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PubMed1993

Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations.

Pharmacologic studies of itraconazole (IZ), a triazole antifungal, indicated unexplained differences between bioassay and chromatographic determinations and large variations in steady-state blood concentrations. We show that concentrations of a hydroxylated metabolite, hydroxyitraconazole (HIZ), are approximately twofold higher than IZ over a range of concentrations. Though HIZ and IZ appear equipotent against selected pathogens, HIZ is two to three times more active against a commonly used bioassay fungus but minimally affects IZ activity. Hence, HIZ probably contributes importantly to the therapeutic activity attributed to IZ and contributes approximately four to six times the activity of IZ in bioassays, explaining discrepancies observed between assay methods.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Sequential actions of the two component peptides of the lantibiotic lacticin 3147 explain its antimicrobial activity at nanomolar concentrations.

Lacticin 3147 is a two-peptide (LtnA1 and LtnA2) lantibiotic produced by Lactococcus lactis subsp. lactis DPC3147 and has inhibitory activity against all gram-positive microorganisms tested. In this study the specific activities of the component peptides (alone or in combination) were determined by using L. lactis subsp. cremoris HP as the target strain. Lacticin 3147 exhibited an MIC50 of 7 nM for each component peptide (in combination), suggesting a peptide stoichiometry of 1:1. Interestingly, the LtnA1 peptide demonstrated independent inhibitory activity, with an MIC50 of 200 nM against L. lactis HP. In parallel studies, the single peptide bacteriocin nisin exhibited an MIC50 of 50 nM against the same target strain. Sequential peptide addition (with an intermediate washing step) demonstrated that LtnA1 must be added before LtnA2 rather than vice versa to observe inhibitory activity. The nanomolar activity of the lacticin peptides suggests the involvement of a docking molecule, speculated to be lipid II. Taken together with the recently determined structure of lacticin 3147 (N. I. Martin, T. Sprules, M. R. Carpenter, P. D. Cotter, C. Hill, R. P. Ross, and J. C. Vederas, Biochemistry, 43:3049-3056, 2004), these data support the hypothesis that the mode of action for lacticin 3147 involves a lipid II binding step (by the mersacidin-like LtnA1 peptide, which would explain its independent inhibitory activity), followed by insertion of the more linear LtnA2 peptide into the target membrane, resulting in pore formation and ultimate cell death.

Anti-Bacterial Agents↗

PubMed1985

Tatlockia micdadei (Pittsburgh pneumonia agent) growth kinetics may explain its infrequent isolation from water and the low prevalence of Pittsburgh pneumonia.

Sediment and indigenous microflora taken from water distribution systems has been shown to promote the survival of Legionella pneumophila. The effect of sediment and indigenous microflora on Tatlockia micdadei (Pittsburgh pneumonia agent, PPA) was evaluated by growth curve experiments. Symbiosis between PPA and environmental bacteria was demonstrated by satellitism experiments. Unlike L. pneumophila, the concentration of PPA remained stationary in test tube suspensions containing both microflora and sediment. The difference in the ecology between the two organisms may explain the infrequent environmental recovery of PPA and, ultimately, the epidemiologic differences between Legionnaires disease and Pittsburgh pneumonia.

Bacteria↗

PubMed1986

Gamma-interferon-induced inhibition of the growth of Rickettsia prowazekii in fibroblasts cannot be explained by the degradation of tryptophan or other amino acids.

