bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrastructural localization of glycoprotein IIIa (GPIIIa, β3 integrin) on placental syncytiotrophoblast microvilli: implications for platelet alloimmunization during pregnancy
Authors: Kumpel Belinda M. , Sibley Karin , Jackson David J. , White Graham , Soothill Peter W.
Published: July 2008

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia due to anti‐human platelet antigen (HPA)‐1a more commonly occurs in first pregnancies, unlike hemolytic disease of the newborn. Anti‐D is produced after D+ fetomaternal hemorrhage; this usually occurs at parturition. Anti‐HPA‐1a could develop during pregnancy if maternal immunization is stimulated by HPA‐1a expressed not only on platelets but also on other fetal cells.

STUDY DESIGN AND METHODS: An ultrastructural study of fetal placental chorionic villi was undertaken to determine the localization of glycoprotein (GP)IIIa carrying the HPA‐1a/1b polymorphism. First trimester and term villi were incubated with a monoclonal antibody (MoAb) to GPIIIa or with positive control MoAbs (anti‐placental alkaline phosphatase and ED822 MoAb) to villous syncytiotrophoblast (ST). Binding of MoAbs was detected with a gold‐conjugated secondary antibody before processing the tissues and examination of ultrathin sections in an electron microscope.

RESULTS: Gold particles were evident on microvilli on the apical surface of ST when labeled with anti‐GPIIIa and the placenta‐specific MoAbs but not with an isotype control antibody. Immunolabeling for anti‐GPIIIa on first trimester ST was similar to that of term ST.

CONCLUSION: The apical surface of the ST is bathed in maternal blood. During the natural regenerative process of human placenta, senescent parts of the ST are shed into maternal blood during pregnancy. This includes both apoptotic ST nuclei and microparticulate ST debris. The presence of GPIIIa on this circulating ST cellular material could be the source of HPA‐1a alloantigen causing primary immunization of susceptible primigravidae early enough for anti‐HPA‐1a to cause fetal thrombocytopenia during a first pregnancy.
A prospective, randomized, double‐blind controlled trial of acetaminophen and diphenhydramine pretransfusion medication versus placebo for the prevention of transfusion reactions
Authors: Kennedy LeAnne D. , Case L. Douglas , Hurd David D. , Cruz Julia M. , Pomper Gregory J.
Published: July 2008

BACKGROUND: Acetaminophen and diphenhydramine are commonly used as pretransfusion medications to prevent transfusion reactions. The purpose of this study was to prospectively compare the risk of transfusion reactions in hematology/oncology patients who receive acetaminophen with diphenhydramine or placebo before transfusion.

STUDY DESIGN AND METHODS: A randomized, double‐blind, placebo‐controlled transfusion reaction study of 315 eligible patients was performed. Inclusion criteria were patients aged 18 to 65 years admitted to the leukemia or bone marrow transplant (BMT) services. Patients were excluded if they had a known allergy to either acetaminophen or diphenhydramine or had a documented history of a febrile or allergic transfusion reaction. All blood products were administered using a leukofilter. Study medications were given 30 minutes before transfusions and no other acetaminophen or diphenhydramine was given within 4 hours of administration of the study medications. Patients were monitored for the development of reaction symptoms within 4 hours after the transfusion.

RESULTS: A total of 154 active drug patients were compared to 161 placebo patients. There was no significant difference in the overall risk of transfusion reactions between the two groups. However, analysis of specific reaction types revealed a significant decrease in the risk of febrile reactions when pretransfusion medication is used in addition to bedside leukoreduction.

CONCLUSIONS: Pretransfusion medication of leukemia or BMT patients without a history of transfusion reaction does not decrease the overall risk of transfusion reactions. However, pretransfusion medication may decrease the risk of febrile nonhemolytic transfusion reactions to leukoreduced blood products.
A severe case of atypical hemolytic uremic syndrome associated with pneumococcal infection and T activation treated successfully with plasma exchange
Authors: Hopkins Courtney K. , Yuan Shan , Lu Qun , Ziman Alyssa , Goldfinger Dennis
Published: July 2008

BACKGROUND: A severe nondiarrheal form of hemolytic uremic syndrome in children is associated with pneumococcal infection (pHUS). Neuraminidase released by the pneumococci may cleave N‐acetylneuraminic acid residues on red blood cells (RBCs), leading to the exposure of the T cryptantigen and polyagglutinability of RBCs, a process known as T activation. Data suggest a pathogenic role of exposed T antigens on glomeruli interacting with naturally occurring anti‐T in the development of renal dysfunction in pHUS. By reducing the levels of anti‐T and neuraminidase, plasma exchange (PE) may have a role in the treatment of severe cases of pHUS.

CASE REPORT: A previously healthy 2‐year‐old boy presented with acute renal failure, thrombocytopenia, microangiopathic hemolytic anemia, pneumococcal infection, and T activation of RBCs. A diagnosis of pHUS was made. Due to rapid clinical decline, daily single‐volume PE with 5 percent albumin replacement was initiated. Infusion of additional plasma was avoided by using only saline‐washed RBCs for transfusion. He made a full recovery after 13 PEs and remained well at follow‐up 7 months later.

RESULTS: Polyagglutinability of RBCs was shown by mixing patient RBCs with five normal donor sera. The agglutination assays with a panel of lectins confirmed the specificity of exposed T antigen as the cause of polyagglutinability.

