bluuebunny/crossref_metadata_2025 huggingface dataset:
Myths about the structure and function of porcine islets
Authors: Bonner‐Weir Susan , Davalli Alberto M. , Scaglia Luisa , Hollister Jennifer , Weir Gordon C.
Published: November 2008

Abstract: As we consider using porcine islets for human transplantation many questions about the porcine ß cells arise. Issues about how many are necessary, how their mass is influenced by glycemic levels, how much they can be renewed, and how to measure their mass need to be addressed. Our knowledge from rodent studies can initially be extrapolated since there are more similarities between mammalian islets than differences. Eventually, porcine islets will need to be studied carefully for these parameters.
Screening of baboons as potential liver donors for humans
Authors: Luo Y. , Tanlguchi S. , Kobayashi T. , Niekrasz M. , Cooper D.K.C.
Published: November 2008

Abstract: The baboon could supply organs for humans, and there may be a particular role for baboon livers in “bridging” patients in terminal hepatic failure who are awaiting a human liver. We have investigated 10 healthy adult baboons in regard to i) hepatic metabolism and ii) the presence of infections that might be transferred to a human recipient with a transplanted organ. Blood was drawn for a general profile of hematologic, metabolic, and biochemical parameters and compared with standard values for humans. All baboons were i) examined by a veterinarian, ii) tuberculin tested, iii) virologically screened, and iv) screened for bacterial, protozoal, helminth, and fungal infections. Tests i–iii were repeated after a 3‐month interval. BUN, LDH, and SGOT levels were higher than in the human in >50% of the cases. Fasting blood glucose, uric acid, cholesterol, albumin, and total bilirubin levels were frequently lower. Serology was positive both for HTLV1 and STLV in three baboons. All baboons were positive for foamy virus, but this was not thought to exclude them as organ donors. There was a high incidence of positivity for DNA viruses (SA8, SA6, HSV, CMV, and EBV) but generally indicated past, rather than active, infection. Hepatitis A serology, but not IgM, was positive in four baboons, but hepatitis B and C were negative in all (except in two where there was transient positivity to hepatitis B). SA11 rotavirus serology was positive in six. No evidence for mycobacterial, protozoal, helminth, or fungal infection was found, although one baboon had positive serology for toxoplasma IgG. We would conclude that six or possibly seven of the 10 baboons would be acceptable as donors of organs for humans. Only the three with positive serology for the retroviruses HTLV1 and STLV would be definitely excluded. A case could be made for also excluding the baboon positive for Toxoplasma IgG.
Aggregation of human platelets induced by porcine endothelial cells is dependent upon both activation of complement and thrombin generation
Authors: Robson Simon C. , Siegel Jonathan B. , Lesnikoski Beth A. , Kopp Christoph , Candinas Daniel , Ryan Una , Bach Fritz H.
Published: November 2008

Abstract: The binding of human xenoreactive antibody (XNA) to porcine endothelium with complement (C) activation via the classical pathways is considered the major event triggering hyperacute rejection (HAR) with microvascular thrombosis in vivo. As C components are linked to key events in blood coagulation, we have examined pathways whereby activation of complement by endothelial cells results in xenogeneic platelet activation in vitro.

Methods: Cultured porcine aortic endothelial cells (pEC), human aortic endothelial cells (HAEC) or human umbilical vein endothelial cells (HUVEC) were prepared in suspension (5 × 106/ml) using EDTA‐collagenase. Human platelet rich plasma (PRP) and washed platelets with platelet poor plasma (PPP) were prepared from control, drug free, volunteer donors. All aggregation tests used a two‐sample, four‐channel, model 560 Ca Lumi‐Aggregometer (Chronolog Corporation, Havertown, PA). Selected assays for complement (C3a; C5b‐C9; CH50; and AP50) were then performed on supernatant fluids. To test the effects of complement inhibition and thrombin antagonists, the following agents were pre‐incubated with PRP (or PPP) in various titrations for 10 min at 37°C prior to combination with pEC in the aggregometer: soluble complement receptor typel (sCR1); Cobra Venom Factor (CVF), heparin, hirudin, and anti‐CD31 (anti‐PECAM). In addition, pEC, HAEC, and HUVEC were incubated with 10–20% human PPP; supernatant fluids were harvested at various time points and used for platelet activation assays and for functional tests of thrombin or levels of thrombin‐antithrombin complexes (TAT).

Results: pEC but not HAEC/HUVEC resulted in activation of PRP or washed platelets only in the presence of supplemental PPP. Platelet activation could be inhibited by pre‐incubation of samples with CVF (2–5 IU/ml to deplete complement components) and to a variable extent with sCRl (1–2 mg/ml). Complement assays confirmed activation of C3 by the classical pathway with reduction of the CH50 while C6 deficient samples also supported platelet activation. Aggregation of platelets was inhibited by preincubation of PRP with concentrations of hirudin (1 unit/ml) and heparin (5–10 units/ml) sufficient to neutralize thrombin generated. Supernatant fluids containing PPP removed from pEC were found to have increased levels of thrombin and thrombin‐antithrombin complexes and could also activate platelets in a hirudin sensitive manner.

