bluuebunny/crossref_metadata_2025 huggingface dataset:
Conceptions of Tuberculosis and Therapeutic Choices in Highland Chiapas, Mexico
Authors: Menegoni Lorenza
Published: November 2004

Tuberculosis continues to be a serious disease among the poor, indigenous population of Highland Chiapas, southern Mexico. Ethnographic fieldwork among Tzeltal Indians has focused on how cultural perceptions of illness and curing influence the Indians' utilization of health care services for tuberculosis diagnosis and treatment. This article presents the views on tuberculosis and health‐seeking activities of several patients in the Tzeltal hamlet of Yochib (municipality of Oxchuc). In this community, religious change (Protestantism) and the presence of a health clinic promoted biological interpretations of illness and acceptance of Western medical treatments. While patients in Yochib do not understand tuberculosis in biomedical terms, they nonetheless utilize Western services (both local and urban) to obtain treatment. Because of the long duration of tuberculosis therapy, however, these patients manifest contrasting attitudes. The article focuses on the cultural factors that influence patients' medical choices, curing strategies, and their decisions to adhere to long‐term treatment regimens.
Carcinoma of Unknown Primary Site: Sequential Treatment with Paclitaxel/Carboplatin/Etoposide and Gemcitabine/Irinotecan: A Minnie Pearl Cancer Research Network Phase II Trial
Authors: Greco F. Anthony , Rodriguez Gladys I. , Shaffer Don W. , Hermann Robert , Litchy Sharlene , Yardley Denise A. , Burris Howard A. , Morrissey Lisa H. , Erland Joan B. , Hainsworth John D.
Published: November 2004

Purpose. To evaluate the efficacy and toxicity of the sequential administration of paclitaxel (Taxol®; Bristol-Myers Squibb; Princeton, NJ), carboplatin (Paraplatin®; Bristol-Myers Squibb), and oral etoposide (VePesid®; Bristol-Myers Squibb) followed by gemcitabine (Gemzar®; Eli Lilly; Indianapolis, IN) and irinotecan (Campostar®; Pfizer Pharmaceuticals; New York, NY) in the first-line treatment of patients with carcinoma of unknown primary site.

Patients and Methods. One hundred thirty-two patients were treated with sequential combination chemotherapy for a maximum of six cycles. All patients had relatively poor prognostic features. Fifty-nine patients had well-differentiated adenocarcinoma, 73 patients had poorly differentiated carcinoma, and 121 patients had performance status scores of 0 or 1.

Results. Thirty-three (30%) of 111 assessable patients (95% confidence interval 27%–33%) had objective responses to treatment (26 partial responses, seven complete responses). The combination of gemcitabine and irinotecan was associated with significantly less toxicity than the triple-drug regimen and improved the responses in several patients (10%). The response rates were similar in the two major histologic tumor types, but were lower for patients with liver-dominant tumors (13%) and higher for patients with lymph-node-dominant tumors (50%). The median progression-free survival time, median survival time, and actuarial survival rates at 1 and 2 years were 5.7 months, 9.1 months, 35%, and 16%, respectively.

Conclusions. Sequential combination chemotherapy with paclitaxel/carboplatin/oral etoposide and gemcitabine/irinotecan is an active treatment for patients with carcinoma of unknown primary site, but overall toxicities are greater than those seen with other combinations of new drugs and survival appears similar to that observed in 264 other patients treated in our four previous phase II trials. A better understanding of the biology of these heterogeneous tumors will likely lead to improved therapy for these patients.
A Randomized Comparison of Every-2-Week Darbepoetin Alfa and Weekly Epoetin Alfa for the Treatment of Chemotherapy-Induced Anemia in Patients With Breast, Lung, or Gynecologic Cancer
Authors: Schwartzberg Lee S. , Yee Lorrin K. , Senecal Frank M. , Charu Veena , Tomita Dianne , Wallace Joel , Rossi Greg
Published: November 2004

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp®; Amgen Inc.; Thousand Oaks, CA) 200 μg every 2 weeks (Q2W) and epoetin alfa (Procrit®; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 μg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11–13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 μg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.
An in situ toxicity identification evaluation method part II: Field validation
Authors: Jr. Burton G. Allen , Nordstrom Juanita F
Published: November 2004