CONCLUSION: The dramatic response seen in this patient suggests that PE utilizing albumin replacement may benefit patients with severe pHUS.
Effects of plasma dilution on tissue factor–induced thrombin generation and thromboelastography: partly compensating role of platelets
Authors: Schols Saskia E.M. , Feijge Marion A.H. , Lancé Marcus D. , Hamulyák Karly , Ten Cate Hugo , Heemskerk Johan W. M. , Van Pampus Elisabeth C.M.
Published: July 2008

BACKGROUND: Bleeding upon major surgery or severe trauma is treated by transfusion with crystalloids, colloids, or plasma. This treatment, however, can lead to dilutional coagulopathy and impaired hemostasis. We investigated the suitability of two integrative coagulation tests to measure the hemostatic activity of diluted plasma.

STUDY DESIGN AND METHODS: Plasma from healthy donors was diluted in vitro with saline or colloid (venofundin or gelofusin). Coagulant activity in response to tissue factor was monitored by calibrated automated thrombin (CAT) generation and rotational thromboelastography (TEG), detecting formation of elastic fibrin clots. Plasma from patients receiving fluid infusion during coronary artery bypass grafting (CABG) was analyzed with the same assays.

RESULTS: Optimal activity of CAT and TEG assays required the presence of 10 pmol per L tissue factor and 4 µmol per L phospholipid vesicles or 100 × 109 platelets (PLTs) per L. Strikingly, thrombin generation and clot formation became impaired at a higher extent of dilution with PLTs present (≤40% plasma) than with phospholipid vesicles present (≤60% plasma). Colloids aggravated the dilution effect on clot formation, but FFP antagonized the dilution effect on thrombin and clot formation. In contrast, fibrinogen and Factor (F)XIII only restored the impaired clot formation. In plasma samples from patients undergoing CABG, CAT and TEG assay variables were altered to an extent corresponding with the volume of fluid infusion.

CONCLUSION: Thrombin generation and clot formation are reduced at a plasma dilution of more than 40 percent. In either process, PLTs can partly compensate for the dilution effect. In vitro dilution with colloids impaired fibrin clot elasticity compared to saline.
A revised method for estimating hepatitis B virus transfusion residual risk based on antibody to hepatitis B core antigen incident cases
Authors: Laperche Syria , Maniez Michèle , Barlet Valérie , El Ghouzzi Marie‐Hélène , Le Vacon Françoise , Levayer Thierry , Lunel Françoise , Morel Pascal , Mouillot Laurence , Piquet Yves , Pillonel Josiane
Published: July 2008

BACKGROUND: To take into account the transient nature of hepatitis B virus (HBV) antigenemia, the calculation of HBV residual risk (RR), based on the incidence/window period model, is adjusted by a correction factor that adds uncertainty to the RR estimates.

STUDY DESIGN AND METHODS: This new method to estimate the RR for HBV is a weighted sum of the RR derived from hepatitis B surface antigen (HBsAg) incident cases and the one derived from antibody hepatitis B core antigen (HBc) incident cases. An anti‐HBc incident case was defined as a donation from a blood donor who had made at least one anti‐HBc–negative donation followed by a donation that was found positive with two different assays within a 3‐year period and positive for at least one of the following markers: 1) antibody to hepatitis B e antigen or hepatitis B e antigen, 2) anti‐HBc immunoglobulin M, 3) HBV DNA, 4) hepatitis B surface antibody without HBV vaccination history, or 5) HBV DNA retrospectively found in the previous donation. Five overlapping 3‐year study periods between 2000 and 2006 were analyzed.

RESULTS: The HBV RR estimated with the classical method ranged from 1.51 (2000‐2002) to 0.69 per million donations in 2004 through 2006 with a decrease in 2002 through 2004 due to only two HBsAg incident cases reported in this period. By applying the revised model, the HBV RR ranged from 1.06 (2000‐2002) to 0.49 per million donations (2004‐2006), with a regular decrease.

CONCLUSION: The new presented model provides HBV RR estimates that do not statistically differ from those obtained with the classical model; however, it provides more accurate data, especially in low endemic areas where the HBsAg incidence is low.
Reduced hemoglobin on day of peripheral blood progenitor cell collection is associated with low graft content of vascular progenitors and increased toxicity after autologous hematopoietic stem cell transplantation
Authors: Kasbia Gurnaam , Al‐Gahtani Farjah , Tay Jason , Labonté Laura , Tinmouth Alan , Ramsay Timothy , Gillingham Akira , Yang Lin , Halpenny Michael , Giulivi Antonio , McDiarmid Sheryl , Huebsch Lothar , Allan David S.
Published: July 2008

BACKGROUND: Tissue damage after hematopoietic stem cell transplantation (HSCT) occurs as a result of high‐dose chemotherapy and radiation. The aim was to determine the importance of pretransplant anemia on toxicity and red blood cell (RBC) transfusion requirements after autologous HSCT.

STUDY DESIGN AND METHODS: A total of 350 patients undergoing autologous HSCT were included in the analysis. Patient factors and pretransplant laboratory values of possible relevance were assessed in multivariate regression analysis.

RESULTS: Reduced hemoglobin (Hb) on the first day of peripheral blood progenitor cell (PBPC) collection was significantly associated with increased organ toxicity after HSCT, as measured by the Seattle criteria. Lower Hb levels at baseline before transplantation, but not at PBPC collection, were significantly associated with increased RBC transfusion requirements. In a second cohort of 28 patients, higher Hb levels on the day of PBPC collection were significantly associated with increased levels of endothelial‐like vascular progenitor cells in PBPC grafts.

