bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytotoxic Effect of Recombinant Mycobacterium tuberculosis CFP‐10/ESAT‐6 Protein on the Crucial Pathways of WI‐38 Cells
Authors: Tsai Kun-Nan , Chan Err-Cheng , Tsai Tsung-Yeh , Chen Kuei-Tien , Chen Chun-Yu , Hung Kenneth , Chen Chung-Ming
Published: June 2009

To unravel the cytotoxic effect of the recombinant CFP‐10/ESAT‐6 protein (rCFES) on WI‐38 cells, an integrative analysis approach, combining time‐course microarray data and annotated pathway databases, was proposed with the emphasis on identifying the potentially crucial pathways. The potentially crucial pathways were selected based on a composite criterion characterizing the average significance and topological properties of important genes. The analysis results suggested that the regulatory effect of rCFES was at least involved in cell proliferation, cell motility, cell survival, and metabolisms of WI‐38 cells. The survivability of WI‐38 cells, in particular, was significantly decreased to 62% with 12.5 μM rCFES. Furthermore, the focal adhesion pathway was identified as the potentially most‐crucial pathway and 58 of 65 important genes in this pathway were downregulated by rCFES treatment. Using qRT‐PCR, we have confirmed the changes in the expression levels of LAMA4, PIK3R3, BIRC3, and NFKBIA, suggesting that these proteins may play an essential role in the cytotoxic process in the rCFES‐treated WI‐38 cells.
Naphthoxy Bounded Ferrocenium Salts as Cationic Photoinitiators for Epoxy Photopolymerization
Authors: Li Zh. Q. , Li M. , Li G. L. , Chen Y. , Wang X. N. , Wang T.
Published: June 2009

To improve the absorption and the bulk of arene ligands, two naphthoxy bounded ferrocenium salts as new cationic photoinitiators, (η6‐α‐naphthoxybenzene) (η5‐cyclopentadienyl) iron hexafluorophosphate (NOFC‐1) and (η6‐β‐naphthoxybenzene) (η5‐cyclopentadienyl) iron hexafluorophosphate (NOFC‐2), were synthesized, characterized, and studied. NOFC‐1 and NOFC‐2 were prepared by the reaction of nucleophilic substitution (SNAr) with naphthol and chlorobenzene‐cyclopentadienyliron salt. Their activity as cationic photoinitiators was studied using real‐time infrared spectroscopy. The results obtained showed that NOFC‐1 and NOFC‐2 are capable of photoinitiating the cationic polymerization of epoxy monomer directly on irradiation with long‐wavelength UV light (365 nm). Comparative studies also demonstrated that they exhibited better efficiency than cyclopentadienyl‐Fe‐cymene hexafluorophosphate (I‐261). When NOFC‐1 and NOFC‐2 were used to efficiently initiate polymerization of epoxide, both rate of polymerization and final conversion increased using benzoyl peroxide (BPO) as sensitizer. DSC studies showed that NOFC‐1 and NOFC‐2 photoinitiators in epoxides possess good thermal stability in the absence of light.
Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia
Authors: Meshinchi Soheil , Appelbaum Frederick R.
Published: June 2009

Hematopoiesis is highly regulated through cytokine-induced stimulation of multiple signal transduction pathways in order to mediate appropriate differentiation and proliferation of specific progenitor populations. Ligand-induced stimulation of the FMS-like tyrosine kinase 3 (FLT3) leads to activation of multiple downstream effector pathways resulting in differentiation and proliferation of specific progenitor cell populations. Genomic alterations of the FLT3 gene, including FLT3 internal tandem duplication (FLT3/ITD) and FLT3 activation loop mutation (FLT3/ALM) lead to autonomous receptor activation, dysregulation of FLT3 signal transduction pathways, contribute to myeloid pathogenesis, and have been linked to response to therapy and clinical outcome. Exploring the mechanisms by which these FLT3 alterations lead to dysregulated proliferation should provide a better understanding of the molecular pathogenesis of acute myeloid leukemia (AML) and may provide insights into potential therapeutic interventions. FLT3 inhibitors are under evaluation for their efficacy in AML patients with FLT3 mutations.
Preclinical Results of Camptothecin-Polymer Conjugate (IT-101) in Multiple Human Lymphoma Xenograft Models
Authors: Numbenjapon Tontanai , Wang Jianyi , Colcher David , Schluep Thomas , Davis Mark E. , Duringer Julienne , Kretzner Leo , Yen Yun , Forman Stephen J. , Raubitschek Andrew
Published: June 2009

Purpose: Camptothecin (CPT) has potent broad-spectrum antitumor activity by inhibiting type I DNA topoisomerase (DNA topo I). It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with relapsed/refractory lymphoma, but with only modest activity. Recently, we have developed a cyclodextrin-based polymer conjugate of 20-(S)-CPT (IT-101). In this study, we evaluated the preclinical antilymphoma efficacy of IT-101 as compared with CPT-11.

Experimental Design: We determined an in vitro cytotoxicity of IT-101, CPT-11, and their metabolites against multiple human lymphoma cell lines. In human lymphoma xenografts, the pharmacokinetics, inhibitions of tumor DNA topo I catalytic activity, and antilymphoma activities of these compounds were evaluated.

