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Biomedical subjects

S Freeman

Publications and source records attributed to S Freeman.

At least 91 records · Page 5Linked to original sources
PubMed1997

Characterization of a linear DNA plasmid from the filamentous fungal plant pathogen Glomerella musae [Anamorph: Colltotrichum musae (Berk. & Curt.) Arx.].

A 7.4-kilobase (kb) DNA plasmid was isolated from Glomerella musae isolate 927 and designated pGML1. Exonuclease treatments indicated that pGML1 was a linear plasmid with blocked 5' termini. Cell-fractionation experiments combined with sequence-specific PCR amplification revealed that pGML1 resided in mitochondria. The pGML1 plasmid hybridized to cesium chloride-fractionated nuclear DNA but not to A + T-rich mitochondrial DNA. An internal 7.0-kb section of pGML1 was cloned and did not hybridize with either nuclear or mitochondrial DNA from G. musae. Sequence analysis revealed identical terminal inverted repeats (TIR) of 520 bp at the ends of the cloned 7.0-kb section of pGML1. The occurrence of pGML1 did not correspond with the pathogenicity of G. musae on banana fruit. Four additional isolates of G. musae possessed extrachromosomal DNA fragments similar in size and sequence to pGML1.

Ascomycota↗
PubMed1997

Effect of cytokine modulation by thalidomide on the granulomatous response in murine tuberculosis.

SETTING: Experimental murine tuberculosis. OBJECTIVE: To evaluate the effect of cytokine modulation by thalidomide on the progression of the lung granulomatous response following aerosol tuberculosis infection in mice. DESIGN: Mice infected by the respiratory route with 200-500 viable Mycobacterium tuberculosis Erdman were treated with daily subcutaneous injections of thalidomide (30 mg/kg) or saline for 4 weeks. The bacillary load, granulomatous response and cytokine production in the lungs were evaluated. RESULTS: Aerosol M. tuberculosis infection resulted in a progressive granulomatous response in the lungs. At 28 days after infection, large granulomata with central necrosis and no apoptosis were observed. The infection induced high serum and lung cytokine mRNA levels. Thalidomide treatment resulted in a significant reduction in tumor necrosis factor-alpha, interleukin 6 (IL-6) and IL-10 protein levels (blood) and mRNA expression (lungs). IL-12 and interferon-gamma were unaffected. The lungs of thalidomide-treated mice had smaller granulomata with apoptotic cells and no necrosis. Thalidomide treatment did not change the bacillary load. CONCLUSION: Thalidomide immunomodulation reduces inflammatory cytokines and concomitant lung pathology following acute aerosol M. tuberculosis infection, without increasing the bacillary load.

Acute Disease↗
PubMed1997

Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.

Chromosomes, Human, Pair 21↗
PubMed1997

Severe allergy to sorbolene cream.

A 40-year-old male developed a constant hand and foot dermatitis in 1980 while using sorbolene cream as a barrier cream at work. He was forced to leave his trade as a motor mechanic because of his hand dermatitis. It was not until 16 years later that he was diagnosed as having an allergic contact dermatitis to chlorocresol secondary to an endogenous hand and foot dermatitis. Chlorocresol is the preservative used in sorbolene cream as well as many corticosteroid creams. Patch testing carried out in 1983 was negative but had omitted testing with chlorocresol or sorbolene cream.

Administration, Topical↗
PubMed1997

Allergic contact dermatitis to multiple sawdust allergens.

A 73-year-old man presented with an 8-year history of a dermatitis affecting his face, dorsum of hands, and forearms. He was a retired cabinet maker but still carried out some timber work at home. He was patch tested and found to be positive to colophony and saw-dust samples from four different timbers: Silky Oak, Queensland Hoop Pine, Radiata Pine and Australian red cedar.

Aged↗
PubMed1997

Allergic contact dermatitis to plants: an analysis of 68 patients tested at the Skin and Cancer Foundation.

Allergic contact dermatitis to plant allergens is a common problem in Australia. We present the cumulative experience of the Contact Dermatitis Clinic of the Skin and Cancer Foundation (Darlinghurst, NSW, Australia) a tertiary referral clinic. Results from a series of 68 patients with positive patch tests to 88 plant allergens are reported. We found that Grevillea species, Compositae, Rhus, Alstroemeria and various timber sawdusts were the most common plant allergens.

Allergens↗
PubMed1997

Allergic contact dermatitis to adhesive tape and contrived disease.

A case of allergic contact dermatitis, caused by colophony in an orthopaedic tape, is presented. This failed to heal, despite removal of the allergen. Only after a period of observation in hospital and, finally, gentle confrontation with the patient, did it become clear that the perpetuation of the dermatitis was an example of contrived disease.

Adult↗
PubMed1997

Caterpillar dermatitis.