We examined the role of amino acid deprivation in gamma-interferon-induced (IFN-gamma) suppression of the growth of Rickettsia prowazekii in mouse L929 cells and human fibroblasts by measuring the amino acid pools in untreated and IFN-gamma-treated cells. In recombinant IFN-gamma-treated cultures of human fibroblasts, tryptophan was undetectable in both the intracellular pool and the extracellular medium. In contrast, tryptophan was not depleted from the intracellular pool or the extracellular medium of L929 cells treated with recombinant IFN-gamma or crude mouse lymphokines. None of the other amino acids measured was severely depleted in IFN-gamma-treated L929 cells and human fibroblasts. Extracts prepared from IFN-gamma-treated human fibroblasts exhibited indoleamine 2,3-dioxygenase activity, converting tryptophan into products that cochromatographed with N-formylkynurenine and kynurenine; however, extracts prepared from untreated human fibroblasts, untreated L929 cells, recombinant IFN-gamma-treated L929 cells, and mouse lymphokine-treated L929 cells did not degrade tryptophan. Human HeLa cells resembled the human fibroblasts in that they degraded tryptophan after IFN-gamma treatment. Similarly, mouse 3T3-A31 cells and mouse embryo fibroblasts resembled mouse L929 cells in that they did not degrade tryptophan. Supplementation of the extracellular medium with additional tryptophan reconstituted the tryptophan pool in mock-infected and R. prowazekii-infected, X-irradiated, IFN-gamma-treated human fibroblasts to values greater than those observed in untreated control cultures. However, reconstitution of the tryptophan pool did not relieve IFN-gamma-induced inhibition of rickettsial growth. Addition of kynurenine or N-formylkynurenine to rickettsia-infected human fibroblasts at concentrations four times the usual tryptophan concentration did not inhibit growth of R. prowazekii. We conclude that neither tryptophan depletion nor depletion of the other amino acids studied explains the inhibitory effect of IFN-gamma on rickettsial growth in mouse L929 cells. In IFN-gamma-treated human fibroblasts, either tryptophan depletion is not involved in the inhibition of rickettsial growth or tryptophan depletion and some other mechanism(s) together contribute to the inhibition of rickettsial growth.

Amino Acids↗

PubMed2005

Fsr-independent production of protease(s) may explain the lack of attenuation of an Enterococcus faecalis fsr mutant versus a gelE-sprE mutant in induction of endocarditis.

An Enterococcus faecalis gelE insertion disruption mutant (TX5128), which produces neither gelatinase (GelE) nor the cotranscribed (in the wild type) serine protease (SprE), was found to be attenuated in a rat endocarditis model with a significant decrease in the endocarditis induction rate versus wild-type E. faecalis OG1RF (GelE(+), SprE(+)). TX5266, which has a nonpolar deletion in fsrB and, like TX5128, is phenotypically GelE(-) under usual conditions, was also studied; fsrB is a homologue of agrB of staphylococci and participates in regulation of gelE-sprE expression. Unexpectedly, TX5266 approximated wild-type OG1RF in the endocarditis model and was significantly less attenuated than TX5128. This is in contrast to other models which have found fsr mutants to be as or more attenuated than TX5128. Further study found that the fsrB mutant produced very low levels of gelatinase activity after prolonged incubation in vitro versus no gelatinase activity with TX5128 and did not show the extensive chaining characteristic of TX5128. Reverse transcription-PCR confirmed that gelE was expressed in TX5266 at a very low level versus wild-type OG1RF and was not expressed at all in TX5128. Possible explanations for the increased induction of endocarditis by TX5266 versus TX5128 include the production of low levels of protease(s) or some other effect(s) of the inactivation of the E. faecalis fsr regulator. The equivalent ability of OG1RF and its fsr mutant to initiate endocarditis may explain why we did not find naturally occurring fsr mutants, which account for ca. 35% of E. faecalis isolates, unrepresented in endocarditis versus fecal isolates.

Animals↗

PubMed2006

A variation of the translation attenuation model can explain the inducible regulation of the pBC16 tetracycline resistance gene in Bacillus subtilis.