Discussion: Platelet and pEC combinations underwent aggregation only in the presence of complement components. This process appeared independent, at least in part, of the assembly of terminal complement components. Consequent pEC generation of thrombin appeared adequate to trigger platelet aggregation which could in turn be inhibited by hirudin or heparin in vitro.
Inhibition of platelet GPIIbIa in an ex vivo model of hyperacute xenograft rejection does not prolong cardiac survival time
Authors: Robson Simon C. , Young Vincent K. , Cook Nigel S. , Kottirsch Georg , Siegel Jonathan B. , Lesnikoski Beth Ann , Candinas Daniel , White David J.G. , Bach Fritz H.
Published: November 2008

Abstract: Discordant cardiac xenografts are rapidly rejected in a process characterized by platelet activation with microvascular thrombosis, termed hyperacute rejection (HAR). The fibrinogen receptor GPIIbIIIa is crucial for the formation of platelet aggregates and potentiates platelet adhesion to subendothelial matrix. We have studied the effects of a specific GPIIbIIIa antagonist (GPI 562) in an ex vivo working heart model using discordant porcine hearts perfused with fresh, heparinized human blood. Stable plasma GPI 562 inhibitory levels were confirmed by inhibition of human platelet aggregation in vitro. Biopsies from the left ventricle of rejected hearts were analyzed by immunopathology. Control porcine hearts (n=8) underwent HAR and ceased functioning at around 60 min. Hearts perfused with human blood containing GPI 562 at 0.5 μM (n=5) appeared to show an initial increase in coronary blood flow relative to controls, but neither this difference nor survival times of the hearts reached significance. Mean cardiac output values were 7.3 ml/g (SEM 2.5) in the experimental group and 5 ml/g (SEM 0.6) in the control group following 5 min of working mode and were comparable at other timepoints. Platelet counts in the perfusate were maintained in the presence of GPI 562, unlike the reduction of over 50% in control samples. Immunohistochemistry suggested decreased platelet vascular plugging as determined by P‐selectin staining in the GPI 562 group, with associated reduction in neutrophil adherence and fibrin deposition. The use of GPI 562 in this ex vivo model conferred no marked benefits with respect to cardiac function and explant survival despite some positive differences on histological comparison. Further studies of this agent, in association with modalities of complement inhibition, are warranted in other models of discordant xenograft rejection.
Cellular xenoresponses: Observation of significant primary indirect human T cell anti‐pig xenoresponses using co‐stimulator‐deficient or SLA class II‐negative porcine stimulators
Authors: Dorling Anthony , Binns Richard , Lechier Robert I.
Published: November 2008

Abstract: We have documented the strength and characteristics of the in vitro human anti‐porcine indirect T cell response using porcine stimulators that were unable to provoke a direct xenoresponse. Our results indicate that HLA‐DR‐restricted and HLA‐DQ‐restricted CD4+ T cells recognise porcine xenoantigens presented by conventional APC, rather than xenospecific B cells. Limiting dilution analysis assays indicate a high precursor frequency of T cells with indirect xenospecificity in the peripheral blood of human responders. These data demonstrate that the indirect response requires no priming, but instead reflects the large number of pig‐specific antigens.
Human anti‐pig T‐cell mediated cytotoxicity
Authors: Yamada Kazuhiko , Seebach Jörg D. , DerSimonian Harout , Sachs David H.
Published: November 2008

Abstract: Miniature swine have a variety of advantages as potential donors for human xenotransplantation, including size, physiological similarities, and breeding characteristics. To investigate the nature of the human anti‐pig xenogeneic cellular response, we performed standard 51Cr‐release cell‐mediated lympholysis (CML) experiments. The major histocompatibility complex (MHC) allele specificity of the xenogeneic cellular response was tested on porcine target cells of three distinct homozygous MHC haplotypes (SLAaa, SLACC, SLAdd) and three intra‐MHC recombinant haplotypes (SLAjj, SLAgg, SLAkk), obtained from our herd of partially inbred miniature swine. After stimulation with irradiated porcine peripheral blood mononuclear cells (PBMC) of SLAaa haplotype, a strong nonspecific cytotoxic response of the bulk culture against xenogeneic targets of all three haplotypes was observed. However, SLA allele specificity could be demonstrated after T cell enrichment, and mapping experiments revealed predominantly SLA class I restriction of xenoreactive cytotoxic T lymphocytes (CTLs), although some class II restriction was also observed. The experiments were repeated in the presence of anti‐T cell monoclonal antibodies, anti‐CD3 (OKT3), anti‐CD2 (35.1), anti‐CD4 (OKT4), or anti‐CD 8 (OKT8). The bulk xenogeneic CML was not inhibited by any of the anti‐T cell antibodies tested. However, after T cell‐enrichment, lysis of porcine targets was significantly inhibited by anti‐CD3 or anti‐CD8 antibody and partially inhibited by anti‐CD2 antibody. In comparable assays, the human allogeneic CML was blocked by anti‐CD3 and anti‐CD8, but not by anti‐CD2 or anti‐CD4 antibodies. Finally, the cytotoxic activity of A3b3, a human CD4+ T‐cell clone, was tested. A3b3 lysed xenogeneic targets of SLAaa haplotype, but not SLACC or allogeneic targets, and was inhibited by anti‐CD4, anti‐CD2, and anti‐CD3 antibodies, but not by anti‐CD8. With the aid of intra‐MHC recombinant haplotypes, the xenogeneic CML reactivity of A3b3 was mapped to SLA class II, suggesting direct xenogeneic recognition of porcine MHC class II antigens by human T cells. Thus, the human anti‐pig cell‐mediated cytotoxic response is similar in magnitude to comparable allogeneic responses, and involves both SLA class I and class II restricted T‐cell mediated cytotoxicity, as well as additional nonspecific killing, possibly by NK cells.
Ratites (ostrich, emu) as potential heart donors for humans: Immunologic, anatomic, and physiologic considerations
Authors: Taniguchi S. , Neefhling F.A. , Oriol R. , Kobayashis T. , Ye Y. , Niekrasz M. , Peters L. , Kosanke S. , Koren E. , Cooper D.K.C.
Published: November 2008