Results: IT-101 and CPT had very high in vitro cytotoxicity against all lymphoma cell lines tested. As compared with CPT-11 and SN-38, IT-101 and CPT had longer release kinetics and significantly inhibit higher tumor DNA topo I catalytic activities. Furthermore, IT-101 showed significantly prolonged the survival of animals bearing s.c. and disseminated human xenografts when compared with CPT-11 at its maximum tolerated dose in mice.

Conclusions: The promising present results provide the basis for a phase I clinical trial in patients with relapsed/refractory lymphoma.
Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma
Authors: Nojima Masanori , Maruyama Reo , Yasui Hiroshi , Suzuki Hiromu , Maruyama Yumiko , Tarasawa Isao , Sasaki Yasushi , Asaoku Hideki , Sakai Hajime , Hayashi Toshiaki , Mori Mitsuru , Imai Kohzoh , Tokino Takashi , Ishida Tadao , Toyota Minoru , Shinomura Yasuhisa
Published: June 2009

Purpose: Epigenetic changes such as DNA methylation play a key role in the development and progression of multiple myeloma. Our aim in the present study was to use genomic screening to identify genes targeted for epigenetic inactivation in multiple myeloma and assess their role in the development of resistance to dexamethasone.

Experimental Design: Gene expression was examined using microarray screening, reverse transcription-PCR, and real-time quantitative PCR. DNA methylation was examined using bisulfite PCR, bisulfite sequencing, and bisulfite pyrosequencing in 14 multiple myeloma cell lines, 87 multiple myeloma specimens, and 12 control bone marrow samples. WST-8 assays were used to assess cell viability after treatment with 5-aza-2′-deoxycytidine and/or dexamethasone.

Results: Microarray analysis was done to screen for genes up-regulated by 5-aza-2′-deoxycytidine. In RPMI8226 cells, 128 genes were up-regulated, whereas 83 genes were up-regulated in KMS12PE cells. Methylation of 22 genes with CpG islands in their 5′ regions, including RASD1, was confirmed. Methylation of RASD1 was associated with its inactivation, which correlated with resistance to dexamethasone. Treating multiple myeloma cells with 5-aza-2′-deoxycytidine restored sensitivity to dexamethasone. Methylation of RASD1 was also detected in a subset of primary multiple myeloma specimens, and the levels of methylation were increased after repeated antitumor treatments. Gene signature analysis revealed various genes to be synergistically induced by treatment with a combination of 5-aza-2′-deoxycytidine plus dexamethasone.

Conclusion: Our findings indicate that epigenetic inactivation of genes, including RASD1, plays a key role in the development of dexamethasone resistance in multiple myeloma. Moreover, they show the utility of demethylation therapy in cases of advanced multiple myeloma.
Activation of p38 Mitogen-Activated Protein Kinase Drives Dendritic Cells to Become Tolerogenic inRetTransgenic Mice Spontaneously Developing Melanoma
Authors: Zhao Fang , Falk Christine , Osen Wolfram , Kato Masashi , Schadendorf Dirk , Umansky Viktor
Published: June 2009

Purpose: The purpose of the study was to investigate signaling molecules involved in the acquisition of tolerogenic properties by dendritic cells (DC) in ret transgenic mice with spontaneous melanoma progression and to target these molecules to overcome the barrier for effective melanoma immunotherapy.

Experimental Design: DC functions and expression patterns of p38 mitogen-activated protein kinase (MAPK) in DCs were evaluated in a ret transgenic murine cutaneous melanoma model, which shows high similarity to human cutaneous melanoma with respect to clinical development. In contrast to transplantation melanoma models (like B16), this model allows the study of melanoma progression under conditions of natural interactions between tumor and host cells over time.

Results: We showed a strong tumor infiltration with immature DCs and a reduction in the number of mature DCs in lymphoid organs during melanoma progression. DCs from melanoma-bearing mice secreted significantly more interleukin 10 and less interleukin 12p70, and showed a decreased capacity to activate T cells compared with DCs from tumor-free animals. Observed DC dysfunction was linked to considerable activation of p38 MAPK. Inhibition of its activity in spleen DCs from tumor-bearing mice led to normalization of their cytokine secretion pattern and T-cell stimulation capacity.

Conclusions: Our data show a critical role of constitutively activated p38 MAPK in the acquirement of tolerogenic pattern by DCs during melanoma progression that contributes to the suppression of antitumor T-cell immune responses. We suggest that new strategies of melanoma immunotherapy can include inhibitors of p38 MAPK activity in DCs.
Urine Analysis and Protein Networking Identify Met as a Marker of Metastatic Prostate Cancer
Authors: Russo Andrea L. , Jedlicka Kimberly , Wernick Meredith , McNally Debbie , Kirk Melissa , Sproull Mary , Smith Sharon , Shankavaram Uma , Kaushal Aradhana , Figg William D. , Dahut William , Citrin Deborah , Bottaro Donald P. , Albert Paul S. , Tofilon Philip J. , Camphausen Kevin
Published: June 2009

Purpose: Metastatic prostate cancer is a major cause of death of men in the United States. Expression of met, a receptor tyrosine kinase, has been associated with progression of prostate cancer.

Experimental Design: To investigate met as a biomarker of disease progression, urinary met was evaluated via ELISA in men with localized (n = 75) and metastatic (n = 81) prostate cancer. Boxplot analysis was used to compare the distribution of met values between each group. We estimated a receiver operating characteristic curve and the associated area under the curve to summarize the diagnostic accuracy of met for distinguishing between localized and metastatic disease. Protein-protein interaction networking via yeast two-hybrid technology supplemented by Ingenuity Pathway Analysis and Human Interactome was used to elucidate proteins and pathways related to met that may contribute to progression of disease.

