bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Convergence of Computing and Telecommunications Systems
Authors: Farber David , Baran Paul 
Published: October 2006

Since we do not know of any completely workable solutions to the problems we have considered, we shall settle for a few general observations:
1) The public availability of socially useful computer communications services is and has been held back by legal battles that are now under way between the potential suppliers.
2) No simple resolution of these issues in the near future seems likely in view of the past conceptual separation of computers and communications doctrines.
3) The current policy is to determine whether the nation shall or shall not have certain computer communications services, by the adversary process. In this process, often only the voices of the loudest adversary suppliers are heard.
4) Although there can be no certainty that better alternatives cannot be devised, we believe that such a possibility assumes a higher probability if the key actors come from the technical community sectors more representative of the future consumers.
5) If we are to have the new services that are possible, we need an approach that makes better use of the technologists' dreams and goals rather than have future prospects excessively bound by lawyers paid to preserve the interests of their clients, irrespective of any secondary consequences.
6) We cannot be sanguine about this possibility, as technological statesmanship is too easily corrupted by the same forces that have placed us in this predicament. Furthermore, even if not corrupted, beneficial cooperation can too readily be regarded as simply collusion.
7) Although we do not have any clear answer, we do know that present approaches are not taking us where we want to go very rapidly and that alternative approaches should at least be considered.
Pharmacokinetic Considerations and Efficacy of Levofloxacin in an Inhalational Anthrax (Postexposure) Rhesus Monkey Model
Authors: Kao L. Mark , Bush Karen , Barnewall Roy , Estep James , Thalacker Frederic W. , Olson Pamela H. , Drusano George L. , Minton Neil , Chien Shuchean , Hemeryck Alex , Kelley Michael F. 
Published: October 2006

ABSTRACT

Because the treatment of inhalational anthrax cannot be studied in human clinical trials, it is necessary to conduct efficacy studies using a rhesus monkey model. However, the half-life of levofloxacin was approximately three times shorter in rhesus monkeys than in humans. Computer simulations to match plasma concentration profile, area under the concentration-time curve (AUC), and time above MIC for a human oral dose of 500 mg levofloxacin once a day identified a dosing regimen in rhesus monkeys that would most closely match human exposure: 15 mg/kg followed by 4 mg/kg administered 12 h later. Approximately 24 h following inhalational exposure to approximately 49 times the 50% lethal doses of
Bacillus anthracis
(Ames strain), monkeys were treated daily with vehicle, levofloxacin, or ciprofloxacin for 30 days. Ciprofloxacin was administered at 16 mg/kg twice a day. Following the 30-day treatment, monkeys were observed for 70 days. Nine of 10 control monkeys died within 9 days of exposure. No clinical signs were observed in fluoroquinolone-treated monkeys during the 30 treatment days. One monkey died 8 days after levofloxacin treatment, and two monkeys from the ciprofloxacin group died 27 and 36 days posttreatment, respectively. These deaths were probably related to the germination of residual spores.
B. anthracis
was positively cultured from several tissues from the three fluoroquinolone-treated monkeys that died. MICs of levofloxacin and ciprofloxacin from these cultures were comparable to those from the inoculating strain. These data demonstrate that a humanized dosing regimen of levofloxacin was effective in preventing morbidity and mortality from inhalational anthrax in rhesus monkeys and did not select for resistance.
Synergism between β-Lactams and Glycopeptides against VanA-Type Methicillin-Resistant
Staphylococcus aureus
and Heterologous Expression of the
vanA
Operon
Authors: Périchon Bruno , Courvalin Patrice 
Published: October 2006