Abstract: The vascular endothelium of all mammals tested to date expresses the αGal epitope, which is a major target for human natural antibodies. Birds, including the ratites (e.g., ostrich and emu) that might prove suitable as donors of hearts for humans, do not express αGal epitopes. Human anti‐emu heart vascular endothelial antibodies were demonstrated not to be anti‐αGal antibodies. The ratite heart is four‐chambered and has many structural similarities to that of humans and other mammals. However, ratite vascular endothelium expresses βGal epitopes, and human plasma was demonstrated to be cytotoxic to both ostrich and emu aortic endothelial cells in culture. In vivo or ex vivo hemoperfusion of emu and ostrich hearts by baboon blood resulted in poor function of both hearts for <1 hour, with histopathologic features of hyperacute rejection seen in the ostrich, but not the emu, heart. We conclude that, despite the absence of αGal epitopes, the ratite offers no advantage over the pig as a donor of organs for humans. Anatomic, histologic, physiologic, and immunologic species‐related differences probably make the ratite heart unsuitable for transplantation into humans.
Improved experimental cardiac xenograft survival with cyclophosphamide and intrathymic donor cells
Authors: Mohiuddin Muhammad M. , Shen Zhenya , Yokoyama Hitoshi , Goldstein Charles , DiSesa Verdi J.
Published: November 2008

Abstract: Tolerance to cardiac allografts can be induced by pretreatment of the recipient with antilymphocyte serum (ALS) and intrathymic donor cells. Our previous efforts to extend this observation to experimental cardiac xenografts in a usually concordant species combination led to antibody and complement mediated hyperacute rejection. Hyperacute rejection can be abrogated by the use of cobra venom factor but this agent even in combination with intrathymic pretreatment is not successful in prolonging xenograft survival in this model. In contrast to the immune response to allografts, which is predominately mediated by T cells, a B cell antibody mediated response plays an important role in xenotransplantation. Cyclophosphamide is active against dividing B cells. In the present experiments in a concordant hamster to rat cardiac xenograft model, we used the combination pretreatment of cyclophosphamide (20 mg/kg IV) injected on days ‐19, ‐16, ‐13, and‐10 prior to heart transplantation, ALS (1 ml intraperitoneally), and hamster spleen cells (25 × 106 intrathymically) given on day ‐18, 1 day after the first dose of cyclophosphamide. Grafted hearts were assessed by daily palpation of the graft pulse through the abdominal wall of the recipient. In untreated control recipients, graft survival was uniformly 3 days. Significant prolongation of graft survival was seen in pretreated animals whose grafts survived 4, 5, 5, 6, and 6 (mean 5.2) days (P<0.01). These studies show that an anti B cell regimen, when coupled with intrathymic pretreatment, results in prolongation of experimental cardiac xenograft survival. However, in contrast to allotransplantation, permanent tolerance cannot be achieved by this pretreatment protocol.
Identification and characterization of monoclonal antibodies that partially block human natural antibody binding to pig endothelial cell xenoantigens
Authors: Kearns‐Jonker Mary , Cramer Donald V. , Fraiman Mark , Middleton Yvette , Shirwan Amal , Swensson Joyce , Wu Guo Duo , Makowka Leonard
Published: November 2008

Abstract: The shortage of human donors for clinical transplantation has led to a serious consideration of the use of non‐human species as organ donors. The major barrier to the clinical use of xenografts from species such as the pig in human transplantation has been the aggressive nature of the immune‐mediated rejection of the graft. We have recently identified the molecular weights of several endothelial cell surface proteins that may be targets of human antibody‐mediated responses to pig aortic endothelial cells (PAEC). In this series of experiments, we produced a panel of rat monoclonal antibodies (Mabs) to PAEC in an effort to identify Mabs that detect pig xenoantigens. Mabs were selected based on flow cytometric binding to PAEC, pig platelets, and various pig cell lines, including a pig kidney cell line (LLC‐PK1) reported to react with human natural antibodies (HNA). Eleven of the eighty‐three antibodies produced were cytotoxic for PAEC. Six of the cytotoxic clones recognized a 44 kDa protein and two of the clones recognized a 115 kDa protein expressed on the surface of PAEC. Since PAEC target antigens recognized by human natural antibodies include both 115 and 44 kDa antigens, these Mab clones were selected for further study. Several distinct patterns of tissue reactivity were demonstrated within this group of antibodies by immunohistochemical analysis; however all monoclonal antibodies were highly reactive with endothelial cells in all tissues examined. Two monoclonal antibodies recognizing antigens that are highly expressed on pig endothelial cells (92–98%) and pig platelets (74–92%), but moderately expressed on pig splenocytes (33–38%), were capable of reproducibly blocking 48–53% of human IgM binding to pig endothelial cells when analyzed with flow cytometry. This data suggests that these Mabs may recognize epitopes of potential significance in the human‐to‐pig xenograft reaction.
Thrombin Inhibition in discordant xenograft rejection
Authors: Lesnikoski Beth‐Ann , Candinas Daniel , Otsu Ichiro , Metternich Rainer , Bach Fritz H. , Robson Simon C.
Published: November 2008

Abstract: Microvascular thrombosis and the associated platelet and endothelial cell activation are prominent observations in xenograft rejection. This pathological picture could be related to the excessive generation of thrombin in the context of either inflammation or putative inter‐species molecular incompatibilities between activated coagulation factors and their natural anticoagulants. Relatively selective thrombin Inhibition with the serine protease inhibitor SDZ MTH 958 (MTH‐958) are independent of heparinoids and anti‐thrombin III. MTH‐958 has been shown to significantly prolong porcine cardiac function during perfusion with human blood in an ex vivo model. The aim of this study was to validate the role of thrombin generation in a rodent model of discordant xenograft rejection in vivo.

