bluuebunny/crossref_metadata_2025 huggingface dataset:
Liver transplant waiting time does not correlate with waiting list mortality: Implications for liver allocation policy
Authors: Freeman Richard B. , Edwards Erick B.
Published: June 2003

Factors associated with the risk for mortality once placed on the liver transplant waiting list and how this risk relates to center-specific waiting time and transplant activity have not been adequately evaluated. We performed this study to determine the association between center-specific waiting time and waiting list mortality among liver transplant candidates stratified by medical urgency at the time of registration. A Cox proportional hazards model was used to calculate 2-year mortality risk for a cohort of 16,414 registrants added to the United Network for Organ Sharing liver transplant waiting list between January 1, 1997, and December 31, 1997. After controlling for confounding variables, we calculated the mortality risk for centers, organ procurement organizations (OPOs), and states. The relation between center-specific waiting list mortality risk and median waiting time or transplant activity was determined by linear regression. In multivariate analyses, higher initial medical urgency status (relative risk [RR] = 12.8; P < .001), increasing age (P < .001), black ethnicity (RR = 1.29; P < .001), history of previous transplant (RR = 1.2; P = .009), certain liver diagnoses, and smaller center size (RR = 1.39; P = .008) were associated with significantly increased waiting list mortality. Candidates with blood type A (RR = 0.87; P < .001) and those with cholestatic cirrhosis as the primary diagnosis (RR = 0.73; P < 0.001) had a reduced risk for dying. There were significant variations in 2-year waiting list mortality risk among centers, OPOs, and states. However, when stratified by medical urgency status at waiting list entry, center-specific waiting time and transplantation rates accounted for almost none of the center-specific waiting list mortality. Although there are variations in waiting list mortality risk among centers, OPOs, and states, there is very little relation between center-specific waiting list mortality and center-specific median waiting time or center-specific transplantation rates when stratified by medical urgency. Waiting time and center transplant rates should not influence liver allocation policy.
Successful reversal of recalcitrant hepatic allograft rejection by photopheresis
Authors: Lehrer Michael S. , Ruchelli Eduardo , Olthoff Kim M. , French Lars E. , Rook Alain H.
Published: June 2003

Extracorporeal photopheresis (ECP) is an immunologic modality that has shown efficacy in the treatment of clonal T-cell diseases, including Sézary syndrome and allograft rejection. In this case report, we expand on this observation to include recalcitrant hepatic allograft rejection. A 14-year-old boy with hepatic allograft rejection refractory to high-dose corticosteroid and lymphocytolytic therapy was treated with 4 sessions of ECP over a 6-week period. After 2 sessions, a liver biopsy showed complete reversal of acute cell-mediated rejection. No opportunistic infections or other adverse events were noted. Photopheresis appears to be a safe and effective modality for the treatment of refractory hepatic allograft rejection.
Liver transplantation in Eastern Europe
Authors: Špicák Julius , Vítko Štefan , Ryska Miroslav , Trunecka Pavel , Belina František , Krawczyk Marek , Perner Ferenc , Taimr Pavel , Šperl Jan , Hrncárková Halima , Peregrín Jan , Filipová Helena , Filip Karel
Published: June 2003

The aim of this report is to evaluate the development of liver transplantation in eastern Europe until mid-1998. Representatives of gastroenterological and hepatological societies of the respective countries answered a questionnaire about the most descriptive items of the issue of liver transplantation. The Baltic countries, together with 6 southern Balkan countries, Moldovia, and Belarus, have not developed a program of liver transplantation. In Ukraine, 7 transplantations were performed, with 3 early deaths. In Russia, 31 liver transplantations were performed, with 8 of the last 12 patients surviving short term. In Slovenia, 1 of 2 patients, and in Yugoslavia, 8 of 9 patients survived. In Croatia and Slovakia, 2 patients each died immediately after surgery. The number of liver transplantations is increasing in both Hungary and Poland. In Hungary, 63 transplantations were performed, with a 1-year survival rate reaching 85%; in Poland, 55 adults and 29 children underwent transplantation, with an actuarial 1-year survival rate of 70%. In former East Germany, 4 centers developed their programs since 1992. A total of 196 transplantations were performed, with 1-year survival rates varying from 80% to 89%. The total spectrum of indications for transplantation was standard, with a greater proportion of hepatocellular cancer compared with Eurotransplant statistics. In the Czech Republic, the first liver transplantation was performed in 1983, but it was not until 1994 that the number of procedures increased steeply. Until mid-1998, a total of 182 transplantations were performed. At the Prague Institute for Clinical and Experimental Medicine, we performed 94 transplantations, with a 1-year patient survival rate of 90.6%. There has been rapid development over the last 3 years in the 3 countries of Central Europe. The progress is influenced by the sweeping political and economic changes.
In Vivo Lysogenic Conversion of Tox
−
Streptococcus pyogenes
to Tox
+
with Lysogenic Streptococci or Free Phage
Authors: Broudy Thomas B. , Fischetti Vincent A.
Published: June 2003

Temperate bacteriophage can transfer toxin-encoding genes between bacteria, often resulting in acquired pathogenicity. However, little is known regarding the effects of the eukaryotic host on the phage-pathogen interaction. Using
Streptococcus pyogenes
as a model, we demonstrate, both in vitro and in vivo, that the eukaryote mediates the efficient induction of toxin-encoding temperate phage and the resultant conversion of Tox
−
flora to Tox
+
. Furthermore, we show that both phage induction and subsequent conversion need not happen in the same mammalian host, as host-to-host phage transmission can result in toxigenic conversion within the secondary host. Ultimately, our findings demonstrate that the eukaryotic host serves as an essential component in the phage-mediated evolution of virulence within the microbial population.
Induction of Protective Immunity againstSchistosoma mansonivia DNA Priming and Boosting with the Large Subunit of Calpain (Sm-p80): Adjuvant Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-4
Authors: Siddiqui Afzal A. , Phillips Troy , Charest Hugues , Podesta Ron B. , Quinlin Martha L. , Pinkston Justin R. , Lloyd Jenny D. , Paz Michelle , Villalovos Rachael M. , Pompa Janet
Published: June 2003