ABSTRACT

Vancomycin resistance of
Staphylococcus aureus
NY-VRSA and VRSA-5 is due to acquisition of a
vanA
operon located in a Tn
1546
-like element. The
vanA
gene cluster of NY-VRSA contained one copy of insertion sequences IS
1251
and IS
1216V
relative to that of VRSA-5. As evidenced by the nature of the late peptidoglycan precursors and by quantification of
d
,
d
-peptidase activities, the vancomycin resistance genes were efficiently expressed in both strains. Study of the stability and inducibility of glycopeptide resistance suggested that low-level glycopeptide resistance of NY-VRSA was most probably due to plasmid instability combined with a long delay for resistance induction. The activity of combinations of vancomycin or teicoplanin with oxacillin against the four VanA-type
S. aureus
strains already reported was tested by single and double disk diffusion, E-test on agar alone or supplemented with antibiotics, the checkerboard technique, and by determining time-kill curves. A strong synergism against the four clinical isolates, with fractional inhibitory concentration indexes from 0.008 to 0.024, was reproducibly observed between the two antibiotics by all methods. These observations indicate that cell wall inhibitors of the β-lactam and glycopeptide classes exert strong and mutual antagonistic effects on resistance to each other against VanA-type methicillin-resistant
S. aureus
.
In Vitro Metacestodicidal Activities of Genistein and Other Isoflavones against
Echinococcus multilocularis
and
Echinococcus granulosus
Authors: Naguleswaran Arunasalam , Spicher Martin , Vonlaufen Nathalie , Ortega-Mora Luis M. , Torgerson Paul , Gottstein Bruno , Hemphill Andrew 
Published: October 2006

ABSTRACT

Echinococcus multilocularis
and
Echinococcus granulosus
metacestode infections in humans cause alveolar echinococcosis and cystic echinococcosis, respectively, in which metacestode development in visceral organs often results in particular organ failure. Further, cystic hydatidosis in farm animals causes severe economic losses. Although benzimidazole derivatives such as mebendazole and albendazole are being used as therapeutic agents, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of a number of isoflavones against
Echinococcus
metacestodes and protoscoleces. The most prominent isoflavone, genistein, exhibits significant metacestodicidal activity in vitro. However, genistein binds to the estrogen receptor and can thus induce estrogenic effects, which is a major concern during long-term chemotherapy. We have therefore investigated the activities of a number of synthetic genistein derivatives carrying a modified estrogen receptor binding site. One of these, Rm6423, induced dramatic breakdown of the structural integrity of the metacestode germinal layer of both species within 5 to 7 days of in vitro treatment. Further, examination of the culture medium revealed increased leakage of parasite proteins into the medium during treatment, but zymography demonstrated a decrease in the activity of metalloproteases. Moreover, two of the genistein derivatives, Rm6423 and Rm6426, induced considerable damage in
E. granulosus
protoscoleces, rendering them nonviable. These findings demonstrate that synthetic isoflavones exhibit distinct in vitro effects on
Echinococcus
metacestodes and protoscoleces, which could potentially be exploited further for the development of novel chemotherapeutical tools against larval-stage
Echinococcus
infection.
Natural Variation Can Significantly Alter the Sensitivity of Influenza A (H5N1) Viruses to Oseltamivir
Authors: Rameix-Welti M. A. , Agou F. , Buchy P. , Mardy S. , Aubin J. T. , Véron M. , van der Werf S. , Naffakh N. 
Published: October 2006

ABSTRACT

Geographic spread of highly pathogenic avian H5N1 influenza viruses may give rise to an influenza pandemic. During the first months of a pandemic, control measures would rely mainly on antiviral drugs, such as the neuraminidase (NA) inhibitors oseltamivir and zanamivir. In this study, we compare the sensitivities to oseltamivir of the NAs of several highly pathogenic H5N1 viruses isolated in Asia from 1997 to 2005. The corresponding 50% inhibitory concentrations were determined using a standard in vitro NA inhibition assay. The

