bluuebunny/crossref_metadata_2025 huggingface dataset:
Resveratrol ameliorates metabolic disorders and muscle wasting in streptozotocin-induced diabetic rats
Authors: Chen Kuan-Hsing , Cheng Mei-Ling , Jing Yu-Hong , Chiu Daniel Tsun-Yee , Shiao Ming-Shi , Chen Jan-Kan
Published: July 2011

Diabetes mellitus (DM) is characterized by dysregulated energy metabolism. Resveratrol (RSV) has been shown to ameliorate hyperglycemia and hyperlipidemia in diabetic animals. However, its overall in vivo effects on energy metabolism and the underlying mechanism require further investigation. In the present study, electrospray ionization-tandem mass spectrometry was employed to characterize the urine and plasma metabolomes of control, streptozotocin-induced DM and RSV-treated DM rats. Using principal component analysis (PCA) and heat map analysis, we discovered significant differences among control and experimental groups. RSV treatment significantly reduced the metabolic abnormalities in DM rats. Compared with the age-matched control rats, the level of carnitine was lower, and the levels of acetylcarnitine and butyrylcarnitine were higher in the urine and plasma of DM rats. RSV treatment ameliorated the deranged carnitine metabolism in DM rats. In addition, RSV treatment attenuated the diabetic ketoacidosis and muscle protein degradation, as evidenced from the attenuation of elevated urinary methyl-histidine and plasma branched-chain amino acids levels in DM rats. The beneficial effects of RSV in DM rats were correlated with activation of hepatic AMP-activated protein kinase and SIRT1 expression, increase of hepatic and muscular mitochondrial biogenesis and inhibition of muscle NF-κB activities. We concluded that RSV possesses multiple beneficial metabolic effects in insulin-deficient DM rats, particularly in improving energy metabolism and reducing protein wasting.
Impact of maternal dietary n-3 and n-6 fatty acids on milk medium-chain fatty acids and the implications for neonatal liver metabolism
Authors: Novak Elizabeth M. , Innis Sheila M.
Published: July 2011

Levels of n-6, n-3, and medium-chain fatty acids (MCFA) in milk are highly variable. Higher carbohydrate intakes are associated with increased mammary gland MCFA synthesis, but the role of unsaturated fatty acids for milk MCFA secretion is unclear. This study addressed whether n-6 and n-3 fatty acids, which are known to inhibit hepatic fatty acid synthesis, influence MCFA in rat and human milk and the implications of varying MCFA, n-6, and n-3 fatty acids in rat milk for metabolic regulation in the neonatal liver. Rats were fed a low-fat diet or one of six higher-fat diets, varying in 16:0, 18:1n-9, 18:2n-6, 18:3n-3, and long-chain (LC) n-3 fatty acids. Higher maternal dietary 18:2n-6 or 18:3n-3 did not influence milk MCFA, but lower maternal plasma triglycerides, due to either a low-fat or a high-fat high-LC n-3 diet led to higher milk MCFA. MCFA levels were inversely associated with 18:1n-9, 18:2n-6, and 18:3n-3 in human milk, likely reflecting the association between dietary total fat and unsaturated fatty acids. High LC n-3 fatty acid in rat milk was associated with lower hepatic Pklr, Acly, Fasn, and Scd1 and higher Hmgcs2 in the milk-fed rat neonate, with no effect of milk 18:1n-9, 18:2n-6, or MCFA. These studies show that the dietary fatty acid composition does not impact MCFA secretion in milk, but the fatty acid composition of milk, particularly the LC n-3 fatty acid, is relevant to hepatic metabolic regulation in the milk-fed neonate.
Leptin in human physiology and pathophysiology
Authors: Mantzoros Christos S. , Magkos Faidon , Brinkoetter Mary , Sienkiewicz Elizabeth , Dardeno Tina A. , Kim Sang-Yong , Hamnvik Ole-Petter R. , Koniaris Anastasia
Published: July 2011

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.
Temporal processing in the auditory core: transformation or segregation?
Authors: Smith Elliot H.
Published: July 2011

Scott et al. ( J Neurophysiol 105: 712–730, 2011) examine temporal processing in auditory Core fields AI and R in the macaque, arguing that temporal properties are the most salient functional differences between these areas. How these results imply transformation of information between AI and R or whether these fields may be processing divergent information somewhat separately is discussed.
Target modality determines eye-head coordination in nonhuman primates: implications for gaze control
Authors: Populin Luis C. , Rajala Abigail Z.
Published: July 2011