The effect of thrombin inhibition with MTH‐958 was tested in both hyperacute rejection (HAR) and delayed xenograft rejection (DXR) after decomplementation with cobra venom factor (CVF) in normal Lewis (Lew) rats and Intrinsic C6 deficiency In PVG (C6‐/PVG) recipient rats. Recipient rats received heterotopic guinea pig cardiac xenografts and were treated with titrated doses of MTH‐958 until the time of graft rejection. Plasma samples at selected time points were examined to confirm effective thrombin inhibition, and rejected grafts were analyzed by immunohistology. MTH‐958 significantly improved graft survival in HAR albeit the extent of prolongation was not marked, but the agent failed to prolong survival In CVF‐treated Lew rats. In C6‐/PVG rats receiving MTH‐958, a significantly reduced graft survival time was observed when compared with C6‐/PVG controls. The grafts from MTH‐958‐treated animals showed dense deposits of C3, IgM, and IgG with fibrin levels similar to controls.

The thrombin antagonist tested could prolong xenograft survival during HAR but had no benefit in DXR. The relative non‐specificity of the serine protease inhibitor MTH‐958 with the potential activation of alternative pathway of complement via the inhibition of factor I could account for the failure to prolong xenograft survival in DXR. The pathogenetic significance of thrombin generation in this situation remains to be determined by the use of more selective and pharmacologically acceptable I anti‐thrombin agents.
Adenoviras‐mediated expression of human CD59 on xenogeneic endothelial cells: Protection against human complement‐mediated lysis and induction of cellular activation by adenoviral transduction
Authors: Charreau Béatrice , Tesson Laurent , David Anne , Cassard Armelle , Quantin Beatrice , Pavirani Andrea , Soulillou Jean‐Paul , Anegon Ignacio
Published: November 2008

Abstract: The expression of human regulators of complement activation in endothelium of a transplanted organ is an approach to overcoming the complement (C)‐mediated rejection of a xenograft. We designed a replication‐deficient adenovirus (Ad) containing the human CD59 cDNA (AdCD59) in order to induce expression of human CD59 on xenogeneic endothelial cells (EC) and confer protection against human C‐mediated lysis. In vitro transduction of rat EC with AdCD59 led to consistent levels of CD59 expression in all cells and significantly reduced EC lysis induced by human xenogeneic natural antibodies (XNA) binding and C activation. In addition, we analyzed whether Ad transduction had modified the phenotype of EC and the xenogeneic recognition of EC by human serum. For this, we first demonstrated that transduction of rat EC with AdCD59 or an Ad carrying the lacZ gene (AdlacZ) markedly enhanced the expression of some cell‐membrane markers of EC activation, including class I MHC antigens and rat CD59, to levels comparable to those obtained with TNFα Up‐regulation of class I MHC antigens was observed for both mRNA and protein expression. In contrast, AdCD59‐mediated gene transfer slightly increase intercellular adhesion molecule‐1 (ICAM‐1) and did not modify the expression of Crry, a rat complement regulatory molecule. Second, we showed that these phenotypic modifications of EC did not affect the expression of the Galαl‐3Gal epitope and the binding of human XNA. In addition, neither AdlacZ‐mediated transduction, nor TNFα treatment, modified the sensitivity of xenogeneic EC to human serum‐mediated lysis. In conclusion, this study demonstrated that transduction of human CD59 with an adenoviral vector conferred resistance to xenogeneic cultured EC against human C‐mediated lysis but is associated with cellular activation of transduced EC. This finding may have important implications for the in vivo protocols and strategies intended to generate safer Ad vectors.
Short‐term suppression of the xeno‐immune response with mCTLA4‐Fc treatment
Authors: Tran Hanh M. , Nickerson Peter W. , Patel Anita , Strom Terry B. , Allen Richard D.M. , O'Connell Philip J.
Published: November 2008

Abstract: A murine CTLA4‐Fc chimeric fusion protein was used to determine if inhibition of the CD28‐B7 pathway for T‐cell activation could result in prolonged or indefinite survival of pancreatic islet xenografts in mice. B6AF1 recipients of Wistar rat pancreatic islet xenografts that received short‐term mCTLA4‐Fc treatment had prolonged graft survival (28 days vs. 9 days) but all animals rejected their grafts. This survival advantage was similar to that achieved with short‐term depletion of CD3+ or CD4+ T cells with 145.2C11 (median graft survival 21 days) or GK1.5 mAb (median graft survival 33 days), respectively. Combined GK1.5, 145.2C11, and mCTLA4‐Fc treatment for the first 2 weeks post‐transplant and maintenance therapy with GK1.5 and mCTLA4‐Fc for the next 4 weeks produced the best results (median survival 63 days). However, islet xenografts were rapidly rejected upon cessation of treatment. Unlike in allografts, short‐term inhibition of the CD28‐B7 pathway with mCTLA4‐Fc did not result in long‐term rat xenograft survival. This suggests that the conditions necessary for quenching xenograft rejection and inducing tolerance differ significantly from those found in allotransplantation and acquired xenograft tolerance may be difficult to achieve.
Possible association between screening BV at the prenatal visit and reduced cervical cerclage: Multi‐center questionnaire in Hokkaido, Japan
Authors: Shimano Satoshi , Kawamura Mituhiro , Sonoda Tomoko , Minakami Hisanori
Published: November 2008

Aims:  To study the screening frequency for cervical cancer, Chlamydia trachomatis (CT) infection, and bacterial vaginosis (BV) among pregnant women, and to study the association between administration of these three screening tests and performance of cervical cerclage (CC) in Hokkaido during 2004.