K
m

for the substrate and the affinity for the inhibitor (

K
i

) of NA were determined for a 1997 and a 2005 virus, using an NA inhibition assay on cells transiently expressing the viral enzyme. Our data show that the sensitivities of the NAs of H5N1 viruses isolated in 2004 and 2005 to oseltamivir are about 10-fold higher than those of earlier H5N1 viruses or currently circulating H1N1 viruses. Three-dimensional modeling of the N1 protein predicted that Glu248Gly and Tyr252His changes could account for increased sensitivity. Our data indicate that genetic variation in the absence of any drug-selective pressure may result in significant variations in sensitivity to anti-NA drugs. Although the clinical relevance of a 10-fold increase in the sensitivity of NA to oseltamivir needs to be investigated further, the possibility that sensitivity to anti-NA drugs could increase (or possibly decrease) significantly, even in the absence of treatment, underscores the need for continuous evaluation of the impact of genetic drift on this parameter, especially for influenza viruses with pandemic potential.
DNA Methylase Activity as a Marker for the Presence of a Family of Phage-Like Elements Conferring Efflux-Mediated Macrolide Resistance in Streptococci
Authors: Figueiredo T. A. , Aguiar S. I. , Melo-Cristino J. , Ramirez M. 
Published: October 2006

ABSTRACT

Recently, two related chimeric genetic elements (Tn
1207.3
and Φ10394.4) were shown to carry the macrolide efflux gene
mef
in
Streptococcus pyogenes
(group A streptococci [GAS]). The dissemination of elements belonging to the Tn
1207.3
/Φ10394.4 family in recent isolates of GAS,
Streptococcus dysgalactiae
subsp.
equisimilis
,
Streptococcus pneumoniae
, and
Streptococcus agalactiae
recovered in Portugal was surveyed. In total, 149 GAS, 18
S. pneumoniae
, 4
S. dysgalactiae
subsp.
equisimilis
, and 5
S. agalactiae
isolates from infections, presenting the M phenotype of macrolide resistance and containing the
mef
gene, were screened for the presence of Tn
1207.3
/Φ10394.4 by PCR targeting open reading frames (ORFs) specific for these related elements. All the GAS isolates tested and one of the
S. dysgalactiae
subsp.
equisimilis
isolates carried Tn
1207.3.
However, neither of these elements was found in the isolates of the other streptococcal species. It was also noted that the DNAs of the isolates carrying Tn
1207.3
were resistant to cleavage by the endonuclease SmaI. Cloning and expression of ORF12 of Tn
1207.3
in
Escherichia coli
showed that it encoded a methyltransferase that rendered DNA refractory to cleavage by SmaI (M.Spy10394I). Using this characteristic as a marker for the presence of the Tn
1207.3
/Φ10394.4 family, we reviewed the literature and concluded that these genetic elements are widely distributed among tetracycline-susceptible GAS isolates presenting the M phenotype from diverse geographic origins and may have played an important role in the dissemination of macrolide resistance in this species.
MUC1 expression and anti-MUC1 serum immune response in head and neck squamous cell carcinoma (HNSCC): a multivariate analysis
Authors: Rabassa Martín E , Croce María V , Pereyra Adrián , Segal-Eiras Amada 
Published: October 2006

AbstractBackgroundHNSCC progression to adjacent tissue and nodes may be mediated by altered glycoproteins and glycolipids such as MUC1 mucin. This report constitutes a detailed statistical study about MUC1 expression and anti-MUC1 immune responses in relation to different clinical and pathological parameters which may be useful to develop new anti HNSCC therapeutic strategies.Patients and methodsFifty three pre treatment HNSCC patients were included: 26 (49.1%) bearing oral cavity tumors, 17 (32.1%) localized in the larynx and 10 (18.8%) in the pharynx. Three patients (5.7%) were at stage I, 5 (9.4%) stage II, 15 (28.3%) stage III and 30 (56.6%) at stage IV. MUC1 tumor expression was studied by immunohistochemistry employing two anti-MUC1 antibodies: CT33, anti cytoplasmic tail MUC1 polyclonal antibody (Ab) and C595 anti-peptidic core MUC1 monoclonal antibody. Serum levels of MUC1 and free anti-MUC1 antibodies were detected by ELISA and circulating immune complexes (CIC) by precipitation in polyethylene glycol (PEG) 3.5%; MUC1 isolation from circulating immune complexes was performed by protein A-sepharose CL-4B affinity chromatography followed by SDS-PAGE and Western blot. Statistical analysis consisted in Multivariate Principal Component Analysis (PCA); ANOVA test (Tukey's test) was employed to find differences among groups; nonparametrical correlations (Kendall's Tau) were applied when necessary. Statistical significance was set to p < 0.05 in all cases.ResultsMUC1 cytoplasmic tail was detected in 40/50 (80%) and MUC1 protein core in 9/50 (18%) samples while serum MUC1 levels were elevated in 8/53 (15%) patients. A significant statistical correlation was found between MUC1 serum levels and anti-MUC1 IgG free antibodies, while a negative correlation between MUC1 serum levels and anti-MUC1 IgM free antibodies was found. Circulating immune complexes were elevated in 16/53 (30%) samples and were also statistically associated with advanced tumor stage. MUC1 was identified as an antigenic component of IgG circulating immune complexes. Moreover, poorly differentiated tumors were inversely correlated with tumor and serum MUC1 detection and positively correlated with node involvement and tumor mass.ConclusionPossibly, tumor cells produce MUC1 mucin which is liberated to the circulation and captured by IgG antibodies forming MUC1-IgG-CIC. Another interesting conclusion is that poorly differentiated tumors are inversely correlated with tumor and serum MUC1 detection.
Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay)
Authors: Panchabhai Tanmay S , Noronha Shaun F , Davis Sanish , Shinde Vishal M , Kshirsagar Nilima A , Gogtay Nithya J 
Published: October 2006