Results: Met distribution was significantly different between the metastatic group and the group with localized prostate cancer and people with no evidence of cancer (P < 0.0001). The area under the curve for localized and metastatic disease was 0.90, with a 95% confidence interval of 0.84 to 0.95. Yeast two-hybrid technology, Ingenuity Pathway Analysis, and Human Interactome identified 89 proteins that interact with met, of which 40 have previously been associated with metastatic prostate cancer.

Conclusion: Urinary met may provide a noninvasive biomarker indicative of metastatic prostate cancer and may be a central regulator of multiple pathways involved in prostate cancer progression.
Effect of Tempol, a Membrane-Permeable Radical Scavenger, on Mesenteric Blood Flow and Organ Injury in a Murine Cecal Ligation and Puncture Model of Septic Shock
Authors: Yuksel B.C. , Serdar S.E. , Tuncel A. , Uzum N. , Ataoglu O. , Atan A. , Hengirmen S. , Iskit A.B. , Guc M.O.
Published: June 2009

Background: Interventions that reduce the generation or the effects of reactive oxygen species exert beneficial effects in a variety of models of septic shock. We investigatedthe effect of tempol, a low-molecular-weight membrane-permeable radical scavenger, on mesenteric blood flow and organ injury in a murine cecal ligation and puncture (CLP) model of septic shock. Materials and Methods: Forty-four Swiss albino mice were anesthetized with chloral hydrate (400 mg/kg, i.p.) and subjected to CLP (except for the sham-operated animals). The animals were divided randomly into 4 groups: the 1st group was sham operated (sham-operated group, n = 10); the 2nd group underwent CLP and was injected with saline (CLP + saline group, n = 12); the 3rd group was sham operated and treated with tempol (10 mg/kg, i.p., sham-treated + tempol group, n = 10); the 4th group underwent CLP and was treated with tempol (10 mg/kg, i.p., CLP + tempol group, n = 12). Mesenteric arterial blood flow (MABF) was measured by Doppler ultrasound. Poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) activity was examined in the liver, lung, and kidneys. Results: In the CLP + saline group, the MABF was significantly lower than in the sham-operated group (p < 0.001). After tempol administration, MABF values significantly increased (p < 0.05). We observed significantly stronger PARP-positive staining in the lungs and kidney glomeruli in the CLP + saline group than in those of the sham-operated group (plung = 0.0148, pglomeruli = 0.0025). A marked reduction in PARP activity was found in the lung and kidney glomeruli of the CLP + tempol group (plung = 0.0026, pglomeruli = 0.0085). There was no significant effect of CLP on PARP activity in the liver and kidney tubuli (pliver > 0.05, ptubuli > 0.05). Conclusion: Tempol improved MABF in a CLP-induced septic shock model. Although tempol could not prevent the activation of PARP in the liver and kidney tubuli, it did attenuate PARP activation in the lung and kidney glomeruli.
New Developments in Lipid Emulsions for Parenteral Nutrition
Authors: Ekman L. , Wretlind A. , Moldawer L.
Published: June 2009

More than one thousand publications have demonstrated the safety and efficacy of today’s lipid emulsions including long chain fatty acids under experimental and clinical conditions. This has resulted in a general acceptance of a dual energy system comprizing both carbohydrates and lipids as non-protein calories in total parenteral nutrition. Non-carnitine-dependent fatty acid has been suggested as a superior energy source in clinical situations where carnitine may be in the subnormal range. A medium chain triglyceride (MCT) emulsion would provide an energy source with a more readily oxidizable substrate. The tolerance of MCT is less than that of long chain triglyceride (LCT), whereby only physical mixtures of these emulsions will be used in humans. A structured lipid (SL) is a triglyceride which includes both medium and long chained fatty acids within the same triglyceride. Emulsions including SL have demonstrated a decreased protein energy expenditure and increased serum albumin in burned animal. The SL has also been superior to LCT emulsions in stimulating muscle protein synthesis and maintaining body weight in hepatectomized animals. These positive effects on protein kinetics have been concomitant with a lower RES involvement during septicemia in burned guinea pigs. Emulsions including fatty acids with odd-number carbons give a possibility to provide a fat emulsion which also could contribute positively to the glucose homeostasis. The omega-3 family of fatty acids has demonstrated a potential pharmacologic effect with regard to their ability to decrease blood viscosity and improve survival rate in endotoxin shock in an experimental model. These observations have been ascribed to changes in thromboxin A2 levels. New lipid emulsions will not only be judged by their properties as nutrients but also with regard to their specific pharmacologic properties.
Interactions between Exogenous Fat and Plasma/Lipoproteins
Authors: Carpentier Y.A. , Richelle M. , Bihain B.E. , Dahlan W. , Haumont D. , Deckelbaum R.J.
Published: June 2009

Fat emulsions are essentially composed of triglycerides and phos-pholipids. Their elimination from the plasma – which is generally rapid is influenced by the amount and the composition of both these components. During their short stay in the vascular compartment, exogenous particles undergo major compositional changes. They acquire various apolipoproteins – namely C-II, C-III, E and A-IV – by transfer from HDL. They also acquire esterified cholesterol from HDL and LDL and transfer exogenous triglycerides and phos-pholipids to these endogenous lipoproteins. These exchanges are affected by the type of triglyceride fatty acids and the amount of phospholipids present in fat emulsions, as well as by the infusion rate. Some 10% of emulsions – with a high phospholipid: triglyceride ratio contain a huge phospholipid excess which can be isolated as a separate fraction from the triglyceride-rich particles. These phospholipids markedly interfere with the metabolism of cholesterol and the plasma lipoprotein profile.
Die Stellung von Carnitin in der klinischen Ernährung
Authors: Böhles H.
Published: June 2009