Expression of the tet resistance gene from plasmid pBC16 is induced by the antibiotic tetracycline, and induction is independent of the native promoter for the gene. The nucleotide sequence at the 5' end of the tet mRNA (the leader region) is predicted to assume a complex secondary structure that sequesters the ribosome binding site for the tet gene. A spontaneous, constitutively expressed tet gene variant contains a mutation predicted to provide the tet gene with a nonsequestered ribosome binding site. Lastly, comparable levels of tet mRNA can be demonstrated in tetracycline-induced and uninduced cells. These results are consistent with the idea that the pBC16 tet gene is regulated by translation attenuation, a model originally proposed to explain the inducible regulation of the cat and erm genes in gram-positive bacteria. As with inducible cat and erm genes, the pBC16 tet gene is preceded by a translated leader open reading frame consisting of a consensus ribosome binding site and an ATG initiation codon, followed by 19 sense codons and a stop codon. Mutations that block translation of cat and erm leaders prevent gene expression. In contrast, we show that mutations that block translation of the tet leader result in constitutive expression. We provide evidence that translation of the tet leader peptide coding region blocks tet expression by preventing the formation of a secondary-structure complex that would, in the absence of leader translation, expose the tet ribosome binding site. Tetracycline is proposed to induce tet by blocking or slowing leader translation. The results indicate that tet regulation is a variation of the translation attenuation model.

Amino Acid Sequence↗

PubMed1989

Impaired expression of certain prereplicative bacteriophage T4 genes explains impaired T4 DNA synthesis in Escherichia coli rho (nusD) mutants.

The Escherichia coli rho 026 mutation that alters the transcription termination protein Rho prevents growth of wild-type bacteriophage T4. Among the consequences of this mutation are delayed and reduced T4 DNA replication. We show that these defects can be explained by defective synthesis of certain T4 replication-recombination proteins. Expression of T4 gene 41 (DNA helicase/primase) is drastically reduced, and expression of T4 genes 43 (DNA polymerase), 30 (DNA ligase), 46 (recombination nuclease), and probably 44 (DNA polymerase-associated ATPase) is reduced to a lesser extent. The compensating T4 mutation goF1 partially restores the synthesis of these proteins and, concomitantly, the synthesis of T4 DNA in the E. coli rho mutant. From analyzing DNA synthesis in wild-type and various multiply mutant T4 strains, we infer that defective or reduced synthesis of these proteins in rho 026-infected cells has several major effects on DNA replication. It impairs lagging-strand synthesis during the primary mode of DNA replication; it delays and depresses recombination-dependent (secondary mode) initiation; and it inhibits the use of tertiary origins. All three T4 genes whose expression is reduced in rho 026 cells and whose upstream sequences are known have a palindrome containing a CUUCGG sequence between the promoter(s) and ribosome-binding site. We speculate that these palindromes might be important for factor-dependent transcription termination-antitermination during normal T4 development. Our results are consistent with previous proposals that the altered Rho factor of rho 026 may cause excessive termination because the transcription complex does not interact normally with a T4 antiterminator encoded by the wild-type goF gene and that the T4 goF1 mutation restores this interaction.

Bacterial Proteins↗

PubMed1985

Protein stabilization explains the gag requirement for transformation of lymphoid cells by Abelson murine leukemia virus.

The single protein encoded by Abelson murine leukemia virus is a fusion of sequence from the retroviral gag genes with the v-abl sequence. Deletion of most of the gag region from the transforming protein results in a virus capable of transforming fibroblasts but no longer capable of transforming lymphoid cells. Smaller deletions in gag reveal that p15 gag sequences are responsible for this effect, whereas deletion of p12 sequences had no effect on lymphoid transformation. In transformed fibroblasts, p15-deleted and normal proteins had similar activities and subcellular localization. When the p15-deleted genome was introduced into previously transformed lymphoid lines, its protein product exhibited a marked instability. The tyrosine-specific autophosphorylation activity per cell was less than 1/20th that of the nondeleted protein. Although pulse-Ia-beling showed that the p15-deleted protein was synthesized efficiently, immunoblotting demonstrated that its steady-state level was less than 1/10th that of the nondeleted Abelson protein. The specific instability of the p15-deleted protein in lymphoid cells explains the requirement of these sequences for lymphoid but not fibroblast transformation.

Abelson murine leukemia virus↗

PubMed1997

Clinical data sets of human immunodeficiency virus type 1 reverse transcriptase-resistant mutants explained by a mathematical model.