When sediments are found to be toxic usually there is a mixture of chemicals present. Often it is important to establish which chemicals contribute to the toxicity. Establishing causality can be difficult and often requires fractionation with subsequent toxicity testing. The sample collection and manipulation process can alter chemical bioavailability and toxicity. An in situ toxicity identification evaluation (iTIE) chamber is described that was placed in sediments and fractionated pore-water chemicals into nonpolar chemicals, metals, and ammonia-type groups. This method was field tested and compared to the laboratory-based, U.S. Environmental Protection Agency (U.S. EPA) toxicity identification evaluation (TIE) method. Field studies were performed at three sites contaminated primarily with polycyclic aromatic hydrocarbons (PAHs) (Little Scioto River, OH, USA), polychlorinated biphenyls (PCBs) (Dicks Creek, OH, USA), and chlorobenzenes (Sebasticook River, ME, USA). Both the iTIE and the U.S. EPA TIE methods used Daphnia magna in 24-h exposures. Although the iTIE and TIE were conducted on sediments from the same location, there was significantly more toxicity observed in the iTIE testing. The dominant chemical classes were separated by the iTIE method and revealed which fractions contributed to toxicity. The loss of toxicity in the TIE approach did not allow for subsequent fractionation and stressor identification. Advantages of the iTIE over the TIE method were greater sensitivity and ability to detect causative toxic chemical fractions; lack of sediment collection and subsequent manipulation; and, thus, reduction in potential artifacts, more realistic exposure with slow, continual pore-water renewal in situ, ability to evaluate pore waters in sandy or rocky substrates where pore waters are difficult to collect, and a quicker phase I evaluation. Limitations of the iTIE method as compared to the TIE methods were extensive pretest assembly process, fewer phase I fractionation possibilities, and restriction to shallow waters. The results of these studies suggest that the iTIE method provides a more accurate and sensitive evaluation of pore water toxicity than the laboratory TIE method.
An amphibian model to test the effects of xenobiotic chemicals on development of the hematopoietic system
Authors: Rollins-Smith Louise A , Hopkins B. Diane , Reiner Laura K
Published: November 2004

A number of manmade chemicals have deleterious effects on the developing immune system. Very few assay systems are available to study the effects of xenobiotics on hematopoietic stem cells. In rodent models, assays require exposure of pregnant females and analysis of the hematopoietic potential of stem cells from the offspring. These models are less relevant to lower vertebrates such as fish or amphibians where exposure of embryos is direct. To overcome this problem, an amphibian model was developed. Diploid (2N) embryos (16–20 h of age) of the South African clawed frog, Xenopus laevis, were exposed to 10 μg/ml diazinon or 10−6 M lead acetate for 2 h. After 2 h, the ventral blood island (VBI) was transplanted from a chemically treated or untreated control embryo to an untreated triploid (3N) host embryo. After 55 d, the contribution of the donor VBI-derived stem cells to populations in the blood, thymus, and spleen was assessed by flow cytometry. Diazinon, but not lead acetate, interfered with the ability of transplanted stem cells to contribute to hematopoiesis. Because amphibian embryos are very sensitive indicators of the toxic effects of chemicals, this VBI assay could be employed to test any toxic chemical that is suspected of having a negative effect on development of the hematopoietic system.
Influence of multiple water-quality characteristics on copper toxicity to fathead minnows (Pimephales promelas)
Authors: Sciera Katherine L , Isely J. Jeffery , Jr. Tomasso Joseph R , Klaine Stephen J
Published: November 2004

Water quality influences the bioavailability and toxicity of copper to aquatic organisms. Understanding the relationships between water-quality parameters and copper toxicity may facilitate the development of site-specific criteria for water quality and result in better protection of aquatic biota. Many studies have examined the influence of a single water-quality parameter on copper toxicity, but the interactions of several characteristics have not been well studied in low-hardness water. The goal of the present research was to examine the interactions among water-quality characteristics and their effects on copper toxicity to larval fathead minnows (Pimephales promelas). The effects of dissolved organic carbon (DOC) concentration, DOC source, pH, and hardness on acute copper toxicity were determined using a complete factorially designed experiment. Hardness, pH, DOC, and interaction of pH and DOC all significantly affected copper toxicity. A predictive model based on these data described 88% of the variability in copper toxicity. This model also explained 58% of the variability in copper toxicity for an independent dataset of South Carolina (USA) waters. The biotic ligand model underpredicted the acute copper toxicity to fathead minnows when compared with observed values.
Genotoxicity in native fish associated with agricultural runoff events
Authors: Whitehead Andrew , Kuivila Kathryn M , Orlando James L , Kotelevtsev Sergey , Anderson Susan L
Published: November 2004

The primary objective of the present study was to test whether agricultural chemical runoff was associated with instream genotoxicity in native fish. Using Sacramento sucker (Catostomus occidentalis), we combined field-caging experiments in an agriculturally dominated watershed with controlled laboratory exposures to field-collected water samples, and we coupled genotoxicity biomarker measurements in fish with bacterial mutagenicity analysis of water samples. We selected DNA strand breakage as a genotoxicity biomarker and Ames Salmonella mutagenicity tests as a second, supporting indicator of genotoxicity. Data from experiments conducted during rainfall runoff events following winter application of pesticides in 2000 and 2001 indicated that DNA strand breaks were significantly elevated in fish exposed to San Joaquin River (CA, USA) water (38.8, 28.4, and 53.6% DNA strand breakage in year 2000 field, year 2000 lab, and year 2001 field exposures, respectively) compared with a nearby reference site (15.4, 8.7, and 12.6% DNA strand breakage in year 2000 field, year 2000 lab, and year 2001 field exposures, respectively). Time-course measurements in field experiments supported a linkage between induction of DNA strand breakage and the timing of agricultural runoff. San Joaquin River water also caused significant reversion mutation in two Ames Salmonella tester strains. Salmonella mutagenicity corroborated in-stream effects, further strengthening a causal relationship between runoff events and genotoxicity. Potentially responsible agents are discussed in the context of timing of runoff events in the field, concordance between laboratory and field exposures, pesticide application patterns in the drainage, and analytical chemistry data.
Bacterial energetics, stoichiometry, and kinetic modeling of 2,4-Dinitrotoluene biodegradation in a batch respirometer
Authors: Zhang Chunlong , Hughes Joseph B
Published: November 2004