CONCLUSION: Our observations suggest that higher Hb levels on the day of PBPC collection may be a marker of reduced toxicity associated with HSCT and increased vascular progenitors in PBPC collections. Further, baseline anemia before transplant may reflect an unfavorable hematopoietic microenvironment that leads to increased RBC transfusion requirements.
Membrane autoantibodies in systemic lupus erythematosus: a case of autoimmune hemolytic anemia, antiphospholipid antibodies, and transient acquired activated protein C resistance
Authors: Staropoli John F. , Van Cott Elizabeth M. , Makar Robert S.
Published: July 2008

BACKGROUND: Warm autoimmune hemolytic anemia and antiphospholipid antibodies (which include lupus anticoagulants and anticardiolipin [ACL] antibodies) are associated, respectively, with approximately 10 and 40 percent of cases of systemic lupus erythematosus (SLE). This study reports a case of SLE presenting with an unusual constellation of findings that included an immunoglobulin M (IgM) cold autoantibody of high thermal amplitude, high‐titer ACL antibodies, and transient acquir ed activated protein C resistance.

CASE REPORT: A previously untransfused, nulligravid 17‐year‐old woman without a significant medical history presented with signs and symptoms of SLE and an extravascular hemolytic anemia. Spontaneous agglutination was noted in blood samples collected for testing. Serologic testing revealed a normal‐titer, high‐thermal‐amplitude IgM red blood cell (RBC) autoantibody but no additional RBC antibodies in the patient's plasma. Additional testing was significant for a high‐titer ACL IgM and a positive test for activated protein C resistance (a screening test for the Factor [F]V Leiden mutation), which prompted initiation of prophylactic anticoagulation. Confirmatory DNA testing for FV Leiden, however, was negative. The patient's symptoms, anemia, RBC autoagglutinins, ACL antibodies, and activated protein C resistance all resolved after 6 weeks of immunosuppression.

CONCLUSION: This case illustrates the wide range of clinical and laboratory findings that autoantibodies against cellular membranes may produce. IgM autoagglutinins of high thermal amplitude associated with a significant extravascular hemolytic anemia may be a presenting feature of SLE. Concomitant antiphospholipid antibodies may interfere with partial thromboplastin time–based tests of hypercoagulability such as that for activated protein C resistance.
Pulmonary pathology of rapidly fatal transfusion‐related acute lung injury reveals minimal evidence of diffuse alveolar damage or alveolar granulocyte infiltration
Authors: Danielson Constance , Benjamin Richard J. , Mangano Mark M. , Mills Charles J. , Waxman Dan A.
Published: July 2008

BACKGROUND: Transfusion‐related acute lung injury (TRALI) is the leading cause of transfusion‐associated death in the United States. Its diagnosis is based on clinical and radiographic changes that are indistinguishable from acute lung injury/acute respiratory distress syndrome (ALI/ARDS). TRALI is presumed to be a form of ALI/ARDS; however, it differs in its triggering events and associated mortality. Two cases of rapidly fatal TRALI in which the postmortem pathology differed from that classically associated with ALI/ARDS are reported.

CASE REPORT: Two men (aged 75 and 83 years) developed rapidly fatal TRALI after receiving single units of plasma for correction of elevated international normalized ratios. The donors were found to have white blood cell (WBC) antibodies that included specificities for WBC antigens expressed by the recipient (HLA Class I or Class II and/or HNA‐3b [5a] antibody). Autopsy findings in both patients revealed bilateral pleural effusions and extensive patchy areas of alveoli filled with proteinaceous fluid. The pulmonary capillaries were congested with red blood cells and WBCs. Diffuse alveolar damage, including interstitial inflammation, intraalveolar granulocyte infiltration, and hyaline membrane formation, were not identified in either case.

CONCLUSION: In both patients the clinical and radiographic findings were indicative of TRALI and indistinguishable from ALI/ARDS. However, diffuse alveolar damage, the classic autopsy finding in ARDS, was not identified, suggesting a different pathogenesis. Further studies are needed on the role of polymorphonuclear cells in the initiating events of TRALI that lead to ALI and the resulting breakdown of the permeability integrity of the alveolar walls.
Monitoring the physiologic stress response: a novel biophysical approach for the rapid detection of bacteria in platelet concentrate
Authors: Rieder Ronald , Zavizion Boris
Published: July 2008

BACKGROUND: Currently approved culture‐based methods for the bacterial testing of platelet concentrates (PCs) require an extended period of time to obtain results. A new approach based on the monitoring of the bacterial response to physiologic stress is presented. Because the stress response is independent of the growth rate, decisive results can be obtained in near real time.

STUDY DESIGN AND METHODS: PCs were spiked with Gram‐positive Staphylococcus epidermidis and Propionibacterium acnes and Gram‐negative Escherichia coli organisms commonly implicated in posttransfusion septic reactions. All suspensions were treated with Triton X‐100 at concentrations that caused human cell lysis while acting as a stressor for bacterial cells. Normalized impedance response (NIR) profiles of these suspensions were recorded using the BioSense Technologies differential impedance sensing platform specifically designed to monitor subtle changes in the dielectric properties of biologic suspensions. Further development of the approach included measurement of NIRs for spiked PCs treated with nonlysing chemical stressors.

