bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer
Authors: Yen Li-Chen , Yeh Yung-Sung , Chen Chao-Wen , Wang Hwei-Ming , Tsai Hsiang-Lin , Lu Chien-Yu , Chang Yu-Tang , Chu Koung-Shing , Lin Shiu-Ru , Wang Jaw-Yuan
Published: June 2009

Purpose: Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy.

Experimental Design: Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing.

Results: Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001).

Conclusions: These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.
A Cohort Study of Cyclin D1 Expression and Prognosis in 602 Colon Cancer Cases
Authors: Ogino Shuji , Nosho Katsuhiko , Irahara Natsumi , Kure Shoko , Shima Kaori , Baba Yoshifumi , Toyoda Saori , Chen Li , Giovannucci Edward L. , Meyerhardt Jeffrey A. , Fuchs Charles S.
Published: June 2009

Purpose: Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (CDKN1B) and p21 (CDKN1A, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].

Experimental Design: Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, KRAS, and BRAF.

Results: Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (P = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; P = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; P = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; P = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (Pinteraction = 0.008). Compared with tumors that were both cyclin D1–negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).

Conclusions: Cyclin D1 overexpression is associated with longer survival in colon cancer.
A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas
Authors: Meyer Tim , Gaya Andrew M. , Dancey Gairin , Stratford Michael R.L. , Othman Shokri , Sharma Surinder K. , Wellsted David , Taylor N. Jane , Stirling J. James , Poupard Linda , Folkes Lisa K. , Chan Pei-san , Pedley R. Barbara , Chester Kerry A. , Owen Karen , Violet John A. , Malaroda Alessandra , Green Alan J. , Buscombe John , Padhani Anwar R. , Rustin Gordon J. , Begent Richard H.
Published: June 2009

Purpose: In preclinical models, radioimmunotherapy with 131I-A5B7 anti–carcinoembryonic antigen (CEA) antibody (131I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas.

Experimental Design: Patients had CEA of 10 to 1,000 μg/L, QTc ≤450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m2 of 131I-A5B7 on day 1 and 45 mg/m2 CA4P given 48 and 72 hours post-131I-A5B7, then weekly for up to seven weeks.

Results: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m2, and CA4P escalated to 54 mg/m2. Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (Ktrans/IAUGC60) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level.

Conclusions: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.
Enhanced Systemic Immune Reactivity to a Basal Cell Carcinoma Associated Antigen Following Photodynamic Therapy
Authors: Kabingu Edith , Oseroff Allan R. , Wilding Gregory E. , Gollnick Sandra O.
Published: June 2009

Purpose: Numerous preclinical studies have shown that local photodynamic therapy (PDT) of tumors enhances systemic antitumor immunity. However, other than single-case and anecdotal reports, this phenomenon has not been examined following clinical PDT. To determine whether PDT in a clinical setting enhances systemic recognition of tumor cells, we examined whether PDT of basal cell carcinoma resulted in an increased systemic immune response to Hip1, a tumor antigen associated with basal cell carcinoma.

Experimental Design: Basal cell carcinoma lesions were either treated with PDT or surgically removed. Blood was collected from patients immediately before or 7 to 10 days following treatment. Peripheral blood leukocytes were isolated from HLA-A2–expressing patients and reactivity to a HLA-A2–restricted Hip1 peptide was measured by INF-γ ELISpot assay.

Results: Immune recognition of Hip1 increased in patients whose basal cell carcinoma lesions were treated with PDT. This increase in reactivity was significantly greater than reactivity observed in patients whose lesions were surgically removed. Patients with superficial lesions exhibited greater enhancement of reactivity compared with patients with nodular lesions. Immune reactivity following PDT was inversely correlated with treatment area and light dose.

Conclusions: These findings show for the first time that local tumor PDT can enhance systemic immune responses to tumors in patients, and validate previous preclinical findings.
Collapse of the CD27+ B-Cell Compartment Associated with Systemic Plasmacytosis in Patients with Advanced Melanoma and Other Cancers
Authors: Carpenter Erica L. , Mick Rosemarie , Rech Andrew J. , Beatty Gregory L. , Colligon Theresa A. , Rosenfeld Myrna R. , Kaplan David E. , Chang Kyong-Mi , Domchek Susan M. , Kanetsky Peter A. , Fecher Leslie A. , Flaherty Keith T. , Schuchter Lynn M. , Vonderheide Robert H.
Published: June 2009

Purpose: Disturbed peripheral blood B-cell homeostasis complicates certain infections and autoimmune diseases, such as HIV and systemic lupus erythematosus, but has not been reported in cancer. This study aimed to investigate whether B-cell physiology was altered in the presence of melanoma and other cancers.

Experimental Design: Flow cytometry was used to identify phenotypic differences in B cells from patients with melanoma and normal donors. In vitro stimulated B cells were assessed for responsiveness and also used as stimulators of allogeneic T cells in mixed lymphocyte reactions.