We have studied eye-head coordination in nonhuman primates with acoustic targets after finding that they are unable to make accurate saccadic eye movements to targets of this type with the head restrained. Three male macaque monkeys with experience in localizing sounds for rewards by pointing their gaze to the perceived location of sources served as subjects. Visual targets were used as controls. The experimental sessions were configured to minimize the chances that the subject would be able to predict the modality of the target as well as its location and time of presentation. The data show that eye and head movements are coordinated differently to generate gaze shifts to acoustic targets. Chiefly, the head invariably started to move before the eye and contributed more to the gaze shift. These differences were more striking for gaze shifts of <20–25° in amplitude, to which the head contributes very little or not at all when the target is visual. Thus acoustic and visual targets trigger gaze shifts with different eye-head coordination. This, coupled to the fact that anatomic evidence involves the superior colliculus as the link between auditory spatial processing and the motor system, suggests that separate signals are likely generated within this midbrain structure.
Impaired inhibitory control of cortical synchronization in fragile X syndrome
Authors: Paluszkiewicz Scott M. , Olmos-Serrano Jose Luis , Corbin Joshua G. , Huntsman Molly M.
Published: July 2011

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.
Dissipative Effect and Tunneling Time
Authors: Bhattacharya Samyadeb , Roy Sisir
Published: July 2011

The quantum Langevin equation has been studied for dissipative system using the approach of Ford et al. Here, we have considered the inverted harmonic oscillator potential and calculated the effect of dissipation on tunneling time, group delay, and the self‐interference term. A critical value of the friction coefficient has been determined for which the self‐interference term vanishes. This approach sheds new light on understanding the ion transport at nanoscale.
C-Silylated Calix[4]Arene as a New Receptor for Aspartate in Polar Solvents
Authors: Zadmard Reza , Ataeian Parinaz , Khalili-Foumeshi Maryam
Published: July 2011

The recognition of aspartic acid derivatives such as N-benzyloxycarbonyl-D-aspartate (NZDA) with the calix[4]arene derivatives with multiple silicon groups at the upper rim in polar solvents is investigated.
Specimen Orientation by Marking the Peripheral End: (Potential) Clinical Advantages in Prostate Biopsy
Authors: Galosi Andrea Benedetto , Muzzonigro Giovanni , Lacetera Vito , Mazzucchelli Roberta
Published: July 2011

The aim of this paper is to identify advantages that could be obtained by orientation of the biopsy specimen using the marking technique. We reviewed our experience (4,500 cases) and the published literature. The peripheral (proximal) end of the fresh specimen is marked with ink soon after needle delivering in a few minutes. It is performed easily in association with pre-embedding method. Five potential clinical advantages were identified: (1) tumor localization, (2) atypical lesions localization and planning rebiopsy strategy, (3) planning surgical strategy, (4) selection criteria for focal therapy and active surveillance, and (5) cost reduction. Peripheral end marking is low cost, easy and reproducible. It drives several potential advantages in cancer diagnosis or isolated atypical lesions, in particular, spatial localization within the biopsy (transition versus peripheral zone, anterior versus posterior, subcapsular versus intraparenchima, and extraprostatic extension) should be easy and reliable. We can add a new pathological parameter: pathological orientation or biopsy polarity.
Effects of Pressure Drops on the Performance Characteristics of Air Standard Otto Cycle
Authors: Huleihil Mahmoud
Published: July 2011

The effects of pressure drops on the performance characteristics of the air standard Otto cycle are reported. The pressure drops are assumed as constant values independent of the engine size. It has been shown that the pressure drops to about 60% of the maximum pressure in the ideal cycle (Curto-Risso et al., 2008). Three different models are studied: constant pressure model, reversible adiabatic expansion model and polytropic expansion model. The findings of this study show that, at this level of pressure drop, the maximum efficiency of the Otto cycle is reduced by 15% approximately based on the constant pressure model. The combined effect of pressure drop with other modes of irreversibility, for example, internal irreversibility and heat leaks, could reduce the maximum efficiency into very low values (approximately 30%). The reversible adiabatic model predicts reduction of 13% in efficiency at 40% pressure drop levels but at the price of zero power production. On the other hand, the polytropic expansion model predicts 40% reduction in efficiency for the same level of pressure drop (40%). All three models show that the power output is very sensitive to pressure drop.
Development of the Lacrimal Apparatus in the Rabbit (Oryctolagus cuniculus) and Its Potential Role as an Animal Model for Humans
Authors: Rehorek S. J. , Holland J. R. , Johnson J. L. , Caprez J. M. , Cray J. , Mooney M. P. , Hillenius W. J. , Smith T. D.
Published: July 2011

Rabbits have been proposed as a model organism for the human lacrimal apparatus (LA), including the nasolacrimal duct (NLD), based principally on comparative studies of adult morphology; however, little is known about its development. The NLD first appears as an incomplete primordium in the subcutaneous region of the primordial eyelid and subsequently elongates to reach the naris. One posterior and three anterior orbital glands are present fetally although one of the anterior glands is soon lost. The NLD follows a tortuous path and passes through a bony canal consisting of lacrimal, maxilla, and maxilloturbinal bones at different regions. Although early developmental similarities exist to haplorhine primates, the narial opening of the NLD resembles strepsirrhines. This distinction, along with the ductal and glandular differences at the orbital end of the NLD, indicates that rabbits may be a poor model for LA drainage in primates, specifically humans.
A Comparative Study of Mouse Hepatic and Intestinal Gene Expression Profiles under PPARαKnockout by Gene Set Enrichment Analysis
Authors: He Kan , Wang Qishan , Yang Yumei , Wang Minghui , Pan Yuchun
Published: July 2011

