bluuebunny/crossref_metadata_2025 huggingface dataset:
Probability of receiving testing in a national lookback program: the English HCV experience
Authors: The English National Blood Service HCV Lookback Collation Co
Published: October 2002

BACKGROUND : The HCV lookback program was designed to trace and offer testing to recipients who received transfusion of blood components from donors subsequently found to be anti‐HCV positive. Only approximately 20 percent of transfusable components entering lookback did result in a recipient obtaining testing through this program.

STUDY DESIGN AND METHODS : Data from English blood centers were collated to describe the outcomes of the HCV lookback program. The data were used to assess factors affecting the likelihood that recipients of lookback components received testing by the program.

RESULTS : In total, 4424 recipients of 6687 blood components that had been issued for transfusion were identified. The lookback resulted in a tested recipient for 1067 components. Factors positively associated with receiving testing in identified recipients were younger age at transfusion, more recent year of transfusion, certain component types, and transfusion under the care of certain medical specialties; these effects were largely explained by the association of these factors with survival after transfusion.

CONCLUSION S: Not accepting testing through this program was largely due to death before the lookback and partly due to inability to access information from records and to decisions that testing was not in recipients' best interests. The probability of obtaining testing through this lookback was associated with several factors that could be used to focus the efforts of similar lookbacks in the future.
Effect of WBC reduction of transfused RBCs on postoperative infection rates in cardiac surgery
Authors: Wallis J.P. , Chapman C.E. , Orr K.E. , Clark S.C. , Forty J.R.
Published: October 2002

BACKGROUND : WBC‐replete blood transfusion has been suggested as an independent cause of increased postoperative infection.

STUDY DESIGN AND METHODS : A total of 597 patients undergoing elective coronary artery or heart valve surgery were randomly assigned to receive plasma‐ reduced (PR), buffy coat‐depleted (BCD), or WBC‐ filtered (WCF) RBCs in the event of requiring blood transfusion. Details of postoperative course were recorded. Further information was collected from the patient's general practitioner 3 months after discharge.

RESULTS
: No significant difference in inpatient infection rates was observed among patients randomly assigned to receive PR, BCD, or WCF RBCs. When only those receiving transfusion were analyzed (n = 509), use of PR RBCs was associated with more events coded as infections (p ≤ 0.05) compared with BCD or WCF RBCs. However, when events coded as urinary tract infections were excluded, there was no significant difference among the three groups. Follow‐up performed after discharge showed no difference in readmission rates, but a higher reported rate of infection in those randomly assigned to receive WCF RBCs (p
< 0.02).

CONCLUSION : No evidence has been found, analyzed by intention to treat, that use of WBC‐reduced, BCD, or WCF RBCs reduces postoperative inpatient infection in patients undergoing cardiac bypass surgery.
Hepatic but not intestinal CYP3A4 displays dose‐dependent induction by efavirenz in humans
Authors: Mouly Stéphane , Lown Kenneth S. , Kornhauser David , Joseph Jeffrey L. , Fiske William D. , Benedek Irma H. , Watkins Paul B.
Published: October 2002

Objective

The capacity of the non‐nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P‐glycoprotein, was evaluated in healthy volunteers during and after a 10‐day treatment course with two different daily doses.

Methods

Cohorts of 12 healthy subjects were randomized (2:1) to receive eitherefavirenz or placebo orally for 10 days. The first cohort received 200 mg efavirenz and the second cohort received 400 mg efavirenz daily. Liver CYP3A4 activity was evaluated on 9 different occasions with use of the erythromycin breath test (ERMBT). Intestinal biopsyspecimens were obtained before the first dose of efavirenz and on the day after administration of the last dose to measure intestinal CYP3A4 and P‐glycoprotein contents by immunoblotting. Efavirenz plasma levels were measured by HPLC, and pharmacokinetic parameters were determined by standard noncompartmental methods.

Results

Efavirenz significantly increased the mean ERMBT result in a dose‐ andtime‐dependent manner, with a 55% mean induction at 400 mg and a 33% mean induction at 200 mg (P < .01, compared with placebo for each treatment). The efavirenz AUC on day 10 correlated with the magnitude of induction (day 11/day 1 ERMBT ratio) when the two dose groups were combined (r = 0.509; P = .04). In contrast, efavirenz treatment had no detectable effect on intestinal CYP3A4 or P‐glycoprotein.

Conclusions

Efavirenz is an inducer of liver CYP3A4 in healthy volunteesrs, and interpatient differences in magnitude of induction is partly explained by variation in systemic drug exposure. However, efavirenz did not appear to induce intestinal CYP3A4 or intestinal P‐glycoprotein. These results suggest that drug interactions caused by induction of CYP3A4 can be liver specific.

Clinical Pharmacology & Therapeutics (2002) 72, 1–9;doi: 10.1067/mcp.2002.124519
Angiotensin‐converting enzyme inhibitor‐induced syndrome of inappropriate secretion of antidiuretic hormone: Case report and review of the literature
Authors: Izzedine Hassane , Fardet Laurence , Launay‐Vacher Vincent , Dorent Richard , Petitclerc Thierry , Deray Gilbert
Published: October 2002

Seventeen cases of severe hyponatremia induced by angiotensin‐converting enzyme (ACE) inhibitor therapy have been reported in the literature. The mechanism of severe hyponatremia induced by ACE inhibitor is not clear. A 60‐year‐old white man with a history of idiopathic dilated cardiomyopathy was treated with enalapril, 20 mg daily, that had been started 2 weeks before heart transplantation. The serum sodium level was 138 mmol/L before initiation of enalapril therapy and 127 mmol/L just before cardiac surgery. In the post‐heart transplantation period, enalapril therapy was withdrawn for the perianesthesia period, and the serum sodium level increased from 127 to 140 mmol/L. One month later, viral myocarditis developed in the patient and enalapril was reintroduced at 20 mg daily. Two weeks later, natremia decreased. Enalapril was discontinued. Three days later the serum sodium level rose to 140 mmol/L. Severe symptomatic hyponatremia induced by the syndrome of inappropriate secretion of antidiuretic hormone should be considered a rare but possible complication associated with ACE inhibitor therapy.