Bei totaler parenteraler Ernahrung von Ratten konnte bei Carnitinsupplementierung in niedriger (10 mg/kg/Tag) und hoher Dosierung (100 mg/kg/Tag) eine hohe bzw. eine niedrige Ketogenität nachgewiesen werden. Die niedrigere Ketogenität bei hochdosierter Carnitinsupplementierung wird als Substratentzug durch den Transport lang-kettiger Fettsäuren als Carnitinkonjugate aus dem mitochondrialen Matrixraum erklärt. Diese Reaktion führt gleichzeitig zu einer verstärkten Freisetzung von intramitochondrialem CoA.
Trends in Clinical Hemapheresis 1986
Authors: Nydegger U.E. , Vaudaux P. , Castelli D.
Published: June 2009

Die präparative Thrombozytapherese und der therapeutische Plasmaaustausch sind zwei Teilgebiete der Hämapherese, welche gegenüber den anderen Bereichen (Granulozytapherese, Stammzellapherese, Immunadsorption) eine über die experimentelle Anwendung hinausragende praktische Bedeutung erlangt haben. Am Berner Inselspital waren im Jahre 1986 ca. 25% aller transfundierten Plättchenkonzentrate durch Thrombozytapherese hergestellt; an anderen Zentren waren es bis zu 40%. Der therapeutische Plasmaaustausch hat zur Entfernung von Auto- und Alloantikörpern, zirkulierenden Antigenen oder Immunkomplexen, monoklonalen Proteinen oder proteinge-bundenen Toxinen und Metaboliten ein häufig angewendetes Indikationsgebiet gefunden. Vor diesem Hintergrund hat denn die 4. Jahresversammlung der Europäischen Gesellschaft für Hämapherese, Interlaken (Schweiz), 1986 ihr wissenschaftliches Programm auf neue Entwicklungsmöglichkeiten und auf Sicherheitsaspekte ausgelegt. In 31 eingeladenen Hauptreferaten und 76 Individualbeiträgen wurden die 280 Teilnehmer aus Europa und Übersee mit den neuesten Entwicklungen konfrontiert. Die vorliegende Arbeit ist ein Querschnitt durch dieses Programm, dessen Hauptvorträge in der Dezember-Nummer (vol. 7, 1986) von Plasma Therapy and Transfusion Technology erschienen sind.
Improvement of the Safety Systems in Cell Separators
Authors: Neumann H.-J. , Meisberger A. , Mathieu B.
Published: June 2009

The new, extended safety requirements for cell separators call for a new generation of machines to address current safety needs. In order to ensure safe treatment, the complete safety concept is of decisive importance – this includes closed seal-less systems, continuous operation, fractions collected externally to teh centrifuge, and pump tubings, connections and clamps which are color and direction coded. ‘Human failure’ as a cause of fault should be excluded for these highly technical appliances – for example, through the use of ‘fail-safe’ circuits, drip-controlloed ACD flow by a separate adjustable pump, detection of damages to blood components by hemolysis control.
Safety of Apheresis Donation
Authors: Sniecinski I.J.
Published: June 2009

Platelet and granulocyte collections have been done for the past 15 years, and studies on the safety of these procedures have been carried out in many institutions in the USA and abroad. In general, no long-term harmful effects have been observed in donors who had undergone frequent cytapheresis. Significant decreases in donor platelet count were noted following repeated plateletapheresis. However, only a few donors became thrombocytopenic (platelet count < 150,000/μl). Interestingly enough, if the donor was allowed time to recover a normal platelet count, subsequent repeated platelet collection did not induce thrombocytopenia. Rebound of platelets has also been a common finding. Intensive granulocyte collections have not reduced the number of circulating granulocytes, nor has there been any report of leukopenia in donors who had undergone frequent leukocytapheresis. The limiting factor has been the need for hydroxyethyl starch as a sedimenting agent and corticosteroids to stimulate the granulocyte release from the marrow, which have known adverse effects of their own. No significant changes in plasma proteins and other biochemical and hematological parameters have been reported in cytapheresis donors. There is widely-held concern that because the collections of platelets and granulocytes are not selective to the exclusion of lymphocytes, the repeated cytapheresis may deplete the circulating lymphocytes with theoretical risk associated with long-term alterations of the immune response. In addition, if a significant number of red blood cells are removed, the frequent apheresis donations may render the donor anemic. Because of these theoretical risks, recommendations have been formulated in the USA in an attempt to ensure the safety of apheresis donors.
Solid Titration of Octacalcium Phosphate
Authors: Pan H.-B. , Darvell B.W.
Published: June 2009