Gene expression profiling of PPARαhas been used in several studies, but fewer studies went further to identify the tissue-specific pathways or genes involved in PPARαactivation in genome-wide. Here, we employed and applied gene set enrichment analysis to two microarray datasets both PPARαrelated respectively in mouse liver and intestine. We suggested that the regulatory mechanism of PPARαactivation by WY14643 in mouse small intestine is more complicated than in liver due to more involved pathways. Several pathways were cancer-related such as pancreatic cancer and small cell lung cancer, which indicated that PPARαmay have an important role in prevention of cancer development. 12 PPARαdependent pathways and 4 PPARαindependent pathways were identified highly common in both liver and intestine of mice. Most of them were metabolism related, such as fatty acid metabolism, tryptophan metabolism, pyruvate metabolism with regard to PPARαregulation but gluconeogenesis and propanoate metabolism independent of PPARαregulation. Keratan sulfate biosynthesis, the pathway of regulation of actin cytoskeleton, the pathways associated with prostate cancer and small cell lung cancer were not identified as hepatic PPARαindependent but as WY14643 dependent ones in intestinal study. We also provided some novel hepatic tissue-specific marker genes.
Local Resection by Combined Laparoendoscopic Surgery for Duodenal Gastrointestinal Stromal Tumor
Authors: Kato Motohiko , Nakajima Kiyokazu , Nishida Toshirou , Yamasaki Makoto , Nishida Tsutomu , Tsutsui Shusaku , Ogiyama Hideharu , Yamamoto Shunsuke , Yamada Takuya , Mori Masaki , Doki Yuichiro , Hayashi Norio
Published: July 2011

Combined laparoendoscopic surgery is a novel surgical method which consists of both endoscopic surgery from inside the gastrointestinal tract and laparoscopic surgery from the outside. We report a case of duodenal GIST, in which combined laparoendoscopic local resection was attempted. The lesion was resected endoscopically using endoscopic submucosal dissection technique under laparoscopic assistance. Laparoscope was used for originating the orientation of the tumor, intra-operative EUS, and monitoring serosal injury from the peritoneal cavity. Postoperative hemorrhage occurred; however, precise orientation of the lesion helped us to manage the patient with minimal invasive reoperation. And thus, the bowel integrity was completely preserved, by avoiding segmental duodenal resection and pancreaticoduodenectomy. This novel, less invasive surgical procedure may become an attractive option for the lesions originating in the anatomically challenging portion of the GI tract for endoscopic or laparoscopic surgery alone.
A Novel Bioinspired Vision System: A Step toward Real-Time Human-Robot Interactions
Authors: Hafiz Abdul Rahman , Alnajjar Fady , Murase Kazuyuki
Published: July 2011

Building a human-like robot that could be involved in our daily lives is a dream of many scientists. Achieving a sophisticated robot's vision system, which can enhance the robot's real-time interaction ability with the human, is one of the main keys toward realizing such an autonomous robot. In this work, we are suggesting a bioinspired vision system that helps to develop an advanced human-robot interaction in an autonomous humanoid robot. First, we enhance the robot's vision accuracy online by applying a novel dynamic edge detection algorithm abstracted from the rules that the horizontal cells play in the mammalian retina. Second, in order to support the first algorithm, we improve the robot's tracking ability by designing a variant photoreceptors distribution corresponding to what exists in the human vision system. The experimental results verified the validity of the model. The robot could have a clear vision in real time and build a mental map that assisted it to be aware of the frontal users and to develop a positive interaction with them.
Why Fuzzy Transform Is Efficient in Large-Scale Prediction Problems: A Theoretical Explanation
Authors: Perfilieva Irina , Kreinovich Vladik
Published: July 2011

In many practical situations like weather prediction, we are interested in large-scale (averaged) value of the predicted quantities. For example, it is impossible to predict the exact future temperature at different spatial locations, but we can reasonably well predict average temperature over a region. Traditionally, to obtain such large-scale predictions, we first perform a detailed integration of the corresponding differential equation and then average the resulting detailed solution. This procedure is often very time-consuming, since we need to process all the details of the original data. In our previous papers, we have shown that similar quality large-scale prediction results can be obtained if, instead, we apply a much faster procedure—first average the inputs (by applying an appropriate fuzzy transform) and then use these averaged inputs to solve the corresponding (discretization of the) differential equation. In this paper, we provide a general theoretical explanation of why our semiheuristic method works, that is, why fuzzy transforms are efficient in large-scale predictions.
Does Botanical Diversity in Sewage Treatment Reed-Bed Sites Enhance Invertebrate Biodiversity?
Authors: Feest Alan , Merrill Ian , Aukett Philippa
Published: July 2011