Abstract

Background
Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population).

Methods
All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC.

Results
It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM).

Conclusion
A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy.
Preliminary data on Pemphigus vulgaris treatment by a proteomics-defined peptide: a case report
Authors: Angelini Giovanni , Bonamonte Domenico , Lucchese Alberta , Favia Gianfranco , Serpico Rosario , Mittelman Abraham , Simone Simone , Sinha Animesh A , Kanduc Darja 
Published: October 2006

Abstract

Background
Although described by Hippocrates in 400 B.C., pemphigus disease still needs a safe therapeutical approach, given that the currently used therapies (i.e. corticosteroids and immunosuppressive drugs) often provoke collateral effects. Here we present preliminary data on the possible use of a proteomics derived desmoglein peptide which appears promising in halting disease progression without adverse effects.

Methods
The low-similarity Dsg349–60REWVKFAKPCRE peptide was topically applied for 1 wk onto a lesion in a patient with a late-stage Pemphigus vulgaris (PV) complicated by diabetes and cataract disease. The peptide was applied as an adjuvant in combination with the standard corticosteroid-based immunosuppressive treatment.

Results
After 1 wk, the treated PV eroded lesion appeared dimensionally reduced and with an increased rate of re-epithelization when compared to adjacent non-treated lesions. Short-term benefits were: decrease of anti-Dsg antibody titer and reduction of the corticosteroid dosage. Long-term benefits: after two years following the unique 1-wk topical treatment, the decrease of anti-Dsg antibody titer persists. The patient is still at the low cortisone dosage. Adverse effects: no adverse effect could be monitored.

Conclusion
With the limits inherent to any preliminary study, this case report indicates that topical treatment with Dsg349–60REWVKFAKPCRE peptide may represent a feasible first step in the search for a simple, effective and safe treatment of PV.
Evidence of recombination in quasispecies populations of a Hepatitis C Virus patient undergoing anti-viral therapy
Authors: Moreno María P , Casane Didier , López Lilia , Cristina Juan 
Published: October 2006

Abstract

Background/Aim
Hepatitis C virus (HCV) has been the subject of intense research and clinical investigation as its major role in human disease has emerged. HCV circulates in vivo as a complex population of different but closely related viral variants, commonly referred to as a quasispecies. The extent to which recombination plays a role in the evolution of HCV quasispecies when patients are undergoing anti-viral therapy is currently unknown. In order to gain insight into these matters, we have performed a phylogenetic analysis of HCV quasispecies populations from six patients undergoing anti-viral therapy.

Methods
Putative recombinant sequences were identified with the use of SimPlot program. Recombination events were confirmed by bootscaning, using putative recombinant sequence as a query. Statistical support for the presence of a recombination event was done by the use of LARD program.

Results
A crossing-over event in the NS5A gene in a HCV strain recovered after four weeks of treatment was identified in quasispecies from a patient with sustained response. Putative parental-like strains were identified as strains circulating in previous weeks on the same patient.

