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1.  Oral progestin induces rapid, reversible suppression of ovarian activity in the cat 
The influence of oral progestin (altrenogest; ALT) on cat ovarian activity was studied using non-invasive fecal steroid monitoring. Queens were assigned to various ALT dosages: 1) 0 mg/kg (control; n = 5 cats); 2) 0.044 mg/kg (LOW; n = 5); 3) 0.088 mg/kg (MID; n = 6); or 4) 0.352 mg/kg (HIGH; n = 6). Fecal estrogen and progestagen concentrations were quantified using enzyme immunoassays for 60 days before, 38 days during and 60 days after ALT treatment. Initiation of follicular activity was suppressed in all cats during progestin treatment, whereas controls continued to cycle normally. Females (n = 6) with elevated fecal estrogens at treatment onset completed a normal follicular phase before returning to baseline and remained suppressed until treatment withdrawal. All cats receiving oral progestin reinitiated follicular activity after treatment, although MID cats experienced the most synchronized return (within 10-16 days). Mean baseline fecal estrogens and progestagens were higher (P < 0.05) after treatment in HIGH, but not LOW or MID cats compared to pre-treatment values. Results demonstrate that: 1) oral progestin rapidly suppresses initiation of follicular activity in the cat, but does not influence a follicular phase that exists before treatment initiation; and 2) queens return to normal follicular activity after progestin withdrawal. This study provides foundational information for research aimed at using progestin priming to improve ovarian response in felids scheduled for ovulation induction and assisted breeding.
doi:10.1016/j.ygcen.2009.12.016
PMCID: PMC2840999  PMID: 20051246
Cat; Progestin; Altrenogest; Ovarian suppression; Fecal hormone monitoring; Estrous cycle
2.  Genetic Diversity among Botulinum Neurotoxin-Producing Clostridial Strains▿  
Journal of Bacteriology  2006;189(3):818-832.
Clostridium botulinum is a taxonomic designation for many diverse anaerobic spore-forming rod-shaped bacteria that have the common property of producing botulinum neurotoxins (BoNTs). The BoNTs are exoneurotoxins that can cause severe paralysis and death in humans and other animal species. A collection of 174 C. botulinum strains was examined by amplified fragment length polymorphism (AFLP) analysis and by sequencing of the 16S rRNA gene and BoNT genes to examine the genetic diversity within this species. This collection contained representatives of each of the seven different serotypes of botulinum neurotoxins (BoNT/A to BoNT/G). Analysis of the16S rRNA gene sequences confirmed previous identifications of at least four distinct genomic backgrounds (groups I to IV), each of which has independently acquired one or more BoNT genes through horizontal gene transfer. AFLP analysis provided higher resolution and could be used to further subdivide the four groups into subgroups. Sequencing of the BoNT genes from multiple strains of serotypes A, B, and E confirmed significant sequence variation within each serotype. Four distinct lineages within each of the BoNT A and B serotypes and five distinct lineages of serotype E strains were identified. The nucleotide sequences of the seven toxin genes of the serotypes were compared and showed various degrees of interrelatedness and recombination, as was previously noted for the nontoxic nonhemagglutinin gene, which is linked to the BoNT gene. These analyses contribute to the understanding of the evolution and phylogeny within this species and assist in the development of improved diagnostics and therapeutics for the treatment of botulism.
doi:10.1128/JB.01180-06
PMCID: PMC1797315  PMID: 17114256
3.  Antitumour activity of XR5944 in vitro and in vivo in combination with 5-fluorouracil and irinotecan in colon cancer cell lines 
British Journal of Cancer  2005;92(4):722-728.
XR5944 (MLN944), a novel bis-phenazine, has demonstrated potent cytotoxic activity against a variety of murine and human tumour models. In the present study, the antitumour activity of XR5944 was investigated in combination with 5-fluorouracil (5-FU) or irinotecan in human colon carcinoma cell lines and xenografts. In vitro cytotoxicity of the combinations following exposure to the drugs sequentially or simultaneously was evaluated by the sulphorhodamine-B assay and interactions were determined using median-effect analysis. Antagonism was observed (CI>1) following exposure of HT29 cells simultaneously to XR5944 and 5-FU or SN38 (active metabolite of irinotecan). In contrast, sequential exposure of either combination in either order demonstrated at least an additive response (CI⩽1). At least an additive response was also observed with these combinations in HCT116 cells regardless of schedule. Antitumour activity in HT29 xenografts in nude mice was enhanced by sequential administration of 5-FU (65 mg kg−1) or irinotecan (CPT-11) (35 mg kg−1) 48 h before XR5944 (5, 10, or 15 mg kg−1) compared to single agent treatment at the same or higher doses. Administration of irinotecan (35 mg kg−1) and XR5944 (15 mg kg−1) just 30 min apart yielded similar efficacy to sequential administration 48 h apart. All combinations were well tolerated. These data suggest that combinations of XR5944 with irinotecan or 5-FU are of significant interest in the treatment of colon cancer.