(1) This study examines the effect of increasing botanical diversity, through reed-bed planting and maintenance regimes, on sewage treatment reed-bed invertebrate biodiversity and the possible enrichment of overall catchment biodiversity. (2) Reed-bed invertebrates were identified as a good indicator group of overall site biodiversity quality and were sampled at a range of sewage treatment reed-bed sites in the same geographical area between May and August 2006 (plus one natural reed-bed control site). Standardised water trapping and pitfall trapping techniques were employed throughout this sampling period. (3) Statistical analysis of the sampling results revealed that the number of plant species recorded was inversely related to terrestrial invertebrate species richness, species conservation value index and biomass within the study sites. For example, the natural reed-bed sampled had the highest botanical diversity but the lowest terrestrial invertebrate species richness. (4) This study has demonstrated that sewage treatment reed-beds support a diverse range of invertebrate species, some of them being of national conservation value. This suggests that sewage treatment reed-beds may be at least as biodiverse as naturally occurring reed-beds and will add to the overall biodiversity and ecohydrology of a catchment whilst saving energy.
Synergistic Apoptosis-Inducing Antileukemic Effects of Arsenic Trioxide andMucuna macrocarpaStem Extract in Human Leukemic Cells via a Reactive Oxygen Species-Dependent Mechanism
Authors: Lu Kuan-Hung , Lee Hui-Ju , Huang Min-Li , Lai Shang-Chih , Ho Yu-Ling , Chang Yuan-Shiun , Chi Chin-Wen
Published: July 2011

The objective of this study was to examine the potential of enhancing the antileukemic activity of arsenic trioxide (ATO) by combining it with a folk remedy, crude methanolic extract ofMucuna macrocarpa(CMEMM). Human leukemia cells HL-60, Jurkat, and Molt-3 were treated with various doses of ATO, CMEMM, and combinations thereof for 24 and 48 h. Results indicated that the combination of 2.5 μM ATO and 50 μg/mL CMEMM synergistically inhibited cell proliferation in HL-60 and Jurkat cell lines. Apoptosis triggered by ATO/CMEMM treatment was confirmed by accumulation of cells in the sub-G1phase in cell cycle analyses, characteristic apoptotic nuclear fragmentation, and increased percentage of annexin V-positive apoptotic cells. Such combination treatments also led to elevation of reactive oxygen species (ROS). The antioxidantsN-acetyl cysteine (NAC), butylated hydroxytoluene, andα-tocopherol prevented cells from ATO/CMEMM-induced apoptosis. The ATO/CMEMM-induced activation of caspase-3 and caspase-9 can be blocked by NAC. In summary, these results suggest that ATO/CMEMM combination treatment exerts synergistic apoptosis-inducing effects in human leukemic cells through a ROS-dependent mechanism and may provide a promising antileukemic approach in the future.
HER2-Affitoxin: A Potent Therapeutic Agent for the Treatment of HER2-Overexpressing Tumors
Authors: Zielinski Rafal , Lyakhov Ilya , Hassan Moinuddin , Kuban Monika , Shafer-Weaver Kimberly , Gandjbakhche Amir , Capala Jacek
Published: July 2011

Purpose: Cancers overexpressing the HER2/neu gene are usually more aggressive and are associated with poor prognosis. Although trastuzumab has significantly improved the outcome, many tumors do not respond or acquire resistance to current therapies. To provide an alternative HER2-targeted therapy, we have developed and characterized a novel recombinant protein combining an HER2-specific Affibody and modified Pseudomonas aeruginosa exotoxin A (PE 38), which, after binding to HER2, is internalized and delivered to the cytosol of the tumor cell, where it blocks protein synthesis by ADP ribosylation of eEF-2.

Experimental Design: The effect of the Affitoxin on cell viability was assessed using CellTiter-Glo (Promega). To assess HER2-specific efficacy, athymic nude mice bearing BT-474 breast cancer, SK-OV-3 ovarian cancer, and NCI-N87 gastric carcinoma xenografts were treated with the Affitoxin (HER2- or Tag-specific), which was injected every third day. Affitoxin immunogenicity in female BALB/c mice was investigated using standard antibody production and splenocyte proliferation assays.

Results: In vitro experiments proved that HER2-Affitoxin is a potent agent that eliminates HER2-overexpressing cells at low picomolar concentrations. Therapeutic efficacy studies showed complete eradication of relatively large BT-474 tumors and significant effects on SK-OV-3 and NCI-N87 tumors. HER2-Affitoxin cleared quickly from circulation (T1/2 < 10 minutes) and was well tolerated by mice at doses of 0.5 mg/kg and below. Immunogenicity studies indicated that HER2-Affitoxin induced antibody development after the third injected dose.

Conclusions: Our findings showed that HER2-Affitoxin is an effective anticancer agent and a potential candidate for clinical studies. Clin Cancer Res; 17(15); 5071–81. ©2011 AACR.
Results of a Phase II Trial of Gemcitabine Plus Doxorubicin in Patients with Recurrent Head and Neck Cancers: Serum C18-Ceramide as a Novel Biomarker for Monitoring Response
Authors: Saddoughi Sahar A. , Garrett-Mayer Elizabeth , Chaudhary Uzair , O'Brien Paul E. , Afrin Larry B. , Day Terry A. , Gillespie M. Boyd , Sharma Anand K. , Wilhoit Christina S. , Bostick Robin , Senkal Can E. , Hannun Yusuf A. , Bielawski Jacek , Simon George R. , Shirai Keisuke , Ogretmen Besim
Published: July 2011

Purpose: Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with gemcitabine (GEM)/doxorubicin (DOX) would be efficacious via reconstitution of C18-ceramide signaling in head and neck squamous cell carcinoma (HNSCC) patients for whom first-line platinum-based therapy failed.