RESULTS: NIR profiles for bacteria conventionally growing under optimal conditions were characterized by an overall increase in the NIR values. In contrast, the corresponding responses from chemically stressed bacteria revealed immediate and continuous decreases in value—enabling bacterial detection in less than 30 minutes.

CONCLUSION: These pilot experiments demonstrated that monitoring of the bacterial stress response is a fast and effective way to detect bacteria in PCs. In addition, special culture conditions are not required for detecting anaerobes and fastidious species.
The Cross‐Sectional Dispersion of Commercial Real Estate Returns and Rent Growth: Time Variation and Economic Fluctuations
Authors: Plazzi Alberto , Torous Walter , Valkanov Rossen
Published: July 2008

We estimate the cross‐sectional dispersions of returns and growth in rents for commercial real estate using data on U.S. metropolitan areas over the sample period 1986 to 2002. The cross‐sectional dispersion of returns is a measure of the risk faced by commercial real estate investors. We document that, for apartments, offices, industrial and retail properties, the cross‐sectional dispersions are time varying. Interestingly, their time‐series fluctuations can be explained by macroeconomic variables such as the term and credit spreads, inflation and the short rate of interest. The cross‐sectional dispersions also exhibit an asymmetrically larger response to negative economics shocks, which may be attributable to credit channel effects impacting the availability of external debt financing to commercial real estate investments. Finally, we find a statistically reliable positive relation between commercial real estate returns and their cross‐sectional dispersion, suggesting that idiosyncratic fluctuations are priced in the commercial real estate market.
Mobility, Residential Location and the American Dream: The Intrametropolitan Geography of Minority Homeownership
Authors: Gabriel Stuart A. , Painter Gary
Published: July 2008

This article applies data from Washington, DC, Chicago and Los Angeles to estimate three‐level nested multinomial logit models of household mobility, residential location and homeownership tenure choice. Model simulation indicates that shocks to income can significantly elevate the homeownership attainment of minority households; however, their urban settlement and homeownership patterns remain substantially more concentrated than those of whites. Simulated equilibration of black economic status with that of whites results in an approximate doubling of homeownership rates among black movers to central city areas. In contrast, homeownership rates among black movers to suburban and outlying areas lag far behind those of whites.
Deed Types, House Prices and Mortgage Interest Rates
Authors: Brasington David M. , Sarama Robert F.
Published: July 2008

When houses are sold they come with a deed attached that spells out the legal guarantees on good title. Some deeds give clues about the characteristics of the seller or the house. Using a 37,043‐observation house price hedonic with a Bayesian spatial error model, we find the type of deed attached to a housing sale can have a dramatic correlation with the sale price. Ten deed types command a discount, and one commands a premium relative to warranty deeds. Mortgage rates for sheriff's deeds and foreclosure deeds are lower than for warranty deeds, indicating more sophisticated buyers.
Clientele Effects and Condo Conversions
Authors: Benjamin John D. , Chinloy Peter , Hardin William G. , Wu Zhonghua
Published: July 2008

During an asset boom a property can develop a new usage. Appreciation investors emerge to change a property's occupant mix or letter grade. Rental investors not intending to change the mix or grade are outbid. Sellers receive a capitalized premium from the new type of bidder. For apartments in Miami‐Fort Lauderdale during 2004–2006, there is an asset pricing premium from condo converters. The price of real estate depends on clienteles in addition to characteristics.
Milling of Zirconia Nanoparticles in a Stirred Media Mill
Authors: Adam Jens , Drumm Robert , Klein Gabi , Veith Michael
Published: July 2008

Dispersions of three different types of zirconia nanoparticles were treated in a stirred media mill. The deployed surface modifier was present during milling and it established separating mechanisms between the particles. The combination of mechanical deagglomeration and chemical surface modification results in stable zirconia colloids with average particle sizes down to 9 nm. In addition to deagglomeration, the milling treatment also causes comminution of nanoparticles. This was indicated for the two coarser types of the examined particles, by increasing surface areas and decreasing primary crystallite sizes. Transmission electron microscopy of the particles confirmed the creation of smaller primary crystallites and a minority of small fragments, but the majority of particles do not undergo comminution into halves or fragments with similar size. Changes of the particles' phase composition, wear of milling media, amorphization of the particles to a small extent, and leaching of Y2O3 dopant have been observed as side effects in the process and are characterized quantitatively. This work describes a process for nanoparticle deagglomeration and preparation of high quality colloids, and informs about occurring side effects, including approaches for their minimization.
Property–Composition–Temperature Modeling of Waste Glass Melt Data Subject to a Randomization Restriction
Authors: Piepel Greg F. , Heredia‐Langner Alejandro , Cooley Scott K.
Published: July 2008

Properties such as viscosity and electrical conductivity of glass melts are functions of melt temperature as well as glass composition. When measuring such a property for several compositions, the property is typically measured at several temperatures for one composition, then at several temperatures for the next composition, and so on. This data collection process involves a restriction on randomization, which is referred to as a split‐plot experiment. The split‐plot data structure must be accounted for in developing property–composition–temperature models and the corresponding uncertainty equations for model predictions. Instead of ordinary least squares (OLS) regression methods, generalized least squares (GLS) regression methods using restricted maximum likelihood (REML) estimation must be used. This article summarizes the methodology for developing property–composition–temperature models and corresponding prediction uncertainty equations using the GLS/REML regression approach. Viscosity data collected on 197 simulated nuclear waste glasses are used to sequentially develop a viscosity‐composition‐temperature model. The final model has 29 terms in 15 components, reduced from the initial model of 44 terms in 22 components. For the initial model, the correct results using GLS/REML regression are compared with the incorrect results obtained using OLS regression.
Genetic and environmental factors reducing the incidence of the storage pest Sitotroga cerealella in maize
Authors: Butrón A. , Romay M. C. , Ordás A. , Malvar R. A. , Revilla P.
Published: July 2008