Results: We show B-cell dysregulation in patients with advanced melanoma (n = 26) and other solid tumors (n = 13), marked by a relative and absolute loss of CD27+ (memory) B cells and associated with an aberrant systemic plasmacytosis. Functionally, B cells from patients with melanoma inefficiently up-regulated immunoregulatory molecules and weakly secreted cytokines in response to CD40 and toll-like receptor 9 agonists. Stimulated B cells from patients induced proliferation of alloreactive CD4+ T cells, but these T cells poorly secreted IFNγ and interleukin-2. These effects were recapitulated by using purified normal donor CD27neg B cells in these same assays, linking the predominance of CD27neg B cells in patients with the observed functional hyporesponsiveness. Indeed, B-cell dysfunction in patients strongly correlated with the extent of loss of CD27+ B cells in peripheral blood.

Conclusions: Disturbed B-cell homeostasis is a previously unrecognized feature of patients with advanced melanoma and other cancers and may represent an unanticipated mechanism of immune incompetence in cancer.
Anti-inflammatory Action of Pterostilbene Is Mediated through the p38 Mitogen-Activated Protein Kinase Pathway in Colon Cancer Cells
Authors: Paul Shiby , Rimando Agnes M. , Lee Hong Jin , Ji Yan , Reddy Bandaru S. , Suh Nanjoo
Published: June 2009

Oxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-α, IFN-γ, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-κB, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38α isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.
The Interaction of a High-Fat Diet and Regular Moderate Intensity Exercise on Intestinal Polyp Development in ApcMin/+ Mice
Authors: Baltgalvis Kristen A. , Berger Franklin G. , Peña Maria Marjorette O. , Davis J. Mark , Carson James A.
Published: June 2009

Diet and exercise are two environmental factors that can alter colon cancer risk. The purpose of this study was to determine if regular moderate-intensity treadmill exercise training could attenuate polyp formation in ApcMin/+ mice fed the Western-style diet. Four-week-old male ApcMin/+ mice (n = 12 per group) were assigned to AIN-76A Control, AIN-76A Exercise, Western Control, or Western Exercise treatment groups. Mice were weaned to these diets and either subjected to regular moderate-intensity treadmill exercise (18 m/min, 60 min/d, 6 d/wk) or remained sedentary for 6 weeks. Mice fed the Western-style diet consumed ∼14% more calories and had 42% more epididymal fat compared with mice fed the AIN-76A diet. Exercise had no effect on fat pad mass with either diet treatment. Exercise reduced total intestinal polyp number by 50% and the number of large polyps (>1 mm diameter) by 67% in AIN-76A–fed mice. The Western-style diet increased polyp number by 75% when compared with AIN-76A–fed mice, but exercise did not decrease polyp number or alter polyp size in mice fed the Western-style diet. Markers of systemic inflammation and immune system function were improved with exercise in mice fed the AIN-76A diet. Mice fed the Western-style diet showed more inflammation and immunosuppression, which were not completely ameliorated by exercise. These data suggest that the induction of adiposity, inflammation, and immunosuppression by the Western-style diet may compromise the beneficial effect of moderate-intensity exercise on the intestinal polyp burden in ApcMin/+ mice.
Interval of Injections of Intramuscular Depot Medroxyprogesterone Acetate in the Long-Term Treatment of Endometriosis-Associated Pain: A Randomized Comparative Trial
Authors: Cheewadhanaraks Sopon , Peeyananjarassri Krantarat , Choksuchat Chainarong , Dhanaworavibul Kriengsak , Choobun Thanapan , Bunyapipat Sathana
Published: June 2009

Aim: To determine the optimal interval of injections of intramuscular depot medroxyprogesterone acetate 150 mg in the long-term treatment of endometriosis-associated pain. Method: 112 patients with symptomatic endometriosis were randomized to receive either injections every month for 6 months, then every 3 months for a total of 15 months or injections every 3 months for 15 months. The primary outcome measure was patients’ satisfaction. Result: At months 3, 6, 9, 12 and 15 of the treatment phase, there was no statistically significant difference of percentages of patients with satisfaction between the two regimens (85.7 vs. 76.8%, 76.8 vs. 73.2%, 66.1 vs. 58.9%, 60.7 vs. 55.4%, 60.7 vs. 55.4%, respectively). Conclusion: The optimal interval of injections of depot medroxyprogesterone acetate 150 mg is every 3 months.
Noninvasive Evaluation of Coronary Endothelial Function following Sirolimus-Eluting Stent Implantation by Using Positron Emission Tomography
Authors: Horigome Mitsuaki , Kumazaki Setsuo , Hattori Naoya , Kasai Hiroki , Horigome Miki , Aizawa Kazunori , Izawa Atsushi , Tomita Takeshi , Tsutsui Hiroshi , Koyama Jun , Sakurai Shunpei , Ikeda Uichi
Published: June 2009