doi:10.1038/sj.bjc.6602403
PMCID: PMC2361868  PMID: 15700035
XR5944; 5-fluorouracil; irinotecan; colon cancer; xenografts; combination therapy
4.  HCV infection should be managed in specialist centres 
Gut  2002;51(5):626-627.
PMCID: PMC1773446  PMID: 12377797
hepatitis C virus; hepatitis C virus infection; specialist centres
5.  Chronic hepatitis C virus infections: predictive value of genotype and level of viraemia on disease progression and response to interferon alpha. 
Gut  1995;36(3):427-432.
The effects of hepatitis C virus genotype and viraemia on disease outcome in patients with chronic hepatitis C virus infection were studied. Patients infected with genotype 1 tended to develop more severe disease, and to respond less well to interferon (IFN) treatment, but no pretreatment variable successfully predicted either the severity of the disease or the response to IFN. Failure to eliminate the virus during the first three months of therapy, however, predicted a failure to derive long term benefit from the current IFN regime. Hence pretreatment variables cannot be used to determine whether individual patients will respond to IFN, but observations during the first three months of therapy can be used to decide which patients will not respond to prolonged therapy. In these patients consideration should be given to changing the IFN dosing regime or using alternative treatments.
PMCID: PMC1382459  PMID: 7698703
6.  Predicting the extension of equivalence classes from primary generalization gradients: the merger of equivalence classes and perceptual classes. 
In Experiment 1, 6 college students were given generalization tests using 25 line lengths as samples with a long line, a short line, and a "neither" option as comparisons. The neither option was to be used if a sample did not go with the other comparisons. Then, four-member equivalence classes were formed. Class 1 included three nonsense words and the short line. Class 2 included three other nonsense words and the long line. After repeating the generalization test for line length, additional tests were conducted using members of the equivalence classes (i.e., nonsense words and lines) as comparisons and intermediate-length lines as samples. All Class 2 comparisons were selected in the presence of the test lines that also evoked the selection of the long line in the generalization test that had been given before equivalence class formation. Class 1 yielded complementary findings. Thus, the preclass primary generalization gradient predicted which test lines acted as members of each equivalence class. Regardless of using comparisons that were nonsense words or lines, the post-class-formation gradients overlapped, showing the substitutability of class members. Experiment 2 assessed the discriminability of the intermediate-length test lines from the Class 1 (shortest) and Class 2 (longest) lines. The test lines that functioned as members of an equivalence class were discriminable from the line that was a member of the same class by training. Thus, these test lines also acted as members of a dimensionally defined class of "long" or "short" lines. Extension of an equivalence class, then, involved its merger with a dimensionally defined class, which converted a close-ended class to an open-ended class. These data suggest a means of predicting class membership in naturally occurring categories.
doi:10.1901/jeab.1997.68-67
PMCID: PMC1284616  PMID: 9241863
7.  Isolation and Characterization of a Pseudomonas Strain Producing Glutaryl-7-Aminocephalosporanic Acid Acylase 
Applied and Environmental Microbiology  1993;59(10):3321-3326.
Several screening methods were developed for the selection of Pseudomonas strains capable of hydrolyzing glutaryl-7-aminocephalosporanic acid to 7-aminocephalosporanic acid. An isolate exhibiting high acylase activity, designated BL072, was identified as a strain of Pseudomonas diminuta. It grew optimally at pH 7 to 8 and at a temperature of 32 to 40°C, but acylase activity was highest when the strain was grown at 28°C. Mutants of BL072 were generated by nitrosoguanidine treatment and screened for increased production of glutaryl-7-aminocephalosporanic acid acylase. A superior mutant gave a fourfold increase in acylase titer. The cell-associated acylase had similar activities against various glutaryl-cephems but had undetectable activity against cephalosporin C. This acylase may prove useful for the conversion of cephalosporin C to 7-aminocephalosporanic acid.