Treatment of human immunodeficiency virus type 1 (HIV-1) infection during the clinical latency phase with drugs inhibiting reverse transcriptase (RT) reduces the HIV-1 RNA load and increases the CD4+ T-cell count. Typically, however, the virus evolves mutations in the RT gene that circumvent the drugs. We develop a mathematical model for this situation. The model distinguishes quiescent from activated CD4+ T cells, incorporates the fact that only activated cells can become productively infected by HIV-1, embodies empirical estimates for the drug resistance and the mutation frequency for each of the HIV-1 drug-resistant mutants, and assumes the antiviral immune response to remain constant over the course of the experiments. We analyze clinical data on the evolution of drug-resistant mutants for the RT inhibitors lamivudine and zidovudine. The results show that the evolutionary sequence of the drug-resistant mutants in both data sets is accounted for by our model, given that lamivudine is more effective than zidovudine. Thus, current empirical estimates of the mutation frequencies and the drug resistances of the mutants suffice for explaining the data. We derive a critical treatment level below which the wild-type HIV-1 RNA load can rebound before the first drug-resistant mutant appears. Our zidovudine data confirm this to be the case. Thus, we demonstrate in the model and the data that the rebound of the HIV-1 RNA load in the case of zidovudine is due to the outgrowth of wild-type virus and the first drug-resistant mutant, whereas that in the case of lamivudine can only be due to the drug-resistant mutants. The evolution of drug resistance proceeds slower in the case of zidovudine because (i) zidovudine is not as effective as lamivudine and (ii) the first zidovudine drug-resistant mutant is competing with the rebounding wild-type virus.

Drug Resistance, Microbial↗

PubMed2002

Resistance to infection by subgroups B, D, and E avian sarcoma and leukosis viruses is explained by a premature stop codon within a resistance allele of the tvb receptor gene.

Here we present the first molecular characterization of the defect associated with an avian sarcoma and leukosis virus (ASLV) receptor resistance allele, tvb(r). We show that resistance to infection by subgroups B, D, and E ASLV is explained by the presence of a single base pair mutation that distinguishes this allele from tvb(s1), an allele which encodes a receptor for all three viral subgroups. This mutation generates an in-frame stop codon that is predicted to lead to the production of a severely truncated protein.

Alleles↗

PubMed2002

Frequent reassortments may explain the genetic heterogeneity of rotaviruses: analysis of Finnish rotavirus strains.

The predominant rotavirus electropherotypes (e-types) during 17 epidemic seasons (1980 through 1997) in Finland were established, and representative virus isolates were studied by nucleotide sequencing and phylogenetic analysis. The virus isolates were either P[8]G1 or P[8]G4 types. The G1 and G4 strains formed one G1 lineage (VP7-G1-1) and one G4 lineage, respectively. Otherwise, they belonged to two P[8] lineages (VP4-P[8]-1 and -2) unrelated to their G types. Phylogenetic analysis of partial sequences of all 11 RNA segments obtained from the strains also revealed genetic diversity among gene segments other than those defining P and G types. With the exception of segments 1, 3, and 10, the sequences of the other segments could be assigned to 2 to 4 different genetic clusters. The results of this study suggest that, in addition to the RNA segments encoding VP4 and VP7, the other RNA segments may segregate independently as well. In total, the 9 predominant e-types represented 7 different RNA segment combinations when the phylogenetic clusters of their 11 genes were determined. The extensive genetic diversity and number of e-types among rotaviruses are best explained by frequent genetic reassortment.

Antigens, Viral↗

PubMed1994

Ubiquitous and tenacious methylation of the CpG site in codon 248 of the p53 gene may explain its frequent appearance as a mutational hot spot in human cancer.