Methods:  Questionnaires were mailed to 70 clinics providing prenatal care only and to 113 hospitals providing prenatal care and performing deliveries. Responses were obtained anonymously.

Results:  A total of 6744 pregnant women received prenatal care at the 36 responding clinics and 24 050 deliveries were performed at the 56 hospitals. The percentage of clinics that screened all pregnant women for cervical cancer, CT infection or BV was 66.7%, 69.4% and 33.3%, respectively, and the corresponding percentages among the hospitals were 87.5%, 87.5% and 57.1%, respectively. Pregnant women found to have CT infection or BV, were all treated. Screening for cervical cancer or CT infection was not associated with the frequency of CC. On the other hand, screening for BV was significantly associated with the frequency of CC (P = 0.0006). The frequency of emergency CC was 0.8% among women who received prenatal care at hospitals that did not perform BV screening, while it was only 0.2 or 0.3% among women who received prenatal care at hospitals that performed BV screening on all pregnant women or on those women who were suspected of having BV, respectively.

Conclusion:  Our results suggest that the frequency of emergency CC may be reduced in women who receive BV screening and subsequent treatment of positive cases during pregnancy.
Resistance of kale varieties to attack by Mamestra brassicae
Authors: Cartea María E. , Soengas Pilar , Ordás Amando , Velasco Pablo
Published: November 2008

1 The objectives of this work were to study the resistance of six kale (Brassica oleracea acephala group) varieties to cabbage moth Mamestra brassicae (L.) expressed as antibiosis and to determine the effect of plant age on larval survival and development.

2 The influence of plant age on resistance was determined using leaves from seedlings and from mature plants. Survival and development of M. brassicae larvae and feeding rates were determined in laboratory bioassays.

3 Leaves from seedlings were more suitable than those of mature plants for establishing differences in resistance. There were significant differences between kale varieties in larval survival, growth rate, leaf feeding, and time to pupation but not pupal weight. The varieties MBG‐BRS0031, MBG‐BRS0351, and MBG‐BRS0287 reduced survival of M. brassicae larvae. Larvae that fed on MBG‐BRS0060 were the heaviest and took the longest time to pupation. MBG‐BRS0031 was consumed significantly less by larvae than were all the other varieties examined. Leaves from mature plants of MBG‐BRS0142 and MBG‐BRS0170 were defoliated significantly less than those of other varieties.

4 In conclusion, the variety MBG‐BRS0031 may be a promising source of resistance to M. brassicae. Leaf antibiotic resistance was shown to play a role in defense against M. brassicae attack but it is not the only possible mechanism of resistance.
Relationship between milk consumption and prostate cancer: a short review
Authors: Givens D. I. , Morgan R. , Elwood P. C.
Published: November 2008

Epidemiological evidence based on both case–control and prospective cohort studies points to an overall positive relationship between consumption of milk/dairy products and the risk of developing prostate cancer. There are inconsistencies in the data, but taken together, the increased relative risk does not seem to be high. A number of mechanisms have been proposed to account for the relationship, with most attention being focused on the involvement of calcium/vitamin D, insulin‐like growth factor‐1 and oestrogens, although it is unlikely that a single factor in milk is implicated. In any event, any added risk of prostate cancer from increased milk consumption has to be set alongside other evidence, which shows that increased milk consumption can provide substantially reduced risk of coronary heart disease, stroke and colorectal cancer, particularly because cardiovascular disease accounts for vastly more deaths than prostate cancer (although the latter is of course restricted to men).
Enrichment of n‐3 fatty acids and conjugated linoleic acid in beef: ProSafeBeef
Authors: Moloney A. P. , Scollan N. D. , Miles L.
Published: November 2008

ProSafeBeef is a 5‐year integrated project funded by the European Commission under the sixth Framework Programme. The overall aim is to advance beef safety and quality across Europe and the work programme spans seven integrated “pillars”. Pillar 3 is concerned with producing safe beef and beef products with enhanced nutritional and eating quality characteristics. A particular focus is on the development of strategies to enhance the concentrations in beef of those fatty acids considered to be of benefit to human health, without causing a detrimental effect on the appearance, shelf‐life or eating quality of the beef. There is accumulating evidence of the importance of long‐chain n‐3 (omega‐3) polyunsaturated fatty acids (PUFAs) for human health and disease prevention, and also evidence from experimental studies that has shown anticarcinogenic, antiatherogenic, and anti‐obesity effects of two isomers of conjugated linoleic acid (CLA). Based on this evidence, the major focus of research efforts to improve the nutritional value of beef has been on increasing the concentration of the n‐3 PUFAs and CLA. Considerable progress has been made within pillar 3 of ProSafeBeef to meet this aim, primarily by manipulating the diet of cattle. Fundamental information on ruminal lipid metabolism and on the control and/or prevention of ruminal hydrogenation of dietary lipids arising from research within ProSafeBeef will facilitate the production of beef with a ‘healthier’ fatty acid profile. Moreover, strategies will be defined for industry on how to optimise nutritional and sensory properties and oxidative quality of beef products, by combining the nutritional enhancement made in the live animal together with target levels of functional ingredients to be added during processing.
EARNEST – the early nutrition programming project
Authors: De La Hunty A.
Published: November 2008