Conclusion
Only one recombinant strain was detected in all patient quasispecies populations studied. The recombination break-point is situated on the PKR-binding region of NS5A. Although recombination may not appeared to be extensive in NS5A genes of HCV quasispecies populations of patients undergoing antiviral therapy, this possibility should be taken into account as a mechanism of genetic variation for HCV.
Mining the Arabidopsis thaliana genome for highly-divergent seven transmembrane receptors
Authors: Moriyama Etsuko N , Strope Pooja K , Opiyo Stephen O , Chen Zhongying , Jones Alan M 
Published: October 2006

AbstractTo identify divergent seven-transmembrane receptor (7TMR) candidates from the Arabidopsis thaliana genome, multiple protein classification methods were combined, including both alignment-based and alignment-free classifiers. This resolved problems in optimally training individual classifiers using limited and divergent samples, and increased stringency for candidate proteins. We identified 394 proteins as 7TMR candidates and highlighted 54 with corresponding expression patterns for further investigation.
Inhibition of c-Jun N-terminal kinase rescues influenza epitope-specific human cytolytic T lymphocytes from activation-induced cell death
Authors: Mehrotra Shikhar , Chhabra Arvind , Hegde Upendra , Chakraborty Nitya G , Mukherji Bijay 
Published: October 2006

AbstractCytolytic T lymphocytes (CTL) play an important role in defense against viral infections. Following clonal expansion and effector functions, a vast majority of the antigen-specific CTL undergoes programmed cell death to maintain homeostasis. We have shown earlier that melanoma epitope-specific CTL are quite sensitive to activation-induced cell death (AICD) even on the secondary encounter of the antigen. Excessive sensitivity of viral antigen-specific CTL to AICD, however, would be counterproductive. It might be argued that although CTL for a “self” epitope might be more prone to AICD for maintaining self-tolerance, viral antigen-specific CTL are likely to be less sensitive to AICD. We show here that influenza matrix protein-derived MP58–66 epitope-specific CTL, activated in vitro and bearing a memory phenotype, are just as sensitive to AICD. The AICD in these CTL is not blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone or by soluble Ig-Fc chimeras of the death receptors [Fas, TNF receptor (TNF-R), TRAIL-RI, TRAIL-RII]. However, the MP58–66-specific CTL can be rescued from AICD by the c-jun-N-terminal kinase (JNK) inhibitor SP600125. These results have implications for immunotherapeutic intervention in rescuing viral epitope-specific CTL from AICD.
The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis
Authors: Li Yankun , Tabas Ira 
Published: October 2006

AbstractTwo features of advanced atherosclerotic lesions are large numbers of macrophages and a heightened state of inflammation. Some of the macrophages appear to be enriched with free cholesterol (FCMφs), and we have shown that this process induces the synthesis and secretion of inflammatory cytokines, including TNF-α and IL-6. However, lesions contain many other macrophages that are not FC-enriched (non-FCMφs). Therefore, we sought to understand how the interaction of these two populations of macrophages would influence the inflammatory response. We show here that non-FCMφs possess a robust ability to deplete TNF-α and IL-6 secreted by FCMφs. The mechanism involves enhanced pinocytic uptake and lysosomal degradation of the FCMφ-secreted cytokines by the non-FCMφs. The FCMφs contribute directly to this process by secreting pinocytosis-stimulatory factors that act on non-FCMφs but not on the FCMφs themselves. One of these pinocytosis-stimulatory factors is M-CSF, which is induced by a process involving cholesterol trafficking to the endoplasmic reticulum and signaling through PI-3K and ERK MAPK pathways. However, one or more other FCMφ-secreted factors are also required for stimulating pinocytosis in non-FCMφs. Thus, FCMφs secrete inflammatory cytokines as well as factors that promote the eventual pinocytosis and degradation of these cytokines by neighboring macrophages. This process may normally serve to prevent prolonged or disseminated effects of inflammatory cytokines during inflammation. Moreover, possible perturbation of stimulated pinocytosis during the progression of advanced atherosclerosis may contribute to the heightened inflammatory state of these lesions.