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PubMed2006

Quantitative evaluation of prion inactivation comparing steam sterilization and chemical sterilants: proposed method for test standardization.

Prions are notoriously resistant to inactivation. To prevent accidental transmission of variant Creutzfeldt-Jakob disease (vCJD), various decontamination procedures have been adopted for re-usable medical devices by the authorities of countries at risk. As the vCJD agent in humans has a wide tissue distribution, practical methods of prion decontamination urgently need to be standardized, as do other sterilization and disinfection procedures (European Committee for Standardization). This article proposes a method using a quantitative murine model, combining observations of the decrease in the infection rate, the increase in the incubation period and a simultaneously performed chemical protein fixation control. In terms of practical application, autoclaving at 134 degrees C for 18 min or 121 degrees C for 30 min, and 1N sodium hydroxide for 15 min reduced the transmission of infectivity by a factor of at least 10(6). Partial efficacy can also be identified by the methodology, particularly for liquid cold sterilants such as glutaraldehyde and peracetic acid solutions.

Animals↗

PubMed2004

Astrocytic proliferation in the piriform cortex of amygdala-kindled subjects: a quantitative study in partial versus fully kindled brains.

Complex partial epilepsy is a seizure disorder in which attacks frequently arise from foci located in the temporal lobes. The amygdala-kindling model is a widely used model of complex partial epilepsy with secondary generalization. The present study was designed to quantitatively assess astrocytic changes in the rat piriform cortex in the amygdala-kindling model of epilepsy. Bromodeoxyuridine-injected subjects were sacrificed 24 h after the first stage 1 or fifth stage 5 seizure. Brain sections were prepared and examined quantitatively. A significantly higher number of dividing astrocytes (identified by co-labeling with antibodies to bromodeoxyuridine and to one of the astrocytic intermediate filament proteins glial fibrillary acidic protein or vimentin) was found in both partially kindled (stage 1) and fully kindled (stage 5) brains. The partially kindled brains had a significantly higher number of double-labeled cells on the side ipsilateral to stimulation. The opposite trend was observed in the fully kindled brains. Differences between the ipsilateral and contralateral sides of the kindled brain may suggest different role(s) for astrocytes in the development and progression of the seizure-prone state.

Amygdala↗

PubMed1997

Cloning in silico.

Cellulose is a major component of plant cell walls, but identification of the enzymes that synthesize it has proven difficult. Now, however, several candidate proteins with sequence homology to bacterial cellulose synthases have been identified by partial sequencing of anonymous cDNA clones from cotton fibers.

Bacteria↗

PubMed1998

Increased plasma P-selectin induced by intravenous administration of endotoxin in rats.

We developed a competitive enzyme immunoassay for detection of rat P-selectin and examined temporal changes of plasma P-selectin levels in an endotoxin-induced injury model in rats. Soluble P-selectin was detected in rat plasma after intravenous administration of lipopolysaccharide (LPS), and increased to a maximum level of five-fold over baseline after 24 hours. Plasma P-selectin was partially purified by gelfiltration and was identified as a 122 kDa band by Western blotting. Using the ELISA system we developed, monitoring of plasma P-selectin has become possible in the rat.

Animals↗

PubMed1999

Persistence, immune specificity, and functional ability of murine mutant ras epitope-specific CD4(+) and CD8(+) T lymphocytes following in vivo adoptive transfer.