A stoichiometric equation and kinetic model were developed and validated using experimental data from batch respirometer studies on the biodegradation of 2,4-dinitrotoluene (DNT). The stoichiometric equation integrates bacterial energetics and is revised from that in a previous study by including the mass balance of phosphorus (P) in the biomass. Stoichiometric results on O2 consumption, CO2 evolution, and nitrite evolution are in good agreement with respirometer data. However, the optimal P requirement is significantly higher than the stoichiometrically derived P, implying potentially limited bioavailability of P and the need for buffering capacity in the media to mitigate the adverse pH effect for optimal growth of DNT-degrading bacteria. An array of models was evaluated to fit the O2/CO2 data acquired experimentally and the DNT depletion data calculated from derived stoichiometric coefficients and cell yield. The deterministic, integrated Monod model provides the goodness of fit to the test data on DNT depletion, and the Monod model parameters (Ks, X0, μmax, and Y) were estimated by nonlinear regression. Further analyses with an equilibrium model (MINTEQ) indicate the interrelated nature of medium chemical compositions in controlling the rate and extent of DNT biodegradation. Results from the present batch respirometer study help to unravel some key factors in controlling DNT biodegradation in complex remediation systems, in particular the interactions between acidogenic DNT bacteria and various parameters, including pH and P, the latter of which could serve as a nutrient, a buffer, and a controlling factor on the bioavailable fractions of minerals (Ca, Fe, Zn, and Mo) in the medium.
Latino(a) students and Caucasian mentors in a rural after‐school program: Towards empowering adult–youth relationships
Authors: Diversi Marcelo , Mecham Connie
Published: November 2004

High rates of immigration, especially from Latin America, have created a large population of immigrant youth, many of whom are having difficulty in American schools. The central goals of our project were to assist in empowering students to find academic success and to foster a more bicultural identity. According to three perspectives (youth, mentor, and coordinator), the adult–youth relationship central to our project has been successful in fostering academic engagement and cross‐cultural relations. Youth improved their grades and reported being more connected to school. Mentors and youth reported trust in their relationship and satisfaction in learning about each other's culture. We also discuss shortcomings in our program and offer suggestions for positive adult–youth practices. © 2005 Wiley Periodicals, Inc. J Comm Psychol 33: 31–40, 2005.
The adoption of innovation in youth organizations: Creating the conditions for youth–adult partnerships
Authors: Zeldin Shepherd , Camino Linda , Mook Carrie
Published: November 2004

Youth–adult partnerships (Y‐APs) for organizational and community change represent an innovative practice in the United States. Innovations are typically a challenge to implement, so it is not surprising that youth organizations are seeking guidance on how to adopt and sustain Y‐APs. This article brings contemporary scholarship to bear on the issue. Through a synthesis of theory, research, and field‐based data, it identifies six managerial guidelines for adopting and beginning to implement the innovative practice of Y‐APs: (1) gain clarity and consensus on the purpose of Y‐AP, (2) mobilize and coordinate a diverse range of stakeholders, (3) create favorable narratives about Y‐AP, (4) construct theories and stories of organizational change, (5) affirmatively address issues of power, and (6) institutionalize new roles for youth. These guidelines depend on stakeholders having adequate time for shared organizational learning. Time for reflective dialogue, however, is a precious commodity in youth organizations, one that is rarely financed by public agencies or private foundations. A major challenge for the future, in terms of the wide‐scale adoption and implementation of innovation, specifically Y‐AP, may therefore lie in the creation of incentives and support for organizational reflection. © 2005 Wiley Periodicals, Inc. J Comm Psychol 33: 121–135, 2005.
Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores
Authors: Hiratani Ichiro , Leskovar Amanda , Gilbert David M.
Published: November 2004

