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Biomedical subjects

H Young

Publications and source records attributed to H Young.

At least 19 recordsLinked to original sources
PubMed2000

Genomic organization and expression of the mouse equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporter 1 (ENT1) gene.

We have cloned and characterized the genomic structure of the mouse gene for the NBMPR-sensitive equilibrative nucleoside transporter (mENT1), which is located on chromosome 17C. About 12-kb of genomic DNA was sequenced including the promoter region, 12 exons, 11 introns, and the 3'-untranslated region. All exon-intron junction sequences conform to the GT/AG rule. Primer extension analysis demonstrated a transcription initiation site located 252 bp upstream of the translation start site. Analysis of the 2.5-kb 5'-flanking sequence shows putative binding sites for several transcription factors, including GATA-1, IRF-2, Pit-1, myogenin, CREB, Sp-1, Ap-2, MAZ, and GR. We demonstrated that mouse ENT1 mRNA was highly expressed in heart, spleen, lung, liver, and testis. Lower levels of expression were detected in brain and kidney. Functional analysis of the 5'-flanking region showed that the nucleotide sequence from -652 to -111 contains cis-regulatory elements that promote gene expression. We found two Sp-1 binding sites (-296/-303, -307/-313) and two MAZ binding sites (-353/-359, -522/-528) in this region. Luciferase assay results suggest that MAZ and Sp-1 transcription factors are important positive regulators of transcription for the ENT1 gene in NG108-15 cells.

3' Untranslated Regions↗
PubMed2000

The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and -1 beta in macrophages.

We previously found that the tryptophan catabolite picolinic acid (PA) is a costimulus for the activation of macrophage effector functions. In this study, we have investigated the ability of PA to modulate the expression of chemokines in macrophages. We demonstrate that PA is a potent activator of the inflammatory chemokines MIP (macrophage inflammatory protein)-1 alpha and MIP-1 beta (MIPs) mRNA expression in mouse macrophages in a dose- and time-dependent fashion and through a de novo protein synthesis-dependent process. The induction by PA occurred within 3 h of treatment and reached a peak in 12 h. The stimulatory effects of PA were selective for MIPs because other chemokines, including monocyte chemoattractant protein-1, RANTES, IFN-gamma-inducible protein-10, MIP-2, and macrophage-derived chemokine, were not induced under the same experimental conditions and were not an epiphenomenon of macrophage activation because IFN-gamma did not affect MIPs expression. Induction of both MIP-1 alpha and MIP-1 beta by PA was associated with transcriptional activation and mRNA stabilization, suggesting a dual molecular mechanism of control. Iron chelation could be involved in MIPs induction by PA because iron sulfate inhibited the process and the iron-chelating agent, desferrioxamine, induced MIPs expression. We propose the existence of a new pathway leading to inflammation initiated by tryptophan catabolism that can communicate with the immune system through the production of PA, followed by secretion of chemokines by macrophages. These results establish the importance of PA as an activator of macrophage proinflammatory functions, providing the first evidence that this molecule can be biologically active without the need for a costimulatory agent.

Adjuvants, Immunologic↗
PubMed2000

Connexin-independent ganciclovir-mediated killing conferred on bystander effect-resistant cell lines by a herpes simplex virus-thymidine kinase-expressing colon cell line.

A novel gap junction-independent mechanism for ganciclovir-mediated bystander effect killing by a herpes simplex virus thymidine kinase (HSV-TK)-expressing SW620 human colon tumor cell line has been characterized. The mechanism of the HSV-TK/GCV bystander effect for many tumor cell lines has been demonstrated to be due to connexin gap junction transfer of phosphorylated ganciclovir (GCV) metabolites; however, there may be as yet uncharacterized connexin-independent mechanisms for the effect. To address this, the bystander effect was further evaluated in a panel of cell lines mixed with homologous HSV-TK-expressing cell lines, a SW620.TK cell line, or a high connexin43-expressing PA-317.TK cell line. Of the 10 cell lines tested, 4 were found to be resistant to bystander effect killing by their homologous HSV-TK-expressing cell lines and the PA-317.TK cells, but all of the cell lines were sensitive to GCV killing when mixed with the SW620.TK cells. The SW620.TK cells were then further evaluated for any indication of extracellular GCV metabolite efflux. Culture medium from SW620.TK cells labeled with [(3)H]GCV was evaluated for the presence of GCV nucleotides by ion-exchange column separation and HPLC analysis. The presence of GCV mono-, di-, and triphosphate metabolites in the medium was detected. Inclusion in the medium of inhibitors of extracellular phosphatases and ecto-ATPases increased the proportion of GCV metabolites recovered. These results indicate that phosphorylated GCV metabolites can be effluxed from SW620.TK cells and that some type of cellular uptake mechanism independent of gap junctions exists for nucleotide entry into neighboring cells.

