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D Young

Publications and source records attributed to D Young.

At least 91 records · Page 5Linked to original sources
PubMed2001

Examination of Y-STR mutations in sex chromosomal abnormality in forensic cases.

The Y-STR typing was carried out on eight DNA samples (three from criminal cases) demonstrating Klinefelter's syndrome. STR types in the X chromosome were randomly distributed. However, some Y-STR markers were distributed within the normal range but restricted to only one or two specific alleles, that is, some specific haplotypes were found in Klinefelter's syndrome. In addition, a single nucleotide polymorphism in DYS390 (transversion of G to A at the 28th position downstream of tandem repeats) was detected in Klinefelter samples. This Y-STR polymorphism and restricted Y-STR alleles in Klinefelter's syndrome is not known, but it might be related to the genesis of Klinefelter's syndrome. We also found that extended standard haplotypes of these samples are extremely rare in the normal population, according to the Y-STR haplotype reference database (YHRD). The extended standard haplotype database in a Japanese population is also reported. In 100 unrelated Japanese, 89 haplotypes were observed, and the haplotype diversity was calculated to be 0.9866.

Crime↗
PubMed2001

Genomics: leprosy - a degenerative disease of the genome.

Analysis of the genome of the leprosy bacillus uncovers evidence of extensive deletion and inactivation of genes. Secluded in a specialised niche, it has discarded much of its genetic heritage, though retaining just enough to be a major human pathogen.

Genome, Bacterial↗
PubMed2001

Pho23 is associated with the Rpd3 histone deacetylase and is required for its normal function in regulation of gene expression and silencing in Saccharomyces cerevisiae.

The Rpd3 histone deacetylase (HDAC) functions in a large complex containing many proteins including Sin3 and Sap30. Previous evidence indicates that the pho23, rpd3, sin3, and sap30 mutants exhibit similar defects in PHO5 regulation. We report that pho23 mutants like rpd3, sin3, and sap30 are hypersensitive to cycloheximide and heat shock and exhibit enhanced silencing of rDNA, telomeric, and HMR loci, suggesting that these genes are functionally related. Based on these observations, we explored whether Pho23 is a component of the Rpd3 HDAC complex. Our results demonstrate that Myc-Pho23 co-immunoprecipitates with HA-Rpd3 and HA-Sap30. Furthermore, similar levels of HDAC activity were detected in immunoprecipitates of HA-Pho23, HA-Rpd3, or HA-Sap30. In contrast, HDAC activity was not detected in immunoprecipitates of HA-Pho23 or HA-Sap30 from strains lacking Rpd3, suggesting that Rpd3 is the HDAC associated with these proteins. However, HDAC activity was detected in immunoprecipitates of HA-Sap30 or HA-Rpd3 from cells lacking Pho23, although levels were significantly lower than those detected in wild-type cells, indicating that Rpd3 activity is compromised in the absence of Pho23. Together, our genetic and biochemical studies provide strong evidence that Pho23 is a component of the Rpd3 HDAC complex, and is required for the normal function of this complex.

Acid Phosphatase↗
PubMed2001

Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies.

Recent studies have provided evidence that breast cancer susceptibility gene products (Brca1 and Brca2) suppress cancer, at least in part, by participating in DNA damage signaling and DNA repair. Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1.Mre11.Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA. Here, we report that there is a qualitative difference in the phosphorylation states of Brca1 between ionizing radiation (IR) and UV radiation. Brca1 is phosphorylated at Ser-1423 and Ser-1524 after IR and UV; however, Ser-1387 is specifically phosphorylated after IR, and Ser-1457 is predominantly phosphorylated after UV. These results suggest that different types of DNA-damaging agents might signal to Brca1 in different ways. We also provide evidence that the rapid phosphorylation of Brca1 at Ser-1423 and Ser-1524 after IR (but not after UV) is largely ataxia telangiectasia mutated (ATM) kinase-dependent. The overexpression of catalytically inactive ATM and Rad3 related (ATR) kinase inhibited the UV-induced phosphorylation of Brca1 at these sites, indicating that ATR controls Brca1 phosphorylation in vivo after the exposure of cells to UV light. Moreover, ATR associates with Brca1; ATR and Brca1 foci co-localize both in cells synchronized in S phase and after exposure of cells to DNA-damaging agents. ATR can itself phosphorylate the region of Brca1 phosphorylated by ATM (Ser-Gln cluster in the C terminus of Brca1, amino acids 1241-1530). However, there are additional uncharacterized ATR phosphorylation site(s) between residues 521 and 757 of Brca1. Taken together, our results support a model in which ATM and ATR act in parallel but somewhat overlapping pathways of DNA damage signaling but respond primarily to different types of DNA lesion.