Cytosine methylation at CpG dinucleotides is thought to cause more than one-third of all transition mutations responsible for human genetic diseases and cancer. We investigated the methylation status of the CpG dinucleotide at codon 248 in exon 7 of the p53 gene because this codon is a hot spot for inactivating mutations in the germ line and in most human somatic tissues examined. Codon 248 is contained within an HpaII site (CCGG), and the methylation status of this and flanking CpG sites was analyzed by using the methylation-sensitive enzymes CfoI (GCGC) and HpaII. Codon 248 and the CfoI and HpaII sites in the flanking introns were methylated in every tissue and cell line examined, indicating extensive methylation of this region in the p53 gene. Exhaustive treatment of an osteogenic sarcoma cell line, TE85, with the hypomethylating drug 5-aza-2'-deoxycytidine did not demethylate codon 248 or the CfoI sites in intron 6, although considerable global demethylation of the p53 gene was induced. Constructs containing either exon 7 alone or exon 7 and the flanking introns were transfected into TE85 cells to determine whether de novo methylation would occur. The presence of exon 7 alone caused some de novo methylation to occur at codon 248. More extensive de novo methylation of the CfoI sites in intron 6, which contains an Alu sequence, occurred in cells transfected with a vector containing exon 7 and flanking introns. With longer time in culture, there was increased methylation at the CfoI sites, and de novo methylation of codon 248 and its flanking HpaII sites was observed. These de novo-methylated sites were also resistant to 5-aza-2'-deoxycytidine-induced demethylation. The frequent methylation of codon 248 and adjacent Alu sequence may explain the enhanced mutability of this site as a result of the deamination of the 5-methylcytosine.

Base Sequence↗

PubMed2004

Pain and joint mobility explain individual subdimensions of the health assessment questionnaire (HAQ) disability index in patients with rheumatoid arthritis.

OBJECTIVE: To explore the associations between individual subdimensions of the health assessment questionnaire (HAQ) and clinical variables in patients with rheumatoid arthritis. METHODS: 304 patients with rheumatoid arthritis (73% female, mean (SD) age, 58 (13) years; disease duration 6 (9) years, 69% rheumatoid factor positive) completed the HAQ for functional capacity (0-3) and a 100 mm visual analogue scale for pain. Grip strength, range of motion of the large joints, Larsen score for radiographic damage of hand and foot joints, and the number of tender and swollen joints were recorded. A logit regression model was used to study associations between subdimensions of the HAQ and other variables. RESULTS: Mean (range) total HAQ score was 0.92 (0 to 2.88) and varied from 0.73 to 1.04 in the subdimensions. Disability was lowest in the "walking" and highest in the "reach" subdimension. Pain was an explanatory variable in all individual subdimensions. Decreased grip strength, limitation of shoulder and wrist motion, and a larger number of swollen and tender joints in the upper extremities were related to several subdimensions. A higher pain score and swollen joint count in the upper extremities, decreased grip strength, and limited motion of wrist, shoulder, and knee joints explained increased disability (higher total HAQ scores). CONCLUSIONS: In patients with rheumatoid arthritis, pain and range of movements of joints have the greatest impact on individual subdimensions of the HAQ. Extent of radiographic damage in peripheral joints and the number of swollen and tender joints are of lesser importance for function.

Activities of Daily Living↗

PubMed1994

Influence of previous exposure to human parvovirus B19 infection in explaining susceptibility to rheumatoid arthritis: an analysis of disease discordant twin pairs.

OBJECTIVES: To assess the association between exposure to parvovirus B19 and susceptibility to rheumatoid arthritis (RA). METHODS: One hundred and fifty five twin pairs (76 monozygotic (MZ) and 79 dizygotic (DZ)), discordant for RA, were tested for the presence of IgG antiparvovirus antibodies using ELISA. The data obtained were analysed using conditional logistic regression, from which odds ratios and 95% confidence intervals were calculated. RESULTS: Overall, there was no association between exposure to parvovirus and RA (OR = 1.2, 95% CI: 0.7-1.7). However, in two subgroups there was a suggestion of an association. These were: (1) pairs where the affected twin was rheumatoid factor (RF) seronegative (OR = 2.0, 95% CI: 0.9-12.4) and (2) in opposite-sexed twin pairs where the affected twin was female (OR = 3.0, 95% CI: 0.9-11.6). CONCLUSION: Previous exposure to parvovirus infection did not explain disease susceptibility in both MZ and DZ discordant pairs with rheumatoid arthritis. This infection, however, might be relevant in some subgroups.

Antibodies, Viral↗

PubMed1983

Inhaling and lung cancer: an anomaly explained.