Objective: Several invasive studies have reported delayed reendothelialization and endothelial dysfunction following sirolimus-eluting stent (SES) implantation. We evaluated the changes in coronary endothelial function following SES implantation by using a noninvasive method that involved positron emission tomography and cold pressor testing (CPT). Methods: The study was conducted on 14 lesions on which percutaneous coronary intervention (PCI) was successively performed. The lesions were classified into 2 groups depending on the PCI performed: the conventional PCI group, in which 7 conventional PCIs (plain old balloon angioplasty or bare-metal stents) were performed, and the SES group, in which 7 SESs were implanted. Coronary endothelial function was defined as the percent increase in the myocardial blood flow (MBF) during CPT. Results: The resting MBF in the segments distal to the PCI sites did not differ between the conventional PCI and SES groups; however, the MBF significantly decreased in the SES group during CPT. Conclusions: These data suggest that SES implantation induces coronary endothelial dysfunction in the segments distal to the PCI sites.
Association of TNFA –308 G/A and TNFRI +36 A/G Gene Polymorphisms with Glaucoma
Authors: Razeghinejad Mohammad Reza , Rahat Feisal , Kamali-Sarvestani Eskandar
Published: June 2009

Objective: TNF-α is one of the most important factors recognized in the pathogenesis of open-angle glaucoma. Therefore, the association of single nucleotide polymorphisms in the TNFRI gene and the promoter region of the TNFA gene with glaucoma susceptibility was investigated in the present study. Method: In total, 223 patients with glaucoma and 202 unrelated controls were genotyped by allele-specific oligonucleotide PCR and PCR- restriction fragment length polymorphism to determine TNFA –308 G/A and TNFRI +36 A/G polymorphisms, respectively. Results: In contrast to TNFRI polymorphisms, the genotypes of TNFA –308 G/A polymorphisms showed a significant difference between patients and controls (p = 0.0025). Of interest, the distribution of TNFA genotypes was significantly different between patients with primary open-angle glaucoma (p = 0.001) or pseudoexfoliative glaucoma (p = 0.001) and controls, while no difference was found when chronic angle-closure glaucoma patients were compared to controls (p = 0.72). Conclusion: In line with studies showing the role of TNF-α in open-angle glaucoma, the results of the present study showed that inheritance of the high producer TNFA –308 A allele might be a susceptibility factor for the development of open-angle glaucoma.
Effect of Erythropoietin on Oxidative Stress and Liver Injury in Experimental Obstructive Jaundice
Authors: Moran M. , Oruc M.T. , Ozmen M.M. , Dikicier E. , Dilektasli E. , Han U. , Besler H.T.
Published: June 2009

Background: To evaluate the time-dependent effects and pathophysiological mechanism of erythropoietin (Epo) on oxidative stress and liver injury resulting from obstructive jaundice in common bile duct-ligated rats. Methods: Wistar Albino rats were divided into 5 groups, each including 8 rats. The sham group underwent laparotomy only, while the Non-Epo-3 and Non-Epo-7 groups underwent common bile duct ligation and were sacrificed 3 and 7 days, respectively, after the operation. The Epo-3 and Epo-7 groups underwent common bile duct ligation and Epo treatment and were sacrificed 3 and 7 days, respectively, after the operation. Blood and tissue samples were collected from all groups for the determination of oxidative injury and hepatocellular damage. Serum total and direct bilirubin levels, alkaline phosphatase, reduced glutathione (GSH), nitric oxide (NO), malondialdehyde (MDA) and white blood cell counts were measured. Results: Significantly higher NO and MDA levels were found in Non-Epo groups than Epo groups. Significantly lower GSH levels were found in the Non-Epo-7 group than the Epo-7 and sham groups. Hepatocellular damage was also found to be reduced in Epo groups. Conclusions: In the present model, while common bile duct ligation increased oxidative injury and hepatocellular damage, treatment with Epo attenuated oxidative injury and hepatocellular damage by decreasing NO and increasing GSH.
Efficacy and Safety of Glucocorticoids Therapy for IgA Nephropathy: A Meta-Analysis of Randomized Controlled Trials
Authors: Cheng Jun , Zhang Xiaohui , Zhang Wen , He Qiang , Tao Xiaojuan , Chen Jianghua
Published: June 2009

Background: Published reports examining the efficacy and safety of glucocorticoids for preserving renal function in immunoglobulin A nephropathy (IgAN) have yielded conflicting results. To systematically evaluate the efficacy and safety of glucocorticoids agents for IgAN, we conducted a meta-analysis of the published randomized controlled trials (RCTs). Methods: MEDLINE, EMBASE, the Cochrane Library and article reference lists were searched for RCTs that compared glucocorticoids with placebo and any other non-immunosuppressive agents for treating IgAN. The quality of the studies was evaluated with the method of the intention-to-treat analysis and allocation concealment, as well as with the Jadad method. Meta-analyses were performed on the outcomes of proteinuria and renal survival and adverse events in patients with IgAN. Results: Seven RCTs involving 386 patients were included in the review. Four RCTs reported renal survival data with Kaplan-Meier survival curves. Overall, glucocorticoid agents had statistically significant effects on improved renal survival (HR 0.20, 95% CI 0.20 to 0.39) and reduction of proteinuria (standardized mean difference SMD, –0.51; 95% CI –0.73 to –0.29) when compared with the control group. Tests for heterogeneity showed no difference in effect among the studies. In general, glucocorticoid agents were well tolerated. Patients receiving glucocorticoids therapy did not have an increased risk of development of type 2 diabetes mellitus, hypertension or Cushingoid adverse effects, while glucocorticoids were associated with a significant increase in the risk of gastrointestinal tract adverse events. Conclusions: The current cumulative evidence suggests that glucocorticoids have statistically significant effects on protecting renal function and reduction of proteinuria in patients with IgAN, but we should be careful for its gastrointestinal tract reaction. In general, glucocorticoids agents are a promising medication and should be investigated further.
Toll-Like Receptor 2 Senses Hepatitis C Virus Core Protein but Not Infectious Viral Particles
Authors: Hoffmann Marco , Zeisel Mirjam B. , Jilg Nikolaus , Paranhos-Baccalà Glaucia , Stoll-Keller Françoise , Wakita Takaji , Hafkemeyer Peter , Blum Hubert E. , Barth Heidi , Henneke Philipp , Baumert Thomas F.
Published: June 2009