Adoptive T-cell transfer has been shown to be a potentially effective strategy for cellular immunotherapy in some murine models of disease. However, several issues remain unresolved regarding some of the basic features involved in effective adoptive transfer, such as the influence of specific peptide antigen (Ag) boost after T-cell transfer, the addition of IL-2 post-T-cell transfer, the trafficking of transferred T cells to lymphoid and nonlymphoid tissues, and the functional stability of recoverable CD4(+) and CD8(+) T cells. We investigated several of these parameters, particularly as they relate to the persistence and maintenance of effector functions of murine CD4(+) and/or CD8(+) T lymphocytes after adoptive cellular transfer into partially gamma-irradiated syngeneic hosts. Our laboratory previously identified murine (H-2(d)) immunogenic CD4(+) and CD8(+) T-cell peptide epitopes reflecting codon 12 ras mutations as tumor-specific Ag. Therefore, the model system chosen here employed epitope-specific MHC class II-restricted CD4(+) T cells and MHC class I-restricted CD8(+) T cells produced from previously immunized BALB/c mice. Between 2 and 7 days after T-cell transfer, recipient mice received various combinations of peptide boosts and/or IL-2 treatments. At different times after the T-cell transfer, spleen and lung tissues were analyzed phenotypically to monitor the persistence of the immune T cells and functionally (via proliferation or cytotoxicity assays) to assess the maintenance of peptide specificity. The results showed that immune donor T lymphocytes (uncultured immune T cells or cloned T cells) were recoverable from the spleens and lungs of recipient mice after transfer. The recovery of Ag-specific T-cell responses was greatest from recipient mice that received peptide boosts and IL-2 treatment. However, mice that received a peptide boost without IL-2 treatment responded nearly as well, which suggested that including a peptide boost after T-cell transfer was more obligatory than exogenous IL-2 treatment to sustain adoptively transferred T cells in vivo. Ag-specific T-cell responses were weak in mice that either received IL-2 alone or did not receive the cognate peptide boost after T-cell transfer. The T-cell clones were also monitored by flow cytometry or RT-PCR based on expression of the T-cell receptor Vbeta-chain, which was previously characterized. Ag-specific T cells were recovered from both spleens and lungs of recipient mice, demonstrating that the T-cell clones could localize to both lymphoid and nonlymphoid tissues. This study demonstrates that both uncultured and in vitro-cloned T lymphocytes can migrate to lymphoid tissues and nonlymphoid (e.g., lung) tissues in recipient hosts and that their functional activities can be maintained at these sites after transfer, if they are exposed to peptide Ag in vivo.

Adoptive Transfer↗

PubMed1998

Meta-analysis of fixed partial denture survival: prostheses and abutments.

STATEMENT OF PROBLEM: Few estimates of the probability of various outcomes associated with replacement of missing teeth with fixed partial dentures have been reported. Existing longitudinal studies have reported widely disparate results for the survival of fixed partial dentures, but these studies have used different definitions of failure and varying periods of follow-up. PURPOSE: This study used meta-analysis to formulate annual probability estimates for three categories of fixed partial denture or abutment survival. METHODS: A systematic review of the English language literature since 1960 identified eight studies that met the preset inclusion criteria. Estimated annual survival proportions were back-calculated based on the Kaplan-Meier model and these proportions were combined through a fixed effects model meta-analysis. The probabilities and corresponding 95% confidence intervals at 5, 10, and 15 years for the three categories of survival are reported. RESULTS: For the aggregate population represented by the limited longitudinal studies available, this meta-analysis indicated that less than 15% of fixed partial dentures were removed or in need of replacement at 10 years; whereas, nearly one third were removed or in need of replacement at 15 years. Less than 5% of abutments were removed at 10 years.

Confidence Intervals↗

PubMed1999

Spatial diffusion of raccoon rabies in Pennsylvania, USA.

Identification of the geographic pattern of diffusion of a wildlife disease could lead to information regarding its control. The objective of this study was to model raccoon-rabies diffusion in Pennsylvania to identify geographic constraints on the diffusion pattern for potential use in bait-vaccination strategies. A trend-surface analysis (TSA) was used as a spatial filter for month to first report by county location. A cubic polynomial model was fitted (R2 = 0.80). Velocity vectors were calculated from the partial derivatives of the model and mapped to demonstrate the instantaneous speed of diffusion at each location. A main corridor of diffusion through the ridge and valley section of the state was evident early in the outbreak. Once the disease reached the northern counties, the disease moved west toward Ohio. I believe that TSA was useful in identifying the pattern of raccoon-rabies diffusion across the stage from the inherent noise of disease-reporting data.

Animals↗

PubMed1996

An eye lens protein-water structure: 1.2 A resolution structure of gammaB-crystallin at 150 K.

gammabeta-crystallin is a structural protein of the eye lens with a role in the maintenance of an even distribution of protein and water over distances around the wavelength of light, preserving lens transparency. The structure of the 174-residue bovine protein has already been determined at room temperature to 1.47 A resolution. By flash freezing the protein crystals, data have now been collected to a nominal resolution limit of 1.2 A as radiation damage was essentially eliminated. The protein-water model has been refined against this data using the program RESTRAIN converging to an R factor of 18.5% with all data. Atomic positions are clearly indicated in the electron-density maps. Discrete bimodal disorder has been visualized for a few side chains. Out of a total of 498 water molecules present in the crystal asymmetric unit, 394 have been modelled and refined at unit occupancy. The solvent structure is extremely well ordered with an average B value of 23.4 A(2). Partially occupied sites have been identified where disorder in the protein induces concomitant disorder in the local solvent structure. The solvent structure covers 97% of the solvent-exposed surface of the protein in the crystal. 126 water molecules are distributed in second and higher hydration shells. There are networks of hydrogen-bonded solvent extending up to 64 molecules in a network, comprising trimers and tetramers as well as five- and six-membered water-ring structures. The hydration of the protein surface is dominated by arginine and aspartate side chains. Extensive cages of highly ordered solvent molecules are also observed around exposed non-polar groups.