Clinical Pharmacology & Therapeutics (2002) 71, 503–507; doi: 10.1067/mcp.2002.124520
Are herbal products dietary supplements or drugs? An important question for public safety
Authors: Stein C. Michael
Published: October 2002

Clinical Pharmacology & Therapeutics (2002) 71, 411–413; doi: 10.1067/mcp.2002.125975
Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P‐glycoprotein
Authors: Kurata Yasuo , Ieiri Ichiro , Kimura Miyuki , Morita Toshihiro , Irie Shin , Urae Akinori , Ohdo Shigehiro , Ohtani Hisakazu , Sawada Yasufumi , Higuchi Shun , Otsubo Kenji
Published: October 2002

Objective

Our objective was to quantitate the contribution of the genetic polymorphism of the human MDR1 gene to the bioavailability and interaction profiles of digoxin, a substrate of P‐glycoprotein.

Methods

The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups (n = 5 each) on the basis of genotyping for the MDR1 gene, in a 4‐dose study after single doses of digoxin alone (0.5 mg orally and intravenously) and coadministered with clarithromycin (400 mg orally for 8 days). The dose of digoxin was reduced during the clarithromycin phase (0.25 mg orally and intravenously).

Results

The bioavailability of digoxin in G/G2677C/C3435, G/T2677C/T3435, and T/T2677T/T3435 subjects were 67.6% ± 4.3%, 80.9% ± 8.9%, and 87.1% ±8.4%, respectively, and the difference betweenG/G2677C/C3435 and T/T2677T/T3435 subjects was statistically significant (P <.05). The MDR1 variants were also associated with differences in disposition kinetics of digoxin, with the renal clearance being almost 32% lower in T/T2677T/T3435 subjects (1.9 ± 0.1 mL/min per kilogram) than G/G2677C/C3435 subjects (2.8 ± 0.3 mL/min per kilogram), and G/T2677C/T3435 subjects having an intermediate value (2.1 ± 0.6 mL/min per kilogram). Coadministration of clarithromycin did not consistently affect digoxin clearance or renal clearance. However, a significant increase in digoxin bioavailability was observed in G/G2677C/C3435subjects (67.6% ± 4.3% versus 85.4% ± 6.1%; P < .05) but not inthe other2 genotype groups.

Conclusion

The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P‐glycoprotein‐mediated drug interaction (Clin Pharmacol Ther 2002;72:209‐19.)

Clinical Pharmacology & Therapeutics (2002) 72, 209–219; doi: 10.1067/mcp.2002.126177
Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir
Authors: Pfister Marc , Labbé Line , Lu Jian‐Feng , Hammer Scott M. , Mellors John , Bennett Kara K. , Rosenkranz Susan , Sheiner Lewis B. ,   the AIDS Clinical Trial Group Protocol 398 Investigators
Published: October 2002

Objective

Pharmacokinetic interactions are expected when human immunodeficiency virus (HIV) protease inhibitors are coadministered because many are both substrates forand inhibitors of CYP3A4. The goal of this model‐based pharmacokinetic analysis was to describe the differences observed in amprenavir pharmacokinetics among treatment arms in the Adult AIDS Clinical Trial Group (AACTG) study protocol 398 and to propose mechanisms toaccount for them.

Methods

One hundred seventy‐six HIV‐positive subjects receiving 1200 mg amprenavir twice daily as part of AACTG protocol 398 were included in the pharmacokinetic study. All patients also received background medications efavirenz, adefovir dipivoxil, and abacavir and, depending on the study arm, placebo or one of the following protease inhibitors: nelfinavir, indinavir, or saquinavir. A population pharmacokinetic model was fitted to a total of 565 amprenavir concentration measurements. The blood samples for concentration measurements were drawn at week 2 (12‐hour pharmacokinetic study, approximately 7 samples per study; 46 patients) and at week 24 (6‐hour pharmacokinetic study, approximately 5samples per study; 10 patients). In addition, samples were collected at 1 or more follow‐up visits (population pharmacokinetic study, 1 to 3 occasions per patient; 150 patients).

Results and Conclusion

Amprenavir intrinsic clearance was significantly reduced relative to placebo by nelfinavir (−41%) and indinavir (−54%)but not by saquinavir. The absolute magnitude of amprenavir intrinsic clearance suggests that CYP3A4 inhibition by nelfinavir and indinavir is balanced by enzymatic induction in the presence of the background drug(s), most likely efavirenz. Amprenavir intrinsic clearance apparently increases by more than 30% between weeks 2 and 24, possibly because of the time course of CYP3A4 induction.