Toll-like receptors (TLRs) are pathogen recognition molecules activating the innate immune system. Cell surface expressed TLRs, such as TLR2 and TLR4, have been shown to play an important role in human host defenses against viruses through sensing of viral structural proteins. In this study, we aimed to elucidate whether TLR2 and TLR4 participate in inducing antiviral immunity against hepatitis C virus (HCV) by sensing viral structural proteins. We studied TLR2 and TLR4 activation by cell culture-derived infectious virions and serum-derived virions in comparison to purified recombinant HCV structural proteins and enveloped virus-like particles. Incubation of TLR2 or TLR4 transfected cell lines with recombinant core protein resulted in activation of TLR2-dependent signaling. In contrast, neither infectious virions nor enveloped HCV-like particles triggered TLR2 and TLR4 signaling. These findings suggest that monomeric HCV core protein but not intact infectious particles are sensed by TLR2. Impairment of interaction between TLR and the core in infectious viral particles may contribute to escape from innate antiviral immune responses.
Fettemulsionen: Grundlagen pathophysiologischer Einflüsse und klinischer Applikationen
Authors: Grünert A.
Published: June 2009

Moderne Fettemulsionen werden in zunehmendem Maβe in der klinischen Ernährungstherapie eingesetzt. Die in der Anfangszeit der Entwicklung von Fettemulsionen aufgetretenen Störeffekte und Nebenwirkungen haben die Einsatzmöglichkeiten und die Handhabung der Fettemulsionen stark negativ beeinfluβt. In der vorliegenden Arbeit werden die modernen Fettemulsionen auf dem Boden der aktuellen Erkenntnisse diskutiert. Das Einsatzprofil der Fettemulsionen hat sich stark verändert, da neben dem ursprünglichen Einsatzbereich als energieliefernde Substrate und essentielle Substrate eine Erweiterung dadurch erfolgte, daβ die Erkenntnis des Aufbaus biologischer Membranen aus Proteinen und Fetten die Fettsäuren als Synthesebausteine einschlieβt. Als besonders bemerkenswert wird auseinandergesetzt, daβ die Indikationsstellungen nicht mehr von spezifischen Krankheitsbildern bestimmt werden, sondern sich nach den Kriterien der Substratkonzentrationen in den biologischen Kompartimenten orientieren. In der Arbeit werden Studien zur Pharmakokinetik von Fett mit dem Ziel der Dosierungsabsicherung dargestellt. Die Einfluβfaktoren die neben den hormonellen Konstellationen und der pathophysiologischen Veränderung des posttraumatischen Stoffwechsels eine groβe Rolle spielen, werden beispielhaft mit dem Einfluβ des Körpergewichts auf den Verlauf der Plasmakonzentrationen der Triglyzeride erläutert. Vor dem Hintergrund der Darstellung eigener klinischer Studien zur Applikation von Fettemulsionen bei Intensivpatienten werden Voraussetzungen definiert, die für die Applikation von Fettemulsionen erfüllt sein müssen, um abgesicherte Indikationen definieren zu können. Abschlieβend wird auf dem Boden pathophysiologischer Wechselbeziehungen zwischen Kohlenhydrat- und Fettstoffwechsel ein analytisches Überwachungsverfahren für die Applikation von Fettemulsionen erläutert und als Überwachungsmaβnahme vorgeschlagen.
Essentielle Fettsäuren in der parenteralen Ernahrung
Authors: Wolfram G.
Published: June 2009