Ataxia Telangiectasia↗
PubMed2001

Lipoprotein access to MHC class I presentation during infection of murine macrophages with live mycobacteria.

Following uptake by macrophages, live mycobacteria initially reside within an immature phagosome that resists acidification and retains access to recycling endosomes. Glycolipids are exported from the mycobacterial phagosome and become available for immune recognition by CD1-restricted T cells. The aim of this study was to explore the possibility that lipoproteins might similarly escape from the phagosome and act as immune targets in cells infected with live mycobacteria. We have focused on a 19-kDa lipoprotein from Mycobacterium tuberculosis that was previously shown to be recognized by CD8(+) T cells. The 19-kDa Ag was found to traffic separately from live mycobacteria within infected macrophages by a pathway that was dependent on acylation of the protein. When expressed as a recombinant protein in rapid-growing mycobacteria, the 19-kDa Ag was able to deliver peptides for recognition by MHC class I-restricted T cells by a TAP-independent mechanism. Entry into the class I pathway was rapid, dependent on acylation, and could be blocked by killing the mycobacteria by heating before infection. Although the pattern of 19-kDa trafficking was similar with different mycobacterial species, preliminary experiments suggest that class I presentation is more efficient during infection with rapid-growing mycobacteria than with the slow-growing bacillus Calmette-Guérin vaccine strain.

Animals↗
PubMed2001

Correlating computed tomography and positron emission tomography scan with operative findings in metastatic colorectal cancer.

INTRODUCTION: Several studies have been performed comparing computed tomography scan with positron emission tomography scan in clinical decision making. Unfortunately, therapeutic decisions are being made based on positron emission tomography scan data without a clear understanding of how well the diagnostic findings correlate with the clinical findings. METHODS: A retrospective review of 41 patients with metastatic colorectal cancer was performed. All patients had both a computed tomography scan and a positron emission tomography scan before surgical exploration. All underwent surgical re-exploration. Findings were divided into hepatic, extrahepatic, and pelvic regions of the abdomen. Computed tomography scan and positron emission tomography scan findings were either confirmed or refuted by the operative findings. RESULTS: Positron emission tomography scan was found to be more sensitive than computed tomography scan when compared with actual operative findings in the liver (100 vs. 69 percent, P = 0.004), extrahepatic region (90 vs. 52 percent, P = 0.015), and abdomen as a whole (87 vs. 61 percent, P < 0.001). Sensitivities of positron emission tomography scan and computed tomography scan were not significantly different in the pelvic region (87 vs. 61 percent, P = 0.091). In each case, specificity was not significantly different between the two examinations. CONCLUSION: Computed tomography scan and positron emission tomography scan are both diagnostic tests useful in the evaluation of metastatic colorectal cancer. However, positron emission tomography scanning is more sensitive than computed tomography scanning and more likely to give the correct result when actual metastatic disease is present.

Abdominal Neoplasms↗
PubMed2001

Changes in body composition as determinants of longitudinal changes in bone mineral measures in 8 to 26-year-old female twins.

Between 1990 and 1998, we conducted a longitudinal study of 286 female twins aged 8 to 25 years at baseline (60 monozygotic (MZ) pairs, 44 dizygotic (DZ) pairs and 78 unpaired twins), measured on average 2.4 times (range 2-6) with an average of 1.8 years between measurements (range 0.7-6.7 years). Areal bone mineral density (ABMD) at the lumbar spine, total hip and femoral neck, total body bone mineral content (BMC), total body soft tissue composition (lean mass and fat mass) were measured by dual-energy X-ray absorptiometry, and height and menarchial status were also recorded. Median annual changes in height were negligible at 4 years post-menarche. During the 'linear growth' period up to 4 years post-menarche, ABMD at the lumbar spine, total hip and femoral neck increased with annual change in lean mass by 1.7 (S.E.0.1), 1.4 (0.1) and 1.0 (0.1) percent per kilogram per year, respectively (all p<0.001), independently of changes in fat mass or height. During the 'post-linear growth' period, ABMD at the total hip and femoral neck increased with annual change in fat mass by 0.3 (0.1) and 0.5 (0.1) percent per kilogram per year (all p < 0.01), independent of change in lean mass. Annual changes in total body BMC were associated with annual changes in lean mass (1.9 (0.2) percent per kilogram), in fat mass (1.3 (0.2) percent per kilogram) and in height (0.7) (0.2) percent per centimeter) during linear growth, and in fat mass (1.0 (0.1)) and lean mass (0.6 (0.1)) percent per kilogram post-linear growth (all p < 0.001). We conclude that changes in bone mineral measures are strongly associated with changes in lean mass during linear growth, while post-linear growth, changes in fat mass are the predominant, although weaker, predictor. These findings suggest that the strong cross-sectional association between bone mineral measures and lean mass is established during growth and development, and that fat mass emerges as a more powerful determinant of bone change in healthy adult females.