A 3-year-old girl presented with recurrent urticarial eruptions presumed due to infestation of her garden with Euproctis edwardsi, Euproctis edwardsi, the mistletoe browntail moth is a variety of hairy caterpillar widely distributed in south-eastern Australia. They are often called 'woolly bears' by children. These caterpillars possess barbed hairs that fragment readily and are difficult to extract from the skin in one piece. Itching urticarial wheals and papular eruptions can follow contact with the caterpillars or their detached hairs. The hairlets may be identified by microscopy from skin scrapings and can be removed by tape stripping or with the aid of fine forceps. The skin lesions are treated symptomatically with calamine lotion, sodium bicarbonate solution and antihistamines. Infestation with Euproctis edwardsi can be minimized by removal of mistletoe from eucalyptus trees and by spraying affected areas with white oil or carbaryl 0.1%.

Animals↗
PubMed1997

Shoe dermatitis.

Chronic foot dermatitis can be disabling and footwear allergy is not always excluded as a cause, partly because patch testing to shoes and their components can be daunting. Once the diagnosis of shoe allergy is made, the difficult problem of finding suitable footwear remains. There is a lack of literature regarding the follow-up of these patients. We analysed the data on 55 patients with allergic contact dermatitis from their shoes and followed them up to see whether knowledge of the allergen had enabled them to find suitable footwear and to improve their dermatitis. The files of 55 patients with shoe allergy were analysed and 48 were followed up. Rubber was the commonest allergen, followed by chromate, p-tertiary-butylphenol-formaldehyde resin and colophony. All parts of the feet were affected, except the interdigital areas. The majority of patients suffered from hyperhidrosis. 43% were atopics, who had a super-added shoe allergy. The mean duration of the foot dermatitis before patch testing was 4 years 8 months. Follow-up of 48 cases showed that 87.5% had either improved or resolved completely. Most of our patients were successful in finding suitable footwear and many differing strategies were used. All patients with foot dermatitis which does not respond to treatment should be patch tested to exclude shoe allergy.

Adhesives↗
PubMed1997

Proposal for a revised international standard series of patch tests.

Worldwide, there are 3 major standard series of patch tests, the European, North American and Japanese, together presenting 32 allergens, the differences between them being the result of regional variation in allergen distribution as well as differences in dermatological opinion. We propose a "minimal" international standard series of 20 allergens, together with an "extended" international standard series of 14 allergens.

Dermatitis, Contact↗
PubMed1996

Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors.

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 microM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with the 3-[4-(pyrid-4-yl)phenyl] derivative 39 (IC50 = 161 nM) showing the best inhibition (following oral dosing) of cholesterol biosynthesis from mevalonate (ED50 = 2.7 mg/kg).

Animals↗
PubMed1996

Inhibition of squalene synthase of rat liver by novel 3' substituted quinuclidines.

Squalene synthase (SQS) is a key enzyme in the biosynthetic pathway for cholesterol and is a target for improved agents to lower plasma levels of low-density lipoprotein (LDL). A series of novel 3' substituted quinuclidines have been discovered as inhibitors of the rat liver microsomal enzyme. In this study, we demonstrate the inhibitory effects in vitro and in vivo, of two examples of the series. When microsomes were preincubated with compounds, before addition of substrate, both 3-(biphenyl-4-yl)quinuclidine (BPQ) and 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH) were found to cause biphasic inhibition of the enzyme with apparent inhibition constants (K'i) for the sensitive phases of 12 nM and 15 nM, respectively. The K'i values for the insensitive phases were 1.8 microM and 2.9 microM, respectively. The two examples inhibited equally both steps of the SQS-catalysed reaction, as shown by parallel inhibition of 3H+ release and labelled squalene formation from [1-3H]farnesyl pyrophosphate (FPP). BPQ and BPQ-OH were shown to be inhibitors of hepatic sterol synthesis from mevalonate with ED50 values of 10.6 and 7.1 mg/kg, respectively, after acute oral administration to the rat. BPQ-OH was chosen for further study and, to determine its selectivity of effect on the mevalonate pathway in vivo, the effect of a dose of 70 mg/kg on the pattern of labelled mevalonate incorporation into the various lipid fractions of the rat liver was examined. As expected, the incorporation into squalene and sterol products was inhibited by about 70%. An appearance of label in fractions corresponding to farnesyl and geranylgeranylpyrophosphates, as well as the corresponding alcohols, was observed in treated but not control animals. In addition, the administration of compound resulted in the appearance of peaks of mevalonate-derived radioactivity in an acidic fraction believed to represent metabolites of farnesol. Such results are consistent with inhibition of the mevalonate pathway at, and not before, SQS. In contrast, there was a significant increase in the incorporation of labelled mevalonate into ubiquinone 10, and the synthesis of dolichols was apparently unchanged. The results suggest a specific effect of BPQ-OH on rat liver SQS. The compound is, therefore, an interesting lead for further investigation of this class of compounds.