Fett ist als Energieträger, als Träger essentieller Fettsauren und fettlöslicher Vitamine ein sehr wichtiger Nahrungsbestandteil. Die Bedeutung von n-6-Fettsäuren, z.B. Linolsäure und Arachidonsäure, in der parenteralen Ernahrung zeigte sich in den letzten 15 Jahren anhand von mehreren Fallen eines manifesten Mangels an essentiellen Fettsauren. Darüber hinaus sind n-3-Fettsäuren, z.B. α-Linolensäure, Eicosapentaensäure und Docosahexaensäure, sehr wahrscheinlich essentielle Nahrungsbestandteile, da aus ihnen eine eigenständige Gruppe von Eicosanoiden mit speziellen biologischen Wirkungen gebildet wird. Der Bedarf von Patienten mit kompletter parenteraler Ernahrung nach schweren Unfällen an den verschiedenen essentiellen Fettsauren ist von speziellem Interesse, insbesondere unter Berücksichtigung der Entstehung und der Prognose von Schock, Schocklunge und Sepsis. Die verfügbaren Fettemulsionen auf Sojaölbasis enthalten n-6- und n-3-Fettsäuren in einem brauchbaren Verhältnis von 7:1. Über den Bedarf an essentiellen Fettsauren bei verschiedenen Krankheitszuständen sind jedoch weitere Informationen sehr notwendig.
Klinische Untersuchungen mit LCT- und MCT-haltigen Fettemulsionen
Authors: Eckart J. , Neeser G. , Adolph M. , Hailer S. , Wolfram G.
Published: June 2009

In dem Bemühen, Energieträger mit hoher Verwertungsrate speziell zur parenteralen Ernährung während des Postaggressionsstoffwechsels bereitzustellen, wurden Fettemulsionen entwickelt, die lang- und mittelkettige Triglyzeride im Verhältnis 1:1 enthalten. Als besondere Vorteile der mittelkettigen Fettsäuren wurden u.a. deren geringe Speicherungs- und hohe Oxidationsrate im Organismus beschrieben. Im Rahmen eines Stufenplans wurde bei vollständig parenteral ernährten Intensivpatienten ein MCT/LCT-Gemisch bzw. eine reine LCT-Emulsion als Bolus und später kontinuierlich verabfolgt. Untersucht wurden u.a. das Verhalten der Triglyzeridkonzentration und der Einzelfettsäuren im Serum und der einzelnen Fettfraktionen sowie die Beeinflussung verschiedener Parameter des Kohlenhydrat- und Fettstoffwechsels. Die Oxidationsrate einer 13C-markierten MCT/LCT-Emulsion wurde auβerdem gemessen. Die Ergebnisse der vergleichenden Fettstudien wurden gegenübergestellt. Der erwartete Befund einer die Verbrennung langkettiger Triglyzeride übersteigenden Oxidationsrate mittelkettiger Triglyzeride wurde bestätigt. Überraschend war, daβ die Oxidationsrate bei kontinuierlicher Fettzufuhr im Rahmen eines vollständigen Emährungsprogramms nur bei einem Mittelwert von 32 ± 6,8% lag. Ungeklärt muβte bleiben, warum sich bei einem Teil der Patienten unter der MCT/LCT-Emulsion höhere Triglyzeridspiegel fanden als während der LCT-Zufuhr. Zu prüfen bleibt, ob die schnelle Spaltung mittelkettiger Triglyzeride zu einem vorübergehenden Aktivitätsverlust der Lipoproteinlipase führt mit begleitendem Triglyzeridanstieg im Serum. Welche Bedeutung MCT/LCT-Emulsionen in Zukunft besitzen werden, bedarf weiterer Untersuchungen. Der Einsatz einer solchen Emulsion könnte bei Schwerverletzten angebracht sein, um mit dem MCT-Anteil dem Organismus bevorzugt Energieträger und mit den langkettigen Triglyzeriden in erster Linie Strukturbestandteile zur Verfügung zu stellen.
Side-Effects and Technical Problems in Cytapheresis with Cell Separators
Authors: Kretschmer V.
Published: June 2009

On the basis of a survey, the acute side-effects and technical problems in a total of 77,525 cytaphereses (IFC 36,530, CFC 40,995) in donors at 39 hemapheresis centers were retrospectively analysed statistically. In general, relevant donor side-effects (0.78%-1.05%) were more rare than the primary donor-independent disturbances (1.65%-2.63%). The donor side-effects predominated merely with the use of the cell separators Haemonetics M30/Belco (1.06% vs. 0.57%). These were mainly circulatory reactions (0.83%), which were generally much more frequent with IFC (0.54%) than with CFC (IBM/Cobe 0.11%, CS-3000 0.19%). Potentially fatal complications were not reported. The frequency of side-effects, disturbances and discontinuations correlated inversely with the separation rate of the individual centers per method. Centers in which two or three methods were applied simultaneously reported a higher frequency of side-effects and disturbances. Hemolysis was only observed with IFC (0.09%), but not with the use of the Haemonetics V50. The greater susceptibility to disturbances of technical/methodological/operational origin essentially results from the more elaborate, but not yet perfected technology, including computer control and monitoring, as well as defects in the production of the much more complicated disposable sets. Thus the highest rate of discontinuations was calculated for the system which is so far the most sophisticated technically (CS-3000, 1.85%). Although the primary donor-independent problems sometimes correlate directly with the manifestation of donor side-effects, the greater technological sophistication of automatically controlled and monitored systems cannot be dispensed with, since only in this way can potentially fatal risks for the donors be largely ruled out. Nevertheless, there remains a residual risk which can be eliminated only with adherence to appropriate regulations and guidelines, such as those which exist at present for the Federal Republic of Germany. In addition, further development of the hardware and software of the cell separators and increased quality of disposable systems are to be aimed for.
Untersuchungen zur Sicherheit der apparativen Zytapherese
Authors: Böhm R. , Borberg H.
Published: June 2009