The replication timing of some genes is developmentally regulated, but the significance of replication timing to cellular differentiation has been difficult to substantiate. Studies have largely been restricted to the comparison of a few genes in established cell lines derived from different tissues, and most of these genes do not change replication timing. Hence, it has not been possible to predict how many or what types of genes might be subject to such control. Here, we have evaluated the replication timing of 54 tissue-specific genes in mouse embryonic stem cells before and after differentiation to neural precursors. Strikingly, genes residing within isochores rich in GC and poor in long interspersed nuclear elements (LINEs) did not change their replication timing, whereas half of genes within isochores rich in AT and long interspersed nuclear elements displayed programmed changes in replication timing that accompanied changes in gene expression. Our results provide direct evidence that differentiation-induced autosomal replication-timing changes are a significant part of mammalian development, provide a means to predict genes subject to such regulation, and suggest that replication timing may be more related to the evolution of metazoan genomes than to gene function or expression pattern.
Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland
Authors: Morroni Manrico , Giordano Antonio , Zingaretti Maria Cristina , Boiani Romina , De Matteis Rita , Kahn Barbara B. , Nisoli Enzo , Tonello Cristina , Pisoschi Catalina , Luchetti Michele M. , Marelli Mariella , Cinti Saverio
Published: November 2004

Mammalian breast adipose tissue is replaced by a milk-secreting gland during pregnancy; the reverse process takes place upon interruption of lactation. Morphological and bromodeoxyuridine studies provide indirect evidence that mouse mammary adipocytes transform into secretory epithelial cells during pregnancy and revert to adipocytes after lactation. By using the
Cre-loxP
recombination system we show that the mammary gland of whey acidic protein (WAP)-
Cre
/
R26R
mice, in which secretory epithelial cells express the lacZ gene during pregnancy, contains labeled adipocytes during involution. Conversely, adipocyte P2-
Cre
/
R26R
mice, in which adipocytes are labeled before pregnancy, contain labeled secretory epithelial cells during pregnancy. We conclude that reversible adipocyte-to-epithelium and epithelium-to-adipocyte transdifferentiation occurs in the mammary gland of adult mice during pregnancy and lactation.
Specificity in lipases: A computational study of transesterification of sucrose
Authors: Fuentes Gloria , Ballesteros Anthonio , Verma Chandra S.
Published: November 2004

Computational conformational searches of putative transition states of the reaction of sucrose with vinyl laurate catalyzed by lipases fromCandida antarctica BandThermomyces lanuginosushave been carried out. The dielectric of the media have been varied to understand the role of protein plasticity in modulating the observed regioselective transesterification. The binding pocket of lipase fromCandidaadapts to the conformational variability of the various substates of the substrates by small, local adjustments within the binding pocket. In contrast, the more constrained pocket of the lipase fromThermomycesadapts by adjusting through concerted global motions between subdomains. This leads to the identification of one large pocket inCandidathat accommodates both the sucrose and the lauroyl moieties of the transition state, whereas inThermomycesthe binding pocket is smaller, leading to the localization of the two moieties in two distinct pockets; this partly rationalizes the broader specificity of the former relative to the latter. Mutations have been suggested to exploit the differences towards changing the observed selectivities.
Expression and purification of recombinant proteins from Escherichia coli: Comparison of an elastin‐like polypeptide fusion with an oligohistidine fusion
Authors: Trabbic‐Carlson Kimberly , Liu Li , Kim Bumjoon , Chilkoti Ashutosh
Published: November 2004

Thermally responsive elastin like polypeptides (ELPs) can be used to purify proteins from Escherichia coli culture when proteins are expressed as a fusion with an ELP. Nonchromatographic purification of ELP fusion proteins, termed inverse transition cycling (ITC), exploits the reversible soluble–insoluble phase transition behavior imparted by the ELP tag. Here, we quantitatively compare the expression and purification of ELP and oligohistidine fusions of chloramphenicol acetyltransferase (CAT), blue fluorescent protein (BFP), thioredoxin (Trx), and calmodulin (CalM) from both a 4‐h culture with chemical induction of the plasmid‐borne fusion protein gene and a 24‐h culture without chemical induction. The total protein content and functional activity were quantified at each ITC purification step. For CAT, BFP, and Trx, the 24‐h noninduction culture of ELP fusion proteins results in a sevenfold increase in the yield of each fusion protein compared to that obtained by the 4‐h–induced culture, and the calculated target protein yield is similar to that of their equivalent oligohistidine fusion. For these proteins, ITC purification of fusion proteins also results in ∼75% recovery of active fusion protein, similar to affinity chromatography. Compared to chromatographic purification, however, ITC is inexpensive, requires no specialized equipment or reagents, and because ITC is a batch purification process, it is easily scaled up to accommodate larger culture volumes or scaled down and multiplexed for high‐throughput, microscale purification; thus, potentially impacting both high‐throughput protein expression and purification for proteomics and large scale, cost‐effective industrial bioprocessing of pharmaceutically relevant proteins.
Studies on recombinant single chain Jacalin lectin reveal reduced affinity for saccharides despite normal folding like native Jacalin
Authors: Sahasrabuddhe Anagh A. , Gaikwad Sushama M. , Krishnasastry M.V. , Khan M. Islam
Published: November 2004