Cell Count↗
PubMed2000

Clinical presentation of mucin-secreting tumors of the pancreas.

BACKGROUND: Pancreatitis and jaundice secondary to ductal obstruction are common in intraductal papillary mucinous tumors (IPMT) of the pancreas. However, the incidence and severity of the complications of obstruction are not well documented. The aim of the study was to investigate the clinical presentation and outcome of 10 patients with IPMT. METHODS: All cases of IPMT diagnosed between 1994 and 1999 were reviewed. RESULTS: Four of the 10 patients developed severe acute illness with systemic complications resulting from ductal obstruction. Three suffered acute cholangitis with sepsis, and 1 developed necrotizing pancreatitis and ARDS. There was 1 postoperative death in a patient with adenocarcinoma. All other patients are alive and well with a median follow-up of 26 months (survival 90%). CONCLUSIONS: Pancreatic or common bile duct obstruction in IPMT may result in acute, life-threatening disease. Aggressive surgical therapy is warranted before development of complications of ductal obstruction or progression of tumor occurs.

Acute Disease↗
PubMed2000

Adenocarcinoma of the rectum with associated colorectal adenomatous polyps in tuberous sclerosis: a case report.

The authors present the case of a 17-year-old girl with tuberous sclerosis (TS) who presented with symptoms of intussusception. Although endoscopically diagnosed with multiple colonic polyps, presumed to be hamartomas, and an invasive rectal adenocarcinoma, postoperative pathology findings confirmed the rectal cancer and showed multiple colonic adenomas. Multiple colonic adenomatous polyps in a young girl with tuberous sclerosis is extremely rare. Furthermore, we believe that this is the first report of an invasive adenocarcinoma of the large intestine occurring in a patient with TS.

Adenocarcinoma↗
PubMed2000

Early evaluation of tumour metabolic response using [18F]fluorodeoxyglucose and positron emission tomography: a pilot study following the phase II chemotherapy schedule for temozolomide in recurrent high-grade gliomas.

Quantitation of metabolic changes in tumours may provide an objective measure of clinical and subclinical response to anticancer therapy. This pilot study assesses the value of quantitation of metabolic rate of glucose (MRGlu) measured in mmol min(-1) ml(-1) to assess early subclinical response to therapy in a relatively non-responsive tumour. Nine patients receiving the CRC Phase II study schedule of temozolomide were assessed with [18F]fluorodeoxyglucose ([18F]FDG) dynamic positron emission tomography (PET) scans prior to and 14 days after treatment with temozolomide given as 750-1000 mg m(-2) over 5 days every 28 days. Tumour MRGlu was calculated and compared with objective response at 8 weeks. Pretreatment MRGlu was higher in responders than non-responders. The responding patient group had a greater than 25% reduction in MRGlu in regions of high focal tumour uptake (HFU). Whole tumour changes in MRGlu did not correlate with response. Percentage change in HFU standardized uptake value (SUV) did discriminate the responding from the non-responding patients, but not as well as with MRGlu. Large differences also occurred in the normal brain SUV following treatment. Thus, MRGlu appeared to be a more sensitive discriminator of response than the simplified static SUV analysis. Changes in MRGlu may reflect the degree of cell kill following chemotherapy and so may provide an objective, quantitative subclinical measure of response to therapy.

Adult↗
PubMed2000

Isolation and characterization of glycopeptide-resistant enterococci from hospitalized patients over a 30-month period.