The Angoumois grain moth, Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae), is found worldwide and infests maize grains in the field and during storage. Transgenic maize resistant to kernel attack by S. cerealella has been developed, but could pose a nutritional risk to humans and livestock. Therefore, alternative sources of resistance posing no threat to consumption should be identified. In this study, our main objectives were to assess genetic variability for kernel damage by S. cerealella under natural infestation and to determine genetic and environmental factors contributing to genotype, year, and genotype*year variability. Factorial regression was performed to obtain a biological explanation for the number of kernels damaged per ear. Seventy‐seven Spanish maize landraces along with six hybrid checks were evaluated in 2004, 2005, and 2006. There was variability for kernel damage by natural infestation of S. cerealella among the landraces: popcorn landraces were among the least damaged, whereas hybrid checks were among the most susceptible genotypes. Plant characteristics associated with ear appearance could be the main stimulatory factors for oviposition and feeding of S. cerealella moths, followed by husk coverage of the ear. It was confirmed that temperature is the main environmental factor affecting S. cerealella development. Genotypes sensitive to infestation by S. cerealella were more negatively affected by higher temperatures than the least attractive genotypes, and lower temperatures reduced the number of kernels damaged on the most susceptible genotypes more than on the least susceptible.
Differential uncertainties and risk attitudes between conventional and organic producers: the case of Spanish arable crop farmers
Authors: Serra Teresa , Zilberman David , Gil José M.
Published: July 2008

The growing importance of economic factors in farmers' decisions to go organic has raised interest in characterizing the economic behavior of organic versus conventional farms. In general, published analyses so far have not considered differential uncertainties, abilities to control production risk, and farmers' risk preferences between conventional and organic practices when comparing these techniques. Our article attempts to assess this issue. We use a model of farmer decision under risk to analyze the differential values between organic and conventional Spanish arable crop farms and to assess the incentives for adoption of organic practices. Results show that organic and conventional farms do have different production risks as well as different aversions to risk. Organic price premiums and subsidies are found to be powerful instruments to motivate adoption of organic techniques.
Horticulture, livelihoods, and urban transition in Africa: evidence from South‐West Cameroon
Authors: Parrot Laurent , Dongmo Clovis , Ndoumbé Michel , Poubom Christine
Published: July 2008

This article documents change in periurban horticulture using repeat surveys in 1995 and 2004 of about 300 households around Muea, Cameroon. Real household incomes increased by 14%, with a large shift from farm to nonfarm income. Within agriculture, activity shifted from staple crops to horticulture, both for sale and in home consumption. In 1995, there were large remittances from farmers involved in periurban horticulture to their village of origin; in 2004 remittances continued and horticultural farmers were also heavily involved in informal financial associations. Periurban horticulture is disproportionately practiced by women and older workers, and plays an important and growing role in African livelihoods.
Molecular response of nasal mucosa to therapeutic exposure to broad‐band ultraviolet radiation
Authors: Mitchell David , Paniker Lakshmi , Sanchez Guillermo , Bella Zsolt , Garaczi Edina , Szell Marta , Hamid Qutayba , Kemeny Lajos , Koreck Andrea
Published: July 2008

Ultraviolet radiation (UVR) phototherapy is a promising new treatment for inflammatory airway diseases. However, the potential carcinogenic risks associated with this treatment are not well understood. UV‐specific DNA photoproducts were used as biomarkers to address this issue. Radioimmunoassay was used to quantify cyclobutane pyrimidine dimers (CPDs) and (6–4) photoproducts in DNA purified from two milieus: nasal mucosa samples from subjects exposed to intranasal phototherapy and human airway (EpiAirway™) and human skin (EpiDerm™) tissue models. Immunohistochemistry was used to detect CPD formation and persistence in human nasal biopsies and human tissue models. In subjects exposed to broadband ultraviolet radiation, DNA damage frequencies were determined prior to as well as immediately after treatment and at increasing times post‐treatment. We observed significant levels of DNA damage immediately after treatment and efficient removal of the damage within a few days. No residual damage was observed in human subjects exposed to multiple UVB treatments several weeks after the last treatment. To better understand the molecular response of the nasal epithelium to DNA damage, parallel experiments were conducted in EpiAirway and EpiDerm model systems. Repair rates in these two tissues were very similar and comparable to that observed in human skin. The data suggest that the UV‐induced DNA damage response of respiratory epithelia is very similar to that of the human epidermis and that nasal mucosa is able to efficiently repair UVB induced DNA damage.
Parkin‐mediated ubiquitination regulates phospholipase C‐γ1
Authors: Dehvari Nodi , Sandebring Anna , Flores‐Morales Amilcar , Mateos Laura , Chuan Yin‐Choy , Goldberg Matthew S. , Cookson Mark R. , Cowburn Richard F. , Cedazo‐Mínguez Angel
Published: July 2008