Sugar binding studies, inactivation, unfolding, and refolding of native Jacalin (nJacalin) from Artocarpus integrifolia and recombinant single‐chain Jacalin (rJacalin) expressed in Escherichia coli were studied by intrinsic fluorescence and thermal and chemical denaturation approaches. Interestingly, rJacalin does not undergo any proteolytic processing in an E. coli environment. It has 100fold less affinity for methyl‐α‐galactose (Ka: 2.48 × 102) in comparison to nJacalin (Ka: 1.58 × 104), and it also binds Thomsen‐Friedenreich (TF) disaccharide (Galβ1–3GalNAc) with less affinity. Overall sugar binding characteristics of rJacalin are qualitatively similar to that of nJacalin (Gal<MeαGal<MeαTFdisaccharide). Circular dichroism studies at near‐ and far‐UV, thermal, and chemical denaturation studies reveal that the rJacalin behaves like nJacalin. Guanidine hydrochloride‐induced denaturation, followed by renaturation, yielded total recovery of sugar binding activity of rJacalin in comparison to partial recovery for nJacalin. This signifies the minor changes in the refolding pathways between native and recombinant lectins. The stability of rJacalin is dramatically reduced in the extreme pH range unlike nJacalin. Both lectins do not bind 1‐anilino‐8‐naphthalene sulfonic acid (ANS) in the pH range of 5 to 12 but they do in the pH range of 1–3. Solute quenching studies of the lectin using acrylamide, KI, and CsCl indicated that the tryptophan residues have full accessibility to the neutral quencher and poor accessibility to ionic quenchers. In summary, biophysical and biochemical studies on the native versus recombinant Jacalin suggest that post‐translational modification, i.e., the processing of Jacalin into two chains is probably not a prerequisite for sugar binding but may be required for higher affinity.
Structural and functional analysis of the gpsA gene product of Archaeoglobus fulgidus: A glycerol‐3‐phosphate dehydrogenase with an unusual NADP+ preference
Authors: Sakasegawa Shin‐Ichi , Hagemeier Christoph H. , Thauer Rudolf K. , Essen Lars‐O. , Shima Seigo
Published: November 2004

NAD+‐dependent glycerol‐3‐phosphate dehydrogenase (G3PDH) is generally absent in archaea, because archaea, unlike eukaryotes and eubacteria, utilize glycerol‐1‐phosphate instead of glycerol‐3‐phosphate for the biosynthesis of membrane lipids. Surprisingly, the genome of the hyperthermophilic archaeon Archaeoglobus fulgidus comprises a G3PDH ortholog, gpsA, most likely due to horizontal gene transfer from a eubacterial organism. Biochemical characterization proved G3PDH‐like activity of the recombinant gpsA gene product. However, unlike other G3PDHs, the up to 85°C thermostable A. fulgidus G3PDH exerted a 15‐fold preference for NADPH over NADH. The A. fulgidus G3PDH bears the hallmarks of adaptation to halotolerance and thermophilicity, because its 1.7‐Å crystal structure showed a high surface density for negative charges and 10 additional intramolecular salt bridges compared to a mesophilic G3PDH structure. Whereas all amino acid residues required for dihydroxyacetone phosphate binding and reductive catalysis are highly conserved, the binding site for the adenine moiety of the NAD(P) cosubstrate shows a structural variation that reflects the observed NADPH preference, for example, by a putative salt bridge between R49 and the 2′‐phosphate.
Decision Making in Medicine and Health Care
Authors: Kaplan Robert M. , Frosch Dominick L.
Published: November 2004

Decision making is central to health policy and medical practice. Because health outcomes are probabilistic, most decisions are made under conditions of uncertainty. This review considers two classes of decisions in health care: decisions made by providers on behalf of patients, and shared decisions between patients and providers. Considerable evidence suggests wide regional variation exists in services received by patients. Evidence-based guidelines that incorporate quality of life and patient preferences may help address this problem. Systematic cost-effectiveness analysis can be used to improve resource allocation decisions. Shared medical decision making seeks to engage patients and providers in a collaborative process to choose clinical options that reflect patient preferences. Although some evidence indicates patients want an active role in making decisions, other evidence suggests that some patients prefer a passive role. Decision aids hold promise for improving individual decisions, but there are still few systematic evaluations of these aids. Several directions for future research are offered.
MAINTENANCE OF SERUM ANTIBODY LEVELS
Authors: Manz Rudolf A. , Hauser Anja E. , Hiepe Falk , Radbruch Andreas
Published: November 2004