Clinical Pharmacology & Therapeutics (2002) 72, 133–141; doi: 10.1067/mcp.2002.126183
Pheochromocytomas and Ganglioneuromas in the Aging Rats: Morphological and Immunohistochemical Characterization
Authors: Pace Virgilio , Perentes Elias , Germann Paul-Georg
Published: October 2002

We investigated, morphologically and immunohistochemically, 74 medullary adrenal tumors, including 64 pheochromocytomas (14 malignant and 50 benign), 9 ganglioneuromas, and 1 malignant schwannoma. The tumors were detected in 2-year-old Wistar and Sprague—Dawley rats from carcinogenicity studies. Morphologically, benign pheochromocytomas were characterized by monomorphic, small, basophilic cells with almost absence of mitoses. Malignant pheochromocytomas presented a low grade of pleomorphism, higher rate of mitoses, necrosis, infiltrative growth and in 1 case metastases in the lung. Ganglioneuromas were characterized by ganglion and neuron-like cells embedded in an eosinophilic matrix containing neurites, Schwann cells, and scant fibrovascular elements. All pheochromocytomas were strongly immunoreactive for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Subpopulations of chromaffin cells expressed chromogranin A (CGA) positivity. Matrix and Schwann cells were positive for S-100 and for glial fibrillary acidic protein (GFAP). In focal areas of the tumors, ganglion cells and axons were positive for neurofilament proteins (NFP) and synaptophysin. Ganglion cells exhibited peripherin and ß-tubulin. Proliferative activity of the tumors was assessed by immunostaining the endogenous cell proliferation associated-antigen Ki-67 and the proliferating cell nuclear antigen (PCNA). As expected, cell proliferation indeces were much higher in malignant pheochromocytomas than in benign, yet ganglioneuromas remained immunonegative. Considering that Ki-67 antigen is more specific for cell proliferation, it should be regarded as marker of choice for supporting the differential diagnosis between benign and malignant pheochromocytomas.
Ezrin turnover and cell shape changes catalyzed by proteasome in oxidatively stressed cells
Authors: Grune Tilman , Reinheckel Thomas , North James A. , Li Rui , Bescos Paloma B. , Shringarpure Reshma , Davies Kelvin J. A.
Published: October 2002

We find that ezrin, a cytoskeletal protein involved in anchoring actin to the cell membrane, is preferentially degraded and resynthesized after oxidative stress. Ezrin was identified using 2‐dimensional gels and amino‐terminal microsequencing as one of a select few [35S]methionine prelabeled proteins degraded in clone 9 rat liver cells exposed to hydrogen peroxide (H2O2). Metabolic labeling of cellular proteins with [35S]methionine after oxidative stress showed that resynthesis of ezrin rose dramatically but carboxyl terminus anti‐ezrin monoclonal antibodies revealed constant intracellular ezrin levels; in other words, degradation and resynthesis were exactly matched. Ezrin degradation was blocked by selective inhibitors of the proteasome (lactacystin, NLVS, and epoxomycin) and by an antisense oligonucleotide directed against the proteasome C2 subunit. H2O2 also caused major changes in cell shape, including significant increases in cell diameter, which must require substantial cytoskeletal rearrangement. Peroxide‐induced increases in cell diameter were, however, blocked by the selective proteasome inhibitor lactacystin. The degradation and resynthesis of ezrin may therefore be an underlying mechanism for overall cell shape changes observed during oxidative stress. Oxidative stress induces extensive protein oxidation and degradation and significant increases in cell blebbing, rounding‐up, and overall size. Our results indicate that all these oxidant‐induced changes may actually be catalyzed by the proteasome.—Grune, T., Reinheckel, T., North, J. A., Li, R., Bescos, P. B., Shringarpure, R., Davies, K. J. A. Ezrin turnover and cell shape changes catalyzed by proteasome in oxidatively stressed cells. FASEB J. 16, 1602–1610 (2002)
The role of caspases in cryoinjury: caspase inhibition strongly improves the recovery of cryopreserved hematopoietic and other cells
Authors: Stroh Christopher , Cassens Uwe , Samraj Ajoy K. , Sibrowski Walter , Schulze‐Osthoff Klaus , Los Marek
Published: October 2002

Cryopreserved cells and tissues are increasingly used for stem cell transplantation and tissue engineering. However, their freezing, storage, and thawing is associated with severe damage, suggesting the need for better cryopreservation methods. Here, we show that activation of caspase‐3 is induced during the freeze‐thaw process. Moreover, we demonstrate that prevention of caspase activation by the caspase inhibitor zVAD‐fmk strongly improves the recovery and survival of several cryopreserved cell types and hematopoietic progenitor cells. A short preincubation with the caspase inhibitor after thawing also enhances the colony‐forming activity of hematopoietic progenitor cells up to threefold. Furthermore, overexpression of Bcl‐2, but not the blockade of the death receptor signaling, confers protection, indicating that cryoinjury‐ associated cell death is mediated by a Bcl‐2‐controlled mitochondrial pathway. Thus, our data suggest the use of zVAD‐fmk as an efficient cryoprotective agent. The addition of caspase inhibitors may be an important tool for the cryopreservation of living cells and advantageous in cell transplantation, tissue engineering, and other genetic technologies.
SAGE transcript profiles of normal primary human hepatocytes expressing oncogenic hepatitis B virus X protein
Authors: Wu Chuan‐Ging , Forgues Marshonna , Siddique Shabina , Farnsworth Julie , Velerie Kristoffer , Wang Xin Wei
Published: October 2002

Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). HBV encodes an oncogenic HBx gene that functions as a transcriptional coactivator of multiple cellular genes. To understand the role(s) of HBx in the early genesis of HCC, we systematically analyzed gene expression profiles by serial analysis of gene expression (SAGE) in freshly isolated human primary hepatocytes infected with a replication‐defective adenovirus containing HBx. A total of 19,501 sequence tags (representing 1443 unique transcripts) were analyzed, which provide a distribution of a transcriptome characteristic of normal hepatocytes and a profile associated with HBx expression. Examples of the targeted genes were confirmed by the Megarray analysis with a significant correlation between quantitative SAGE and Megarray (r = 0.8, P> 0.005). In HBx‐expressing hepatocytes, a total of 57 transcripts (3.9%) were induced, and 46 transcripts (3.3%) were repressed by more than fivefold. Interestingly, most of the HBxup‐regulated transcripts can be clustered into three major classes, including genes that encode ribosomal proteins, transcription factors with zinc‐finger motifs, and proteins associated with protein degradation pathways. These results suggest that HBx may function as a major regulator in common cellular pathways that, in turn, regulate protein synthesis, gene transcription, and protein degradation.
Bioreactors mediate the effectiveness of tissue engineering scaffolds
Authors: Pei Ming , Solchaga Luis A. , Seidel Joachim , Zeng Li , Vunjak‐Novakovic Gordana , Caplan Arnold I. , Freed Lisa E.
Published: October 2002

We hypothesized that the mechanically active environment present in rotating bioreactors mediates the effectiveness of three‐dimensional (3D) scaffolds for cartilage tissue engineering. Cartilaginous constructs were engineered by using bovine calf chondrocytes in conjunction with two scaffold materials (SM) (benzylated hyaluronan and polyglycolic acid); three scaffold structures (SS) (sponge, non‐woven mesh, and composite woven/non‐woven mesh); and two culture systems (CS) (a bioreactor system and petri dishes). Construct size, composition [cells, glycosaminoglycans (GAG), total collagen, and type‐specific collagen mRNA expression and protein levels], and mechanical function (compressive modulus) were assessed, and individual and interactive effects of model system parameters (SM, SS, CS, SM∗CS and SS∗CS) were demonstrated. The CS affected cell seeding (higher yields of more spatially uniform cells were obtained in bioreactor‐grown than dish‐grown 3‐day constructs) and subsequently affected chondrogenesis (higher cell numbers, wet weights, wet weight GAG fractions, and collagen type II levels were obtained in bioreactor‐grown than dish‐grown 1‐month constructs). In bioreactors, mesh‐based scaffolds yielded 1‐month constructs with lower type I collagen levels and four‐fold higher compressive moduli than corresponding sponge‐based scaffolds. The data imply that interactions between bioreactors and 3D tissue engineering scaffolds can be utilized to improve the structure, function, and molecular properties of in vitro‐generated cartilage.
Genetic and pharmacological dissection of pathways involved in the angiotensin II‐mediated depression of baroreflex function
Authors: Wong Liang‐Fong , Polson Jaimie W. , Murphy David , Paton Julian F. R. , Kasparov Sergey
Published: October 2002

Heart failure and hypertension are associated with increases in angiotensin II (ANG II) activity. One brain area where ANG II effects may be particularly important in these situations is the nucleus of the solitary tract (NTS). Located in the dorsomedial medulla, the NTS is the termination site of baroreceptor afferents and is essential for mediating the baroreflex. In hypertensive animals the baroreflex is impaired; this may be reversed by antagonizing ANG II AT1 receptors in the NTS. Recently, we showed that the baroreflex depressant action of ANG II in the NTS is mediated by activation of endothelial nitric oxide synthase (eNOS) and enhanced release of GABA. Using conventional pharmacological tools and a range of adenoviral‐mediated expression of dominant negative proteins, we have determined the intracellular pathway(s) in the NTS by which ANG II activates eNOS. Our data indicate that ANG II acting in the NTS depresses the baroreflex via aGq protein‐mediated activation of phospholipase C, which through 1,4,5‐inositol triphosphate causes release of calcium from the IP3‐sensitive intracellular stores and calcium‐calmodulin formation. In contrast, multiple site disruption of a pathway leading to eNOS activation via the serine/threonine kinase Akt was ineffective.—Wong, L.‐F., Polson, J. W., Murphy, D., Paton, J. F. R., Kasparov, S. Genetic and pharmacological dissection of pathways involved in the angiotensin II‐mediated depression of baroreflex function. FASEB J. 16, 1595–1601 (2002)
IL‐1J potentiates heat‐activated currents in rat sensory neurons: involvement of IL‐1RI, tyrosine kinase, and protein kinase C
Authors: Obreja Otilia , Rathee Parvinder K. , Lips Kathrin S. , Distler Carsten , Kress Michaela
Published: October 2002

Interleukin 1β (IL‐1β) is a proinflammatory cytokine that maintains thermal hyperalgesia and facilitates the release of calcitonin gene‐related peptide from rat cutaneous nociceptors in vivo and in vitro. Brief applications of IL‐1β to nociceptive neurons yielded a potentiation of heat‐activated inward currents (Iheat) and a shift of activation threshold toward lower temperature without altering intracellular calcium levels. The IL‐1β‐induced heat sensitization was not dependent on G‐protein‐coupled receptors but was mediated by activation of protein kinases. The nonspecific protein kinase inhibitor staurosporine, the specific protein kinase C inhibitor bisindolylmaleimide BIM1, and the protein tyrosine kinase inhibitor genistein reduced the sensitizing effect of IL‐1β whereas negative controls were ineffective. RT‐PCR and in situ hybridization revealed IL‐1RI but not RII expression in neurons rather than surrounding satellite cells in rat dorsal root ganglia. IL‐1β acts on sensory neurons to increase their susceptibility for noxious heat via an IL‐1RI/PTK/ PKC‐dependent mechanism.—Obreja, O., Rathee, P. K., Lips, K. S., Distler, C., Kress, M. IL‐1J potentiates heat‐activated currents in rat sensory neurons: involvement of IL‐1RI, tyrosine kinase, and protein kinase C. FASEB J. 16, 1497–1503 (2002)
Physiological role of tumor necrosis factor α in traumatic muscle injury
Authors: Warren Gordon L. , Hulderman Tracy , Jensen Nancy , McKinstry Michael , Mishra Michael , Luster Michael I. , Simeonova Petia P.
Published: October 2002