In February 1996, a Hospital Infection Control Practices Advisory Committee-style screening program was commenced to isolate and subsequently characterize glycopeptide-resistant enterococci (GRE) from patients at a hospital trust in Glasgow, Scotland. Over the next 30 months, GRE were isolated from 154 patients. GRE were isolated from patients in traditionally high-risk areas such as the renal unit and intensive care unit and also in areas considered to be lower risk, including medical wards and associated long-stay geriatric hospitals. The majority (90%) of isolates were Enterococcus faecium vanB. The remaining isolates consisted of seven E. faecalis (vanA), three E. gallinarum (vanC), and a further six E. faecium (five vanA, one both vanA and vanB) isolates. Analysis of SmaI-digested DNA by pulsed-field gel electrophoresis revealed that 34 of 40 (85%) VanB E. faecium isolates were identical or closely related, while 11 of 13 (85%) VanA GRE were distinct. High-level aminoglycoside resistance was seen in less than 8% of isolates. VanB E. faecium isolates were almost uniformly resistant to ampicillin and tetracycline. In this study, GRE have been isolated over a prolonged period from a broad range of patients. Glycopeptide resistance within the study hospital trust appeared to be mainly due to the clonal dissemination of a single strain of E. faecium VanB.

Aminoglycosides↗
PubMed2000

Rectal gonorrhoea in homosexual men: source of infection.

The objective of this retrospective study was to determine the possible source of infection in homosexual men with rectal gonorrhoea: the probable source of rectal gonorrhoea was identified in 46/155 cases. Although the urethra was the site of infection in 33 (72%) of these contacts, only pharyngeal gonorrhoea was identified in 9 (20%) men. In 25/26 cases, there was concordance in the auxo/serotypes of Neisseria gonorrhoeae between contacts with urethral gonorrhoea and the index men with rectal gonorrhoea. Eleven out of 12 pharyngeal isolates were of the same auxo/serotype as the index cases. This study supports the hypothesis that rectal gonorrhoea in homosexual men can be acquired from the oropharynx. Because infection at this site is an independent risk factor for acquisition of HIV, screening for rectal and pharyngeal gonorrhoea should be offered to men who have sex with men, even when there is no history of unprotected receptive anal intercourse.

Adolescent↗
PubMed2000

Enzywell recombinant enzyme immunoassay for the serological diagnosis of syphilis.

The aim of this study was to evaluate Enzywell TP, a new rapid enzyme immunoassay (EIA) that uses 2 recombinant Treponema pallidum antigens for the serological diagnosis of syphilis. Specificity was evaluated by screening 1055 unselected bloods requesting serological tests for syphilis in parallel with Enzywell TP and the Syphilis ICE EIA which is our standard screening test for syphilis. Sensitivity was evaluated using a panel of 159 known treponemal sera representing various stages of syphilis and 5 treponemal sera detected on screening. The specificity of Enzywell TP on initial and repeat testing (99.6% and 99.7% respectively) was similar to that of the Syphilis ICE test (99.8% and 99.9% respectively). The sensitivity of Enzywell TP (100%) was similar to that of Syphilis ICE (99.4%): both tests were significantly more sensitive (P=0.01) than the fluorescent antibody absorbed test (94.5%) but not the T. pallidum particle agglutination (TPPA) assay (99.4%). Both Enzywell TP and Syphilis ICE were positive with sera from 16 known HIV-infected patients who had been treated for syphilis many years previously (mean 9.4 years) confirming the value of these tests in excluding previous syphilis in HIV-infected individuals. We conclude that the Enzywell recombinant EIA is simple, rapid, highly sensitive and specific, and is a welcome addition to the range of currently available diagnostic tests for syphilis.

Antibodies, Bacterial↗
PubMed2000

1,25-dihydroxyvitamin D3 synthetic analogs inhibit spontaneous metastases in a 1,2-dimethylhydrazine-induced colon carcinogenesis model.