▪ Abstract  In vertebrates, serum antibodies are an essential component of innate and adaptive immunity and immunological memory. They also can contribute significantly to immunopathology. Their composition is the result of tightly regulated differentiation of B lymphocytes into antibody-secreting plasma blasts and plasma cells. The survival of antibody-secreting cells determines their contribution to the immune response in which they were generated and to long-lasting immunity, as provided by stable serum antibody levels. Short-lived plasma blasts and/or plasma cells secrete antibodies for a reactive immune response. Short-lived plasma blasts can become long-lived plasma cells, probably by competition with preexisting plasma cells for occupation of a limited number of survival niches in the body, in a process not yet fully understood. Limitation of the number of long-lived plasma cells allows the immune system to maintain a stable humoral immunological memory over long periods, to react to new pathogenic challenges, and to adapt the humoral memory in response to these antigens.
Differential effects of α- and β-defensin on cytokine production by cultured human bronchial epithelial cells
Authors: Sakamoto Noriho , Mukae Hiroshi , Fujii Takeshi , Ishii Hiroshi , Yoshioka Sumako , Kakugawa Tomoyuki , Sugiyama Kanako , Mizuta Yohei , Kadota Jun-ichi , Nakazato Masamitsu , Kohno Shigeru
Published: November 2004

Defensins are cysteine-rich cationic antimicrobial peptides that play an important role in innate immunity and are known to contribute to the regulation of host adaptive immunity. In addition to direct antimicrobial activities, it has been recently reported that α-defensins, mainly present in neutrophils in the lung, have a cytotoxic effect and induce IL-8 production from airway epithelial cells. Although β-defensins are expressed in epithelial cells in various tissues, including lung, there are no reports of their effects on cytokine synthesis in airway epithelial cells. The aim of the present study was to determine the effects of both α- and β-defensins on the cytokine production, transcription factor binding activity, and cytotoxicity in primary cultured human bronchial epithelial cells (HBECs). We used human neutrophil peptide-1 (HNP-1; α-defensin) and human β-defensin-2 (HBD-2) to stimulate HBECs. The results showed that treatment of HBECs with HNP-1, but not HBD-2, increased IL-8 and IL-1β mRNA expression in a dose-dependent manner and also enhanced IL-8 protein secretion and NF-κB DNA binding activity. The 24-h treatments with >20 μg/ml of HNP-1 or >50 μg/ml of HBD-2 were cytotoxic to HBECs. These results suggest that α- and β-defensins have different effects on cytokine synthesis by airway epithelial cells, and we speculate that they play different roles in inflammatory lung diseases.
Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats
Authors: Offer Sarit , Yedgar Saul , Schwob Ouri , Krimsky Miron , Bibi Haim , Eliraz Abraham , Madar Zecharia , Shoseyov David
Published: November 2004

Phospholipase A2 (PLA2) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. The PLA2 enzymes include the secretory (sPLA2) and cytosolic (cPLA2) isoforms, which are assumed to act synergistically in production of eicosanoids that are involved in inflammatory processes. However, growing evidence raises the possibility that in airways and asthma-related inflammatory cells (eosinophils, basophils), the production of the bronchoconstrictor cysteinyl leukotrienes (CysLT) is linked exclusively to sPLA2, whereas the bronchodilator prostaglandin PGE2 is produced by cPLA2. It has been further reported that the capacity of airway epithelial cells to produce CysLT is inversely proportional to PGE2 production. This seems to suggest that sPLA2 and cPLA2 play opposing roles in asthma pathophysiology and the possibility of a negative feedback between the two isoenzymes. To test this hypothesis, we examined the effect of a cell-impermeable extracellular sPLA2 inhibitor on bronchoconstriction and PLA2 expression in rats with ovalbumin (OVA)-induced asthma. It was found that OVA-induced bronchoconstriction was associated with elevation of lung sPLA2 expression and CysLT production, concomitantly with suppression of cPLA2 expression and PGE2 production. These were reversed by treatment with the sPLA2 inhibitor, resulting in amelioration of bronchoconstriction and reduced CysLT production and sPLA2 expression, concomitantly with enhanced PGE2 production and cPLA2 expression. This study demonstrates, for the first time in vivo, a negative feedback between sPLA2 and cPLA2 and assigns opposing roles for these enzymes in asthma pathophysiology: sPLA2 activation induces production of the bronchoconstrictor CysLT and suppresses cPLA2 expression and the subsequent production of the bronchodilator PGE2.
Mechanical ventilation induces alterations of the ubiquitin-proteasome pathway in the diaphragm
Authors: DeRuisseau Keith C. , Kavazis Andreas N. , Deering Melissa A. , Falk Darin J. , Van Gammeren Darin , Yimlamai Tossaporn , Ordway George A. , Powers Scott K.
Published: November 2004