Considerable morbidity and mortality result from schistosomiasis, an affliction affecting an estimated 200 million people. Although schistosomicidal drugs and other control measures (including public hygiene and snail control) exist, the advent of an efficacious vaccine remains the most potentially powerful means for controlling this disease. We have targeted a vaccine candidate (large subunit of calpain, Sm-p80) because of its consistent immunogenicity, protective potential, and integral role in surface membrane biogenesis of schistosomes. Since surface membrane renewal appears to be one of the major phenomena employed by schistosomes to evade the host's immune system; an immune response directed against Sm-p80 should render the parasite susceptible to immune clearance from the host by both providing a focus of attack and by potentially impairing the membrane repair process. In the present study, we have employed DNA immunization protocols using Sm-p80 with plasmids encoding granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Sm-p80 by itself provided 39% protection (P= ≤0.0001) against challenge infection in C57BL/6 mice. This protection was increased to 44% (P= ≤0.0001) when the plasmid encoding GM-CSF was coadministered with Sm-p80 DNA. Coinjection of plasmid DNA encoding IL-4 with Sm-p80 DNA yielded a protection level of 42% (P= ≤0.0001). Statistically, the protection conferred by including GM-CSF, but not IL-4, was significantly greater than that when only Sm-p80 was used. Sm-p80 DNA by itself elicited strong responses that include IgG2A and IgG2B antibody isotypes. The introduction of GM-CSF DNA with Sm-p80 DNA led to distinct increases in total IgG and IgG1 titers, whereas the coadministration of IL-4 DNA with Sm-p80 DNA resulted in a slight elevation of IgG1 and IgG3 titers and in some reduction of IgG2A and IgG2B titers. Our data again indicate that Sm-p80 can be an excellent candidate for a schistosomiasis vaccine.
Recombinant Soluble CD14 Reduces Severity of Intramammary Infection byEscherichia coli
Authors: Lee Jai-Wei , Paape Max J. , Elsasser Theodore H. , Zhao Xin
Published: June 2003

The interaction among gram-negative bacteria, the innate immune system, and soluble CD14 (sCD14) has not been well documented. The effect of recombinant bovine sCD14 (rbosCD14) on milk somatic cell count (SCC), bacterial clearance, and cytokine production was investigated by using a bovine intramammaryEscherichia coliinfection model. We first determined whether rbosCD14 would increase the SCC during a lipopolysaccharide (LPS) challenge. Three quarters of each of six healthy lactating cows were injected with either 0.3 μg of LPS, 0.3 μg of LPS plus 100 μg of rbosCD14, or saline. In comparison with quarters injected with LPS alone, the SCC was twofold higher (P< 0.05) in quarters injected with LPS plus rbosCD14 after the challenge. We therefore hypothesized that whenE.colibacteria invade the mammary gland, sCD14 in milk would interact with LPS and rapidly recruit neutrophils from the blood to eliminate the bacteria before establishment of infection. To test this hypothesis, two quarters of each of nine healthy cows were challenged with either 50 CFU ofE.coliplus saline or 50 CFU ofE.coliplus 100 μg of rbosCD14. Quarters challenged withE.coliplus rbosCD14 had a more rapid recruitment of neutrophils, which was accompanied by a faster clearance of bacteria, lower concentrations of tumor necrosis factor alpha and interleukin-8 in milk, and milder clinical symptoms, than challenged quarters injected with saline. Results indicate that increasing the concentration of sCD14 in milk may be a potential strategy with which to prevent or reduce the severity of infection by coliform bacteria.
Disruption of the ICOS-B7RP-1 Costimulatory Pathway Leads to Enhanced Hepatic Immunopathology and Increased Gamma Interferon Production by CD4 T Cells in Murine Schistosomiasis
Authors: Rutitzky Laura I. , Özkaynak Engin , Rottman James B. , Stadecker Miguel J.
Published: June 2003

Morbidity and mortality in schistosomiasis are largely due to an immune response mediated by CD4 T lymphocytes. Since lymphocyte activation is shaped by costimulatory signals, the specific functions of different costimulatory pathways are of increasing interest. We now examined the role of the inducible costimulatory molecule (ICOS) and its ligand B7-related protein 1 (B7RP-1) in the experimental murine schistosome infection by blocking this costimulatory pathway with monoclonal antibody against ICOS, administered daily by intraperitoneal injection during the patent phase of the disease. The treated mice exhibited enhanced hepatic immunopathology characterized by enlarged egg granulomas and pronounced parenchymal inflammation with hepatocellular necrosis, resulting in elevated liver enzyme levels in serum. Most strikingly, there was a sharp increase in gamma interferon (IFN-γ) production by schistosome egg antigen-stimulated granuloma cells, bulk mesenteric lymph node (MLN) cells, and purified MLN CD4 T cells, which contrasted with a more discreet change in the Th2-type cytokines interleukin 4 (IL-4) and IL-10. These findings suggest that the ICOS-B7RP-1 costimulatory pathway serves primarily to control IFN-γ production, thereby promoting a cytokine environment conducive to limited hepatic damage.
TheDrosophila melanogasterToll Pathway Participates in Resistance to Infection by the Gram-Negative Human PathogenPseudomonas aeruginosa
Authors: Lau Gee W. , Goumnerov Boyan C. , Walendziewicz Cynthia L. , Hewitson Jennifer , Xiao Wenzhong , Mahajan-Miklos Shalina , Tompkins Ronald G. , Perkins Lizabeth A. , Rahme Laurence G.
Published: June 2003