In a retrospective analysis 1568 platelet apheresis procedures and 652 leukocytaphereses performed from April 1976 to June 1986 were examined. 886 procedures were performed using the Fenwal CS 3000, 777 with the IBM 2997, and 293 with the Haemonetics V50, whereas in 264 procedures the Model 30 was used. The study aims to answer 3 donor-related questions: To what extent are the blood cells changed by the donation? How does the donor respond to the technical requirements of the donation, such as length of the procedure, blood volume processed, amount of concentrate removed during the donation? How often did side-effects or undesired reactions occur? We found that thrombocytapheresis led to a decrease in platelets in the peripheral blood of between 20% (CS3000) and 33.7% (IBM), and an increase in leukocytes of between 4.24% (IBM) and 17.8% (Model 30), whereas erythrocytes, hemoglobin and hematocrit showed a similar decrease witin a range of between 1.1% and 2.67% in all systems. Following leukocytapheresis the leukocyte counts of the peripheral blood were decreased by up to 12 % erythrocyte counts by up to 5% and platelets between 15% (IBM) and 29% (Model 30). The list of irregularities included technical problems and donor reactions (e.g., citrate reactions, reactions of blood circulation, and blood flow in the donor). There were no serious side-effects. Early terminations of 42 (= 1.9%) donations were for prophylactic reasons exclusively. Few moderate undesired reactions occurred (4 = 0.2%), but none of the donors contributing to the more than 2,000 donations were ever hospitalized, demonstrating the safety of cytapheresis with all separators.
Side-Effects of Cytapheresis with Cell Separators
Authors: Höcker P. , Wagner A.
Published: June 2009

The rate of procedure-related side-effects was evaluated in 11,895 cytaphereses performed with a Haemonetics® 30 (H-30) cell processor (2,486 procedures) or with a Haemonetics® V-50 (H-50) cell processor (6,813 procedures) or with the Fenwal CS-3000® cell processor (2,596 procedures). The overall rate of side-effects was 7.41% (absolute number 881). There was a significant difference between female and male donors concerning the frequency of hypotension episodes and citrate toxicity related reactions. There were also distinct differences between the single cell separator types concerning the frequency and type of side effects. Hypotension episodes and citrate-related reactions were observed most frequently during cytapheresis with the H-30 (7.65 and 2.96% respectively). Venous access and technical problems appeared more often when the H-50 or the CS-3000 were used. Thus both the H-50 as well as the CS-3000 cell separators allow safe cytapheresis with a low number of side-effects.
The Safety of and the Strain on the Donor during Thrombocytapheresis on the Cell Separator
Authors: Basler H.D. , Steinfelder C. , Hartnack U. , Kretschmer V.
Published: June 2009

The study deals with the question as to what extent and under which existing personal characteristics does thrombocytapheresis on the cell separator (Fenwal CS-3000) lead to psychological stress for the blood donor? A comparison is made with the stress experienced during the established 450 ml full-blood donation. Because of the different procedural conditions, it was postulated that the donation on the cell separator creates greater psychological stress than the established type of donation. To examine this hypothesis, a sample group of 76 cell-separator and full-blood donors were asked to complete a questionnaire concerning the stress they experienced and their attitude before, during, and after the donation. Their personalities were also examined. A control group of 45 full-blood donors was examined in the same way. No significant statistical difference was found regarding the extent of stress under both conditions of donation. These findings are verified by the general satisfaction expressed by the cell-separator donors. Although it is confirmed that the personal cost to the donor is greater, it involves, on the other hand, a greater commitment, a positive evaluation of the more intimate involvement of the donor, and an increase in self-esteem. Since it could not be proven that there is an increase in the amount of stress during cell-separator donation, it also seems plausible that no clear decrease in stress would be observed after repeated donations. On the whole, it seems that the cell separator is well accepted by the donors. The extent of experienced stress is related to the donor’s habitual anxiety and negative expectations. Since negative expectations can be influenced, it is to be expected that an informative conversation in a quiet atmosphere would further decrease the stress experienced.
Significance of Eicosapentaenoic Acid (EPA) in Nutritional Support
Authors: Meng H.C.
Published: June 2009