The degenerative and regenerative roles of tumor necrosis factor α (TNF‐α), a pro‐inflammatory cytokine with pleiotropic functions, were investigated by using TNF receptor 1 and 2 double knockout (TNFR‐DKO) and TNF‐α antibody neutralized mice following traumatic freeze injury to the tibialis anterior muscle. In wild‐type control mice, TNF‐α mRNA transcripts and protein increased following injury and gradually returned to control (uninjured) levels by 13 days. A reduction in MyoD mRNA expression occurred in TNF–α‐deficient mice, although there were no visible differences in MyoD immunostaining or histological characteristics in regenerating muscles. At 5 days post‐injury, the reductions in isometric strength in TNFR‐DKO and TNF–α‐depleted mice did not differ from that of wild‐type mice but by 13 days after injury, the TNFR‐DKO and TNF–αdepleted mice exhibited strength deficits twice that of wild‐type mice (i.e., 27–31% vs 13%). Muscle injury was also accompanied by increased expression of interleukin‐6 (IL‐6), but IL–6‐deficient mice demonstrated MyoD expression and recovery of isometric strength similar to that of wild‐type mice. These data indicate that TNF‐α is involved in the recovery of muscle function after traumatic muscle injury, and this effect might be associated with modulation of muscle regulatory genes, including MyoD.
Protection of innate immunity by C5aR antagonist in septic mice
Authors: Huber‐Lang Markus S. , Riedeman Niels C. , Sarma J. Vidya , Younkin Ellen M. , McGuire Stephanie R. , Laudes Ines J. , Lu Kristina T. , Guo Ren‐Feng , Neff Thomas A. , Padgaonkar Vaishalee A. , Lambris John D. , Spruce L. , Mastellos D. , Zetoune Firas S. , Ward Peter A.
Published: October 2002

Innate immune functions are known to be compromised during sepsis, often with lethal consequences. There is also evidence in rats that sepsis is associated with excessive complement activation and generation of the potent anaphylatoxin C5a. In the presence of a cyclic peptide antagonist (C5aRa) to the C5a receptor (C5aR), the binding of murine 125I‐C5a to murine neutrophils was reduced, the in vitro chemotactic responses of mouse neutrophils to mouse C5a were markedly diminished, the acquired defect in hydrogen peroxide (H2O2) production of C5a‐exposed neutrophils was reversed, and the lung permeability index (extravascular leakage of albumin) in mice after intrapulmonary deposition of IgG immune complexes was markedly diminished. Mice that developed sepsis after cecal ligation/puncture (CLP) and were treated with C5aRa had greatly improved survival rates. These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5a‐induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP.—Huber‐Lang, M. S., Riedeman, N. C., Sarma, J. V., Younkin, E. M., McGuire, S. R., Laudes, I. J., Lu, K. T., Guo, R.‐F., Neff, T. A., Padgaonkar, V. A., Lambris, J. D., Spruce, L., Mastellos, D., Zetoune, F. S., Ward, P. A. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J. 16, 1567–1574 (2002)
Function of β‐amyloid in cholesterol transport: a lead to neurotoxicity
Authors: Yao Zhi‐Xing , Papadopoulos Vassilios
Published: October 2002

Amyloid β‐peptide (Aβ), Aβ precursor protein (APP), apolipoprotein E (apoE), and elevated cholesterol levels have been linked to Alzheimer's disease (AD) pathology. High cholesterol levels increase APP and apoE expression in human NT2 neuron progenitor cells. A cholesterol‐ rich environment also induces processing of APP, leading to the formation of Aβ and Aβ peptide fragments. Using a novel method, we determined that 1) cholesterol binds to Aβ at a‐secretase cleavage site; 2) Aβ17–40 rather than Aβ1–40 prevents cholesterol from binding to apoE; 3) Aβ1–40 inhibits cholesterol from binding to low‐density lipoprotein (LDL), leading to decrease cholesterol influx and intracellular cholesterol levels; 4) the binding of cholesterol to apoE or LDL was abolished completely in presence of Aβ1–42. Increased extracellular free cholesterol levels are toxic to neurons; this toxicity is prevented by specific lipoproteins, such as high‐ density lipoproteins, which maintain their ability to bind cholesterol in the presence of Aβ. We propose that one of the physiological functions of Aβ and APP is to control cholesterol transport. AD is associated with increased Aβ production. High cholesterol levels also lead to overproduction of Aβ. Aβ blocks cholesterol trafficking and changes cholesterol homeostasis leading to neurodegeneration and the onset and/or progression of AD pathology.
Managing change to enhance Web‐based services in the Arabian Gulf libraries
Authors: Sajjad Ahmed Syed
Published: October 2002

An e‐mail survey of seven Arabian Gulf university libraries was conducted in order to ascertain which types of Web‐based services they offer to users. The study specifically looked at the provision of access to Web‐based services such as catalogues, search engines, forms, etc. through the respective library Web sites. Findings showed that almost all libraries are offering Web‐based services to users in one way or the other. This paper also discusses ways to improve and reinforce provision of such Web‐based services, including effective methods of creating awareness and delivering the orientation and training necessary to create a positive environment for change. Finally, the results of the study may be helpful especially to librarians of the Arabian Gulf libraries in enhancing or developing quality web‐based services.
Escherichia coliInsertion Sequence IS150: Transposition via Circular and Linear Intermediates
Authors: Haas Markus , Rak Bodo
Published: October 2002