The Early Nutrition Programming Project, EARNEST, is a large research programme which brings together a multi‐disciplinary team of international scientists and leaders in key areas of the early nutrition programming field from major research centres across 16 EU countries. The integrated programme of work includes experimental studies in humans, prospective observational studies and mechanistic animal work including physiological studies, cell culture models and molecular techniques. It is funded by the EC under the Sixth Framework Programme for Research and Technical Development and is co‐ordinated by the University of Munich. The project started in 2005 and will run to 2010. The first results are now becoming available.
ADP‐induced platelet aggregation in acute ischemic stroke patients on aspirin therapy
Authors: Cha J.‐K. , Jeon H.‐W. , Kang M.‐J.
Published: November 2008

Background and purpose:  Aspirin is an important therapeutic regimen to prevent the recurrent ischemic events or death after acute ischemic stroke. In this study, we evaluated the relationship between the extent of adenosine diphosphate (ADP) ‐induced platelet aggregation and outcome in acute ischemic stroke patients on aspirin therapy.

Methods:  We selected 107 acute ischemic stroke patients who had been prescribed aspirin and evaluated platelet function test by using optic platelet aggregometer test after 5 days of taking it and investigated the prognosis 90 days after ischemic events. Kaplan–Meyer curve was used for survival analysis.

Results:  After stratification of the subjected patients by tertiles of ADP‐induced platelet aggregation, the events rates were 7.4%, 9.3% and 30.8% (P = 0.023). In multiple logistic regression analysis, old age over 70 years (OR, 13.7; 95% CI, 2.14–88.07; P = 0.001) and the increased ADP‐induced platelet aggregation had independent significance to the risk of primary end‐points after acute ischemic stroke (OR, 1.1; 95% CI 1.01 to 1.20; P = 0.026).

Conclusions:  This study showed that the increased ADP‐induced platelet aggregation under using aspirin is associated with poor outcome after acute ischemic stroke.
A systematic review of the epidemiology of multiple sclerosis in South America
Authors: Cristiano E. , Patrucco L. , Rojas J. I.
Published: November 2008

Hundreds of publications dealing with the prevalence of multiple sclerosis (MS) throughout the world exist, but little data have been published from South America. Epidemiological studies of MS vary according to environmental, racial and genetic factors; a better understanding of MS in South America would help us to elucidate the disease pattern in this population. The aim of this study is to review the evidence relevant to MS epidemiology in South America. We performed a systematic review of articles of MS epidemiology in South America, with special emphasis on those providing information on the incidence and prevalence of MS (population‐based studies). Six papers provided information on MS epidemiology. One paper used the capture‐recapture methodology, while the remainder employed traditional methods to collect the data. Population‐based studies showed an MS prevalence rate ranging from 1.48 to 17 per 100 000 inhabitants. Available data suggest that the prevalence of MS is lower in South America than in developed countries. The reason for this observation is unknown. Some investigators suggest that certain environmental factors like sun exposure and vitamin D supplementation or the called ‘hygiene hypothesis’ may protect this population. Future studies will contribute to elucidate the etiology of that difference.
Value relevance of advertising expenditure: A review of the literature
Authors: Ali Shah Syed Zulfiqar , Akbar Saeed
Published: November 2008

This paper presents a review of the relevant empirical literature on advertising value relevance. The current dominant accounting practice is to treat advertising as a current period expense. There has been growing evidence, however, to suggest that advertising should be viewed as an investment in long‐term brand equity. While the primary focus is on the valuation studies of advertising expenditure, the paper also provides an overview of various other studies that relate advertising to profitability or sales of the firm or industry to investigate the effects of advertising expenditure. As a consequence, it is emphasized that there has been a recent shift to the use of valuation models in exploring the nature of advertising expenditure. Since market value captures both the current and future profitability effects of advertising, valuation models are often seen as a better alternative in exploring the intangible nature of advertising expenditure. It is found that the bulk of evidence on advertising value relevance comes from the US, where there has historically been greater disclosure of advertising expenditure. There appears to be little evidence on this matter in the UK, however. This may largely be attributed to the lack of advertising data availability in the UK.
Population viability analysis for captive breeding and reintroduction of the endangered Columbia basin pygmy rabbit
Authors: Zeoli L. F. , Sayler R. D. , Wielgus R.
Published: November 2008

Captive breeding has become globally important in endangered species recovery, yet it is fraught with problems such as maintenance of genetic diversity, and adaptation to captivity. We studied survival and population dynamics of a captive population of endangered Columbia Basin pygmy rabbits Brachylagus idahoensis, from 2003 to 2007, to evaluate its potential for supporting reintroduction and recovery of wild extirpated populations in shrub‐steppe ecosystems of eastern Washington, USA. We developed stochastic population viability analysis models in Vortex and RAMAS to assess performance and surplus production of the captive population. This pygmy rabbit population has low adult survival beyond 1 year and dependency on high juvenile recruitment for population growth. Low juvenile survival and high variability in stochastic growth rates result in high variability in annual productivity. Our analysis showed that the captive population at n=75 cannot sustain a steady annual harvest of ≥30 rabbits for reintroduction and supplementation without increasing the risk of quasi‐extinction (n=30) to 59%. We conducted sensitivity analysis on maternity, carrying capacity and survival rates to identify critical values for model parameters that would lower extinction risk to the captive population when used as a source of rabbits for reintroduction. Increasing juvenile survival and recruitment into the first breeding class is the most effective method for enhancing the breeding program. Our population models suggest that captive breeding and recovery programs for short‐lived lagomorphs present significant conservation challenges because of the need to rapidly grow such populations to overcome demographic and genetic challenges.
Retinoic acid receptor‐related orphan receptor α regulates a subset of cone genes during mouse retinal development
Authors: Fujieda Hiroki , Bremner Rod , Mears Alan J. , Sasaki Hiroshi
Published: November 2008