Pseudomonas aeruginosais a gram-negative pathogen that infects immunocompromised and cystic fibrosis patients. The molecular basis of the host-P. aeruginosainteraction and the effect of specificP. aeruginosavirulence factors on various components of the innate immunity pathways are largely unknown. We examine interactions betweenP. aeruginosavirulence factors and components of innate immunity response in theDrosophila melanogastermodel system to reveal the importance of the Toll signaling pathway in resistance to infection by theP. aeruginosahuman isolate PA14. Using the two PA14-isogenic mutantsplcSanddsbA, we show thatDrosophilaloss-of-function mutants of Spatzle, the extracellular ligand of Toll, and Dorsal and Dif, two NF-κB-like transcription factors, allow increasedP. aeruginosainfectivity within fly tissues. In contrast, a constitutively active Toll mutant and a loss-of-function mutant of Cactus, an IκB-like factor that inhibits the Toll signaling, reduce infectivity. Our finding that Dorsal activity is required to restrictP. aeruginosainfectivity inDrosophilaprovides direct in vivo evidence for Dorsal function in adult fly immunity. Additionally, our results provide the basis for future studies into interactions betweenP. aeruginosavirulence factors and components of the Toll signaling pathway, which is functionally conserved between flies and humans.
Infectious Agent and Immune Response Characteristics of Chronic Enterocolitis in Captive Rhesus Macaques
Authors: Sestak Karol , Merritt Christopher K. , Borda Juan , Saylor Elizabeth , Schwamberger Shelle R. , Cogswell Frank , Didier Elizabeth S. , Didier Peter J. , Plauche Gail , Bohm Rudolf P. , Aye Pyone P. , Alexa Pavel , Ward Richard L. , Lackner Andrew A.
Published: June 2003

Chronic enterocolitis is the leading cause of morbidity in colonies of captive rhesus macaques (Macaca mulatta). This study's aim was to identify the common enteric pathogens frequently associated with chronic enterocolitis in normal, immunocompetent rhesus monkeys and to elucidate the influence of this clinical syndrome on the host immune system. We analyzed the fecal specimens from 100 rhesus macaques with or without clinical symptoms of chronic diarrhea. Retrospective analysis revealed an increased incidence ofCampylobacterspp. (Campylobacter coliandCampylobacter jejuni),Shigella flexneri,Yersinia enterocolitica, adenovirus, andStrongyloides fulleborniin samples collected from animals with chronic diarrhea (P< 0.05). The presence of additional enteric pathogens, such asEscherichia coli, carrying the eaeA intimin or Stx2c Shiga toxin virulence genes,Balantidium coli,Giardia lamblia,Enterocytozoon bieneusi, andTrichuris trichiurawas found in all animals regardless of whether diarrhea was present. In addition, the upregulation of interleukin-1α (IL-1α), IL-3, and tumor necrosis factor alpha cytokine genes, accompanied by an increased presence of activated (CD4+CD69+) T lymphocytes was found in gut-associated lymphoid tissues collected from animals with chronic enterocolitis and diarrhea in comparison with clinically healthy controls (P< 0.05). These data indicate that chronic enterocolitis and diarrhea are associated, in part, with a variety of enteric pathogens and highlight the importance of defining the microbiological status of nonhuman primates used for infectious disease studies. The data also suggest that chronic colitis in rhesus macaques may have potential as a model of inflammatory bowel disease in humans.
Mis-Takes in Research: Errors or Opportunities?
Authors: Malinski Violet M.
Published: June 2003

This column explores the issue of mistakes in research, from the mismatch of theoretical framework and design to methodological errors. Rather than a discussion of such issues from the usual mistake as problem perspective, the author has chosen to present a view of mistake as golden opportunity for reflection and collegial sharing of ideas generated by the research as an integral part of the learning process. Following a brief discussion of normal science versus revolutionary thinking, and of the views of philosophers Kuhn, Popper, and Feyerabend, the author makes an appeal for tolerance, closing with ideas for advancing nursing science on purpose.
The Meaning of the Family: Lived Experiences of Turkish Women Immigrants in Germany
Authors: Zielke-Nadkarni Andrea
Published: June 2003

The basic premise underpinning this research is that the family plays a key role in understanding and providing adequate nursing care for an ill member. To understand the family, the view on what members are as a family and what meanings are attributed to their various roles is of central importance for nurses. Since Turkish Muslim families who live as migrants in Germany differ considerably in their own understanding of themselves in their German environment, qualitative research, based on Spradley’s developmental research sequence method, was conducted with nine Turkish women in order to learn about the meaning of family for them.
Effects of Short–Term Leptin Exposure on Triglyceride Deposition in Rat Liver
Authors: Roden Michael , Anderwald Christian , Fürnsinn Clemens , Waldhäusl Werner , Lohninger Alfred
Published: June 2003