Octacalcium phosphate (OCP) is of considerable importance as a precursor in the formation of dental enamel and an intermediate phase in the precipitation of hydroxyapatite (HAp) in bone. However, agreement is poor on the solubility product (pKsp), possibly due to the formation of the more stable phase HAp. The system was investigated using solid titration, which has shown reliability in work on HAp and related fluoride minerals, with OCP in 100 mM KCl at 37.0 ± 0.1°C. The constitution of the end point precipitate was determined by X-ray diffraction and selected-electron area diffraction; the particle morphology and elements present were examined by high-resolution field emission scanning, transmission electron microscopy and energy-dispersive X-ray analysis. The titration curve for OCP was found for pH ∼3.4–7.4. The precipitate was HAp at pH 3.6 and 4.5; no residual OCP or other phase was detected. Dicalcium phosphate dihydrate (DCPD) was then found to form at pH 3.6 on further addition of OCP titrant after equilibrium had been achieved, possibly due to easier nucleation at lower pH. However, markedly crystalline HAp was formed in equilibrium for OCP titration with HAp seeding, verifying HAp as the more stable phase. A solubility isotherm for OCP was not obtained as HAp appears to be less soluble in the pH range studied. This adds weight to the view that HAp may be the most stable phase of all calcium phosphates, with further doubt being cast on DCPD being the most stable phase below pH 4.2. However, metastable DCPD may form in an Ostwald succession, depending on supersaturation and nucleation conditions.
Genetic Polymorphisms of the Serotonin Transporter, but Not the 2a Receptor or Nitric Oxide Synthetase, Are Associated with Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease
Authors: Ulrich Silvia , Hersberger Martin , Fischler Manuel , Nussbaumer-Ochsner Yvonne , Treder Ursula , Russi Erich W. , Speich Rudolf
Published: June 2009

Background: Pulmonary hypertension (PH) is prognosti- cally important in chronic obstructive pulmonary disease (COPD). Since PH only weakly correlates with hypoxemia, other factors must play a role. Objective: To investigate whether polymorphisms of the serotonin transporter (5HTT), serotonin-2a receptor (5HTR2a) and endothelial nitric oxide synthetase (eNOS) are related to PH in COPD. Methods: In 59 COPD patients who underwent right heart catheterization, 6-min walking distance, NYHA functional class, pulmonary function tests, blood gases and 5HTT, 5HTR2a and eNOS (4ab and T298C) polymorphisms were determined. Results: Forty-nine COPD patients in NYHA functional class III–IV were included. Ten were excluded due to comorbid causes of PH (mainly chronic thromboembolic). PH (mPAP ≧25 mm Hg) was present in 55% and usually mild, but out of proportion (mPAP ≧40 mm Hg) in 12%. Patients with PH had significantly higher frequencies of the 5HTT-L-allele (52%) compared to individuals without PH (36%), and LL homozygote patients had more severe PH. In patients with out-of-proportion PH, the L-allelic frequency was even 75%. We found no association of 5HTR2a and eNOS polymorphism with PH in COPD. Conclusions: In this COPD cohort we confirm that PH is frequent and usually mild, but out of proportion in a subgroup. We found a significant association of the L-allelic variant of 5HTT with PH overall and especially in out-of-proportion PH. These findings may point towards a role of the serotonin system in COPD-PH and warrant further studies.
Persistent Pleuropulmonary Air Leak Treated with Autologous Blood: Results from a University Hospital and Review of Literature
Authors: Oliveira Frederico H.S. , Cataneo Daniele C. , Ruiz, Jr. Raul L. , Cataneo Antonio J.M.
Published: June 2009

Background: Persistent air leak after pulmonary resection is a difficult complication for thoracic surgeons to manage. Objectives: To show the results of our experience treating persistent pleuropulmonary air leak with autologous blood and review the literature on this specific method of treatment. Methods: Retrospective study of patients with persistent aerial pleuropulmonary fistula treated with autologous blood. The patient’s own blood was collected from a peripheral vein and directly introduced through the pleural drain. An inverted siphon was located in the drainage system to avoid prolonged clamping of the drain. This siphon impeded blood return but not air escape. Results: Between January 2001 and August 2008, 27 patients were treated by the above method. Patient age ranged from 2 to 74 years, and 78% were male. Each procedure used a mean quantity of 92 ml blood. Mean persistent air leak time before pleurodesis was 10.6 days and mean time to fistula resolution after pleurodesis was 1.5 days. Twenty-three (85%) patients had persistent pleuropulmonary air leak closed with the above procedure. Conclusion: Treating persistent pleuropulmonary air leak with autologous blood is promising, but further studies are required to quantify its real effectiveness.
The Compliance with Supplemented Diet by Chronic Uremics and Their Nutritional Status
Authors: Giovannetti S.
Published: June 2009

The compliance with the low-protein, supplemented diet is facilitated or hindered by psychological, social and toxic (severe uremia) factors; however, the most important factor which induces good compliance in patients is the fear of dialysis. The early effect of poor compliance is the appearance of intoxication related to renal failure and the consequent appearance of the uremic syndrome. The assessment of compliance with the low-protein intake is done quite easily by measuring urea appearance; however, regular clinical and laboratory controls are mandatory: anthropometric measurements, evaluation of the serum concentrations of proteins (especially those having a rapid turnover) and the evaluation of thyroid function -which is depressed in a state of malnutrition and improves following nutritional therapy – are adequate for detecting a state of malnutrition following poor compliance.
Amino Acid Therapy for Patients with Chronic Renal Failure
Authors: Bergström J. , Ahlberg M. , Alvestrand A. , Fürst P.
Published: June 2009