Color vision is supported by retinal cone photoreceptors that, in most mammals, express two photopigments sensitive to short (S‐opsin) or middle (M‐opsin) wavelengths. Expression of the Opn1sw and Opn1mw genes, encoding S‐opsin and M‐opsin, respectively, is under the control of nuclear receptors, including thyroid hormone receptor β2 (TRβ2), retinoid X receptor γ (RXRγ), and RORβ, a member of the retinoic acid receptor‐related orphan receptor (ROR) family. We now demonstrate that RORα, another member of the ROR family, regulates Opn1sw, Opn1mw, as well as Arr3 (cone arrestin) in the mouse retina. RORα expression is detected in cones by postnatal day 3 and maintained through adulthood. The retinas of staggerer mice, carrying a null mutation of RORα, show significant down‐regulation of Opn1sw, Opn1mw, and Arr3. RORα acts in synergy with cone‐rod homeobox transcription factor (Crx), to activate the Opn1sw promoter in vitro. Chromatin immunoprecipitation assays reveal that RORα directly binds to the Opn1sw promoter, Opn1mw locus control region, and the Arr3 promoter in vivo. Our data suggest that RORα plays a crucial role in cone development by directly regulating multiple cone genes.
Treatment of Acute Hepatic Failure by Hemoperfusion over Baboon and Human Livers: Alphafetoprotein Levels in Serum
Authors: Gundermann Karl‐Josef , Lie Tschong Su
Published: November 2008

Twelve patients with acute liver failure, two patients with cirrhotic failure of the liver, and one patient in the terminal stage of cirrhotic liver were treated. The patients had grade IV or V hepatic coma. Twenty‐seven perfusions were carried out, each lasting 8 to 27 hours, with one to four perfusions per patient. Eight patients with acute liver failure were brought out of the coma. Six of them showed sufficient clinical symptoms of hepatic regeneration; five of these could be discharged. These results suggest that 60% of complete clinical recovery of consciousness from grade IV or V coma in acute hepatic failute is possible with this therapy.

The three patients with liver cirrhosis treated with a total of five hemoperfusions did awaken, but died because of insufficient hepatic regeneration.

The serum alphafetoprotein (AFP) levels were examined. In those patients brought out of the coma, a rapid increase of AFP up to 260–500 ng/ml was observed. These levels remained high for several weeks in the patients who survived. In the patients who died of liver insufficiency, AFP levels increased only slightly or briefly, so AFP could be a good criterion for determining the prognosis for coma patients with this treatment.
Superiority of Hemofiltration to Hernodialysis for Treatment of Chronic Renal Failure: Comparative Studies Between Hernofiltration and Hernodialysis on Dialysis Disequilibrium Syndrome
Authors: Kishimoto T. , Yamagami S. , Tanaka H. , Ohyama T. , Yamamoto T. , Yamakawa M. , Nishino M. , Yoshimoto S. , Maekawa M.
Published: November 2008

Comparative studies on dialysis disequilibrium syndrome and vascular instability were performed with patients on conventional hemodialysis and on post‐dilution hemofiltration. Sixteen patients on a chronic hemofiltration program were studied and a cross‐over study protocol examining the dialysis disequilibrium syndrome was carried out contrasting hemodialysis and hemofiltration. All patients showed a comparative intolerance to conventional hemodialysis. A notably lower incidence of dialysis disequilibrium syndrome was observed in hernofiltration than in hemodialysis. The effect of hemofiltration on dialysisresistant hypertension was not consistent. Normalization of blood pressure was observed in three out of six hypertensive patients with a decrease in plasma renin activity. Hemofiltration seemed to have favorable effects on secondary hyperparathyroidism and hyperphosphatemia. In order to test the hypothesis that hemofiltration resulted in transport of fluid and solutes from the intracellular to the extracellular, and thence to the ultrafiltrate compartment, the urea concentration of total effluent, serum, and cerebrospinal fluid were measured during hemofiltration and hemodialysis. While the total amount of urea removed was comparable between hemofiltration and hemodialysis on a small dialyzer, during hemofiltration the decay curve of the serum urea concentration was more delayed and urea in the cerebrospinal fluid was more efficiently removed than in hemodialysis. We conclude that, compared with hemodialysis, hemofiltration gives rise to less decrease of plasma osmolality and circulating plasma volume without red cell swelling, better compensation of acidosis despite less infusion of acetate to the patients, and less paradoxical acidosis in cerebrospinal fluid with a lower urea concentration gradient between cerebrospinal fluid and plasma. These findings may explain the significantly lower incidence of dialysis disequilibrium syndrome observed during hemofiltration.
Hernodiafiltration With Sodium Concentration‐Controlled Dialysate
Authors: Maeda K. , Saito A. , Kawaguchi S. , Asada A. , Niwa T. , Ohta K. , Kobayashi K.
Published: November 2008

