH during early postnatal life would induce differential long-term alteration in growth and cardiovascular regulation. Methods: Sprague-Dawley rat pups were exposed to room air or to one of two patterns of IH (clustered vs. dispersed) from 1 to 7 days of life. Body weight was measured daily for the first 8 days and weekly from weeks 2 to 8. Blood pressure (BP) and heart rate were measured weekly from weeks 4 to 8 using a noninvasive tail-cuff method for awake, nonanesthetized animals. Results: Exposure to both patterns of repetitive IH induced early growth restriction followed by later catch-up of growth to controls 3 weeks after completion of IH exposures. IH-exposed rats exhibited a sustained decrease in heart rate regardless of the hypoxic exposure paradigm employed. In contrast, a differential response was seen for arterial pressure; the clustered paradigm was associated with a significantly lower BP versus controls, while the pups exposed to the dispersed paradigm showed no effect on BP. Conclusion: We speculate that repetitive IH during a critical developmental window and regardless of IH exposure paradigm contributes to prolonged changes in sympathovagal balance of cardiovascular regulation.
Cardiovascular Comorbidities for Prediction of Progression-Free Survival in Patients with Metastatic Renal Cell Carcinoma Treated with Sorafenib
Authors: Szmit Sebastian , Zaborowska Magdalena , Waśko-Grabowska Anna , Żołnierek Jakub , Nurzyński Paweł , Filipiak Krzysztof J. , Opolski Grzegorz , Szczylik Cezary
Published: June 2012

Background/Aims: The purpose of the present study was to determine the relationship between iatrogenic arterial hypertension or baseline cardiovascular comorbidities and outcomes in metastatic renal cell cancer (mRCC) patients treated with sorafenib. Methods: The study included 148 mRCC patients treated with sorafenib, 63 patients (43%) had preexisting hypertension, 18 patients (12%) coronary artery disease, and 15 patients (10%) mild heart failure. Resting blood pressure (BP) was monitored by clinic and home measurements. Sorafenib-induced hypertension was defined as systolic BP ≥140 and/or diastolic BP ≥90 mm Hg during the first month of treatment. Results: Preexisting cardiovascular comorbidities were not associated with worsening prognosis of patients with mRCC treated with sorafenib. During the first month of treatment, sorafenib-induced hypertension was diagnosed in 76 patients (51.4%), and these patients had a significantly longer PFS (p < 0.00001) and a significantly lower overall mortality risk (p = 0.038). Patients with preexisting and sorafenib-induced hypertension had the longest PFS (p < 0.00001). Conclusions: Sorafenib-induced hypertension is a positive predictive factor in mRCC patients treated with sorafenib, especially in patients with a history of hypertension.
Quality Control throughout the Production Process of Infant Food
Authors: Hamrin Pia , Hoeft Birgit
Published: June 2012

The manufacture of infant food is a highly complex process and needs an effective quality control beyond classical in-process parameters and a final microbiological analysis. To ensure a safe end -product, various tools, such as the Hazard Analysis Critical Control Points (HACCP), have been developed to facilitate the management of food safety. Every single infant formula ingredient must have an excellent quality and safety approach because even if an ingredient is used in very small quantities in a single product, serious consequences may arise if the quality and product safety are not taken seriously by the ingredient manufacturer. The purpose of this article was twofold: firstly, to briefly describe existing Quality Management Systems and, secondly, to highlight the consequences of non-quality.
Non-Breast Milk Feeding in Developing Countries: Challenge from Microbial and Chemical Contaminants
Authors: Weisstaub Gerardo , Uauy Ricardo
Published: June 2012

Complementary foods based on cow’s milk or gruels consumed by children in developing countries are often contaminated by bacteria during preparation, and ambient temperature rapidly increases microbial load. Thus infant formula or other weaning foods may cause diarrhea in young infants accounting for 25–33% of all deaths <5 years globally. Environmental chemicals such as metals (As, Pb, Cu) and nitrates can cause vomiting/diarrea. Polychlorinated biphenyls derived from plastics, present in formula and/or breast milk, are endocrine disruptors (the potential threats are not fully quantifiable). The prevailing view is that benefits from breastfeeding outweigh potential risks.
Safety Standards in Infant Nutrition: A United States Perspective
Authors: Bier Dennis M.
Published: June 2012