Prolonged mechanical ventilation (MV) results in diaphragmatic atrophy due, in part, to an increase in proteolysis. These experiments tested the hypothesis that MV-induced diaphragmatic proteolysis is accompanied by increased expression of key components of the ubiquitin-proteasome pathway (UPP). To test this postulate, we investigated the effect of prolonged MV on UPP components and determined the trypsin-like and peptidylglutamyl peptide hydrolyzing activities of the 20S proteasome. Adult Sprague-Dawley rats were assigned to either control or 12-h MV groups ( n = 7/group). MV animals were anesthetized, tracheostomized, and ventilated with room air for 12 h. Animals in the control group were acutely anesthetized but not exposed to MV. Compared with controls, MV animals demonstrated increased diaphragmatic mRNA levels of two ubiquitin ligases, muscle atrophy F-box (+8.3-fold) and muscle ring finger 1 (+19.0-fold). However, MV did not alter mRNA levels of 14-kDa ubiquitin-conjugating enzyme, polyubiquitin, proteasome-activating complex PA28, or 20S α-subunit 7. Protein levels of 14-kDa ubiquitin-conjugating enzyme and proteasome-activating complex PA28 were not altered following MV, but 20S α-subunit 7 levels declined (−17.7%). MV increased diaphragmatic trypsin-like activity (+31%) but did not alter peptidylglutamyl peptide hydrolyzing activity. Finally, compared with controls, MV increased ubiquitin-protein conjugates in both the myofibrillar (+24.9%) and cytosolic (+54.7%) fractions of the diaphragm. These results are consistent with the hypothesis that prolonged MV increases diaphragmatic levels of key components within the UPP and that increases in 20S proteasome activity contribute to MV-induced diaphragmatic proteolysis and atrophy.
Chemoreflex control of breathing during wakefulness in healthy men and women
Authors: Jensen Dennis , Wolfe Larry A. , O'Donnell Denis E. , Davies Gregory A. L.
Published: November 2004

This study used a modified CO2 rebreathing procedure to examine the effect of gender on the chemoreflex control of breathing during wakefulness in healthy men ( n = 14) and women ( n = 14). Women were tested in the follicular phase of the menstrual cycle. During rebreathing trials, subjects hyperventilated to reduce the partial pressure of end-tidal CO2 (PetCO2) below 25 Torr and were then switched to a rebreathing bag containing a normocapnic hypoxic or hyperoxic gas mixture. During the trial, PetCO2 increased, while O2 was maintained at a constant level. The point at which ventilation began to rise as PetCO2 increased was identified as the ventilatory recruitment threshold (VRT). Ventilation below the VRT was measured, and the slope of the ventilatory response above the VRT was determined. Gender had no effect on the hyperoxic or hypoxic VRT for CO2. Central chemoreflex sensitivity was significantly greater in men than women but not after correction for forced vital capacity. Measures of peripheral chemoreflex sensitivity were similar between genders. However, the slope of the tidal volume (Vt) response to hyperoxic and hypoxic CO2 rebreathing (corrected and uncorrected) was greater in men than women, respectively. We conclude that central chemoreflex sensitivity is greater in men compared with women as reflected by differences in ventilatory (uncorrected) and Vt (corrected and uncorrected) responses to CO2. However, gender has no significant effect on the central chemoreflex VRT for CO2. The peripheral chemoreflex control of breathing during wakefulness is similar between men and women.
Forging Mandalic Space: Bhaktapur, Nepal's Cow Procession and the Improvisation of Tradition
Authors: Price Grieve Gregory
Published: November 2004

In 1995, as part of Bhaktapur, Nepal's Cow Procession, the new suburban neighborhood of Suryavinayak celebrated a "forged" goat sacrifice. Forged religious practices seem enigmatic if one assumes that traditional practice consists only of the blind imitation of timeless structure. Yet, the sacrifice was not mechanical repetition; it could not be, because it was the first and only time it was celebrated. Rather, the religious performance was a conscious manipulation of available "traditional" cultural logics that were strategically utilized during the Cow Procession's loose carnivalesque atmosphere to solve a contemporary problem — what can one do when one lives beyond the borders of religiously organized cities such as Bhaktapur? This paper argues that the "forged" sacrifice was a means for this new neighborhood to operate together and improvise new man. d. alic space beyond the city's traditional cultic territory.
Measuring Dynamic Bipolarity in Positive and Negative Activation
Authors: Vautier Stéphane , Raufaste Eric
Published: November 2004

The dynamic bipolarity of the positive and negative affective activation, measured with the PANAS scales, was studied using a pre-post design with an intervening experiment. The correlations between (a) the initial positive and negative constructs and (b) the respective change scores were estimated, random and systematic error being removed owing to a convenient structural equation modeling technique. Results demonstrated that a moderate perturbation may induce a medium correlation between latent change scores. Both strict dynamic independence and bipolarity were rejected. This result highlights the importance of individual differences in the way people perceive their affective changes. It is concluded that the PANAS two-factor model of affect provides only an approximate view of the structure and dynamics of mood.
Supportive Care
Authors: Wingard John R. , Nichols W. Garrett , McDonald George B.
Published: November 2004

To optimize treatment outcomes for hematologic malignancies, minimizing the consequences of treatment complications requires as much skill as the choice of the treatment itself. Myelosuppression and immunosuppression are frequent complications and have potentially serious infectious consequences. Invasive fungal infections and infections from respiratory viruses are increasing in frequency and have life-threatening potential. Damage to vital organs, especially the liver, is another important concern. In this chapter, the scope of invasive fungal and respiratory viral infections, recent insights into the pathogenesis of hepatic sinusoidal injury, and recent developments that impact prevention and treatment approaches for these complications are described.