Changes in the fatty acid profile of plasma total lipids in patients maintained on TPN were determined in 2 studies. In the first study, 20 newborns, 2–25 days of age, receiving comparable nitrogen, calories and fat were divided into 2 groups of 10 in each. A safflower oil emulsion (Liposyn® 20%) containing no α-linolenic acid was given to the Group 1 subjects, while a modified emulsion containing 3% of α-linolenic acid in safflower oil supplying 5.6% of total calories was given to those of Group 2. Plasma α-linolenic acid of the Group 1 infants was 0 throughout. The decrease in EPA and DHA was 85% and 65%, respectively, after 10–15 days of therapy. In the subjects of Group 2, there was an increase in both α-linolenic acid and EPA. A similar decrease (63%) in DHA similar to that of Group 1 infants was observed. In the second study, results of 2 representative adult patients are reported. One patient was given a soybean oil emulsion (Intralipid®, 10%) that contains 7–8% of α-linolenic acid in the oil, furnishing about 11% of total calories. The other patient received a safflower oil emulsion (Liposyn, 10%) that contains no α-linolenic acid. Each patient received 500 ml of the respective emulsion daily for 3 weeks. The plasma α-linolenic acid of the patient who received the safflower oil emulsion remained 0 throughout. EPA showed a 67% decrease in 21 days. DHA remained at low levels throughout. In the other patient given the soybean oil emulsion, plasma α-linolenic acid, EPA and DHA were all increased during the 3-week study period. Conclusion: α-Linolenic acid supplying about 5.6% of total calories daily may be inadequate in infants. In adults, α-linolenic acid furnishing about 11% of the total calories may be high. It appears that EPA and perhaps DHA may play a significant role in nutritional support in infants, and their supplementation appears to be required. This is less clear in adults unless the conversion of EPA/DHA is impaired. Further investigation to study some metabolic parameters is necessary to document the physiological significance of EPA/DHA in patients maintained on nutritional support.
A System of Calibrating Microtomography for Use in Caries Research
Authors: Schwass D.R. , Swain M.V. , Purton D.G. , Leichter J.W.
Published: June 2009

Desktop microcomputed tomography (micro-CT) offers a non-invasive 3-dimensional analysis of structures and their physical properties. To date, the use of micro-CT has mostly involved qualitative observations, with the extent of quantitative analysis relying on automated internal calibration by the micro-CT control software. However, the value of such calibration is limited by machine drift. For an accurate quantitative use of micro-CT, it is recognized that external means of calibration are needed. A novel system of calibration standards, also known as ‘phantoms’, is presented. A range of low mineral concentration phantoms involving triethylene glycol dimethacrylate/glycerolate dimethacrylate resin mixed with commercial pure hydroxyapatite (HAP), from 0.07 to 1.05 g/cm3, was fabricated. Sintered HAP was impregnated with the same resin, producing phantoms with medium-level mineral concentrations up to 1.90 g/cm3. These phantoms were easy to create, proved accurate and stable with repeated use, and were found to mimic the composite nature of dental enamel and dentine structures under investigation.
Increased Bronchoalveolar Lavage Fluid CD1c Expressing Dendritic Cells in Idiopathic Pulmonary Fibrosis
Authors: Tsoumakidou M. , Karagiannis K.P. , Bouloukaki I. , Zakynthinos S. , Tzanakis N. , Siafakas N.M.
Published: June 2009

Background: Chronic inflammation is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis and is associated with persistent activation of immune responses. These are largely controlled by dendritic cells (DCs). Although large numbers of DCs infiltrate the lungs of patients with IPF, there are no similar reports in bronchoalveolar lavage fluid (BALF). Objectives: We aimed to investigate DC populations in BALF of IPF patients. Methods: CD1c+ myeloid DCs, BDCA3high myeloid DCs, BDCA2+ plasmacytoid DCs and CD83+ mature DCs were identified by flow cytometry in the BALF of 10 IPF patients and 10 controls. DC numbers were expressed as percentages of total BALF leukocytes. Results: CD1c+ myeloid DCs were increased in IPF patients versus controls [median (ranges in parentheses) 1.16% (0.25–3.97) vs. 0.61% (0.19–1.10), p = 0.01]. There was also a trend towards increased BDCA3high myeloid DCs [0.57% (0.23–0.88) vs. 0.28% (0.07–0.96), p = 0.07]. No differences were reported in BDCA2+ DCs and CD83+ DCs between IPF patients and controls. Conclusions: IPF is associated with an increase in percentages of BALF myeloid DCs. Considering that such an increase was not observed in CD83+ mature DCs, most of these DCs should be immature.
Antiviral Activity of Innate Immune Protein ISG15
Authors: Harty Ronald N. , Pitha Paula M. , Okumura Atsushi
Published: June 2009

The host innate immune response, including the production of type-I IFN, represents the primary line of defense against invading viral pathogens. Of the hundreds of IFN-stimulated genes (ISGs) discovered to date, ISG15 was one of the first identified and shown to encode a ubiquitin-like protein that functions, in part, as a modifier of protein function. Evidence implicating ISG15 as an innate immune protein with broad-spectrum antiviral activity continues to accumulate rapidly. This review will summarize recent findings on the innate antiviral activity of ISG15, with a focus on the interplay between ubiquitination and ISGylation pathways resulting in modulation of RNA virus assembly/budding. Indeed, ubiquitination is known to be proviral for some RNA viruses, whereas the parallel ISGylation pathway is known to be antiviral. A better understanding of the antiviral activities of ISG15 will enhance our fundamental knowledge of host innate responses to viral pathogens and may provide insight useful for the development of novel therapeutic approaches designed to enhance the immune response against such pathogens.
The Innate Immune Response: An Important Partner in Shaping Coxsackievirus-Mediated Autoimmunity
Authors: Richer Martin J. , Horwitz Marc S.
Published: June 2009