IS150, a member of the widespread IS3family, contains two consecutive out-of-phase open reading frames,orfAandorfB, that partially overlap. These open reading frames encode three proteins, InsA, InsB, and the InsAB protein, which is jointly encoded by both open reading frames by means of programmed translational frameshifting. We demonstrate that the InsAB protein represents the IS150element's transposase. In vivo, the wild-type IS150element generates circular excision products and linear IS150molecules. Circular and linear species have previously been detected with mutant derivatives of other members of the IS3family. Our finding supports the assumption that these products represent true transposition intermediates of members of this family. Analysis of the molecular nature of these two species suggested that the circular forms are precursors of the linear molecules. Elimination of InsA synthesis within the otherwise intact element led to accumulation of large amounts of the linear species, indicating that the primary role of InsA may be to prevent abortive production of the linear species and to couple generation of these species to productive insertion events.
A Single Nucleotide Exchange in the
wzy
Gene Is Responsible for the Semirough O6 Lipopolysaccharide Phenotype and Serum Sensitivity of
Escherichia coli
Strain Nissle 1917
Authors: Grozdanov Lubomir , Zähringer Ulrich , Blum-Oehler Gabriele , Brade Lore , Henne Anke , Knirel Yuriy A. , Schombel Ursula , Schulze Jürgen , Sonnenborn Ulrich , Gottschalk Gerhard , Hacker Jörg , Rietschel Ernst T. , Dobrindt Ulrich
Published: October 2002

Structural analysis of lipopolysaccharide (LPS) isolated from semirough, serum-sensitive
Escherichia coli
strain Nissle 1917 (DSM 6601, serotype O6:K5:H1) revealed that this strain's LPS contains a bisphosphorylated hexaacyl lipid A and a tetradecasaccharide consisting of one
E
.
coli
O6 antigen repeating unit attached to the R1-type core. Configuration of the GlcNAc glycosidic linkage between O-antigen oligosaccharide and core (β) differs from that interlinking the repeating units in the
E
.
coli
O6 antigen polysaccharide (α). The
wa∗
and
wb∗
gene clusters of strain Nissle 1917, required for LPS core and O6 repeating unit biosyntheses, were subcloned and sequenced. The DNA sequence of the
wa∗
determinant (11.8 kb) shows 97% identity to other R1 core type-specific
wa∗
gene clusters. The DNA sequence of the
wb∗
gene cluster (11 kb) exhibits no homology to known DNA sequences except
manC
and
manB
. Comparison of the genetic structures of the
wb∗
O6
(
wb∗
from serotype O6) determinants of strain Nissle 1917 and of smooth and serum-resistant uropathogenic
E
.
coli
O6 strain 536 demonstrated that the putative open reading frame encoding the O-antigen polymerase Wzy of strain Nissle 1917 was truncated due to a point mutation. Complementation with a functional
wzy
copy of
E
.
coli
strain 536 confirmed that the semirough phenotype of strain Nissle 1917 is due to the nonfunctional
wzy
gene. Expression of a functional
wzy
gene in
E
.
coli
strain Nissle 1917 increased its ability to withstand antibacterial defense mechanisms of blood serum. These results underline the importance of LPS for serum resistance or sensitivity of
E
.
coli
.
Inducible Control of Virulence Gene Expression inListeria monocytogenes: Temporal Requirement of Listeriolysin O during Intracellular Infection
Authors: Dancz Christina E. , Haraga Andrea , Portnoy Daniel A. , Higgins Darren E.
Published: October 2002

We have constructed alacrepressor/operator-based system to tightly regulate expression of bacterial genes during intracellular infection byListeria monocytogenes. AnL. monocytogenesstrain was constructed in which expression of listeriolysin O was placed under the inducible control of an isopropyl-β-d-thiogalactopyranoside (IPTG)-dependent promoter. Listeriolysin O (LLO) is a pore-forming cytolysin that mediates lysis ofL. monocytogenes-containing phagosomes. Using hemolytic-activity assays and Western blot analysis, we demonstrated dose-dependent IPTG induction of LLO during growth in broth culture. Moreover, intracellular growth of the inducible-LLO (iLLO) strain in the macrophage-like cell line J774 was strictly dependent upon IPTG. We have further shown that iLLO bacteria trapped within primary phagocytic vacuoles can be induced to escape into the cytosol following addition of IPTG to the cell culture medium, thus yielding the ability to control bacterial escape from the phagosome and the initiation of intracellular growth. Using the iLLO strain in plaque-forming assays, we demonstrated an additional requirement for LLO in facilitating cell-to-cell spread in L2 fibroblasts, a nonprofessional phagocytic cell line. Furthermore, the efficiency of cell-to-cell spread of iLLO bacteria in L2 cells was IPTG dose dependent. The potential use of this system for determining the temporal requirements of additional virulence determinants of intracellular pathogenesis is discussed.
Roles of PucR, GlnR, and TnrA in Regulating Expression of the
Bacillus subtilis
ure
P3 Promoter
Authors: Brandenburg Jaclyn L. , Wray, Lewis V. , Beier Lars , Jarmer Hanne , Saxild Hans H. , Fisher Susan H.
Published: October 2002