Journal Article↗

PubMed2006

Histological and ultrastructural analysis of white matter damage after naturally-occurring spinal cord injury.

Detailed analysis of the structural changes that follow human clinical spinal cord injury is limited by difficulties in achieving adequate tissue fixation. This study bypasses this obstacle by examining the spinal cord from paraplegic domestic animals, enabling us to document the ultrastructural changes at different times following injury. In all but one case, injury resulted from a combination of contusion and compression. There was infarction and hemorrhage, followed by gray matter destruction and the rapid development of a variety of white matter changes including axon swelling and myelin degeneration. Axons greater than 5 microm in diameter were more susceptible to degenerative changes, whereas smaller axons, particularly those in the subpial region, were relatively well preserved. Demyelinated axons were seen within 2 weeks after injury and, at later time points, both Schwann cell and oligodendrocyte remyelination was common. More subtle white matter abnormalities were identified by examining sagittal sections, including focal accumulation of organelles in the axoplasm and partial and paranodal myelin abnormalities. These observations serve to validate observations from experimental models of spinal contusion but also highlight the complexity of naturally occurring (ie, clinical) spinal injury. They also raise the possibility that focal abnormalities such as paranodal demyelination may contribute to early axonal dysfunction and possibly to progressive tissue damage.

Animals↗

PubMed2006

Integrative investigation of metabolic and transcriptomic data.

BACKGROUND: New analysis methods are being developed to integrate data from transcriptome, proteome, interactome, metabolome, and other investigative approaches. At the same time, existing methods are being modified to serve the objectives of systems biology and permit the interpretation of the huge datasets currently being generated by high-throughput methods. RESULTS: Transcriptomic and metabolic data from chemostat fermentors were collected with the aim of investigating the relationship between these two data sets. The variation in transcriptome data in response to three physiological or genetic perturbations (medium composition, growth rate, and specific gene deletions) was investigated using linear modelling, and open reading-frames (ORFs) whose expression changed significantly in response to these perturbations were identified. Assuming that the metabolic profile is a function of the transcriptome profile, expression levels of the different ORFs were used to model the metabolic variables via Partial Least Squares (Projection to Latent Structures--PLS) using PLS toolbox in Matlab. CONCLUSION: The experimental design allowed the analyses to discriminate between the effects which the growth medium, dilution rate, and the deletion of specific genes had on the transcriptome and metabolite profiles. Metabolite data were modelled as a function of the transcriptome to determine their congruence. The genes that are involved in central carbon metabolism of yeast cells were found to be the ORFs with the most significant contribution to the model.

Algorithms↗

PubMed2002

A ubiquitin C-terminal hydrolase is required to maintain osmotic balance and execute actin-dependent processes in the early C. elegans embryo.

In the early Caenorhabditis elegans embryo, establishment of cell polarity and cytokinesis are both dependent upon reorganization of the actin cytoskeleton. Mutations in the cyk-3 gene cause maternal effect embryonic lethality. Embryos produced by homozygous cyk-3 mutant animals become multinucleate. We have further analyzed the cyk-3 mutant phenotype and have found that cyk-3 mutant embryos fail to properly polarize the actin cytoskeleton and fail to segregate germline determinants. In addition, they fail to assemble an intact cleavage furrow. However, we have found that cyk-3 mutant embryos are intrinsically defective in osmotic regulation and that the cytokinesis defects can be partially rescued by providing osmotic support. The cyk-3 gene has been identified and found to encode a ubiquitin C-terminal hydrolase that is active against model substrates. These data indicate that the deubiquitination of certain substrates by CYK-3 is crucial for cellular osmoregulation. Defects in osmoregulation appear to indirectly affect actin-dependent processes.

Actin Cytoskeleton↗

PubMed2006

Classification of chemical and biological warfare agent simulants by surface-enhanced Raman spectroscopy and multivariate statistical techniques.