Leptin has recently been suggested to play a role in the pathogenesis of hepatic steatosis. Consequently, this study was designed to examine the direct effects of portal leptin on the intrahepatic lipid contents in the postabsorptive state. Rat livers (n = 6 per group) were perfused in a recirculating system and portally infused with leptin (0.5 nmol/L, 5 nmol/L, and 25 nmol/L), insulin (10 nmol/L), leptin (5 nmol/L) plus insulin (10 nmol/L), glucagon (1 nmol/L), or vehicle (control). Intrahepatic contents of triglycerides, free cholesterol, cholesteryl esters, and free fatty acids were determined from the lipid extract of frozen livers by capillary gas chromatography. Short–term leptin infusion increased total triglycerides in a concentration–dependent (0.5 nmol/L: 2.8 ± 0.4 mg/g, 5 nmol/L: 7.0 ± 0.5 mg/g, 25 nmol/L: 8.3 ± 1.0 mg/g) and time–dependent manner. Total triglycerides also rose during exposure to insulin plus leptin (7.2 ± 0.6 mg/g) but fell during glucagon infusion (2.6 ± 0.2 mg/g; control: 4.3 ± 0.3 mg/g; P < .05). Leptin, insulin, and glucagon increased intrahepatic free cholesterol (P < .05). Free fatty acids were also higher during leptin exposure (0.5 nmol/L: 1.28 ± 0.08 mg/g, 5 nmol/L: 0.47 ± 0.01 mg/g, 25 nmol/L: 0.48 ± 0.04 mg/g, control: 0.38 ± 0.03 mg/g; P < .05). In conclusion, hyperleptinemia increases hepatic triglyceride content and may therefore contribute to hepatic steatosis in hyperleptinemic obese patients.
Protein Kinase Activation by Warm and Cold Hypoxia–Reoxygenation in Primary–Cultured Rat Hepatocytes-Jnk1/Sapk1 Involvement in Apoptosis
Authors: Crenesse Dominique , Gugenheim Jean , Hornoy Joelle , Tornieri Karine , Laurens Marina , Cambien Beatrice , Lenegrate Gaelle , Cursio Rafaele , De Souza Georges , Auberger Patrick , Heurteaux Catherine , Rossi Bernard , Schmid-Alliana Annie
Published: June 2003

Ischemia–reperfusion procedures induced severe hepatic damages owing to different processes related to hypoxia and reoxygenation (H/R) phases, including the consecutive oxygen free radical (OFR) release. Stress–activated protein kinases (SAPKs) could be activated by extracellular stimuli. The aim of this study was to show whether H/R stress conditions could stimulate these kinases, and especially c–jun–N–terminal kinase (JNK1/SAPK1), to reveal a potential role of JNK1/SAPK1 in the control of hepatocyte apoptosis. Primary cultured rat hepatocytes, isolated from other liver cells and blood flow, were subjected to warm and cold hypoxia–reoxygenation phases mimicking surgical and transplant conditions. The activation status of SAPKs was evaluated by immunoprecipitation or Western–blotting experiments, whereas apoptosis was assessed by measuring caspase activation and internucleosomal DNA fragmentation in vitro and by TUNEL reaction, in vivo. Hypoxia, and especially hypoxia–reoxygenation, significantly increased JNK1/SAPK1 activation in cultured hepatocytes. Either in warm or cold conditions, OFR scavengers (N–Acetylcystein, Di–Phenyleneiodonium, Deferoxamine) decreased this stimulation. Warm ischemia–reperfusion also led to JNK activation. Hypoxia and especially hypoxia–reoxygenation induced programmed cell death in vivo and in vitro. This last phenomenon was inhibited when hepatocytes were treated with SB 202190, which was described as a potent inhibitor of p38 and JNK activities. Altogether, these results confirmed that JNK1/SAPK1 was activated during the hypoxia–reoxygenation process, and that this activity participated in the onset of the apoptosis program.
No Significant Correlation Exists Between Core Promoter Mutations, Viral Replication, and Liver Damage in Chronic Hepatitis B Infection
Authors: Chun Yoon Keun , Kim Jee Youn , Woo Hong Jung , Oh Soo Myung , Kang Insug , Ha Joohun , Kim Sung Soo
Published: June 2003

Hepatitis B virus (HBV) core promoter mutants have been proposed to contribute to severe liver damage by increasing viral loads, but this has not yet been clearly shown. To examine the effects of core promoter mutants on viral load and liver damage, we first developed a polymerase chain reaction (PCR)–based semiquantitative HBV DNA detection method with a high sensitivity (able to detect as low as 103 molecules/mL). Then we cloned 12 predominant core promoter mutants from 41 chronic hepatitis B patients. The in vitro promoter and replication activities of these mutants were similar to those of wild–type virus. However, viral load was highly variable, and this was dependent on individual patients rather than mutant type. In addition, there was no mutant type that showed any unique correlation with alanine transaminase (ALT) levels. Viral load was not significantly correlated with ALT level in both cross–sectional and longitudinal studies. Quantitation of HBV levels also revealed no clear correlation between hepatitis B e antigen (HBeAg) status and viral load. Taken together, these results indicated that the replication activity of core promoter mutants has little effect on viral load, and that viral load does not correlate with the severity of liver damage or with HBeAg status.
Linear and Circular Plasmid Content in
Borrelia burgdorferi
Clinical Isolates
Authors: Iyer Radha , Kalu Ogori , Purser Joye , Norris Steven , Stevenson Brian , Schwartz Ira
Published: June 2003

The genome of
Borrelia burgdorferi
, the etiologic agent of Lyme disease, is composed of a linear chromosome and more than 20 linear and circular plasmids. Typically, plasmid content analysis has been carried out by pulsed-field gel electrophoresis and confirmed by Southern hybridization. However, multiple plasmids of virtually identical sizes (e.g., lp28 and cp32) complicate the interpretation of such data. The present study was undertaken to investigate the complete plasmid complements of
B. burgdorferi
clinical isolates cultivated from patients from a single region where early Lyme disease is endemic. A total of 21 isolates obtained from the skin biopsy or blood samples of Lyme disease patients were examined for their complete plasmid complements by Southern hybridization and plasmid-specific PCR analysis. All clinical isolates harbored at least six of the nine previously characterized cp32s. Fourteen isolates harbored all B31-like linear plasmids, and seven isolates simultaneously lacked lp56, lp38, and some segments of lp28-1. The distinctive plasmid profile observed in these seven isolates was specific to organisms that had ribosomal spacer type 2 and pulsed-field gel type A, which implies a clonal origin for this genotype. The presence of nearly identical complements of multiple linear and circular plasmids in all of the human isolates suggests that these plasmids may be particularly necessary for infection, adaptation, and/or maintenance in the infected host.
Antibody Specificities and Effect of Meningococcal Carriage in Icelandic Teenagers Receiving the Norwegian Serogroup B Outer Membrane Vesicle Vaccine
Authors: Wedege Elisabeth , Kuipers Betsy , Bolstad Karin , van Dijken Harry , Frøholm L. Oddvar , Vermont Clementien , Caugant Dominique A. , van den Dobbelsteen Germie
Published: June 2003