Mutations in parkin cause autosomal recessive forms of Parkinson’s disease (PD), with an early age of onset and similar pathological phenotype to the idiopathic disease. Parkin has been identified as an E3 ubiquitin ligase that mediates different types of ubiquitination, which has made the search for substrates an intriguing possibility to identify pathological mechanisms linked to PD. In this study, we present PLCγ1 as a novel substrate for parkin. This association was found in non‐transfected human neuroblastoma SH‐SY5Y cells as well as in stable cell lines expressing parkin WT and familial mutants R42P and G328E. Analysis of cortical, striatal and nigral human brain homogenates revealed that the interaction between parkin and PLCγ1 is consistent throughout these regions, suggesting that the interaction is likely to have a physiological relevance for humans. Unlike many of the previously identified substrates, we could also show that the steady‐state levels of PLCγ1 is significantly higher in parkin KO mice and lower in parkin WT human neuroblastoma cells, suggesting that parkin ubiquitination of PLCγ1 is required for proteasomal degradation. In line with this idea, we show that the ability to ubiquitinate PLCγ1 in vitro differs significantly between WT and familial mutant parkin. In this study, we demonstrate that parkin interacts with PLCγ1, affecting PLCγ1 steady state protein levels in human and murine models with manipulated parkin function and expression levels. This finding could be of relevance for finding novel pathogenic mechanisms leading to PD.
The peroxynitrite evoked contractile depression can be partially reversed by antioxidants in human cardiomyocytes
Authors: Hertelendi Zita , Tóth Attila , Borbély Attila , Galajda Zoltán , Édes István , Tósaki Árpád , Papp Zoltán
Published: July 2008

In this study, we aimed to determine the contribution of peroxynitrite‐dependent sulfhydryl group (SH) oxidation to the contractile dysfunction in permeabilized left ventricular human cardiomyocytes using a comparative approach with the SH‐oxidant 2,2′‐dithiodipyridine (DTDP). Additionally, different antioxidants: dithiothreitol (DTT), reduced glutathione (GSH) or N‐acetyl‐L‐cysteine (NAC) were employed to test reversibility. Maximal isometric active force production (Fo) and the maximal turnover rate of the cross‐bridge cycle (ktr,max) illustrated cardiomyocyte mechanics. SH oxidation was monitored by a semi‐quantitative Ellman’s assay and by SH‐specific protein biotinylation. Both peroxynitrite and DTDP diminishedFoin a concentration‐dependent manner (EC50,peroxynitrite= 49 μM; EC50,DTDP= 2.75 mM). However,ktr,maxwas decreased only by 2.5‐mM DTDP, but not by 50 μM peroxynitrite. The diminution ofFoto zero by DTDP was paralleled by the complete elimination of the free SH groups, while the peroxynitrite‐induced maximal reduction in free SH groups was only to 58 ± 6% of the control (100%). The diminutions inFoand free SH groups evoked by 2.5‐mM DTDP were completely reverted by DTT. In contrast, DTT induced only a partial restoration inFo(ΔFo,:∼13%;P< 0.05) despite full reversion in protein SH content after 50 μM peroxynitrite. Although, NAC or DTT were equally effective onFoafter peroxynitrite exposures, NAC or GSH did not restoreFoorktr,maxafter DTDP treatments. Our results revealed that the peroxynitrite‐evoked cardiomyocyte dysfunction has a small, but significant component resulting from reversible SH oxidation, and thereby illustrated the potential benefit of antioxidants during cardiac pathologies with excess peroxynitrite production.
Technical limits of comparison of step‐sectioning,immunohistochemistry and RT‐PCR on breast cancer sentinel nodes: a study on methacarn‐fixed tissue
Authors: Daniele Lorenzo , Annaratone Laura , Allia Elena , Mariani Sara , Armando Enrico , Bosco Martino , Macrì Luigia , Cassoni Paola , D’Armento Giuseppe , Bussolati Gianni , Cserni Gabor , Sapino Anna
Published: July 2008

The optimal pathological assessment of sentinel nodes (SLNs) in breast cancer is a matter of debate. Currently, multilevel histological evaluation and immunohistochemistry (IHC) are recommended, but alternative RT‐PCR procedures have been developed. To assess the reliability of these different procedures, we devised a step‐sectioning protocol at 100 micron‐intervals of 74 SLNs using methacarn fixation. mRNA was extracted from sections collected from levels 4 to 5. Mammaglobin, CEA and CK19 were used for RT‐PCR. mRNA extraction was successful in 69 SLNs. Of these, 7 showed macrometastases (>2mm), 2 showed micrometastases (<2 mm) and 7 showed isolated tumour cells (ITC) by IHC. RT‐PCR was positive for the three markers in 6 of 7 macrometastases and in 1 of 2 micrometastases. In the 2 RT‐PCR negative cases, metastases were detected only on sections distant from those analysed by RT‐PCR. CEA and/or CK19 were positive by RT‐PCR in 3 of 7 ITC and in 23 morphologically negative SLNs. In conclusion, the main goal of our study was to show that the use of alternate sections of the same sample for different procedures is the key reason for the discrepancies between molecular and morphological analyses of SLN. We believe that only prospective studies with quantitative mRNA analysis of specific metastatic markers on the whole lymph node can elucidate the utility of molecular assessments of SLN.
Immunological features of α‐synuclein in Parkinson's disease
Authors: Roodveldt Cintia , Christodoulou John , Dobson Christopher M.
Published: July 2008