Experimental Design: Patients received GEM (1,000 mg/m2) and DOX (25 mg/m2) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements.

Results: We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major nonhematologic toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival was 1.6 months (95% CI: 1.4–4.2) with a median survival of 5.6 months (95% CI: 3.8–18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C18-ceramide elevation in patients with CR/PR/SD in comparison with patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment.

Conclusions: Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C18-ceramide elevation might be a novel serum biomarker of chemotherapy response. Clin Cancer Res; 17(18); 6097–105. ©2011 AACR.
Pharmacogenetic Angiogenesis Profiling for First-line Bevacizumab plus Oxaliplatin-Based Chemotherapy in Patients with Metastatic Colorectal Cancer
Authors: Gerger Armin , El-Khoueiry Anthony , Zhang Wu , Yang Dongyun , Singh Harpreet , Bohanes Pierre , Ning Yan , Winder Thomas , LaBonte Melissa J. , Wilson Peter M. , Benhaim Leonor , Paez David , El-Khoueiry Rita , Absenger Gudrun , Lenz Heinz-Josef
Published: July 2011

Purpose: There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.

Experimental Design: A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).

Results: The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31–0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36–0.99; adjusted P = 0.046, respectively). The minor allele of HIF1α rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (Pact = 0.003).

Conclusion: In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy. Clin Cancer Res; 17(17); 5783–92. ©2011 AACR.
Frequency of Rearrangements in Lynch Syndrome Cases Associated with MSH2: Characterization of a New Deletion Involving both EPCAM and the 5′ Part of MSH2
Authors: Pérez-Cabornero Lucia , Sanz Mar Infante , Sampedro Eladio Velasco , Aras Enrique Lastra , Becares Alberto Acedo , Pino Cristina Miner , Domínguez Mercedes Durán
Published: July 2011

Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch repair genes and leads to a high risk of colorectal and endometrial cancer. It was recently shown that constitutional 3′ end deletions of EPCAM could cause Lynch syndrome in tissues with MSH2 deficiency. We aim to establish the spectrum of mutations in MSH2-associated Lynch syndrome cases and their clinical implications. Probands from 159 families suspected of having Lynch syndrome were enrolled in the study. Immunohistochemistry and microsatellite instability (MSI) analyses were used on the probands of all families. Eighteen cases with MSH2 loss were identified: eight had point mutations in MSH2. In 10 Lynch syndrome families without MSH2 mutations, EPCAM-MSH2genomic rearrangement screening was carried out with the use of multiplex ligation–dependent probe amplification and reverse transcriptase PCR. We report that large germline deletions, encompassing one or more exons of the MSH2 gene, cosegregate with the Lynch syndrome phenotype in 23% (8 of 35) of MSI families tested. A new combined deletion EPCAM-MSH2 was identified and characterized by break point analysis, encompassing from the 3′ end region of EPCAM to the 5′ initial sequences of the MSH2 (c.859-1860_MSH2:646-254del). EPCAM-MSH2 fusion transcript was isolated. The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome. Cancer Prev Res; 4(10); 1556–62. ©2011 AACR.
Biomarkers in Neonatal Posthemorrhagic Hydrocephalus
Authors: Merhar Stephanie
Published: July 2011

Posthemorrhagic hydrocephalus (PHH) is a rare but serious outcome among premature babies in the NICU, with consequences including mortality and severe neurodevelopmental disabilities. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. Various cerebrospinal fluid biomarkers have been studied in infants with PHH in order to recognize the causes, diagnose brain injury, and predict neurodevelopmental outcomes. This systematic review summarizes studies on biomarkers of extracellular matrix activity, fibrinolysis/coagulation, hypoxia/cell death, and inflammation in the cerebrospinal fluid of infants with PHH.
Low Birth Weight Is Associated with Reduced Nephron Number and Increased Blood Pressure in Adulthood in a Novel Spontaneous Intrauterine Growth-Restricted Model in Yucatan Miniature Swine
Authors: Myrie Semone B. , McKnight Leslie L. , Van Vliet Bruce N. , Bertolo Robert F.
Published: July 2011