In order to substantiate the role of vitamin D applicability for the prevention of colon cancer and its spontaneous metastases, the effect of 1,25-dihydroxyvitamin D3 and its synthetic analogs, 1, 25-dihydroxy-16,23Z-diene-26,27-hexafluoro-D3 (Ro 25-5317) and 1, 25-dihydroxy-16,23E-diene-26,27-hexafluoro-19-nor-D3 (Ro 25-9022), have been evaluated in a 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis model in Sprague-Dawley rats. In animals maintained on 2.75 nmol/kg 1,25-dihydroxyvitamin D3 diet no statistical difference was seen in tumor incidence when compared with control while in animals on 3.0 nmol/kg 1,25-dihydroxyvitamin D3 diet, the incidence of tumors was significantly lower. In animals maintained on 3.0 nmol/kg Ro 25-5317 diet also no statistical difference was seen in tumor incidence compared with control while in animals on 3. 5 nmol/kg Ro 25-5317 diet the incidence of tumors was significantly lower. The incidence of tumors in the group of animals maintained on 3.0 nmol/kg and 3.5 nmol/kg Ro 25-9022 was significantly lower, at 32.1% and 27.6% respectively, compared to control. In the two groups of animals maintained on the 1,25-dihydroxyvitamin D3 diet no significant difference in the incidence of metastasis was seen. In the group of animals maintained on 3.0 nmol/kg Ro 25-5317 diet only regional metastases were seen. However, no metastases developed in the rats on 3.5 nmol/kg Ro 25-5317 diet. After administration of 3.0 nmol/kg Ro 25-9022 diet, metastases developed in a significantly less number of animals while no metastases occurred in the rats maintained on the 3.5 nmol/kg Ro 25-9022 diet. The above studies will provide a scientific basis for the progression into further clinical trials in the treatment, and/or chemoprevention of human colorectal cancer.

1,2-Dimethylhydrazine↗
PubMed1999

NMR structure and dynamics of monomeric neutrophil-activating peptide 2.

Neutrophil-activating peptide 2 (NAP-2), which demonstrates a range of proinflammatory activities, is a 72-residue protein belonging to the alpha-chemokine family. Although NAP-2, like other alpha-chemokines, is known to self-associate into dimers and tetramers, it has been shown that the monomeric form is physiologically active. Here we investigate the solution structure of monomeric NAP-2 by multi-dimensional 1H-NMR and 15N-NMR spectroscopy and computational modelling. The NAP-2 monomer consists of an amphipathic, triple-stranded, anti-parallel beta-sheet on which is folded a C-terminal alpha-helix and an aperiodic N-terminal segment. The backbone fold is essentially the same as that found in other alpha-chemokines. 15N T1, T2 and nuclear Overhauser effects (NOEs) have been measured for backbone NH groups and used in a model free approach to calculate order parameters and conformational exchange terms that map out motions of the backbone. N-terminal residues 1 to 17 and the C-terminus are relatively highly flexible, whereas the beta-sheet domain forms the most motionally restricted part of the fold. Conformational exchange occurring on the millisecond time scale is noted at the top of the C-terminal helix and at proximal residues from beta-strands 1 and 2 and the connecting loop. Dissociation to the monomeric state is apparently responsible for increased internal mobility in NAP-2 compared with dimeric and tetrameric states in other alpha-chemokines.

Magnetic Resonance Spectroscopy↗
PubMed1999

De novo mosaic add(3) characterized to be trisomy 14q31-qter using spectral karyotyping and subtelomeric probes.

We describe a 19-year-old patient with a de novo mosaic add(3) chromosome (extra material of unknown origin on the 3q). The use of spectral karyotyping and fluorescence in situ hybridization using subtelomeric probes permitted the full characterization of the cytogenetic abnormality. The additional material on 3q was found to originate from 14q31-qter. This is one of the few reported cases with trisomy 14q31-qter and is the first mosaic case.

Adult↗
PubMed1999

Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.

[18F]-fluorodeoxyglucose ([18F]-FDG) uptake is enhanced in most malignant tumours which in turn can be measured using positron emission tomography (PET). A number of small clinical trials have indicated that quantification of the change in tumour [18F]-FDG uptake may provide an early, sensitive, pharmacodynamic marker of the tumoricidal effect of anticancer drugs. This may allow for the introduction of subclinical response for anticancer drug evaluation in early clinical trials and improvements in patient management. For comparison of results from smaller clinical trials and larger-scale multicentre trials a consensus is desirable for: (i) common measurement criteria; and (ii) reporting of alterations in [18F]-FDG uptake with treatment. This paper summarises the current status of the technique and recommendations on the measurement of [18F]-FDG uptake for tumour response monitoring from a consensus meeting of the European Organization for Research and Treatment of Cancer (EORTC) PET study group held in Brussels in February 1998 and confirmed at a subsequent meeting in March 1999.