Antibody specificities of pre- and postvaccination serum samples from 40 (53%) teenagers who received three doses of the Norwegian
Neisseria meningitidis
serogroup B vaccine (B:15:P1.7,16) during a previous trial in Iceland (Perkins et al., J. Infect. Dis.
177:
683-691, 1998) were analyzed with serum bactericidal activity (SBA) and immunoblotting assays with reference and isogenic meningococcal H44/76 vaccine strains. The H44/76 variants demonstrated significant vaccine-induced SBA to P1.7,16 PorA and Opc but not to PorB, Opa5.5, and a heterologous PorA protein. On blots, immunoglobulin G levels to all these proteins increased significantly after vaccination. Measurement of SBA to the two main variable regions (P1.7 and P1.16) on the P1.7,16 PorA with PorA deletion mutants revealed significantly higher activity to the P1.7,− and P1.−,16 mutants compared to the P1.7,16 strain, indicating exposure of new accessible epitopes. Only 12 (30%) serum samples showed distinct decreases with these or the P1.−,− mutant, with most samples containing SBA to the P1.7 and P1.16 combination. In contrast, P1.16-specific antibodies were mainly found on blots. Thirteen of the vaccinees (32.5%) were carriers of meningococci at the time of the third dose, of whom four (30.8%) harbored strains of the ET-5 complex. Carriage of P1.15 strains was generally reflected in ≥4-fold increases in SBA and distinct immunoglobulin G binding to the P1.19,15 PorA on blots. Although vaccination did not elicit bactericidal activity to the serotype 15 PorB, most carriers of serotype 15 strains showed ≥4-fold increases in SBA to this antigen.
Construction and Characterization of aPseudomonas aeruginosaMucoid Exopolysaccharide-Alginate Conjugate Vaccine
Authors: Theilacker Christian , Coleman Fadie T. , Mueschenborn Simone , Llosa Nicolas , Grout Martha , Pier Gerald B.
Published: June 2003

Deterioration of lung function in patients with cystic fibrosis (CF) is closely associated with chronic pulmonary infection with mucoidPseudomonas aeruginosa. The mucoid exopolysaccharide (MEP) fromP. aeruginosahas been shown to induce opsonic antibodies in mice that are protective against this chronic infection. MEP-specific opsonic antibodies are also commonly found in the sera of older CF patients lacking detectableP. aeruginosainfection. When used in a human vaccine trial, however, MEP only minimally induced opsonic antibodies. To evaluate whether conjugation of MEP to a carrier protein could improve its immunogenicity, we bound thiolated MEP to keyhole limpet hemocyanin (KLH) by using succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) as a linker. In contrast to the native MEP polymer, the MEP-KLH conjugate vaccine induced high titers of MEP-specific immunoglobulin G (IgG) in C3H-HeN mice and in a rabbit. Sera from mice immunized with MEP-KLH conjugate, but not from animals immunized with comparable doses of native MEP, demonstrated opsonic killing activity. Vaccination with MEP-KLH conjugate induced opsonic antibodies broadly cross-reactive to heterologous mucoid strains ofP. aeruginosa. Preexisting nonopsonic antibodies to MEP are found in normal human sera, including young CF patients, and their presence impedes the induction of opsonic antibodies. Induction of nonopsonic antibodies by either intraperitoneal injection of MEP or injection or feeding of the cross-reactive antigen, seaweed alginate, reduced the level of overall IgG elicited by follow-up immunization with the MEP-KLH conjugate. However, the opsonic activity was lower only in the sera of MEP-KLH conjugate-immunized mice with preexisting antibodies induced by MEP but not with antibodies induced by seaweed alginate. Immunization with MEP-KLH elicited a significant proportion of antibodies specific to epitopes involving O-acetate residues, and this subpopulation of antibodies mediated opsonic killing of mucoidP. aeruginosain vitro. These results indicate that conjugation of MEP to KLH significantly enhances its immunogenicity and the elicitation of opsonic antibodies in mice and rabbits, that the conjugate induces opsonic antibodies in the presence of preexisting nonopsonic antibodies, and that opsonic antibodies to MEP are directed at epitopes that include acetate residues on the uronic acid polymer.
Pseudomonas aeruginosa
ExoU, a Toxin Transported by the Type III Secretion System, Kills
Saccharomyces cerevisiae
Authors: Rabin Shira D. P. , Hauser Alan R.
Published: June 2003

ExoU, a protein transported by the type III secretion system of
Pseudomonas aeruginosa
, is an important cytotoxin, though its mechanism of action is unclear. Here we show that the intracellular expression of ExoU is cytotoxic to
Saccharomyces cerevisiae
. Furthermore, internal amino- and carboxyl-terminal deletions confirmed that regions of ExoU previously shown to be essential for killing mammalian cells were also required for killing yeast cells. These findings indicate that
S. cerevisiae
is a useful model organism for the study of ExoU.
Nonsugar Sweeteners—Time for Transparency and Caution
Authors: Sylvetsky Allison C. , Rebolledo Natalia , Krieger James W.
Published: January 2024