Background: Impaired fetal growth and rapid postnatal growth are associated with programming of hypertension and metabolic syndrome in adulthood. Objectives: This study evaluated this phenomenon in a novel spontaneous intrauterine growth-restricted (IUGR) model in Yucatan miniature pigs. Methods: IUGR piglets (n = 6, 3 days old, 0.73 ± 0.11 kg) were paired with a normal weight (NW) same-sex littermate (n = 6, 1.11 ± 0.13 kg), fed milk replacer for 4 weeks followed by a standard diet ad libitum for 5 h/day. At 9 months of age, arterial blood pressure (BP) telemeters were implanted to assess BP before (0.5% NaCl) and after (4.5% NaCl) a 7-day salt-loading period. At 10 months of age, nephron numbers were determined. Results: Prior to sexual maturity, IUGR pigs showed greater (p < 0.05) relative feed intake and experienced significant catch-up growth. Adult IUGR pigs also had higher BP (diastolic BP: 93.8 ± 5.5 vs. 90.0 ± 8.7 mm Hg, p < 0.05) and 43% fewer nephrons per kidney (p < 0.05). Nephron number was positively associated with birth weight and negatively correlated with BP (p < 0.05). Acute salt loading increased BP in both groups (p < 0.05); however, the degree of salt sensitivity was similar between groups (p > 0.05). Conclusions: In conclusion, IUGR piglets have reduced nephron endowment associated with a modest BP increase in early adulthood. This new model can be used to conduct longitudinal mechanistic studies on the early programming phenomenon.
Early Transient Hypoglycemia Is Associated with Increased Albumin Nitration in the Preterm Infant
Authors: Wayenberg Jean-Louis , Cavedon Catia , Ghaddhab Chiraz , Lefèvre Nicolas , Bottari Serge P.
Published: July 2011

Background: The clinical significance of early transient hypoglycemia (ETH), a frequent event in preterm newborns, is a highly controversial issue. In experimental models, hypoglycemia has been reported to cause oxidative stress. Among the reactive species, early generated peroxynitrite is responsible for protein nitration and lipid peroxidation, a process referred to as nitrative stress. Objectives: The aim of the present study is to investigate whether ETH is associated with protein nitration in the preterm newborn. Methods: Using a novel highly sensitive ELISA, we quantified plasma nitroalbumin (PNA) as a marker of peroxynitrite generation in 72 preterm newborns (28–36 weeks), among which 25 had a glycemia level of <2.5 mmol/l during the first hour of life (H1). Results: PNA was significantly higher in ETH than in normoglycemic infants at H1 [median = 6.3 (3.8–8.8) vs. 3.4 ng/ml (2.1–5.1), p = 0.027] and at day 1 [median = 6.6 (5.6–15.3) vs. 3.9 ng/ml (2.3–4.6), p = 0.014]. PNA was inversely correlated with glycemia at H1 (r = –0.30, p = 0.01) and at day 1 (r = –0.63, p = 0.001). In ETH infants, lactatemia was inversely correlated with PNA. At day 1, PNA was higher in ETH infants treated by gavage than in those treated with intravenous dextrose [median = 8.9 ng/ml (7.1–10.4) vs. 4.4 ng/ml (2.6–5.7), p = 0.008]. Conclusions: These results indicate that ETH is associated with increased peroxynitrite generation resulting in systemic protein nitration in premature newborns. Treatment of ETH with intravenous dextrose is associated with lower PNA levels than gavage.
Subcutaneous Peripheral Neurostimulation for the Treatment of Severe Chronic Poststernotomy Neuralgia
Authors: Peyravi Morad , Capelle Hans-Holger , Fischer Stefan , Haverich Axel , Krauss Joachim K.
Published: July 2011

Objective:Poststernotomy pain frequently develops after sternotomy in thoracic and cardiovascular surgery, and may affect patients’ quality of life. In some cases of severe poststernotomy neuralgia, pharmacologic therapy does not provide adequate relief. Case Report: We report on a 42- year-old woman who underwent sternotomy for aortic and mitral valve replacement. She developed severe chronic poststernotomy neuralgia that was refractory to medical treatment. After local anesthesia markedly but only transiently alleviated pain, we considered the option of subcutaneous peripheral neurostimulation (SPNS). Plate electrodes were implanted bilaterally in the parasternal region at the site of maximal pain. After a period of test stimulation, the electrodes were connected to a dual-channel implantable pulse generator. SPNS induced paresthesias in the painful area. Revision surgery was necessary twice because of electrode migration. Chronic SPNS markedly alleviated pain (visual-analog scale, VAS, 9/10 preoperatively, 2/10 postoperatively) and allodynia (VAS 9/10 preoperatively, 2/10 postoperatively) at the last available follow-up, 15 months postoperatively. Conclusions: SPNS may be a viable treatment option in patients with severe chronic poststernotomy neuralgia.
Cow’s Milk and the Emergence of Group B Streptococcal Disease in Newborn Babies
Authors: Ismail A.Q. , Yeates D.G.R. , Marciano A. , Goldacre M. , Anthony M.
Published: July 2011