In the United States, the general standard for food safety is reasonable certainty of causing no harm under the intended conditions of use. In contrast to food safety policy in some other countries, the United States treats foods for infants and children no differently than foods for adults, other than requiring additional standards for infant formulas. In the United States, food safety falls under the regulatory control of more than a dozen government agencies. The principal responsibility is shared by the US Food and Drug Administration (FDA) and the US Department of Agriculture (USDA), but significant additional oversight authority is granted to the Environmental Protection Agency (EPA), the Centers for Disease Control and Prevention (CDC), and others. Furthermore, while a large number of legislative statutes provide the basis for regulatory oversight, the principal laws that govern food safety are the Federal Food, Drug and Cosmetic Act, the Federal Meat, Poultry Products and Egg Products Inspection Acts, and the Food Safety Modernization Act. The latter statute, enacted in 2011, has provided for a broad range of new industry responsibilities for the safe manufacture of food products and has significantly expanded federal enforcement authority for violations.
Pulmonary Manifestation of Novel Swine-Origin Influenza A (H1N1) Virus (S-OIV) Infection in Immunocompromised Patients: Initial Findings with Multidetector Computed Tomography
Authors: Laqmani A. , Adam G. , Regier M.
Published: June 2012

Objective: To describe initial multidetector computed tomographic (MDCT) findings of novel swine-origin influenza A (H1N1) virus (S-OIV) infection in immunocompromised patients and to evaluate whether or not identification of certain abnormalities can help predict patients who are at risk for a severe clinical course. Subjects and Methods: This retrospective study included 13 patients with confirmed S-OIV infection suffering from an underlying immunodeficiency or who were receiving immunosuppressive therapy. All patients underwent MDCT of the thorax due to respiratory distress. All data were read by two independent radiologists who described the type and pattern of opacities, distribution and extent of the abnormalities observed. Adverse outcome measures were defined as acute respiratory distress syndrome with the need for mechanical ventilation, extracorporeal membrane oxygenation or death. Results: MDCT revealed pulmonary manifestations in 12 (92%) of 13 individuals. Six (50%) patients showed an adverse outcome with development of acute respiratory distress syndrome, 4 of these died. The most common findings were ground-glass opacities (10/12; 83%) and pulmonary consolidation (7/12; 58%) predominantly with a bilateral distribution. Reticular pattern and a tree-in-bud appearance were found in 3/12 (25%), respectively. Bilateral opacities with extensive involvement of the lung parenchyma were most predictive of a severe clinical course. Conclusion: The MDCT scan in immunocompromised patients with confirmed S-OIV infection frequently revealed pulmonary abnormalities, which included ground-glass opacities and consolidations. Therefore, prediction of an adverse clinical outcome could be made in patients with MDCT findings demonstrating bilateral extensive consolidations, often combined with ground-glass opacities.
Testicular Tumor Ultrasound Characteristics and Association with Histopathology
Authors: McDonald Michael W. , Reed Amanda B. , Tran Peter T. , Evans L. Andrew
Published: June 2012

Introduction: This study was undertaken to develop knowledge of ultrasound characteristics of germ cell testicular neoplasms, associate these characteristics with histopathologic tumor types, and lay a foundation for study of ultrasound findings in benign versus malignant testicular lesions. Materials and Methods: The medical records and ultrasound images of 107 patients with testicular tumor were reviewed. Demographic and clinical characteristics and ultrasound findings of patients with seminoma were compared to those of patients with non-seminoma. Results: 55 patients had seminoma (1 bilateral) and 52 non-seminoma. Ultrasound images of seminoma were more often hypoechoic, homogeneous, and lobulated than those of non-seminoma (p < 0.001). Images of non-seminoma were more often heterogeneous and cystic (p < 0.001). There was no difference in tumor size, multiplicity, presence of calcium or lesion margination. Testicular microlithiasis was more common in seminoma (p < 0.02). Conclusion: Careful analysis of ultrasound images can permit an educated assessment of testicular tumor histopathology.
Vitamin E as a Functional and Biocompatibility Modifier of Synthetic Hemodialyzer Membranes: An Overview of the Literature on Vitamin E-Modified Hemodialyzer Membranes
Authors: Piroddi Marta , Pilolli Francesca , Aritomi Masaharu , Galli Francesco
Published: June 2012