This Viewpoint discusses the growing presence of nonsugar sweeteners (NSSs) in the food supply and mounting concerns about their use, which suggest that disclosure of the amounts of NSS in food and beverages and restrictions on their use in products marketed to children are warranted.
Ursodeoxycholic Acid‐Decorated Zwitterionic Nanoparticles for Orally Liver‐Targeted Close‐Looped Insulin Delivery
Authors: Ma Yuhong , Wang Wei , Li Caihua , Han Fuwei , He Mujiao , Zhong Yinan , Huang Dechun , Chen Wei , Qian Hongliang
Published: January 2024

Oral insulin therapies targeting the liver and further simulating close‐looped secretion face significant challenges due to multiple trans‐epithelial barriers. Herein, ursodeoxycholic acid (UDCA)‐decorated zwitterionic nanoparticles (NPs) (UC‐CMs@ins) are designed to overcome these barriers, target the liver, and respond to glycemia, thereby achieving oral one‐time‐per‐day therapy. UC‐CMs@ins show excellent mucus permeability through the introduction of zwitterion (carboxy betaine, CB). Furthermore, UC‐CMs@ins possess superior cellular internalization via proton‐assisted amino acid transporter 1 (PAT1, CB‐receptor) and apical sodium‐dependent bile acid transporter (ASBT, UDCA‐receptor) pathways. Moreover, UC‐CMs@ins exhibit excellent endolysosomal escape ability and improve the basolateral release of insulin into the bloodstream via the ileal bile acid‐binding protein and the heteromeric organic solute transporter (OSTα‐ OSTβ) routes compared with non‐UDCA‐decorated C‐CMs@ins. Therefore, CB and UDCA jointly overcome mucus and intestinal barriers. Additionally, UC‐CMs@ins prevent insulin degradation in the gastrointestinal tract for crosslinked structure, improve insulin accumulation in the liver for UDCA introduction, and effectively regulate glycemia for “closed‐loop” glucose control. Surprisingly, oral ingestion of UC‐CMs@ins shows a superior effect on glycemia (≈22 h, normoglycemia) and improves postprandial glycemic levels in diabetic mice, illustrating the enormous potential of the prepared NPs as a platform for oral insulin administration in diabetes treatment.
Material‐Intrinsic NIR‐Fluorescence Enables Image‐Guided Surgery for Ceramic Fracture Removal
Authors: Nißler Robert , Totter Elena , Walter Sebastian G. , Metternich Justus T. , Cipolato Oscar , Nowack Dimitri , Gogos Alexander , Herrmann Inge K.
Published: January 2024

Hip arthroplasty effectively treats advanced osteoarthritis and is therefore entitled as “operation of the 20th century.” With demographic shifts, the USA alone is projected to perform up to 850 000 arthroplasties annually by 2030. Many implants now feature a ceramic head, valued for strength and wear resistance. Nonetheless, a fraction, up to 0.03% may fracture during their lifespan, demanding complex removal procedures. To address this, a radiation‐free, fluorescence‐based image‐guided surgical technique is presented. The method uses the inherent fluorescence of ceramic implant materials, demonstrated through chemical and optical analysis of prevalent implant types. Specifically, Biolox delta implants exhibited strong fluorescence around 700 nm with a 74% photoluminescence quantum yield. Emission tails are identified extending into the near‐infrared (NIR‐I) biological transparency range, forming a vital prerequisite for the label‐free visualization of fragments. This ruby‐like fluorescence could be attributed to Cr within the zirconia‐toughened alumina matrix, enabling the detection of even deep‐seated millimeter‐sized fragments via camera‐assisted techniques. Additionally, fluorescence microscopy allowed detection of µm‐sized ceramic particles, enabling debris visualization in synovial fluid as well as histological samples. This label‐free optical imaging approach employs readily accessible equipment and can seamlessly transition to clinical settings without significant regulatory barriers, thereby enhancing the safety, efficiency, and minimally invasive nature of fractured ceramic implant removal procedures.
One‐Step Synthesis of Hydrogel Adhesive with Acid‐Responsive Tannin Release for Diabetic Oral Mucosa Defects Healing
Authors: Su Kaize , Li Jinxuan , Wu Xiaoxian , Deng Duanyu , Gu Han , Sun Ying , Wang Xu , Huang Wenhuan , Wang Yan , Shang Xiangcun , Xue Cuiyu , Liang Lihua , Li Xiaofang , Li Dongli , Ang Song , Zhang Kun , Wu Panpan , Wu Keke
Published: January 2024

The complex preparation, weak wet tissue adhesion, and limited biological activity of traditional oral wound dressings usually impede their efficient treatment and healing for diabetic oral mucosal defects. To overcome these problems, a novel hydrogel adhesive (named CFT hydrogel) is rapidly constructed using a one‐step method based on dual‐dynamic covalent cross‐linking. Compared with the commercial oral patches, the CFT hydrogel shows superior in vivo (rat tongue) wet tissue adhesion performance. Additionally, the CFT hydrogel exhibits unique acid‐responsive properties, thereby facilitating the release of bioactive molecule tannic acid in the acidic diabetic wound microenvironment. And a series of in vitro experiments substantiate the favorable biocompatibility and bioactivity properties (including antibacterial, antioxidative, anti‐inflammatory, and angiogenetic effects) exhibited by CFT hydrogel. Moreover, in vivo experiments conducted on a diabetic rat model with oral mucosal defects demonstrate that the CFT hydrogel exhibits significant efficacy in protecting against mucosal wounds, alleviating inflammatory reactions, thereby facilitating the wound‐healing process. Taken together, this study provides a promising and comprehensive therapeutic option with great potential for the clinical management of oral mucosa defects in diabetic patients.
Glutathione Depletion‐Induced Versatile Nanomedicine for Potentiating the Ferroptosis to Overcome Solid Tumor Radioresistance and Enhance Immunotherapy
Authors: Song Huijuan , Sun Hao , He Ningning , Xu Chang , Du Liqing , Ji Kaihua , Wang Jinhan , Zhang Manman , Gu Yeqing , Wang Yan , Liu Qiang
Published: January 2024