Animals↗
PubMed1996

Inhibition of squalene synthase in vitro by 3-(biphenyl-4-yl)-quinuclidine.

Squalene synthase (SQS) catalyses a step following the final branch in the pathway of cholesterol biosynthesis. Inhibition of this enzyme, therefore, is an approach for the treatment of atherosclerosis with the potential for low side effects. We have characterised the inhibition of rat liver microsomal SQS by 3-(biphenyl-4-yl)quinuclidine (BPQ). BPQ follows slow binding kinetics in that the rate of accumulation of product decreases with time if the inhibitor is added when the assay is started. Preincubation of BPQ and SQS leads to a biphasic dose-response where accumulation of product is linear with time only for the sensitive phase. When the farnesyl pyrophosphate (FPP) substrate is present at 19.6 microM, approximately 77% of the SQS activity is sensitive to the inhibitor (vOs) and the remainder is insensitive (vOi). The apparent inhibition constants (K'i values) are respectively K'is = 4.5 nM and K'ii = 1300 nM. Similar biphasic behaviour is exhibited by other inhibitors and in microsomes prepared from human and marmoset liver. As the concentration of FPP is reduced below 19.6 microM, there is a decrease in the relative contribution from vOi. Conversely, the value of K'is for BPQ remains constant when the FPP concentration is changed, showing noncompetitive kinetics with respect to this substrate. Possible causes of the observed kinetics are discussed. Inhibition by BPQ is said to follow tight binding kinetics because the value of K'is is similar to the concentration of inhibitor binding sites. Thus, to avoid an artefactual variation in potency when the enzyme concentration is varied, it is necessary to allow for the effects of depletion of free inhibitor. Furthermore, estimates of potency that average activity across the two phases are influenced by the relative contributions of each phase. These contributions differ according to the FPP concentration and the species used as the source of microsomes. Thus, it is necessary to separate the phases to compare measurements made in different experiments. Our observations indicate that careful experimental design and data analysis are required to characterise the kinetics of SQS inhibitors.

Animals↗
PubMed1996

Synthesis and iron binding studies of myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate, and iron binding studies of all myo-inositol tetrakisphosphates.

The first syntheses of the natural products myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate are described. The protected key intermediates 4,5,6-tri-O-benzoyl-myo-inositol and (+/-)-3,4,5,6-tetra-O-benzyl-myo-inositol were phosphorylated with dibenzyl N,N-di-isopropylphosphoramidite in the presence of 1H-tetrazole and subsequent oxidation of the phosphite. The crystal structures of the synthetic intermediates (+/-)-1-O-(tert-butyldiphenylsilyl)-2,3,O-cyclohexylidene-myo-inos itol and (+/-)-4,5,6-tri-O-benzoyl-1-O-(tert-butyldiphenylsilyl)-2,3-O-cycl ohexylidene- myo-inositol are reported. myo-Inositol 1,2,3-trisphosphate, (+/-)-myo-inositol 1,2-bisphosphate, and all isomeric myo-inositol tetrakisphosphates were evaluated for their ability to alter HO. production in the iron-catalysed Haber-Weiss reaction. The results demonstrated that a 1,2,3-grouping of phosphates in myo-inositol was necessary for inhibition, also that (+/-)-myo-inositol 1,2-bisphosphate potentiated HO. production. myo-Inositol 1,2,3-trisphosphate resembled myo-inositol hexakisphosphate (phytic acid) in its ability to act as a siderophore by promoting iron-uptake into Pseudomonas aeruginosa.

Binding Sites↗
PubMed1996

Acyclic nucleosides as antiviral compounds.

Acyclovir is an effective drug for the treatment of HSV and VZV infections, which after phosphorylation to the triphosphate, inhibits viral DNA polymerase. Acyclovir has low oral bioavailability, therefore prodrugs have been developed, and the L-valyl ester, valaciclovir, recently has been licensed for the treatment of shingles. Ganciclovir is used against CMV, and famciclovir, a lipophilic prodrug of penciclovir, is marketed for shingles. The acyclic nucleoside phosphonates are active against thymidine kinase-resistant viral strains. Promising analogs are PMEA (in clinical trial for the treatment of AIDS) and (S)-HPMPC (good in vivo activity against HSV, VZV, CMV, and EBV). Oligonucleotides incorporating acyclic nucleosides at the 3'-and 5'-ends, or constituted of amino acyclic nucleosides, are resistant to cleavage by nucleases and may be useful in antisense and/or antigene therapy. HEPT is active against HIV-1: It binds in a hydrophic pocket on reverse transcriptase, rather than in the polymerase active site. Some acyclic nucleosides are potent inhibitors of purine and pyrimidine nucleoside phosphorylase. These compounds may have a therapeutic niche in combination therapy with antiviral and anticancer nucleosides, and in the treatment of diseases involving the T-cell.

2-Aminopurine↗