Initial results demonstrating the ability to classify surface-enhanced Raman (SERS) spectra of chemical and biological warfare agent simulants are presented. The spectra of two endospores (B. subtilis and B. atrophaeus), two chemical agent simulants (dimethyl methylphosphonate (DMMP) and diethyl methylphosphonate (DEMP)), and two toxin simulants (ovalbumin and horseradish peroxidase) were studied on multiple substrates fabricated from colloidal gold adsorbed onto a silanized quartz surface. The use of principal component analysis (PCA) and hierarchical clustering were used to evaluate the efficacy of identifying potential threat agents from their spectra collected on a single substrate. The use of partial least squares-discriminate analysis (PLS-DA) and soft independent modeling of class analogies (SIMCA) on a compilation of data from separate substrates, fabricated under identical conditions, demonstrates both the feasibility and the limitations of this technique for the identification of known but previously unclassified spectra.

Biological Warfare↗

PubMed2004

Characterization of bovine homologues of granulysin and NK-lysin.

Granulysin and NK-lysin are antimicrobial proteins found in the granules of human and swine cytotoxic lymphocytes. A murine counterpart to granulysin has not been identified to date, indicating the importance of additional models to fully characterize the role of granulysin-like molecules in the immune response to infectious disease. Two partial nucleotide sequences corresponding to the complete functional domain of granulysin and NK-lysin were amplified from bovine PBMC mRNA. Following stimulation with phorbol ester and calcium ionophore, expression of the bovine gene was detected in CD3(+) T cells, CD4(+) T cells, CD8(+) T cells, WC1(+) gammadelta T cells, and PBMC depleted of CD3(+) T cells, but was absent in CD21(+) cells and CD14(+) cells. Intracellular flow cytometry and immunoblotting confirmed the presence of protein corresponding to the bovine granulysin homologue in activated T lymphocytes and PBMC. Synthetic human, bovine, and swine peptides corresponding to the C terminus of helix 2 through helix 3 region of granulysin displayed potent antimicrobial activity against Escherichia coli, Salmonella enteritidis, Staphylococcus aureus, and Mycobacterium bovis bacillus Calmette-Guérin. Human and bovine peptides corresponding to helix 2 displayed antimycobacterial activity against M. bovis bacillus Calmette-Guérin. Expression of the bovine gene was detected in laser microscopy-dissected lymph node lesions from an M. bovis-infected animal. The identification of a biologically active bovine homologue to granulysin demonstrates the potential of the bovine model in characterizing the role of granulysin in the immune response to a variety of infectious agents.

Amino Acid Sequence↗

PubMed1995

The twitcher mouse: a model for Krabbe disease and for experimental therapies.

The twitcher is a naturally-occurring mouse mutant caused by an abnormality in the gene coded for galactosylceramidase. It is therefore genetically equivalent to human globoid cell leukodystrophy (Krabbe disease). Affected mice develop clinical symptoms at the onset of the active myelination period and, if untreated, die by 35 +/- days. The pathology is very similar to that in human disease. Toxicity of galactosylsphingosine (psychosine) that accumulates abnormally in the nervous system is considered to be primarily responsible for the pathogenesis. Transplantation of bone marrow cells from normal donors is partially effective and triples the life span of affected mice to 100 +/- days with evidence of remyelination in the CNS. The mutation responsible for the twitcher mutant has recently been identified. It is expected that this model will be useful for basic studies on treatment of this group of genetic disorders affecting the brain through transgenic and/or gene therapy approaches.

Animals↗

PubMed2000

Multivariate data analysis using D-optimal designs, partial least squares, and response surface modeling: A directional approach for the analysis of farnesyltransferase inhibitors.

We have investigated the combined use of partial least squares (PLS) and statistical design principles in principal property space (PP-space), derived from principal component analysis (PCA), to analyze farnesyltransferase inhibitors in order to identify "activity trends" (an approach we call a "directional" approach) and quantitative structure-activity relationships (QSAR) for a congeneric series of inhibitors: the benzo[f]perhydroisoindole (BPHI) series. Trends observed in the PCA showed that the descriptors used were relevant to describe our structural data set by clearly identifying two well-defined structural subclasses of inhibitors. D-Optimal design techniques allowed us to define a training set for PLS study in PP-space. Models were derived for each biological assay under evaluation: the in vitro Ki-Ras and cellular HCT116 tests. Each of these assay-based sets was subdivided once more into two subsets according to two structural classes in this BPHI series as revealed by the PCA model. The response surface modeling (RSM) methodology was used for each subset, and the corresponding RSM plots helped us identify "activity trends" exploited to guide further analogue design. For more precise activity predictions more refined PLS models on constrained PP-spaces were developed for each subset. This approach was validated with predicted sets and demonstrates that useful information can be extracted from just a few very informative and representative compounds. Finally, we also showed the potential use of such a strategy at an early stage of an optimization process to extract the first "activity trends" that might support decision making and guide medicinal chemists in the initial design of new analogues and/or lead followup libraries.