Conservative therapy in advanced chronic renal failure is based on low-protein diet. Precautions have to be taken so that the patient does not develop protein deficiency. By supplementing low-protein diets with essential amino acids orally (as tablets) this risk can be minimized. Uremic patients have specific requirements for some amino acids which can be fulfilled by modifying the composition of the amino acid preparation. By supplementing a low-protein diet (–0.3 g protein/kg B.W./day) with an amino acid mixture which contains proportionally more valine and less leucine and isoleucine than prescribed by the Rose formula and, in addition, histidine and tyrosine. the amino acid abnormalities in plasma and muscle can be improved and nitrogen equilibrium maintained.
Effects of a Low-Phosphorus, Low-Protein Diet Supplemented with Essential Amino Acids and Keto Analogues on ‘Overt’ Diabetic Nephropathy
Authors: Barsotti G. , Navalesi R. , Morelli E. , Giampietro O. , Ciardella F. , Cupisti A. , Giovannetti S.
Published: June 2009

In this paper we studied the effects of a low-protein, low-phosphorus supplemented diet in 8 type I diabetics with “overt’ diabetic nephropathy and mild or severe renal insufficiency. We examined the following parameters: the rate of decline of creatinine clearance, the urinary protein loss, the total serum protein, the daily insulin requirement, the serum fasting glucose, the pattern of serum lipids (serum total cholesterol, HDL cholesterol and serum triglycerides), the mean blood pressure and body weight. The rate of decline of creatinine clearance decreased monthly from 1.48 ± 0.20 ml/min during a previous 15.6-month period of unrestricted protein diet (UPD), to 0.13 ± 0.3 ml/min during the 11.4 months on the supplemented diet (SD). The mean blood pressure did not differ during UPD (130.9 ± 7.0 mmHg) and during SD (128.1 ± 1.6 mmHg). Urinary protein loss significantly decreased on SD. and total serum protein increased. The daily insulin requirement and the serum fasting glucose levels significantly decreased on SD. Serum cholesterol was lower during SD than during UPD, while serum HDL cholesterol and serum triglycerides were not significantly modified. In some patients the body weight decreased on SD as a consequence of the disappearance of edema. In conclusion, on the basis of these preliminary observations, the SD slows the progression of renal failure and seems to exert several beneficial and no unwanted side-effects in renal failure of type I diabetics.
Influence of Diet and Underlying Renal Disease on the Rate of Progression of Chronic Renal Failure
Authors: Gretz N. , Meisinger E. , Strauch M.
Published: June 2009

The data presented demonstrate that the underlying renal disease and the type of diet used are considerably influencing the rate of progression of chronic renal failure. In relative terms the course of the renal disease is mostly changed in patients suffering from glomerulo-nephritis, while in absolute terms patients suffering from polycystic kidney disease exhibit the slowest rate of progression. The comparison suggests that a low-protein diet purely based on vegetarian food might considerably slow down the overall rate of progression of chronic renal failure. This finding is supported by results obtained in animal experiments.
Conservative Long-Term Treatment of Chronic Renal Failure with Keto Acid and Amino Acid Supplementation
Authors: Schmicker R. , Vetter K. , Lindenau K. , Fröhling P.T. , Kokot F.
Published: June 2009

In a group of 119 patients with advanced chronic renal failure (serum creatinine level 733 ± 186 μmol/l) the effect of a low-protein diet supplemented with essential amino acids (EAA) or their keto analogues (KA) on uremic metabolism and rehabilitation status was investigated. The protein intake amounted to 0.4 g/kg B.W./day, the phosphorus intake 0.4–0.6 g/day and the energy supply 120–150 kJ/kg B.W./day. In 51 patients there was a substitution with EAA and in 68 patients with their KA. The mean duration of dietary treatment in this study was 19 months (6–64 months). During this time, the serum creatinine increased from 733 + 186 to 1,220 ± 256 μmol/l, whereas the urea nitrogen values remained relatively constant at between 26 and 30 mmol/l. There were no signs of protein malnutrition (nitrogen balance, serum transferrin and serum protein were normal). The hemoglobin concentration remained at > 5 mmol/l with creatinine levels of 1,220 ± 256 μmol/l. During the substitution with KA, there was a significantly greater decrease in serum phosphate (p < 0.05) and parathyroid hormone (PTH) (p < O.01) as compared with the uremics given EAA. In addition, we found a significant increase in testosterone (p < O.Ol) in patients supplemented with KA. Despite advanced chronic renal failure there was a good degree of rehabilitation (full-time work: 21%; part-time work: 66.4%). It can be concluded that a low-protein diet supplemented with EAA or KA can improve the uremic metabolism, rehabilitation status and safely postpone the start of maintenance dialysis.
The 9p21 Myocardial Infarction Risk Allele Increases Risk of Peripheral Artery Disease in Older People
Authors: Cluett Christie , McDermott Mary McGrae , Guralnik Jack , Ferrucci Luigi , Bandinelli Stefania , Miljkovic Iva , Zmuda Joseph M. , Li Rongling , Tranah Greg , Harris Tamara , Rice Neil , Henley William , Frayling Timothy M. , Murray Anna , Melzer David
Published: June 2009

Background—

A common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single-nucleotide polymorphism) is strongly associated with myocardial infarction and major arterial aneurysms. An association with peripheral arterial disease (PAD) was also reported in a sample younger than 75 years, but this disappeared on removal of respondents with a myocardial infarction history, resulting in an odds ratio of 1.09 for PAD (
P
=0.075). We aimed at estimating the association of this variant with an Ankle-Brachial Index (ABI) and PAD in 3 older populations.