Background: Group B streptococcus (GBS), the most significant cause of neonatal bacterial sepsis, is thought to have emerged in the 1960s. GBS also causes mastitis in cows, and there is indirect evidence that human GBS is derived from a bovine ancestor. Objective: A major change in the collection of milk from farms, using bulk tanks rather than churns, occurred in the 1960s. We sought to define the temporal relationship between this change in farming and the emergence of GBS neonatal disease. Methods: We searched PubMed for reports of GBS disease from 1930 until 1980 to more exactly determine the time of emergence of neonatal infection and supported this data with UK hospital admission statistics for GBS infections. We identified the dates of the change from churns to bulk tanks by searching the internet and books for information on the history of milk transportation, farming and milk collection in the UK. Results: There are no PubMed reports of neonatal GBS disease between 1930 and 1950, and reports from the UK only emerged in the mid-1960s, confirming the notion that GBS neonatal infection was a newly emergent disease in the 1960s. No national data on hospital admissions are available around this time, but the Oxford Record Linkage Study, with admission data available for Oxford from 1968, showed no cases of neonatal disease until 1974. Cow’s milk collection in the UK switched to bulk tank between 1960 and 1979, and publications relating to GBS disease emerged soon after. Conclusions: There is a temporal relationship between the emergence of neonatal GBS disease reports in the UK in the 1960s and a change in cow’s milk collection. This finding may be a temporal coincidence or may add support to the notion that human GBS was historically derived from a bovine ancestor.
Longitudinal Manganese-Enhanced Magnetic Resonance Imaging of Delayed Brain Damage after Hypoxic-Ischemic Injury in the Neonatal Rat
Authors: Widerøe Marius , Brekken Christian , Kavelaars Annemieke , Pedersen Tina Bugge , Goa Pål Erik , Heijnen Cobi , Skranes Jon , Brubakk Ann-Mari
Published: July 2011

Background: Hypoxia-ischemia (HI) in the neonatal brain results in a prolonged injury process. Longitudinal studies using noninvasive methods can help elucidate the mechanisms behind this process. We have recently demonstrated that manganese-enhanced magnetic resonance imaging (MRI) can depict areas with activated microglia and astrogliosis 7 days after hypoxic-ischemic brain injury. Objective: The current study aimed to follow brain injury after HI in rats longitudinally and compare manganese enhancement of brain areas to the development of injury and presence of reactive astrocytes and microglia. Methods: The Vannucci model for hypoxic-ischemic injury in the neonatal rat was used. Pups were injected with either MnCl2 or saline after 6 h and again on day 41 after HI. Longitudinal MRI (T1 weighted) was performed 1, 3, 7 and 42 days after HI. The brains were prepared for immunohistochemistry after the final MRI. Results: There was severe loss of cerebral tissue from day 7 to day 42 after HI. Most manganese-enhanced areas in the hippocampus, thalamus and basal ganglia at day 7 were liquefied after 42 days. Manganese-enhancement on day 42 corresponded to areas of activated microglia and reactive astrocytes in the remaining cortex, hippocampus and amygdala. However, the main area of enhancement was in the remaining thalamus in a calcified area surrounded by activated microglia and reactive astrocytes. Conclusion: Manganese-enhanced MRI can be a useful tool for in vivo identification of cerebral tissue undergoing delayed cell death and liquefaction after HI. Manganese enhancement at a late stage seems to be related to the accumulation of manganese in calcifications and gliotic tissue.
Functional Dilatation and Medial Remodeling of the Renal Artery in Response to Chronic Increased Blood Flow
Authors: Roan Jun-Neng , Yeh Chin-Yi , Chiu Wen-Cheng , Lee Chou-Hwei , Chang Shih-Wei , Jiangshieh Ya-Fen , Tsai Yu-Chuan , Lam Chen-Fuh
Published: July 2011

Background/Aims: Renal blood flow (RBF) is tightly regulated by several intrinsic pathways in maintaining optimal kidney blood supply. Using a rat model of aortocaval (AC) fistula, we investigated remodeling of the renal artery following prolonged increased blood flow. Methods: An AC fistula was created in the infrarenal aorta of anesthetized rats, and changes of blood flow in the renal artery were assessed using an ultrasonic flow probe. Morphological changes and expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 in the remodeled renal artery were analyzed. Results: Blood flow in the renal artery increased immediately after creation of AC fistula, but normal RBF was restored 8 weeks later. The renal artery dilated significantly 8 weeks after operation. Expression of endothelial nitric oxide synthase and matrix metalloproteinase-2 was upregulated shortly after blood flow increase, and returned to baseline levels after 3 weeks. Histological sections showed luminal dilatation with medial thickening and endothelial cell-to-smooth muscle cell attachments in the remodeled renal artery. Conclusion: Increased RBF was accommodated by functional dilatation and remodeling in the medial layer of the renal artery in order to restore normal blood flow. Our results provide important mechanistic insight into the intrinsic regulation of the renal artery in response to increased RBF.
‘A Man Paints with His Brains and Not with His Hands’ (Michelangelo)
Authors: Cervoni Edoardo
Published: July 2011

The goals of a post-stroke rehabilitation plan are very specific to each patient. The side of the body affected by hemiplegia can influence the rehabilitation plan, as people with right-sided hemiplegia may also have difficulties with speech and language (aphasia). Because of the aphasia, drawing may remain a crucial instrument of creative expression and the clinical case presented highlights how this goal may also be successfully achieved in the elderly by using the left hand.
Vascular Risk Factors and Dementia: 40-Year Follow-Up of a Population-Based Cohort
Authors: Rönnemaa Elina , Zethelius Björn , Lannfelt Lars , Kilander Lena
Published: July 2011