Alkyl and Aryl Transferases↗

PubMedDate not supplied

[Limitations and alternatives to the implementation of a program for drug users at risk of HIV infection using the Social Network Approach].

The authors describe the development of a preventive program focused on intravenous drug users at risk of HIV infection, using the Social Network Approach as the intervention model. The authors describe the project's steps in a large university hospital in southern Brazil, emphasizing the unique methods and techniques developed by the treatment staff. Problems encountered during the project development are discussed, aimed at identifying the reasons why the program only achieved partial success. The authors identify critical issues, such as the use of a new technique not previously tried in Brazil, difficulties in maintaining IV drug users in treatment, lack of infrastructure for walk-in treatment, and the challenge of motivating staff and patients to continue treatment. The authors conclude by listing suggestions aimed at facilitating the development of new projects based on the same conceptual model.

Community Networks↗

PubMed2006

Computational prediction and experimental verification of HVA1-like abscisic acid responsive promoters in rice (Oryza sativa).

Abscisic acid (ABA) is one of the central plant hormones, responsible for controlling both maturation and germination in seeds, as well as mediating adaptive responses to desiccation, injury, and pathogen infection in vegetative tissues. Thorough analyses of two barley genes, HVA1 and HVA22, indicate that their response to ABA relies on the interaction of two cis-acting elements in their promoters, an ABA response element (ABRE) and a coupling element (CE). Together, they form an ABA response promoter complex (ABRC). Comparison of promoters of barley HVA1 and it rice orthologue indicates that the structures and sequences of their ABRCs are highly similar. Prediction of ABA responsive genes in the rice genome is then tractable to a bioinformatics approach based on the structures of the well-defined barley ABRCs. Here we describe a model developed based on the consensus, inter-element spacing and orientations of experimentally determined ABREs and CEs. Our search of the rice promoter database for promoters that fit the model has generated a partial list of genes in rice that have a high likelihood of being involved in the ABA signaling network. The ABA inducibility of some of the rice genes identified was validated with quantitative reverse transcription PCR (QPCR). By limiting our input data to known enhancer modules and experimentally derived rules, we have generated a high confidence subset of ABA-regulated genes. The results suggest that the pathways by which cereals respond to biotic and abiotic stresses overlap significantly, and that regulation is not confined to the level transcription. The large fraction of putative regulatory genes carrying HVA1-like enhancer modules in their promoters suggests the ABA signal enters at multiple points into a complex regulatory network that remains largely unmapped.

Abscisic Acid↗

PubMed2004

Gestational trophoblastic neoplasia in American Indians.

OBJECTIVE: To analyze gestational trophoblastic neoplasia (GTN) trends among American Indians (AI) using population-based data. STUDY DESIGN: GTN incidence, by race and age, was calculated using data collected by the New Mexico Tumor Registry over 29 years (1973-2001). Live birth, pregnancy and women at risk were tabulated using data derived from the state's vital record annual reports and from the registry. Statistical methods included trends analysis and Poisson regression. There is no national registry in the United States for all GTN. Therefore, the Surveillance, Epidemiology and End Results (SEER) database was used to identify choriocarcinoma cases in American Indians between 1973 and 1999. RESULTS: Within New Mexico, 1,082 cases of GTN were identified among 752,374 live births and 904,831 pregnancies, with ratios of 1:695 and 1:836, respectively, affecting 234 AI, 355 non-Hispanic whites (NHW), 463 Hispanic whites (HW) and 30 other nonwhites. Ratios per live births (pregnancy), respectively, were significantly higher in AI (AI 1:439 [1:487], NHW 1:739 [1:949], HW 1:783 [1:903]), as was age-adjusted incidence per 100,000 woman-years (AI 10.62, NHW 3.53, HW 5.15; all P<.0001). Using Poisson models with live birth and woman-year denominators, AI were found to be at increased risk for all GTN histologic subsets (complete, partial and invasive hydatidiform mole and choriocarcinoma). Of 524 total gestational choriocarcinoma cases identified within SEER, 8 (1.8%) affected American Indians; of them, 7 were from New Mexico. CONCLUSION: In New Mexico, AI continue to be at higher risk of GTN than are other groups. Given the rarity of choriocarcinoma within SEER, especially among AI, the New Mexico dataset provides the best available estimate of trends in U.S. AI GTN risk.

Black or African American↗