Methods and Results—

We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging, and Health, Aging, and Body Composition studies. In 2630 white individuals (mean age, 76.4 years), the C allele at rs1333049 was associated with lower mean ABI measures and with an increased prevalence of PAD. These associations remained after removal of baseline and incident myocardial infarction cases over a 6-year follow-up for both ABI (−0.017 ABI units; 95% CI, −0.03 to −0.01;
P
=1.3�10
−4
) and PAD (per allele odds ratio, 1.29; 95% CI, 1.06 to 1.56;
P
=0.012). These associations also remained after adjustment for known atherosclerosis risk factors, including diabetes mellitus, smoking, hypercholesterolemia, and hypertension.

Conclusions—

The C allele at rs1333049 is associated with an increased prevalence of PAD and lower mean ABI. This association was independent of the presence of diagnosed myocardial infarction and atherosclerotic risk factors in 3 older white populations.
Dynamic Interactions Between Musical, Cardiovascular, and Cerebral Rhythms in Humans
Authors: Bernardi Luciano , Porta Cesare , Casucci Gaia , Balsamo Rossella , Bernardi Nicolò F. , Fogari Roberto , Sleight Peter
Published: June 2009

Background—

Reactions to music are considered subjective, but previous studies suggested that cardiorespiratory variables increase with faster tempo independent of individual preference. We tested whether compositions characterized by variable emphasis could produce parallel instantaneous cardiovascular/respiratory responses and whether these changes mirrored music profiles.

Methods and Results—

Twenty-four young healthy subjects, 12 musicians (choristers) and 12 nonmusician control subjects, listened (in random order) to music with vocal (Puccini’s “Turandot”) or orchestral (Beethoven’s 9th Symphony adagio) progressive crescendos, more uniform emphasis (Bach cantata), 10-second period (ie, similar to Mayer waves) rhythmic phrases (Giuseppe Verdi’s arias “Va pensiero” and “Libiam nei lieti calici”), or silence while heart rate, respiration, blood pressures, middle cerebral artery flow velocity, and skin vasomotion were recorded. Common responses were recognized by averaging instantaneous cardiorespiratory responses regressed against changes in music profiles and by coherence analysis during rhythmic phrases. Vocal and orchestral crescendos produced significant (
P
=0.05 or better) correlations between cardiovascular or respiratory signals and music profile, particularly skin vasoconstriction and blood pressures, proportional to crescendo, in contrast to uniform emphasis, which induced skin vasodilation and reduction in blood pressures. Correlations were significant both in individual and group-averaged signals. Phrases at 10-second periods by Verdi entrained the cardiovascular autonomic variables. No qualitative differences in recorded measurements were seen between musicians and nonmusicians.

Conclusions—

Music emphasis and rhythmic phrases are tracked consistently by physiological variables. Autonomic responses are synchronized with music, which might therefore convey emotions through autonomic arousal during crescendos or rhythmic phrases.
Urinary N-Terminal Prohormone Brain Natriuretic Peptide Excretion in Patients With Chronic Heart Failure
Authors: Linssen Gerard C.M. , Damman Kevin , Hillege Hans L. , Navis Gerjan , van Veldhuisen Dirk J. , Voors Adriaan A.
Published: June 2009

Background—

Urinary excretion is currently regarded as the main mechanism of elimination of N-terminal prohormone brain natriuretic peptide (NT-proBNP). The clinical implications and the value of measurement of urinary NT-proBNP in patients with heart failure are largely unknown.

Methods and Results—

We studied 94 patients (age, 58±11 years; 79% men) with chronic heart failure (CHF) and 20 age- and sex-matched healthy control subjects. Glomerular filtration rate and effective renal plasma flow were measured as clearance of
125
I-iothalamate and
131
I-hippuran, respectively. NT-proBNP levels were determined in both plasma and 24-hour urine collections. Mean left ventricular ejection fraction of CHF patients was 0.28±0.09. Plasma NT-proBNP levels were higher in CHF patients compared with control subjects (median, 547 versus 41 pg/mL;
P
<0.001). Urinary NT-proBNP excretion, however, was substantially lower in CHF patients (median, 0.13 versus 2.3 mL/min;
P
<0.001). Urinary NT-proBNP excretion was independent of estimated glomerular filtration rate. In both CHF patients and control subjects, there was a strong and inverse relation between plasma NT-proBNP concentrations and urinary NT-proBNP excretion (
r
=−0.72 and
r
=−0.65 respectively; both
P
<0.001). Decreased renal plasma flow in CHF was significantly associated with a lower excretion of NT-proBNP (
P
=0.026).

Conclusions—

Urinary NT-proBNP excretion is lower in patients with CHF compared with control subjects and is inversely related to plasma NT-proBNP. Urinary NT-proBNP is associated with renal plasma flow but not with estimated glomerular filtration rate. Elevated levels of plasma NT-proBNP in patients with CHF might be explained not only by myocardial stress but also by a marked decrease in urinary excretion.
Opposite Effects of Training in Rats With Stable and Progressive Pulmonary Hypertension
Authors: Handoko M.L. , de Man F.S. , Happé C.M. , Schalij I. , Musters R.J.P. , Westerhof N. , Postmus P.E. , Paulus W.J. , van der Laarse W.J. , Vonk-Noordegraaf A.
Published: June 2009

Background—

Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment. However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training.