A high level of reduced glutathione is a major factor contributing to the radioresistance observed in solid tumors. To address this radioresistance associated with glutathione, a cinnamaldehyde (CA) polymer prodrug, referred to as PDPCA, is fabricated. This prodrug is created by synthesizing a pendent CA prodrug with acetal linkages in a hydrophobic block, forming a self‐assembled into a core–shell nanoparticle in aqueous media. Additionally, it encapsulates all‐trans retinoic acid (ATRA) for synchronous delivery, resulting in PDPCA@ATRA. The PDPCA@ATRA nanoparticles accumulate reactive oxygen species through both endogenous and exogenous pathways, enhancing ferroptosis by depleting glutathione. This approach demonstrates efficacy in overcoming tumor radioresistance in vivo and in vitro, promoting the ferroptosis, and enhancing the cytotoxic T lymphocyte (CTL) response for lung tumors to anti‐PD‐1 (αPD‐1) immunotherapy. Furthermore, this study reveals that PDPCA@ATRA nanoparticles promote ferroptosis through the NRF2‐GPX4 signaling pathway, suggesting the potential for further investigation into the combination of radiotherapy and αPD‐1 immune checkpoint inhibitors in cancer treatment.
Tunable 2D Electron‐ and 2D Hole States Observed at Fe/SrTiO3 Interfaces
Authors: Düring Pia M. , Rosenberger Paul , Baumgarten Lutz , Alarab Fatima , Lechermann Frank , Strocov Vladimir N. , Müller Martina
Published: January 2024

Oxide electronics provide the key concepts and materials for enhancing silicon‐based semiconductor technologies with novel functionalities. However, a basic but key property of semiconductor devices still needs to be unveiled in its oxidic counterparts: the ability to set or even switch between two types of carriers—either negatively (n) charged electrons or positively (p) charged holes. Here, direct evidence for individually emerging n‐ or p‐type 2D band dispersions in STO‐based heterostructures is provided using resonant photoelectron spectroscopy. The key to tuning the carrier character is the oxidation state of an adjacent Fe‐based interface layer: For Fe and FeO, hole bands emerge in the empty bandgap region of STO due to hybridization of Ti‐ and Fe‐ derived states across the interface, while for Fe3O4 overlayers, an 2D electron system is formed. Unexpected oxygen vacancy characteristics arise for the hole‐type interfaces, which as of yet had been exclusively assigned to the emergence of 2DESs. In general, this finding opens up the possibility to straightforwardly switch the type of conductivity at STO interfaces by the oxidation state of a redox overlayer. This will extend the spectrum of phenomena in oxide electronics, including the realization of combined n/p‐type all‐oxide transistors or logic gates.
Functionality Modulation Toward Thianthrene‐based Metal‐Free Electrocatalysts for Water Splitting
Authors: Sadhukhan Arnab , Karmakar Arun , Koner Kalipada , Karak Shayan , Sharma Rahul Kumar , Roy Avishek , Sen Prince , Dey Krishna Kishor , Mahalingam Venkataramanan , Pathak Biswarup , Kundu Subrata , Banerjee Rahul
Published: January 2024

The development of metal‐free bifunctional electrocatalysts for hydrogen and oxygen evolution reactions (HER and OER) is significant but rarely demonstrated. Porous organic polymers (POPs) with well‐defined electroactive functionalities show superior performance in hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Precise control of the active sites' local environment requires careful modulation of linkers through the judicious selection of building units. Here, a systematic strategy is introduced for modulating functionality to design and synthesize a series of thianthrene‐based bifunctional sp2 C═C bonded POPs with hollow spherical morphologies exhibiting superior electrocatalytic activity. This precise structural tuning allowed to gain insight into the effects of heteroatom incorporation, hydrophilicity, and variations in linker length on electrocatalytic activity. The most efficient bifunctional electrocatalyst THT‐PyDAN achieves a current density of 10 mA cm─2 at an overpotential (η10) of ≈65 mV (in 0.5 m H2SO4) and ≈283 mV (in 1 m KOH) for HER and OER, respectively. THT‐PyDAN exhibits superior activity to all previously reported metal‐free bifunctional electrocatalysts in the literature. Furthermore, these investigations demonstrate that THT‐PyDAN maintains its performance even after 36 h of chronoamperometry and 1000 CV cycling. Post‐catalytic characterization using FT‐IR, XPS, and microscopic imaging techniques underscores the long‐term durability of THT‐PyDAN.
Hot‐Carrier Cooling Regulation for Mixed Sn‐Pb Perovskite Solar Cells
Authors: Yan Wenjian , Li Chongwen , Peng Cheng , Tan Shuchen , Zhang Jiakang , Jiang Haokun , Xin Feifei , Yue Fang , Zhou Zhongmin
Published: January 2024