Expression of the P3 promoter of the
Bacillus subtilis ureABC
operon is activated during nitrogen-limited growth by PucR, the transcriptional regulator of the purine-degradative genes. Addition of allantoic acid, a purine-degradative intermediate, to nitrogen-limited cells stimulated transcription of
ure
P3 twofold. Since urea is produced during purine degradation in
B. subtilis
, regulation of
ureABC
expression by PucR allows purines to be completely degraded to ammonia. The nitrogen transcription factor TnrA was found to indirectly regulate
ure
P3 expression by activating
pucR
expression. The two consensus GlnR/TnrA binding sites located in the
ure
P3 promoter region were shown to be required for negative regulation by GlnR. Mutational analysis indicates that a cooperative interaction occurs between GlnR dimers bound at these two sites.
B. subtilis
is the first example where urease expression is both nitrogen regulated and coordinately regulated with the enzymes involved in purine transport and degradation.
Emotional arousal and gender differences in aggression: A meta‐analysis
Authors: Knight George P. , Guthrie Ivanna K. , Page Melanie C. , Fabes Richard A.
Published: October 2002

This meta‐analysis investigated the possibility that gender differences in aggression, and the variability in these differences, are a function of gender differences in the regulation of arousal generated in emotionally evocative contexts. The sample of studies for this analysis was based on an exhaustive search of the relevant research reports from 1965–1999. Studies were excluded from the sample if they were case studies; investigated spousal/familial or societal violence, war, suicide, or political violence; involved clinical or deviant participants; included fewer than 10 participants; included all male, all female, all non‐Caucasian, or non‐US/non‐Canadian participants. Based on previous evidence that males may be more easily aroused by aggressive‐relevant emotional stimuli than females, and that males may have more difficulty regulating emotionally arousing states than females, we hypothesized that the magnitude of the gender differences in aggression would covary, in a nonlinear manner, with the emotional evocativeness of the study context. Consistent with our hypothesis, the magnitude of gender differences in aggression was relatively small in research contexts that appeared to produce no or large increments in emotional arousal and larger (favoring males) in contexts that appeared to produce small or medium increments in emotional arousal. Aggr. Behav. 28:366–393, 2002. © 2002 Wiley‐Liss, Inc.
Occurrence of acute monocytic leukemia in a case of untreated Waldenström's macroglobulinemia
Authors: Murashige Naoko , Tabanda Rosa , Zalusky Ralph
Published: October 2002

Acute myeloid leukemia is a rare complication of untreated Waldenström's macroglobulinemia. Although two such cases have been reported, occurrence of acute monocytic leukemia, FAB M5b subtype, in a patient with untreated Waldenström's macroglobulinemia has not been reported. The patient had distinct foci with clear demarcation of lymphoid infiltrates and myeloid infiltrates in the bone marrow, representing Waldenström's macroglobulinemia and acute monocytic leukemia, indicating the concurrence of two primary malignancies. Am. J. Hematol. 71:94–97, 2002. © 2002 Wiley‐Liss, Inc.
The decision to continue: The experiences and needs of parents who receive a prenatal diagnosis of holoprosencephaly
Authors: Redlinger‐Grosse Krista , Bernhardt Barbara A. , Berg Kate , Muenke Maximilian , Biesecker Barbara B.
Published: October 2002

Holoprosencephaly (HPE) is a condition characterized by a defect in the development of the midline embryonic forebrain. When detected prenatally, the diagnosis of HPE offers parents a poor but often uncertain prognosis. Since the majority of parents receiving a prenatal diagnosis of an abnormality terminate their pregnancies, few studies have examined parents' experiences and needs surrounding the decision to continue a pregnancy. We present a descriptive study of in‐depth interviews with 24 parents who chose to continue their pregnancy after receiving a prenatal diagnosis of HPE. Parents were asked about their decision‐making process to continue the pregnancy. Qualitative analysis was used to identify common themes that emerged from these parents' experiences. The results suggest that most parents did not make an active decision about continuing the pregnancy. Rather, they described a more subtle decision‐making process that evolved over time and consisted of several factors. These factors included the parents' religious and personal beliefs, past experiences, and the uncertainty involved in the diagnosis of HPE. Throughout the decision‐making process, they described informational, emotional, and supportive needs from family, friends, and health professionals. All of these factors contributed to the evolution of the parents' decision to continue the pregnancy and the acceptance of their decision. Results of this exploratory study suggest health care professionals need to work with parents as they make their decision to continue an affected pregnancy. The results also provide the groundwork for prospective investigation into parents' decision‐making process as they receive and adjust to prenatal diagnoses of an abnormality. Published 2002 Wiley‐Liss, Inc.
Association of nonsyndromic Wilms tumor with premature centromere division (PCD)
Authors: Méhes K. , Kajtár P. , Kosztolányi G.
Published: October 2002

Wilms tumor was discovered in a 22‐month‐old otherwise healthy girl. Her pretreatment karyotype proved to be normal 46,XX with total premature division (PCD) in 21% of her lymphocyte mitoses. This phenomenon was not seen in the parents. PCD was found in less than 4% of lymphocyte mitoses of five other children with Wilms tumor. The individual finding provides further evidence for a relation of PCD to tumorigenesis; however, elucidation of the question needs further systematic studies.
Agnathia‐otocephaly complex: Report of three cases with involvement of two different Carnegie stages
Authors: Schiffer Christiane , Tariverdian Gholamali , Schiesser Monika , Thomas Mary C. , Sergi Consolato
Published: October 2002

Three fetuses with agnathia‐otocephaly complex representing different degrees of embryonic maldevelopment are reported. The study of the three cases and of the anterior embryonic disc supports the concept that an altered embryologic development might have taken place at Carnegie stages 10 (embryonic days 22 or 23) and 11 (embryonic days 23–26). Karyotypic abnormalities and aberrant gene expression of sonic hedgehog and paired‐related homeobox genes are discussed as the cytogenetic and molecular basis of agnathia‐otocephaly complex. © 2002 Wiley‐Liss, Inc.
Lymphedema–lymphangiectasia–mental retardation (Hennekam) syndrome: A review
Authors: Van Balkom Inge D.C. , Alders Mariel , Allanson Judith , Bellini Carlo , Frank Ulrich , De Jong Greetje , Kolbe Ingeborg , Lacombe Didier , Rockson Stan , Rowe Peter , Wijburg Frits , Hennekam Raoul C.M.
Published: October 2002