Methods and Results—

Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25±3.9 to 62±3.9 minutes;
P
<0.001). Moreover, capillary density increased significantly (from 1.21±0.12 to 1.51±0.07 capillaries per cardiomyocyte;
P
<0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135±14 to 276±18 leukocytes per 1 mm
2
;
P
<0.001).

Conclusions—

In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings.
Safety and Efficacy of Recombinant Activated Factor VII
Authors: Gill Ravi , Herbertson Mike , Vuylsteke Alain , Olsen Peter Skov , von Heymann Christian , Mythen Monty , Sellke Frank , Booth Frank , Schmidt Thomas Andersen
Published: June 2009

Background—

Blood loss is a common complication of cardiac surgery. Evidence suggests that recombinant activated factor VII (rFVIIa) can decrease intractable bleeding in patients after cardiac surgery. Our objective was to investigate the safety and possible benefits of rFVIIa in patients who bleed after cardiac surgery.

Methods and Results—

In this phase II dose-escalation study, patients who had undergone cardiac surgery and were bleeding were randomized to receive placebo (n=68), 40 μg/kg rFVIIa (n=35), or 80 μg/kg rFVIIa (n=69). The primary end points were the number of patients suffering critical serious adverse events. Secondary end points included rates of reoperation, amount of blood loss, and transfusion of allogeneic blood. There were more critical serious adverse events in the rFVIIa groups. These differences did not reach statistical significance (placebo, 7%; 40 μg/kg, 14%;
P
=0.25; 80 μg/kg, 12%;
P
=0.43). After randomization, significantly fewer patients in the rFVIIa group underwent a reoperation as a result of bleeding (
P
=0.03) or required allogeneic transfusions (
P
=0.01).

Conclusions—

On the basis of this preliminary evidence, rFVIIa may be beneficial for treating bleeding after cardiac surgery, but caution should be applied and further clinical trials are required because there is an increase in the number of critical serious adverse events, including stroke, in those patients randomized to receive rFVIIa.
Twenty-Five-Year Outcome of Pediatric Coronary Artery Bypass Surgery for Kawasaki Disease
Authors: Kitamura Soichiro , Tsuda Etsuko , Kobayashi Junjiro , Nakajima Hiroyuki , Yoshikawa Yoshiro , Yagihara Toshikatsu , Kada Akiko
Published: June 2009

Background—

The long-term outcome of pediatric coronary artery bypass for patients with severe inflammatory coronary sequelae secondary to Kawasaki disease is unknown.

Methods and Results—

One hundred fourteen children and adolescents ranging in age from 1 to 19 (median, 10) years at operation were followed up for as long as 25 years with a median of 19 years. The number of distal anastomoses was 1.7±0.8 per patient, and the internal thoracic artery was used in all but 3, most frequently for left anterior descending artery lesions. Saphenous vein grafts were used in 24 patients, mostly for non-left anterior descending artery lesions. Patients underwent multiple angiograms to evaluate their coronary and graft status. There was no operative or hospital mortality. Both 20- and 25-year survival rates were 95% (95% confidence interval [CI], 88 to 98). Five deaths occurred, all cardiac in origin. Cardiac event-free rates at 20 and 25 years were 67% and 60% (95% CI, 46 to 72), respectively. Percutaneous coronary intervention and reoperation were the most common events. Overall, the 20-year graft patency rate was 87% (95% CI, 78 to 93) for internal thoracic artery grafts (n=154) and 44% (95% CI, 26 to 61) for saphenous vein grafts (n=30) (
P
<0.001), and the rate for non-left anterior descending artery lesions was also significantly better for arterial grafts (87% [95% CI, 73 to 94]; n=59) than for saphenous vein grafts (42% [95% CI, 23 to 60]; n=27) (
P
=0.002). Eighty-eight patients (77%) remain on medications, but all 109 survivors are presently symptom free in their daily activities.

Conclusions—

Although the 25-year survival was excellent after pediatric coronary bypass for Kawasaki disease, the event-free rate declined progressively. This reality mandated continued follow-up. Reinterventions successfully managed most cardiac events. An internal thoracic artery graft was the most favorable for children.
Arginase II Knockout Mouse Displays a Hypertensive Phenotype Despite a Decreased Vasoconstrictory Profile
Authors: Huynh Ngan N. , Andrews Karen L. , Head Geoffrey A. , Khong Sacha M.L. , Mayorov Dmitry N. , Murphy Andrew J. , Lambert Gavin , Kiriazis Helen , Xu Qi , Du Xiao-Jun , Chin-Dusting Jaye P.F.
Published: June 2009

Arginase upregulation is associated with aging and cardiovascular diseases. In this study we report on the cardiovascular phenotype of the arginase II knockout (KO) mouse. We demonstrate that vascular sensitivity and reactivity altered over time in these animals such that no influence on responses to vasoconstrictor activity was observed in 7-week-old KO mice, but dampened responses to norepinephrine and phenylephrine were observed by 10 and 15 weeks with Rho kinase influencing these effects in the 15-week-old animals. Despite these dampened vasoconstrictory responses, KO mice demonstrated increased mean arterial pressure from 8 weeks old. This hypertensive phenotype was associated with an increase in left ventricular weight, left ventricular systolic pressure, and diminished diastolic function. KO mice also show enhanced plasma norepinephrine turnover, suggesting an increased sympathetic outflow. In conclusion, our data suggest that global loss of arginase II activity results in hypertension. We suggest that this strain of mouse warrants further investigation as a potentially novel model of hypertension.