The rapid relaxation of hot carriers leads to energy loss in the form of heat and consequently restricts the theoretical efficiency of single‐junction solar cells; However, this issue has not received much attention in tin‐lead perovskites solar cells. Herein, tin(II) oxalate (SnC2O4) is introduced into tin‐lead perovskite precursor solution to regulate hot‐carrier cooling dynamics. The addition of SnC2O4 increases the length of carrier diffusion, extends the lifetime of carriers, and simultaneously slows down the cooling rate of carriers. Furthermore, SnC2O4 can bond with uncoordinated Sn2+ and Pb2+ ions to regulate the crystallization of perovskite and enable large grains. The strongly reducing properties of the C2O42− can inhibit the oxidation of Sn2+ to Sn4+ and minimize the formation of Sn vacancies in the resulting perovskite films. Additionally, as a substitute for tin(II) fluoride, the introduction of SnC2O4 avoids the carrier transport issues caused by the aggregation of F– ions at the interface. As a result, the SnC2O4‐treated Sn‐Pb cells show a champion efficiency of 23.36%, as well as 27.56% for the all‐perovskite tandem solar cells. Moreover, the SnC2O4‐treated devices show excellent long‐term stability. This finding is expected to pave the way toward stable and highly efficient all‐perovskite tandem solar cells.
Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma
Authors: Sebak Aya A. , Abdel‐Halim Mohammad , Abdelrahman Mostafa , Mohamed Gehad , El‐Tayeb Tarek , Gomaa Iman
Published: January 2024

The complexity of the tumor microenvironment (TME) and nutrient competition represent the main causes of therapy resistance in cancers, including malignant melanoma (MM). Photodynamic therapy (PDT), through a cascade of events including its ability to induce significant immune responses, causes tumor eradication. However, the high pigmentation level of melanoma, lack of adequate accumulation of photosensitizers (PSs) in the target tissue as well as their nonspecific toxicity represent three main obstacles to obtaining satisfactory responses in melanoma. To prevail over these challenges, this study employs a depigmentation strategy followed by a nano‐mediated topical application of PDT using a chlorophyllin derivative as PS, focusing on the evaluation of the immunomodulatory and metabolic regulatory axes of PDT in melanoma. Photo‐immunomodulation is assessed in a melanoma mouse model using a nanocarrier system of the PS. Markers of the immunosuppressive microenvironment and T cell exhaustion, as independent immune hallmarks, are quantified. The histopathology of the spleen and skin/tumor is evaluated. The amino acid profile is quantified from normal skin or tumor biopsies using UHPLC‐MS/MS. Around 80% of the 300 nm transethosomal ferrous chlorophyllin (fC‐TEs) are retained in the tumor over 24 h upon topical application. Arbutin 2% gel not only decreased the melanin content of tumors but also regulated the expression of interleukin 12 (IL‐12), IL‐10, transforming growth factor beta (TGF‐β), and tumor necrosis factor‐alpha (TNF‐α). Additionally, the nano‐mediated PDT strategy decreased the expression of programmed cell death protein 1 (PD‐1) and its ligand 1 (PD‐L1) and reduces the activity of arginase 1 (Arg1) through an upregulation of miRNA155. A mild recruitment of megakaryocytes (MKs) is observed in the spleen of the PDT group. This special localization of MKs depicts effector immune properties. Lastly, the combination of PDT and arbutin restores the normal tissue levels of arginine (Arg), and glutamine (Gln) and lavished those of tryptophan (Trp). Nano‐mediated PDT represents a novel immunotherapeutic approach in melanoma by a triple modulation of the immune suppressive TME, immune checkpoint signaling, and reprogrammed tumor metabolism.
Climate change disclosure and evolving institutional investor salience: Roles of the Principles for Responsible Investment
Authors: Azuma Kentaro , Higashida Akira
Published: January 2024

This study investigates the relationship between climate change disclosure and institutional investors. A particular focus of the present study is the question of if and how the relationship is affected by the Principles for Responsible Investment (PRI). A relevant context to the question is shareholder engagement, where institutional investors' legitimacy affects the outcomes. Thus, this study examines Japan, where shareholder engagement is the main pathway for institutional investors to convey their ESG‐related influence to investee companies. Using the stakeholder salience theory as a theoretical framework, the empirical results of analyzing 17,604 firm‐year eXtensible Business Reporting Language (XBRL) documents of listed Japanese companies provide evidence for the following. First, institutional stakeholders' holding ratio has positively influenced corporate climate change disclosure (power). Second, the positive influence of institutional investors is more significant when PRI‐signed institutional investors are present (legitimacy). Third, the aforementioned relations gained statistical significance gradually during the analysis period (urgency). Fundamentally, this study shows that the stakeholder salience theory contributes to a deeper understanding of the relationship.
A systematic review of literature on homicide followed by suicide and mental state of perpetrators
Authors: Theodorou Alexis , Sinclair Helen , Ali Saima , Sukhwal Seema , Bassett Christopher , Hales Heidi
Published: January 2024

Background

Homicide followed by suicide is rare, devastating and perpetrated worldwide. It is commonly assumed that the perpetrator had a mental disorder, raising concomitant questions about prevention. Though events have been reported, there has been no previous systematic review of the mental health of perpetrators.

Aims

Our aims were twofold. First, to identify whether there are recognisable subgroups of homicide–suicides in published literature and, secondly, to investigate the relationship between perpetrator mental state and aspects of the incident.

Methods

We conducted a systematic review of published literature on studies of homicide followed within 24 h by suicide or serious suicide attempt that included measures of perpetrator mental state.

Results

Sixty studies were identified, most from North America or Europe. Methodologically, studies were too heterogeneous for meta‐analysis. They fell into three main groups: family, mass shooter, and terrorist with an additional small mixed group. There was evidence of mental illness in a minority of perpetrators; its absence in the remainder was only partially evidenced. There was no clear association between any specific mental illness and homicide–suicide type, although depression was most cited. Social role disjunction, motive, substance misuse and relevant risk or threat behaviours were themes identified across all groups. Pre‐established ideology was relevant in the mass shooter and terrorism groups. Prior trauma history was notable in the terrorist group.

Conclusion

Research data were necessarily collected post‐incident and in most cases without a standardised approach, so findings must be interpreted cautiously. Nevertheless, they suggest at least some preventive role for mental health professionals. Those presenting to services with depression, suicidal ideation, relationship difficulties and actual, or perceived, changes in social position or role would merit detailed, supportive assessment over time.