Aims: Our aim was to evaluate the longitudinal associations of individual and multiple vascular risk factors with the subsequent development of dementia and Alzheimer’s disease (AD). Methods: The Uppsala Longitudinal Study of Adult Men started in 1970 when the 2,268 participants were 50 years old. Baseline investigations included determinations of blood pressure, fasting glucose, cholesterol, BMI and smoking status. Over a maximum follow-up of 40 years, 349 participants were diagnosed with dementia, out of which 127 had AD. Analyses were repeated using a re-examination of the cohort at 70 years of age as a baseline. Results: No associations between vascular risk factors and AD were found. For all-type dementia, the association between high systolic blood pressure and dementia was the most consistent. High fasting glucose was associated with increased risk of all-type dementia only when measured at 70 years. Individuals with both an APOE Ε4 allele and vascular risk factors had the greatest dementia risk. Conclusion: Vascular risk factors influence the future risk of dementia, in particular vascular and mixed-type rather than AD. The impact of vascular risk factors on dementia in a longitudinal study depends on the age at baseline and the length of follow-up.
Relative Familial Clustering of Cerebral Versus Coronary Ischemic Events
Authors: Banerjee Amitava , Silver Louise E. , Heneghan Carl , Welch Sarah J.V. , Mehta Ziyah , Banning Adrian P. , Rothwell Peter M.
Published: July 2011

Background—

Few population-based studies have ascertained both cerebral and coronary events or considered their relative heritability. Differences in heritability of transient ischemic attack and ischemic stroke versus acute coronary syndromes (ACS) may inform risk prediction, genetic studies, and understanding of disease mechanisms.

Methods and Results—

In a population-based study of all acute vascular events, irrespective of age, we studied family history of myocardial infarction (MI), stroke, and related risk factors in first-degree relatives. To allow for differences in rates of affected first-degree relatives caused by differences in disease incidence, we looked at the extent to which parental history was associated with affected siblings within disease category. Nine hundred six probands (604 men; mean age, 70 years) with ACS and 1015 (484 men; mean age, 73 years) with cerebral events had complete family history data. In ACS probands, parental MI was associated with MI in ≥1 sibling (1 parent with MI: odds ratio, 1.48; 1.04 to 2.10;
P
=0.03; both parents with MI: odds ratio, 5.97; 3.23 to 11.03;
P
<0.0001). In probands with cerebral events, however, parental stroke was not associated with sibling stroke. The overall frequency of ≥2 siblings with the same condition was also greater in probands with ACS than in those with cerebral events (odds ratio, 5.43; 3.03 to 9.76;
P
<0.00001), despite similar overall incidence of MI and stroke in our study population. One hundred forty-two (15.7%) cases of ACS occurred in families with ≥2 affected first-degree relatives compared with 56 (5.1%) transient ischemic attack/strokes. All results were similar when analyses were confined to probands with MI only versus stroke only, and independent of smoking.

Conclusions—

Heritability of coronary events was greater than that of cerebral events, such that MI was more likely to cluster in families than was stroke.
Percutaneous Repair of Paravalvular Prosthetic Regurgitation
Authors: Sorajja Paul , Cabalka Allison K. , Hagler Donald J. , Rihal Charanjit S.
Published: July 2011

Background—

Percutaneous repair has emerged as a potential therapy for patients with prosthetic paravalvular regurgitation. However, there is a relative paucity of data on the feasibility and outcome of this procedure.

Methods and Results—

All patients in whom percutaneous paravalvular regurgitation closure was attempted at our hospital were identified and included. Under echocardiographic and fluoroscopic guidance, patients underwent implantation of ≥1 an Amplatzer Septal Occluder, Duct Occluder, Muscular Ventricular Septal Defect Occluder, or Vascular Plug II. Percutaneous repair of 141 paravalvular defects was attempted in 115 patients (age, 67±12 years; men, 53%) with heart failure, hemolytic anemia, or both and who were at high risk of open surgery (mean estimated Society of Thoracic Surgeons mortality, 6.9%). Devices were implanted in 125 defects (89% of total defects), including in 19 patients with multiple defects. Because of the complexity of the procedures, wire exteriorization was required in 29 patients. Overall, successful percutaneous closure (defined as ≤1+ residual regurgitation) was achieved in 88 (77%) patients. Procedural time decreased with increasing case experience for percutaneous repair of both perimitral and periaortic defects. Overall, the 30-day complication rate was 8.7% (sudden and unexplained death, 1.7%; stroke, 2.6%; emergency surgery, 0.9%; bleeding, 5.2%). Two devices embolized during the procedure and were retrieved without sequelae. No procedural deaths occurred, but 2 (1.7%) patients died by 30 days.

Conclusions—

Percutaneous repair of paravalvular prosthetic regurgitation can be performed with a reasonable rate of procedural success and may be an initial therapeutic option, particularly in patients at significant risk for open surgery. Increased case experience is associated with shorter procedural time.