Along with one century of history, research has provided many solutions for hemodialysis (HD) biomaterials, encompassing several generations of copolymers that have found wide application in the development of hollow-fiber dialyzer membranes. Polysulfone-based biomaterials have gained increasing consideration and are now the gold standard in the production of biocompatible hemodialyzers. However, even the highest biocompatibility now available cannot exclude that dialyzer membranes and the overall extracorporeal circulation may produce at the subclinical level immunoinflammatory reactions and thus an increased cardiovascular risk of patients on regular HD therapy. The lipophilic antioxidant and radical scavenger vitamin E has been used (as α-tocopherol) to modify cellulosic and synthetic hollow-fiber membranes with the ultimate goal to neutralize harmful reactive species and to mimic lipid structures of blood cell plasmalemma and lipoprotein particles. Besides filtration and biocompatibility, this modifier has introduced a third function of dialyzer membranes, namely ‘antioxidant bioactivity’. Vitamin E can also serve as a template molecule to produce synthetic redox-active and -silent (non-antioxidant) modifiers for future generations of dialyzer membranes. This mini-review article describes the evolution of vitamin E-derived copolymers as a generation of biomaterials that has offered a clinical challenge and still represents a chance to further improving the quality of HD therapy.
A Two-Step Hanging Maneuver for a Complete Resection of Couinaud’s Segment I
Authors: Uchiyama Hideaki , Itoh Shinji , Higashi Takahiro , Korenaga Daisuke , Takenaka Kenji
Published: June 2012

Background: A hepatic resection of Couinaud’s segment I is a challenging procedure because it is located deep in the abdominal cavity and surrounded by large blood vessels. A new technique, called the ‘two-step hanging maneuver,’ was applied to completely resect Couinaud’s segment I. Methods: A 59-year-old male was diagnosed with hepatocellular carcinoma in Couinaud’s segment I. A hanging tape was positioned from the groove between the middle and left hepatic veins to the groove between the right and left Glisson sheaths via the posterior hepatic surface after all short hepatic veins were divided. The liver was split into the left and right hemilivers (step 1). The hanging tape was positioned into the fissure of the ligamentum venosus, then Couinaud’s segment I was completely resected after dividing the liver parenchyma between segments I and IV by hanging the tape medially (step 2). Results: The operation time was 435 min. No blood transfusions were necessary and there were no complications. Conclusion: This technique allowed resection of a tumor located in Couinaud’s segment I without mobilization of the tumor and safely divided the liver parenchyma via only an anterior approach.
Solid-State and Submerged Fermentations Show Different Gene Expression Profiles in Cephalosporin C Production by Acremonium chrysogenum
Authors: López-Calleja A.C. , Cuadra T. , Barrios-González J. , Fierro F. , Fernández F.J.
Published: June 2012

Despite the importance of Acremonium chrysogenum as the only cephalosporin C (CPC) producer, there is still a limited understanding about the molecular mechanisms regulating antibiotic biosynthesis in this fungus. Based on the previously described relationship between environmental pH and antibiotic production in numerous filamentous fungi, we studied the expression of genes related to CPC production in A. chrysogenum. We report for the first time similarities and differences, characterizing CPC production by A. chrysogenum under a variable pH environment, in submerged and solid-state fermentation. This characterization is supported by measurements of parameters, like CPC production, pH, growth, and expression levels of several genes involved, directly or indirectly, in CPC production. Interesting differences in intermediate (Pen N) and certain biosynthetic gene expression levels were observed. Our results point out some relationships between physiological features and gene expression that open important improvement perspectives for both culture systems.
Amphotericin B-Induced in vitro Postantifungal Effect on Candida Species of Oral Origin
Authors: Ellepola A.N.B.
Published: June 2012

Objective: The aim of this investigation was to measure the postantifungal effect (PAFE) of 6 different oral Candida species following exposure to amphotericin B. Materials and Methods: Five oral isolates each of Candida albicans, Candida tropicalis, Candida krusei, Candida parapsilosis, Candida glabrata and Candida guilliermondii (total of 30 isolates) were examined for the presence of PAFE after 1 h of exposure to the minimum inhibitory concentration of amphotericin B. The PAFE was determined as the difference in time (hours) required for the growth of the drug-free control and the drug-exposed test cultures to increase to 0.05 absorbance level following removal of amphotericin B. Results: The mean duration of amphotericin B-induced PAFE was lowest for C. albicans (5.91 ± 0.31 h) and greatest for C. parapsilosis (12.72 ± 0.11 h), while C. guilliermondii (8.32 ± 0.33 h), C. glabrata (8.43± 0.21 h), C. krusei (9.68 ± 0.23 h) and C. tropicalis (10.98 ± 0.18 h) elicited intermediate values. Conclusion: Even a limited exposure to sublethal concentrations of amphotericin B suppressed growth of Candida species of oral origin. The significant variation in amphotericin B-induced PAFE amongst different Candida species may have clinical implications in terms of amphotericin B regimens used in the management of oral candidiasis.
Rasburicase for Huge Hepatocellular Carcinoma with Tumor Lysis Syndrome: Case Report
Authors: Chao Chia-Ter , Chiang Chih-Kang
Published: June 2012