To protect against viral infection, the immune response is critically dependent on innate sensing mechanisms to provide rapid detection of pathogens and allow for the development of an appropriate adaptive immune response. Mounting evidence suggests that mechanistic differences in the sensing of viruses by the innate immune response can contribute to the development of autoimmunity. Coxsackieviruses are common human pathogens that have been linked to the induction of autoimmune diseases such as chronic autoimmune myocarditis and type 1 diabetes. In this review, we will discuss the current knowledge of the interactions between coxsackievirus and the innate immune system and how these interactions can potentially lead to the induction of autoimmune diseases.
Measure and Countermeasure: Type I IFN (IFN-α/β) Antiviral Response against West Nile Virus
Authors: Daffis Stephane , Suthar Mehul S. , Gale, Jr. Michael , Diamond Michael S.
Published: June 2009

As a first line of defense after viral infection, host cells develop an intrinsic immune response to control virus dissemination and protect against serious infection. Recent experiments have shown a dominant role of the IFN-α/β response in protection against lethal West Nile virus (WNV) by limiting the cellular and tissue tropism of infection. This review will focus on advances in identifying the host sensors that detect WNV and the adaptor molecules and signaling pathways that regulate the induction of IFN-α/β defenses that limit WNV replication, spread and pathogenesis.
Histotopographic Study of the Fibroadipose Connective Cheek System
Authors: Macchi Veronica , Tiengo Cesare , Porzionato Andrea , Stecco Carla , Vigato Enrico , Parenti Anna , Azzena Bruno , Weiglein Andreas , Mazzoleni Francesco , De Caro Raffaele
Published: June 2009

The purpose of this study was to investigate the morphology of the superficial musculoaponeurotic system (SMAS). Eight embalmed cadavers were analyzed: one side of the face was macroscopically dissected; on the other side, full-thickness samples of the parotid, zygomatic, nasolabial fold and buccal regions were taken. In all specimens, a laminar connective tissue layer (SMAS) bounding two different fibroadipose connective layers was identified. The superficial fibroadipose layer presented vertically oriented fibrous septa, connecting the dermis with the superficial aspect of the SMAS. In the deep fibroadipose connective layer, the fibrous septa were obliquely oriented, connecting the deep aspect of the SMAS to the parotid-masseteric fascia. This basic arrangement shows progressive thinning of the SMAS from the preauricular district to the nasolabial fold (p < 0.05). In the parotid region, the mean thicknesses of the superficial and deep fibroadipose connective tissues were 1.63 and 0.8 mm, respectively, whereas in the region of the nasolabial fold the superficial layer is not recognizable and the mean thickness of the deep fibroadipose connective layer was 2.9 mm. The connective subcutaneous tissue of the face forms a three-dimensional network connecting the SMAS to the dermis and deep muscles. These connective laminae connect adipose lobules of various sizes within the superficial and deep fibroadipose tissues, creating a three-dimensional network which modulates transmission of muscle contractions to the skin. Changes in the quantitative and qualitative characteristics of the fibroadipose connective system, reducing its viscoelastic properties, may contribute to ptosis of facial soft tissues during aging.
Progression of Chronic Renal Failure in Patients Given Keto Acids Following Amino Acids
Authors: Walser M. , LaFrance N. , Ward L. , VanDuyn M.A.
Published: June 2009

Twelve patients with chronic renal failure who exhibited a progressive decline in 24-h creatinine clearance despite being given, for 2–10 months, a diet containing 0.3 g of protein/kg ideal weight and 7–9 mg of phosphorus/kg ideal weight supplemented with vitamins, CaCOj, and 10 g per day of essential amino acids, were changed to a supplement containing predominantly keto acids. In 6 patients whose serum creatinine levels were 7.5 mg/dl or greater at changeover, progression continued unabated. In 6 patients with serum creatinine levels at changeover of 6.5 – 7.4 mg/dl, one was non-compliant with the diet and progressed to dialysis. In the other 5, progression, measured as the rate of change of a bimonthly radioisotope clearance, has been undetectable during the ensuing 1–2 years.
Hyperfiltration due to Amino and Keto Acid Supplements of Low-Protein Diets: Influence on Proteinuria
Authors: Meisinger E. , Gretz N. , Strauch M.
Published: June 2009

In 12 male ⅚ nephrectomized Sprague-Dawley rats we analyzed the influence of commercially available amino/keto acid supplements on proteinuria. The addition of different supplements to an 8% protein diet resulted in an increase of preexisting proteinuria. Keto acids per se do not seem to cause a remarkable degree of proteinuria/hyper-filtration. Our data underline the importance of the protein content of a low-protein diet and the composition of amino/keto acid supplements, as these factors per se can cause hyperfiltration and might accelerate progression of chronic renal failure.