Introduction

Importance of inflammation processes in PD pathology

Stimulation of microglia by αSyn

αSyn‐triggered stimulation of the innate immune system

Other proteins up‐regulated by αSyn‐triggered microglial activation

αSyn and apoptosis of immune cells

Links between αSyn and astrocytes or oligodendrocytes

αSyn and the humoural immune system in PD

Expression of αSyn in immunocompetent cells

Prospects for αSyn‐ and immune‐based therapeutic approaches in PD

Concluding remarks

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence, in the brain, of intra‐cellular protein inclusions highly enriched in aggregated α‐synuclein (αSyn), known as Lewy bodies. The onset of PD is accompanied by a local immune reaction in regions of the brain affected by the inclusions, although the mechanism that leads to pathogenesis is far from clear. It is, however, established that disease onset and progression are characterized by sustained activation of microglia, which is linked to significant dopaminergic neuron loss in the substantia nigra. A recent body of evidence indicates that aggregated or modified αSyn can indeed trigger the activation of microglia, inducing a lethal cascade of neuroinflammation and eventually, neuronal loss, pointing at aggregated and modified forms of αSyn as a primary cause of PD pathogenesis. By releasing toxic factors, or by phagocy‐tosing neighbouring cells, activated microglia and astrocytes may form a self‐perpetuating cycle for neuronal degeneration. Additional findings suggest a link between αSyn and humoural‐mediated mechanisms in PD. In this review, we attempt to recapitulate our current understanding of PD physiopathology focused on αSyn and its links with the immune system, as well as of novel and promising therapeutic avenues for the treatment of PD and of other synucleinopathies.
Trypanosoma cruzi in non‐human primates with a history of stillbirths: a retrospective study (Papio hamadryas spp.) and case report (Macaca fascicularis)
Authors: Grieves Jessica L. , Hubbard Gene B. , Williams Jeff T. , VandeBerg John L. , Dick, Jr Edward J. , López‐Alvarenga Juan C. , Schlabritz‐Loutsevitch Natalia E.
Published: July 2008

Background  Congenital transmission of Trypanosoma cruzi has been described in humans and experimental work has been conducted with mice, but not with non‐human primates (NHPs).

Methods  We conducted a retrospective study of female baboons (Papio hamadryas spp.) naturally seropositive or seronegative for T. cruzi with history of fetal loss, and we report a stillbirth in a cynomolgus macaque (Macaca fascicularis) with placental T. cruzi amastigotes.

Results  There were no differences in menstrual cycle parameters and the number of fetal losses between seropositive and seronegative baboons with history of fetal loss. The amount of parasite DNA detected using quantitative polymerase chain reaction (Q‐PCR) in M. fascicularis placenta was within the range detected in infected baboon tissues.

Conclusions  There is no evidence that chronic maternal T. cruzi infection causes fetal loss in baboons. Q‐PCR is a useful diagnostic tool to study archived NHP placentas.
Spontaneous heart disease in the adult chimpanzee (Pan troglodytes)
Authors: Seiler Brittany M. , Dick Jr Edward J. , Guardado‐Mendoza Rodolfo , VandeBerg John L. , Williams Jeff T. , Mubiru James N. , Hubbard Gene B.
Published: July 2008

Background  A high incidence of heart disease, especially idiopathic cardiomyopathy (IC), is seen in chimpanzees (Pan troglodytes).

Methods  We reviewed clinical records and necropsy reports of 87 adult chimpanzees for possible causes of heart disease/IC. We examined age, sex, cause of death, weight, diet, environment, infectious diseases, experimental uses and clinical pathology.

Results  The overall prevalence of heart disease in chimpanzees was 67.81%; the prevalence of IC was 51.72%. The prevalence of IC was significantly higher in males (60.32%) than that in females (29.17%, P = 0.009). The prevalence of other heart disease was higher in females (25%) than that in males (12.70%, P = 0.165). Heart failure occurred in 47.13% of chimpanzees. Heart disease was the primary cause of death in 34.49% of chimpanzees; 29.88% died of unknown causes.

Conclusions  We found no evidence that diet, environment, viral agents, experimental use or disease exposure contributed to the deaths resulting from IC in chimpanzees.
Natural Chagas disease in four baboons
Authors: Williams Jeff T. , Dick Jr Edward J. , VandeBerg John L. , Hubbard Gene B.
Published: July 2008

Background  Chagas disease is common in Central and South America and the southern United States. The causative agent is Trypanosoma cruzi (order Kinetoplastida, family Trypanosomatidae), a kinetoplastid protozoan parasite of humans and other vertebrates. It is a serious public health issue and the leading cause of heart disease and cardiovascular death in Central and South America. In 1984, a colony baboon was discovered to be infected with T. cruzi.

Methods  As the initial diagnosis was made by microscopic observation of the amastigote forms of T. cruzi in myocardial fibers, T. cruzi amastigotes have been identified in three additional baboons.

Results  The primary findings were similar in all four baboons and were congestive heart failure with edema of dependent areas, hydrothorax, hydropericardium, and multifocal to diffuse lymphoplasmacytic myocarditis.