In Section I, Dr. John Wingard describes the advantages and disadvantages of various treatment options for invasive infections by the two chief fungal pathogens, Candida and Aspergillus. Adjunctive therapies and practical considerations that clinicians should weigh in choosing one or another of the various agents are discussed. The studies that have evaluated antifungal prophylaxis and empirical treatment strategies are reviewed. Finally, new approaches such as combination therapy, new diagnostics, and efforts to bolster host immunity are considered.

In Section II, Dr. W. Garrett Nichols describes the epidemiology of community-acquired respiratory viruses (CRV) in patients with hematologic malignancies. Risk factors, clinical syndromes, and possible indirect effects of CRV infections are discussed. Treatment and prevention options are reviewed.

In Section III, Dr. George McDonald describes sinusoidal obstruction syndrome (once known as hepatic veno-occlusive disease). Recent insights into pathogenesis are described. Diagnostic criteria and the advantages and disadvantages of various diagnostic methods are reviewed and prognosis is considered. Prevention and treatment options are discussed.
Congenital and Acquired Neutropenia
Authors: Berliner Nancy , Horwitz Marshall , Loughran Thomas P.
Published: November 2004

Our understanding of the pathogenesis of congenital and acquired neutropenia is rapidly evolving. New ground-breaking observations have identified the genes responsible for many of the congenital neutropenia syndromes and are also providing new insights into normal neutrophil commitment and differentiation. Acquired neutropenia remains a poorly understood syndrome, although new insights into its pathogenesis are also emerging, especially with regard to subsets of immune neutropenia.

In Section I, Dr. Marshall Horwitz reviews the current understanding of the genetic basis, molecular pathology, and approaches to treatment of congenital neutropenia and cyclic hematopoiesis. Mutations in the ELA2 gene, which encodes for neutrophil elastase, cause cyclic hematopoiesis. ELA2 mutations are also the most common cause of congenital neutropenia, where their presence may equate with a more severe clinical course and higher frequency of leukemic progression. Emerging evidence indicates interrelatedness with Hermansky Pudlak syndrome and other disorders of neutrophil and platelet granules.

In Section II, Dr. Nancy Berliner presents an overview of the clinical approach to the evaluation and treatment of acquired neutropenia. This includes a review of the pathogenesis of primary and secondary immune neutropenia, drug-induced neutropenia, and non-immune chronic idiopathic neutropenia of adults. Studies used to evaluate patients for potential immune neutropenia are reviewed. Management issues, especially the use of granulocyte colony-stimulating factor (G-CSF), are discussed.

In Section III, Dr. Thomas Loughran, Jr., reviews the pathogenesis and clinical manifestations of large granular lymphocyte (LGL) leukemia. Possible mechanisms of neutropenia are discussed. In particular, discussion focuses on the relationship between LGL leukemia, rheumatoid disease, and Felty’s syndrome, and the complex interplay of defects in neutrophil production, distribution, destruction, and apoptosis that underly the development of neutropenia in those syndromes.
Symptomatic hypogammaglobulinemia in infancy and childhood – clinical outcome and in vitro immune responses
Authors: Kidon Mona Iancovici , Handzel Zeev T , Schwartz Rivka , Altboum Irit , Stein Michael , Zan-Bar Israel
Published: November 2004

Background

Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution.

Methods

Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed.

Results

32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. Clinical presentation: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients.

Conclusions

The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign.
Effect of Ampicillin on the kinetics of colonization of Streptococcus pneumoniae and Lactobacillus fermentum in the respiratory tract of mice
Authors: Cangemi de Gutiérrez Rosa , Santos Viviana , Cecilia Marta , Silva Clara , Nader-Macías María Elena
Published: November 2004

Ampicillin was selected to further study the effect of this antibiotic on the colonization capability of S. pneumoniae and L. fermentum intranasally inoculated in a mice experimental model. The sensitivity of S. pneumoniae and L. fermentum to antibiotics was evaluated by different "in vitro" techniques. The results showed that both microorganisms have a typical pattern of sensitivity to antibiotics in these assays. The "in vivo" experiments showed that the treatment with Ampicillin increased the number of lactobacilli and neumococci in the groups of mice treated only with one of the microorganisms. In those mice treated with Lactobacillus, challenged later with neumococci and treated with Ampicillin, the pathogen in lung decreased on the 4th day, disappearing completely after on. The histological studies showed that the antibiotic treatment decreased the inflammatory response produced by the pathogen at the lung and trachea levels.