The Hennekam syndrome is an infrequently reported heritable entity characterized by lymphedema, lymphangiectasia, and developmental delay. Here we add an additional 8 patients, and compare their findings to the 16 cases from the literature. The lymphedema is usually congenital, can be markedly asymmetrical, and, often, gradually progressive. Complications such as erysipelas are common. The lymphangiectasias are present in the intestines, but have also been found in the pleura, pericardium, thyroid gland, and kidney. Several patients have demonstrated congenital cardiac and blood vessel anomalies, pointing to a disturbance of angiogenesis in at least some of the patients. Facial features are variable, and are chiefly characterized, in a typical patient, by a flat face, flat and broad nasal bridge, and hypertelorism. Facial features are thought to mirror the extent of intrauterine facial lymphedema, or may be caused by lymphatic obstruction that affects the early migration of neural crest tissue. Other anomalies have included glaucoma, dental anomalies, hearing loss, and renal anomalies. The psychomotor development varies widely, even within a single family, from almost normal development to severe mental retardation. Convulsions are common. The existence of 10 familial cases, equal sex ratio, increased parental consanguinity rate (4/20 families), and absence of vertical transmission are consistent with an autosomal recessive pattern of inheritance. It seems likely that most (but not all) manifestations of the entity can be explained as sequences of impaired prenatal and postnatal lymphatic flow, suggesting that the causative gene(s) should have a major function in lymphangiogenesis. © 2002 Wiley‐Liss, Inc.
Digesta passage and fiber digestibility in captive white‐faced sakis (Pithecia pithecia)
Authors: Norconk Marilyn A. , Oftedal Olav T. , POWER Michael L. , JAKUBASZ Michael , Savage Anne
Published: October 2002

Wild white‐faced sakis (Pithecia pithecia) ingest primarily seeds that provide a diet that is lipid‐rich and moderately high in dietary fiber. Although little anatomical information is available on sakis, evidence from other vertebrate seed predators suggests that such a diet is correlated with adaptations in gut morphology or physiology. Milton [1984] reported a 20 hr transit time (TT=transit time or time of first appearance in feces) of a particulate marker for a single monk saki (Pithecia monachus). This suggests that TT for Pithecia sakis may be four to five times longer than what has been reported for soft‐fruit‐eating platyrrhines, such as Ateles and Cebus. During a captive study, we calculated an average TT of 14.7±0.4hr (n=5 trials started in the evening) for a chromic oxide (Cr2O3) marker that follows liquid digesta and TTs of 14.5hr (trial started the previous evening) and 23.0hr (trial started the previous morning) for two trials using particulate markers. Mean retention time (MRT) for the liquid marker ranged from 15.3hr to 37.7hr in four trials that lasted longer than 90hr. Marker recovery was incomplete for the particulate markers in these trials, and thus MRT could only be determined for the liquid phase marker. Three 5‐day trials on a low‐fiber, blended diet revealed high fiber fraction digestibilities (neutral detergent fiber (NDF)=77.4% and acid detergent fiber (ADF)=74.4%). Data collected for this study and nutritional data from wild sakis suggest that pitheciin seed predators may have a potential for fiber digestibility that is intermediate between ripe‐pulp frugivores and folivores. Am. J. Primatol. 58:23–34, 2002. © 2002 Wiley‐Liss, Inc.
Paleodemographic comparison of a catastrophic and an attritional death assemblage
Authors: Margerison Beverley J. , Knüsel Christopher J.
Published: October 2002

The aim of this contribution is to examine the effect of an indiscriminate epidemic on a population to assess whether or not a catastrophic event can be identified from examination of paleodemographic data. Using paleodemographic techniques, the death assemblage from the Royal Mint site, London, a Black Death cemetery dated 1349 AD, is compared with that from St. Helen‐on‐the‐Walls, York, which dates from the twelfth to the sixteenth centuries AD. The Royal Mint site represents a catastrophic cemetery, while that of St. Helen‐on‐the‐Walls is of an attritional type. Certain features of the paleodemographic profile of the plague victims suggest that the population had been affected by factors other than natural wastage. Three factors are proposed which may define an indiscriminate catastrophic event in preindustrial populations. Am J Phys Anthropol 119:134–143, 2002. © 2002 Wiley‐Liss, Inc.
Wlds mice are resistant to paclitaxel (taxol) neuropathy
Authors: Wang Min Sheng , Davis Albert A. , Culver Deborah G. , Glass Jonathan D.
Published: October 2002

The WldS mouse is a unique mutant strain that demonstrates the remarkable phenotype of prolonged survival of transected axons (“slow Wallerian degeneration”). In these studies, we tested whether this neuroprotective phenotype extends to axonal degeneration seen in a progressive peripheral neuropathy. WldS and wild‐type mice were intoxicated with the cancer chemotherapeutic agent paclitaxel (Taxol). The severity of the resultant sensory neuropathy was compared with behavioral, physiological, and pathological measures. WldS mice were resistant to paclitaxel neuropathy by all measures, and the resistance was because of protection against axonal degeneration. These studies demonstrate for the first time that the WldS mouse is more than a slow Wallerian degeneration phenotype, emphasizing the mechanistic link between Wallerian degeneration and peripheral neuropathy. Understanding how this mutant gene confers protection against axonal degeneration will provide important clues toward prevention of axonal degeneration in several human neurological disorders.