An objective index of inhaling cigarette smoke based on carboxyhaemoglobin concentrations and the carbon monoxide yields of cigarettes was used to investigate possible systematic differences in the extent of inhaling among light and heavy smokers when classified according to their self described inhaling habits. A total of 2108 men who smoked cigarettes were studied. Heavy smokers (20 or more cigarettes a day) had a higher average inhaling index than light smokers (fewer than 20 cigarettes a day) both among those who said that they inhaled and among those who said that they did not. This observation, together with indirect evidence that heavy smokers who inhale deeply may to some extent avoid depositing smoke condensate on their main bronchial epithelium, explains a hitherto unresolved anomaly--namely, that the risk of lung cancer is less among heavy cigarette smokers who say that they inhale than it is among those who say that they do not inhale.

Adult↗

PubMed1993

Explaining variations in prescribing costs across England.

OBJECTIVE: To derive a predictive model for national prescribing behaviour in terms of basic morbidity and demographic factors. DESIGN: 24 demographic, morbidity, and practice factors were entered into a multiple regression analysis to determine the net ingredient cost per patient. SETTING: The 90 family health service authorities in England for 1989. RESULTS: For net ingredient cost per patient only two demographic factors (numbers of pensioners and the mobility of the registered population measured by list inflation) and two morbidity related factors (standardised mortality ratios and numbers of prepayment certificates issued) significantly contributed to a multiple regression model. This model explained 81% of the variation in net ingredient cost per registered patient between family health services authorities. The model also enabled a weighting factor of 4.6 (95% confidence interval 3.2 to 6.7) to be derived for the net ingredient cost for elderly patients (compared with the existing prescribing unit factor of 3). CONCLUSIONS: The model shows that variations in prescribing costs essentially reflect demand. It also suggests that the current prescribing unit value of 3 for patients aged 65 or more underestimates the extra costs of prescribing for elderly patients.

Drug Costs↗

PubMed1993

Unravelling gossamer with boxing gloves: problems in explaining the decline in smoking.

For about three decades countries such as Australia, Great Britain, and the United States have been turning up the heat on tobacco advertising. Encouraging, sometimes dramatic falls in consumption have followed. On any given day in 1993 smokers in such countries are exposed to a welter of news, information, persuasion, and policies designed to turn them off smoking. For a long time explanations and evaluations of the effects of these policies and interventions have been tied to oversimplified causal models when the reality is rather more messy and complicated. Four factors largely explain the reluctance of researchers to move beyond these models: the reductionist tradition of science; the explanatory privileging of recent events and factors; pragmatic concern for policy "tractable" factors; and the relation of funding to the evaluative process. Broader research approaches to understanding changes in complex behaviours such as smoking are required--for example, qualitative methods.

Australia↗

PubMed1999

Explaining differences in English hospital death rates using routinely collected data.

OBJECTIVES: To ascertain hospital inpatient mortality in England and to determine which factors best explain variation in standardised hospital death ratios. DESIGN: Weighted linear regression analysis of routinely collected data over four years, with hospital standardised mortality ratios as the dependent variable. SETTING: England. SUBJECTS: Eight million discharges from NHS hospitals when the primary diagnosis was one of the diagnoses accounting for 80% of inpatient deaths. MAIN OUTCOME MEASURES: Hospital standardised mortality ratios and predictors of variations in these ratios. RESULTS: The four year crude death rates varied across hospitals from 3.4% to 13.6% (average for England 8.5%), and standardised hospital mortality ratios ranged from 53 to 137 (average for England 100). The percentage of cases that were emergency admissions (60% of total hospital admissions) was the best predictor of this variation in mortality, with the ratio of hospital doctors to beds and general practitioners to head of population the next best predictors. When analyses were restricted to emergency admissions (which covered 93% of all patient deaths analysed) number of doctors per bed was the best predictor. CONCLUSION: Analysis of hospital episode statistics reveals wide variation in standardised hospital mortality ratios in England. The percentage of total admissions classified as emergencies is the most powerful predictor of variation in mortality. The ratios of doctors to head of population served, both in hospital and in general practice, seem to be critical determinants of standardised hospital death rates; the higher these ratios, the lower the death rates in both cases.

Data Collection↗