PMCID: PMC182454  PMID: 16349067
8.  Clonal analysis of a bladder cancer cell line: an experimental model of tumour heterogeneity. 
British Journal of Cancer  1990;61(3):369-376.
The continuous cell line UCRU BL 17CL was derived from a human invasive bladder cancer and expresses elements of transitional, squamous and glandular differentiation. Nine clones of this line were established by limit dilution and have been extensively characterised. Only six of these clones grew subcutaneously in nude mice. Of these, three have exhibited local invasion, each in one of five implanted mice. Although all xenografts expressed transitional, squamous and glandular elements, different histological subtypes predominated within each clone. Only clones which grew in nude mice formed colonies in semi-solid medium, and each responded differently to the influence of medium that had been conditioned by the growth of UCRU BL 17CL, suggesting the possible secretion of a growth factor by these cells. The DNA content and lectin binding profiles of the clones also reflected the heterogeneity of the line. UCRU BL 17CL and the nine clones provide a unique model for the study of tumour heterogeneity, progression and differentiation, and the potential autocrine regulation of growth of bladder cancer.
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PMCID: PMC1971293  PMID: 2328200
9.  The management of chronic hepatitis C virus infection. 
Gut  1995;37(4):449-454.
PMCID: PMC1382891  PMID: 7489926
10.  Dose-response relationship in multistage carcinogenesis: promoters. 
Environmental Health Perspectives  1994;102(Suppl 1):255-264.
Published dose-response curves of promoters of multistage carcinogenesis were selected that met the combined criteria of long study times, multiple doses, and low doses. In rat liver, 12 dose-response studies of 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta-, and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected. These promoters were studied for 7-86 weeks and either altered hepatic foci or hepatic cancer were determined. The doses ranged from 1 ng (TCDD) to 400 mg (chloroform). In mouse skin, 10 dose-response studies of 4 promoters (12-O-tetradecanoylphorbol-13-acetate [TPA], anthralin, chrysarobin, and 2,6-di-tert-butyl-4-hydroperoxyl-2,5-cyclohexadienone [BHTOOH]) were selected. In these mouse skin studies the doses ranged from 0.425 nmole (TPA) to 20,000 nmole (BHTOOH) per mouse. The length of time promoters were applied to the skin varied between 15 and 60 weeks. Either skin papillomas or carcinomas were determined. The dose-response relationships are presented on the basis of moles of promoter, percentage of the fully effective promoting dose, or percentage of the acute oral rat LD50. The degree of concavity of the dose-response curves was determined. The available dose-response data are critiqued and discussed on the basis of future research needs for biologically based cancer risk assessment models.
PMCID: PMC1566890  PMID: 8187717
11.  SKN7, a yeast multicopy suppressor of a mutation affecting cell wall beta-glucan assembly, encodes a product with domains homologous to prokaryotic two-component regulators and to heat shock transcription factors. 
Journal of Bacteriology  1993;175(21):6908-6915.
A search for genes which, at elevated copy number, could suppress the growth defect in a strain disrupted at the KRE9 locus has identified the SKN7 gene. SKN7 was mapped to the right arm of chromosome VIII and is predicted to encode a 70-kDa protein, Skn7p, with a region of homology to the DNA binding domain of the Saccharomyces cerevisiae heat shock transcription factor, Hsf1p. Skn7p also has a domain which shows similarity to the prokaryotic receiver modules found on an extensive family of two-component response regulators, including the products of the rcsC and barA genes. SKN7 did not suppress other mutations in the (1-->6)-beta-glucan biosynthetic pathway, suggesting that SKN7 does not act as a general bypass suppressor of this glucan.
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PMCID: PMC206816  PMID: 8226633
12.  The yeast KRE9 gene encodes an O glycoprotein involved in cell surface beta-glucan assembly. 
Molecular and Cellular Biology  1993;13(10):6346-6356.
The yeast KRE9 gene encodes a 30-kDa secretory pathway protein involved in the synthesis of cell wall (1-->6)-beta-glucan. Disruption of KRE9 leads to serious growth impairment and an altered cell wall containing less than 20% of the wild-type amount of (1-->6)-beta-glucan. Analysis of the glucan material remaining in a kre9 delta null mutant indicated a polymer with a reduced average molecular mass. kre9 delta null mutants also displayed several additional cell-wall-related phenotypes, including an aberrant multiply budded morphology, a mating defect, and a failure to form projections in the presence of alpha-factor. Double mutants were generated by crossing kre9 delta strains with strains harboring a null mutation in the KRE1, KRE6, or KRE11 gene, and each of these double mutants was found to be inviable in the SEY6210 background. Similar crosses with null mutations in the KRE5 and SKN1 genes indicated that these double mutants were no more severely affected than kre5 delta or kre9 delta single mutants alone. Antibodies were generated against Kre9p and detected an O glycoprotein of approximately 55 to 60 kDa found in the extracellular medium of a strain overproducing Kre9p.