When hemofiltration and hernodialysis are compared, the former is more effective in removing larger substances, whereas the latter is superior in removing small substances. We consider hemodiafiltration, in which the advantages of the two treatment methods can be adopted, as the most effective and practical method. In the studies of hemodiafiltration, we demonstrated that disequilibrium syndrome associated with the treatment can be prevented by employing a high sodium concentration in the dialysate. The dialysate was successfully used for treating intracel‐lular overhydration. However, it could not be used without causing adverse effects such as thirst in patients whose intracellular overhydration had already been treated and resulted in increase in their body weight. However, these patients were treated successfully by decreasing the high sodium concentration gradually or in a stepwise manner.
Mitral Valve Replacement with Dura Mater Bioprostheses
Authors: Martelli V. , Wain W. H. , Bodnar E. , Ross D. N.
Published: November 2008

Dura mater bioprostheses for cardiac valve replacement were first introduced in Brazil. They have been used since 1975 at the National Heart Hospital, London, as a mitral valve replacement instead of fascia lata valves or inverted aortic homograft valves. During this period 120 patients have had dura mater valves inserted in the mitral position; 29 also received an aortic valve replacement, 6 with dura mater, 20 with an aortic homograft, 2 with an aortic xeno‐graft and 1 with a prosthetic valve. Perivalvular leaks occurred with seven of these mitral valves, and another seven presented with detached cusps. All but one of these 14 valves were replaced. Emboli have occurred in four of the patients, one of whom died after 35 months with thrombus on the aortic valve, but with an unaffected mitral valve. There were 15 early deaths, a hospital mortality of 12.5%. and 10 late deaths, a postoperative mortality of 9.5%. Actuarial analysis has shown a four‐year postoperative survival of 78.970.
The Effects of Homologous Cross‐Circulation and In Situ Liver Perfusion on Fulrninant Hepatic Failure Rats
Authors: Mohsini Khawar , Lister Colin , Chang Thomas M.S.
Published: November 2008

A galactosamine‐induced fulminant hepatic failure (FHF) rat model was used to study the effects of homologous cross‐circulation and in situ liver perfusion. Cross‐circulation with homologous donors did not significantly improve the survival time or recovery rate of grade II hepatic coma rats. Homologous in situ liver perfusion significantly improved the survival time and recovery in FHF only when started in grade II coma; it has no effect in the later stage of coma.
Prostacyclin Eliminates the Thrombocytopenia Associated with Charcoal Hemoperfusion and Minimizes Heparin and Fibrinogen Consumption
Authors: Woods Hugh Feidhlim , Weston Michael John , Bunting Stuart , Moncada Salvador , Vane John
Published: November 2008

To evaluate the effects of prostacyclin (PGI2) on the bioin‐compatibility of charcoal hemoperfusion (CHP), platelet counts, platelet aggregate formation as measured by screen filtration pressure (SFP), plasma fibrinogen levels, and heparin activity monitored by calcium‐thrombin clotting times (Ca‐TCT) were compared during CHP in healthy dogs with heparin alone or heparin plus PGI2. Platelet losses (25 ± 6 vs 83 ± 2%: mean ± SEM), rise in SFP (65 ± 6 vs 249 ± 25 mmHg), and fibrinogen consumption (20 ± 5 vs 46 ± 6%) were significantly less during CHP with PGI2 than with heparin only. In addition, rapid neutralization of heparin, as monitored by Ca‐TCT, during CHP was prevented by PGL2. The use of PGI2 may allow a proper evaluation of the efficacy of CHP in conditions such as fulminant hepatic failure where, hitherto, incompatibility between blood and charcoal may have had deleterious effects.
Hydrostatic Ultrafiltration During Hemodialysis Using Decreasing Sodium Dialysate
Authors: Chen Wei‐Tzuoh , Ing Todd S. , Daugirdas John T. , Humayun Hamid M. , Brescia Donald J. , Gandhi Vasant C. , Hano Jessie E. , Kheirbek Ali O.
Published: November 2008

Twelve patients underwent hemodialysis using dialysate containing 130 mEq/L sodium, and, on a separate occasion, dialysis using a dialysate of constantly decreasing sodium concentration (from 150 to 133 mEq/L). Hydrostatic ultra‐filtration during dialysis was performed at a constant rate (900 ml/hr) during both treatments, and was continued until a substantial drop in mean arterial pressure (‐15%) or symptoms were observed. A double‐blind comparison of the two treatment modalities was thus achieved.

At the end of ultrafiltration, significantly more fluid had been removed using decreasing sodium dialysate (2.9 ± 0.3 kg) than when using the low‐sodium dialysate (1.9 ± 0.2 kg, P<0.001). Plasma sodium concentration at the end of ultra filtration using decreasing sodium dialysate was not significantly different from the predialysis level.

Hydrostatic ultrafiltration using a dialysate of decreasing sodium level may prove to be a useful means of removing excess fluid asymptomatically from dialysis patients.
A Seven‐Month Survival of a Calf with an Artificial Heart Designed for Human Use
Authors: Mochizuki Takaaki , Lawson John H. , Olsen Don B. , Fukumasu Hiroyuki , Daitoh Nobuyoshi , Jarvik Robert , Kessler Thomas R. , Pons A. B. , Hastings Larry , Razzeca Kristin J. , Nielsen Steven D. , Kolff W. J.
Published: November 2008

A Jarvik‐7 type of pneumatic artificial heart, which was specifically designed to fit the anatomy and hemodynamic requirements of human patients, was implanted in a calf in an experiment to test the hemodynamic performance of the artificial heart. The experiment lasted for 221 days, longer than any animal had ever lived without its natural heart, despite the fact that the calf increased its body weight to 171 kg. The calf showed typical signs of low cardiac output before its death, but the direct cause of death was intestinal bleeding. At autopsy, it was discovered that the low cardiac output was due to severe pannus around the left inflow valve, as diagnosed earlier by changes in the pneumatic pressure wave form.