Conclusions  A baboon animal model of Chagas disease could contribute significantly to the development of therapies for the disease in humans.
A PDZ‐Binding Motif Controls Basolateral Targeting of Syndecan‐1 Along the Biosynthetic Pathway in Polarized Epithelial Cells
Authors: Maday Sandra , Anderson Eric , Chang Henry C. , Shorter James , Satoh Ayano , Sfakianos Jeff , Fölsch Heike , Anderson James M. , Walther Zenta , Mellman Ira
Published: July 2008

The cell surface proteoglycan, syndecan‐1, is essential for normal epithelial morphology and function. Syndecan‐1 is selectively localized to the basolateral domain of polarized epithelial cells and interacts with cytosolic PDZ (PSD‐95, discs large, ZO‐1) domain‐containing proteins. Here, we show that the polarity of syndecan‐1 is determined by its type II PDZ‐binding motif. Mutations within the PDZ‐binding motif lead to the mislocalization of syndecan‐1 to the apical surface. In contrast to previous examples, however, PDZ‐binding motif‐dependent polarity is not determined by retention at the basolateral surface but rather by polarized sorting prior to syndecan‐1’s arrival at the plasma membrane. Although none of the four known PDZ‐binding partners of syndecan‐1 appears to control basolateral localization, our results show that the PDZ‐binding motif of syndecan‐1 is decoded along the biosynthetic pathway establishing a potential role for PDZ‐mediated interactions in polarized sorting.
Chemical and Biological Folding Contribute to Temperature‐Sensitive ΔF508 CFTR Trafficking
Authors: Wang Xiaodong , Koulov Atanas V. , Kellner Wendy A. , Riordan John R. , Balch William E.
Published: July 2008

Proteostasis (Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science 2008;319:916–919) refers to the biology that maintains the proteome in health and disease. Proteostasis is challenged by the most common mutant in cystic fibrosis, ΔF508, a chloride channel [the cystic fibrosis transmembrane conductance regulator (CFTR)] that exhibits a temperature‐sensitive phenotype for coupling to the coatomer complex II (COPII) transport machine for exit from the endoplasmic reticulum. Whether rescue of export of ΔF508 CFTR at reduced temperature simply reflects energetic stabilization of the chemical fold defined by its primary sequence or requires a unique proteostasis environment is unknown. We now show that reduced temperature (30°C) export of ΔF508 does not occur in some cell types, despite efficient export of wild‐type CFTR. We find that ΔF508 export requires a local biological folding environment that is sensitive to heat/stress‐inducible factors found in some cell types, suggesting that the energetic stabilization by reduced temperature is necessary, but not sufficient, for export of ΔF508. Thus, the cell may require a proteostasis environment that is in part distinct from the wild‐type pathway to restore ΔF508 coupling to COPII. These results are discussed in the context of the energetics of the protein fold and the potential application of small molecules to achieve a proteostasis environment favoring export of a functional form of ΔF508.
Paediatricians' attitudes and practices towards HPV vaccination
Authors: Ishibashi Kimiko L. , Koopmans Joy , Curlin Farr A. , Alexander Kenneth A. , Ross Lainie Friedman
Published: July 2008

Aim: In June 2006, the human papillomavirus (HPV) vaccine, Gardasil, was licensed for use in the United States. We examined whether paediatricians would recommend the vaccine, obstacles they encountered and characteristics associated with not recommending the HPV vaccine to all eligible patients.

Methods: Four hundred fifty general paediatricians, 200 members of the section of infectious diseases and 200 members of the section of adolescent medicine of the American Academy of Pediatrics web‐based directory were surveyed.

Results: Of 752 eligible paediatricians, 373 (50%) responded. Eighty‐eight percent (292 of 332) of respondents stated that they would give the vaccine to all, 36 (11%) would give it to some and 4 (1%) would give it to none of their eligible patients. The main obstacles were cost and safety; a minority expressed concern about the vaccine's potential impact on adolescent sexual activity. Physicians who would not recommend HPV vaccination to all eligible patients were more likely to be generalists, have higher intrinsic religiosity, self‐describe as conservative, report later adoption of new drugs/vaccines, and would not encourage vaccinating their own daughter or the daughter of a close friend.

Conclusion: Although paediatricians are highly supportive of the HPV vaccine, certain characteristics may predict reluctance to immunize.
Reduction in hospitalizations of children
Authors: Santos Erica , Gonçalves de Sousa Alexandre , Marques Ana Paula Lerner , Bussamra Maria Helena CF , Zukerman Eliova , Schvartsman Cláudio
Published: July 2008

Aim: The aim of the study was to reduce the number of hospitalizations in a population of children enrolled in the Einstein Program of the Paraisópolis Community, in São Paulo, Brazil, particularly hospitalizations caused by respiratory diseases.

Methods: All hospitalizations of this paediatric population enrolled in the Einstein Program of the Paraisópolis Community Outpatient Clinic were followed up between 2002 and 2004. The following four strategies to reduce or control respiratory diseases with an impact on hospitalizations were established: specific protocol, educational activities, vaccination against pneumococci and vaccination against influenza.

Results: In 2002, 1025 hospitalizations due to all causes were recorded. This number significantly decreased to 862 hospitalizations in 2004 after implementation of the program, corresponding to a reduction of 15.9% (p < 0.0001). Hospitalizations due to respiratory diseases decreased by 23.37% (p < 0.02), and those due to cases of wheezing bronchitis fell by 51.61% (p < 0.001).

Conclusion: The strategies chosen and implemented in the Einstein Program of the Paraisópolis Community Outpatient Clinic over the first 6 months of 2003 were effective in reducing the number of children's hospital admissions due to respiratory disease.