Objective: To report a case of huge hepatocellular carcinoma associated with tumor lysis syndrome and its management. Clinical Presentation and Intervention: A 51-year-old hepatitis B carrier visited our clinic with progressive weight loss over recent months. Abdominal ultrasonography and magnetic resonance imaging revealed a huge hepatic mass in a cirrhotic liver, identified as hepatocellular carcinoma. A hepatologist and surgeon recommended transarterial chemoembolization followed by hepatectomy. The patient underwent the procedure, with the complication of tumor lysis syndrome. He was treated with a single high dose (9 mg) of rasburicase and his clinical condition improved dramatically, with acute kidney injury subsiding without emergent hemodialysis. Conclusions: This was a case of hepatocellular carcinoma with tumor lysis syndrome and acute kidney injury, treated successfully with rasburicase.
Retro-Orbital Metastasis from Differentiated Thyroid Carcinoma in a Radioiodine Therapy-Naïve Patient: Any Lesson Learned?
Authors: Okere P.C.N. , Tushar M.
Published: June 2012

Objective: To present the case of a radioiodine therapy-naïve thyroid cancer patient with postthyroidectomy diplopia. Clinical Presentation and Intervention: A 63-year-old male patient presented with goiter. Histology performed after thyroidectomy proved follicular thyroid cancer. Without 131I therapy, diplopia occurred from metastasis to the right medial rectus muscle. Improvement followed after one therapy dose of 131I. Conclusion: Postoperative radioiodine was important in managing this patient with differentiated thyroid cancer. This case showed that retro-orbital metastasis should be considered as a differential diagnosis in a patient with thyroid cancer who presents with unilateral diplopia.
Ossification of Ligamentum Flavum in Middle East Arabs: A Hospital-Based Study
Authors: Al-Jarallah Khaled , Al-Saeed Osama , Shehab Diaa , Dashti Khaledah , Sheikh Mehraj
Published: June 2012

Objective: To investigate the frequency of ossification of the ligamentum flavum (OLF) in the spine among the Arab population in Kuwait using magnetic resonance imaging (MRI) surveillance of the whole spine. Subjects and Methods: A consecutive series of 102 patients with low back pain were recruited from the outpatient clinic of Mubarak Al-Kabeer Hospital, Kuwait. MRI of the whole spine in the sagittal plane was obtained in at least two sequences (T1 and T2). The OLF was defined as low signal intensity thickening of the ligament in both T1 and T2 sequences on the posterior margin of the spinal canal, causing indentation of the theca with or without cord compression. Results: Of the 102 cases, 19 (18.6%) patients had OLF. Of the 19 positive cases, 12 (63.2%) were present at a single level, and 7 (36.8%) at multiple levels. A total of 26 OLF segments were identified in the following anatomical distribution: cervical: 15 (57.7%); upper thoracic (T1–T4): 1 (3.8%); mid thoracic (T5–T8): 4 (15.4%); lower thoracic (T9–T12): 4 (15.4%), and lumbar region: 2 (7.7%). Of the 19 OLF patients, 2 (10.5%) had tandem ossification of the posterior longitudinal ligament in the cervical spine and were symptomatic. Conclusions: The frequency of OLF appears to be high among this hospital-based cohort of the Arab population. OLF should be kept in mind if a patient presents with radiculopathy, particularly in the cervical region, for which surgical intervention is contemplated.
Patupilone (Epothilone B) for Recurrent Glioblastoma: Clinical Outcome and Translational Analysis of a Single-Institution Phase I/II Trial
Authors: Oehler Christoph , Frei Karl , Rushing Elisabeth J. , McSheehy Paul M.J. , Weber Dirk , Allegrini Peter R. , Weniger Dorothea , Lütolf Urs M. , Knuth Alexander , Yonekawa Yasuhiro , Barath Krisztina , Broggini-Tenzer Angela , Pruschy Martin , Hofer Silvia
Published: June 2012

Background: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6–9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. Methods: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m2, every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. Results: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5–17 months) and 45% (95% CI, 14–76), respectively. Median PFS was 1.5 months (95% CI, 1.3–1.7 months) and PFS6 was 22% (95% CI, 0–46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. Conclusions: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.
The Experimental Production of Intercoronary Arterial Anastomoses and their Functional Significance
Authors: BLUMGART HERRMAN L. , ZOLL PAUL M. , FREEDBERG A. STONE , GILLIGAN D. ROURKE
Published: June 2012

Animal experiments were done to learn the degree of coronary narrowing required to produce the larger intercoronary collateral channels, their speed of development, and the degree of protection afforded the myocardium. Twelve or more days of 75 per cent narrowing were required to produce sufficiently rich anastomotic communications to protect the myocardium from damage, and to permit survival after superimposed acute complete occlusion. The physiologic and pathologic significance of the intercoronary collateral communications and the clinical implications in coronary artery disease are discussed.