Antineoplastic Agents↗
PubMed1999

Characterization of Royal Gala apple aroma using electronic nose technology-potential maturity indicator.

Changes in aroma of apple harvested at four different maturities were measured at harvest and after short-term storage using electronic aroma sensors ("electronic nose") and classical headspace/gas chromatography methods. Stored fruits were also evaluated by a trained sensory panel. Compared with headspace/gas chromatography, the electronic nose was found to be more sensitive ( approximately 40 times) in terms of sample size. The sampling procedure for the electronic nose was much less complex. Using discriminant function analysis, both methods classified the apples tested into groups according to harvest date. After storage, the groupings were more diffuse. Results from sensory testing showed partial separation along the first linear discriminant but did not classify the apple into distinct groups. Important differences between treatments were found for "overall flavor", "acid flavor" intensity, "crispness", "cider/fermented aroma", "vegetative aroma", and "canned pear aroma".

Electronics↗
PubMed1999

A genomic screen of autism: evidence for a multilocus etiology.

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying </=10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.

Adolescent↗
PubMed1999

Left ventricular function during interval and steady state exercise.

PURPOSE: Interval training (INT) is a commonly used method of exercise training in both athletic and clinical populations. Although we generally understand left ventricular (LV) function during steady state (SS) exercise, there are no data regarding LV function during INT. METHODS: We studied eight healthy, physically active volunteers during upright cycle ergometry during 15 min of both SS and INT, at the same average power output (90% individual anaerobic threshold), using first pass radionuclide ventriculography. During INT (60s/60s), measures of LV function were made during work (220 W) after 4 and 12 min and during recovery (120 W) after 7 and 15 min. These were compared with the average of four temporally matched measures made during SS (170 W). RESULTS: During INT, LV ejection fraction increased from rest (67 +/- 6%) to 77 +/- 5, 80 +/- 5, 77 +/- 5 and 79 +/- 4% after 4, 7, 12, and 15 min, respectively. During SS, LV ejection fraction was not significantly different at rest (70 +/- 4%) or during exercise (76 +/- 4, 79 +/- 4, 80 +/- 3, and 81 +/- 3%) after 4, 7, 12, and 15 min, respectively. Other measures of LV function (HR, BP, LV volumes, cardiac output, systemic vascular resistance, peak emptying, and filling rates) were likewise similar during temporally matched measurements during INT and SS. CONCLUSIONS: Although there were the expected transitions of ejection fraction with work and recovery, the overall hemodynamic picture during INT was very similar to SS. These data suggest that LV function during INT is not substantially different to that during SS.

Aged↗
PubMed1999

Public nutrition in emergencies: an overview of debates, dilemmas and decision-making.

This paper introduces and discusses the main themes and issues arising from the workshop 'International Public Nutrition in Emergencies: The Potential for Improving Practice'. Good co-ordination within the nutrition sector of the international humanitarian response system has led to a range of achievements in recent years. Major constraints to improving programme impact remain, however, including misconceptions about the scope of nutrition among the wider humanitarian system, which tends to give it a narrow focus on malnutrition and feeding people. In contrast to this limited view, the Public Nutrition approach brings a more broad-based emphasis to assessing and responding to nutritional problems in emergencies, and takes into account the wider social, economic and political causes of malnutrition. Six case study presentations illustrated the various components of a Public Nutrition approach, including in-depth assessment, analysis and tailoring programmes accordingly. Additional presentations considered the nature of vulnerability, the concept of Public Nutrition, the responsibilities for addressing nutritional problems and some of the operational tools and frameworks in current use. Participants agreed on the necessity of raising levels of awareness and understanding among all actors in the humanitarian sphere about the impact of their actions on nutrition. Strategies for achieving this included developing better multi-sectorial working relationships and also strengthening relationships with donors and key decision-makers in the humanitarian system. Other related strategies included institutional learning, training and capacity building, particularly in relation to institutions based in developing countries and building upon initiatives such as the Sphere Project, which has successfully brought together the various actors within the humanitarian system in order to improve quality of response.

Decision Making↗