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PMCID: PMC364693  PMID: 8413233
13.  Effects of delayed reinforcement on infant vocalization rate. 
Three previous studies have failed to demonstrate conditioning in infants using a 3-s delay of reinforcement. The effects of a delayed reinforcement schedule on vocalization rates therefore were explored in a single-subject repeated-reversal experimental design for 3 4- to 6-month-old normally developing infants. Each infant received delayed social reinforcement from his or her parent for vocalizing. The comparison condition was a schedule of differential reinforcement of behavior other than vocalizations to control for elicitation by social stimulation. An operant level of infant vocalizations was the initial condition, after which the differential reinforcement schedule was implemented in an across-subjects multiple baseline design. Infants' vocalization rates increased above levels measured during differential reinforcement following onset of the delayed reinforcement condition. Also, vocalization rates decreased during differential reinforcement compared to operant levels. The successful use of delayed reinforcement schedules with infants in this study, as opposed to others, is discussed in terms of procedural differences among them.
doi:10.1901/jeab.1992.58-1
PMCID: PMC1322109  PMID: 1645095
14.  Molecular basis for defective secretion of the Z variant of human alpha-1-proteinase inhibitor: secretion of variants having altered potential for salt bridge formation between amino acids 290 and 342. 
Molecular and Cellular Biology  1989;9(4):1406-1414.
Human alpha-1-proteinase inhibitor (A1PI) deficiency, associated with the Z-variant A1PI (A1PI/Z) gene, results from defective secretion of the inhibitor from the liver. The A1PI/Z gene exhibits two point mutations which specify amino acid substitutions, Val-213 to Ala and Glu-342 to Lys. The functional importance of these substitutions in A1PI deficiency was investigated by studying the secretion of A1PI synthesized in COS cells transfected with A1PI genes altered by site-directed mutagenesis. This model system correctly duplicates the secretion defect seen in individuals homozygous for the A1PI/Z allele and shows that the substitution of Lys for Glu-342 alone causes defective secretion of A1PI. The substitution of Lys for Glu-342 eliminates the possibility for a salt bridge between residues 342 and 290, which may decrease the conformational stability of the molecule and thus account for the secretion defect. However, when we removed the potential to form a salt bridge from the wild-type inhibitor by changing Lys-290 to Glu (A1PI/SB-290Glu), secretion was not reduced to the 19% of normal level seen for A1PI/Z-342Lys; in fact, 75% of normal secretion was observed. When the potential for salt bridge formation was returned to A1PI/Z-342Lys by changing Lys-290 to Glu, only 46% of normal secretion was seen. These data indicate that the amino acid substitution at position 342, rather than the potential to form the 290-342 salt bridge, is the critical alteration leading to the defect in A1PI secretion.
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PMCID: PMC362557  PMID: 2786139
15.  Improved DNA hybridization method for detection of acyclovir-resistant herpes simplex virus. 
Antimicrobial Agents and Chemotherapy  1987;31(10):1465-1469.
A simplified DNA hybridization method was developed to detect acyclovir-resistant isolates of herpes simplex virus. Herpes simplex virus-infected cell cultures in microtiter plates were treated with concentrations of acyclovir ranging from 8 to 0.015 micrograms/ml. At 48 h postinfection, infected cells were lysed by a one-step procedure and lysates were absorbed to membranes. Without further treatment, membranes were hybridized by using a herpes simplex virus-specific radioiodinated probe. The membranes were then washed and counted in a gamma counter. The elapsed time for assay performance was 4 h. Parallel plaque reduction assays were performed for comparison. The mean 50% inhibitory dose of in vivo- and in vitro-derived acyclovir-resistant, thymidine kinase-negative isolates was greater than 2 micrograms/ml by DNA hybridization. The 50% inhibitory dose of acyclovir-susceptible, thymidine kinase-positive isolates ranged from 0.01 to 1.1 micrograms/ml. This assay is simple and objective and should facilitate antiviral susceptibility testing in diagnostic laboratories.
PMCID: PMC174972  PMID: 2829708
16.  Respiratory infectivity of a recently isolated Egyptian strain of Rift Valley fever virus. 
Infection and Immunity  1981;33(3):848-853.
The respiratory infectivity of a strain of Rift Valley fever virus isolated in Egypt (strain ZH-501) was compared with that of one isolate from Uganda (Entebbe strain) and two isolates from South Africa (strains SA-51 and SA-75). Studies were performed with ICR mice which were infected by exposure to infectious aerosols composed of particles with a mass median diameter of 0.96 micrometer. The respiratory median lethal doses for ZH-501, Entebbe, SA-51, and SA-75 were 2.2, 1.9, 2.6, and 1.9 log10 plaque-forming units, respectively. Although these values are statistically different, the biological implications of such differences seem unimportant. In an additional study of pathogenesis, a single group of mice was infected with 3.1 log10 plaque-forming units of ZH-501, and tissues were assayed sequentially through 96 h postinfection. Between 6 and 30 h, demonstration of an increasing virus concentration only in the lungs indicated that initial replication occurred there; however, determination of histopathological changes did not reveal evidence of pneumonia. Virus was isolated from the liver by 48 h, and the ultimate outcome of infection was a fulminating and fatal hepatic necrosis.
PMCID: PMC350789  PMID: 7287187
17.  Microbial growth on hydrocarbons: terminal branching inhibits biodegradation. 
A variety of octane-utilizing bacteria and fungi were screened for growth on some terminally branched dimethyloctane derivatives to explore the effects of iso- and anteiso-termini on the biodegradability of such hydrocarbons. Of 27 microbial strains tested, only 9 were found to use any of the branched hydrocarbons tested as a sole carbon source, and then only those hydrocarbons containing at least one iso-terminus were susceptible to degradation. Anteiso-or isopropenyl termini prevented biodegradation. None of the hydrocarbonoclastic yeasts tested was able to utilize branched-hydrocarbon growth sustrates. In the case of pseudomonads containing the OCT plasmid, whole-cell oxidation of n-octane was poorly induced by terminally branched dimethyloctanes. In the presence of a gratuitous inducer of the octane-oxidizing enzymes, the iso-branched 2,7-dimethyloctane was slowly oxidized by whole cells, whereas the anteiso-branched 3,6-dimethyloctane was not oxidized at all. This microbial sampling dramatically illustrated the deleterious effect of alkyl branching, especially anteiso-terminal branching, on the biodegradation of hydrocarbons.
PMCID: PMC243570  PMID: 539824
18.  Enzyme recruitment allows the biodegradation of recalcitrant branched hydrocarbons by Pseudomonas citronellolis. 
Experiments were carried out to construct pseudomonad strains capable of the biodegradation of certain recalcitrant branched hydrocarbons via a combination of alkane and citronellol degradative pathways. To promote the metabolism of the recalcitrant hydrocarbon 2,6-dimethyl-2-octene we transferred the OCT plasmid to Pseudomonas citronellolis, a pseudomonad containing the citronellol pathway. This extended the n-alkane substrate range of the organism, but did not permit utilization of the branched hydrocarbon even in the presence of a gratuitous inducer of the OCT plasmid. In a separate approach n-decane-utilizing (Dec+) mutants of P. citronellolis were selected and found to be constitutive for the expression of medium- to long-chain alkane oxidation. The Dec+ mutants were capable of degradation of 2,6-dimethyl-2-octene via the citronellol pathway as shown by (i) conversion of the hydrocarbon to citronellol, determined by gas-liquid chromatography-mass spectrometry, (ii) induction of geranyl-coenzyme A carboxylase, a key enzyme of the citronellol pathway, and (iii) demonstration of beta-decarboxymethylation of the hydrocarbon by whole cells. The Dec+ mutants had also acquired the capacity to metabolize other recalcitrant branched hydrocarbons such as 3,6-dimethyloctane and 2,6-dimethyldecane. These studies demonstrate how enzyme recruitment can provide a pathway for the biodegradation of otherwise recalcitrant branched hydrocarbons.
PMCID: PMC243565  PMID: 539823
20.  Wasted Medical Potential 
British Medical Journal  1964;2(5419):1269.
PMCID: PMC1817194
21.  Our War Chest 
British Medical Journal  1946;1(4447):503.
PMCID: PMC2058607
22.  Bitterness 
British Medical Journal  1945;2(4422):477.
PMCID: PMC2060498

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