Absorptiometry, Photon↗
PubMed2001

Extent of linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in human populations: implications for prostate cancer risk.

While studies have implicated alleles at the CAG and GGC trinucleotide repeats of the androgen receptor gene with high-grade, aggressive prostate cancer disease, little is known about the normal range of variation for these two loci, which are separated by about 1.1 kb. More importantly, few data exist on the extent of linkage disequilibrium (LD) between the two loci in different human populations. Here we present data on CAG and GGC allelic variation and LD in six diverse populations. Alleles at the CAG and GGC repeat loci of the androgen receptor were typed in over 1000 chromosomes from Africa, Asia, and North America. Levels of linkage disequilibrium between the two loci were compared between populations. Haplotype variation and diversity were estimated for each population. Our results reveal that populations of African descent possess significantly shorter alleles for the two loci than non-African populations (P<0.0001). Allelic diversity for both markers was higher among African Americans than any other population, including indigenous Africans from Sierra Leone and Nigeria. Analysis of molecular variance revealed that approx. 20% of CAG and GGC repeat variance could be attributed to differences between the populations. All non-African populations possessed the same common haplotype while the three populations of African descent possessed three divergent common haplotypes. Significant LD was observed in our sample of healthy African Americans. The LD observed in the African American population may be due to several reasons; recent migration of African Americans from diverse rural communities following urbanization, recurrent gene flow from diverse West African populations, and admixture with European Americans. This study represents the largest genotyping effort to be performed on the two androgen receptor trinucleotide repeat loci in diverse human populations.

Africa↗
PubMed2001

The role of multimedia interactive programs in training for laparoscopic procedures.

BACKGROUND: The application of minimally invasive techniques to the performance of abdominal surgery by general surgeons has been perhaps the greatest advance in the history of general surgery. The safe adoption of many of these procedures, however, has been hampered by significant obstacles, mainly due to the problem of providing adequate training for surgeons. Outside of animal and cadaver labs, most training has been didactic in nature, and adoption rates after completion of these courses are discouraging. Multimedia interactive training has been used in a number of high-tech industries with great success. A >60% improvement in the learning curve after multimedia interactive training, as compared to traditional didactic training, has been reported. Multimedia interactive training programs for surgeons that use content and input from multiple experts in laparoscopic procedures have now been developed. METHODS: Residents from a general surgery residency program who used these programs were asked to rate their effectiveness in increasing their knowledge and comfort level prior to their participation in a real procedure as the primary surgeon or first assistant. A comparison to other traditional training techniques was also made. Eleven residents completed 41 programs designed to teach one of five different laparoscopic procedures-cholecystectomy, fundoplication, appendectomy, colon resection, or hernia repair. RESULTS: On a scale of 1 to 10, with 10 being the highest, the residents reported that the multimedia interactive training programs raised their knowledge level of the procedure from 6.0 to 8.7 (+2.7 point value increase after using the multimedia interactive program). The programs increased their comfort level when actually called on to perform or assist with the procedure from 5.3 to 8.1 (+2.8 point value increase after using the multimedia interactive program). In comparing the value of training methods for learning laparoscopic procedures, the residents rated text, lectures, videos, and animal labs at 4.7, 5.1, 6.0 and 7.3, respectively. By comparison, the residents rated the multimedia interactive training program at 8.8. CONCLUSION: The use of multimedia interactive training programs in addition to current laparoscopic training courses may help to increase the safe adoption of laparoscopic procedures. These programs may be a beneficial adjunct to residency training programs.

Adult↗
PubMed2001

Quantitative comparison of expression with adeno-associated virus (AAV-2) brain-specific gene cassettes.

This study compared a range of mammalian CNS expression cassettes in recombinant adeno-associated virus (AAV-2) vectors using strong endogenous promoter sequences, with or without a strong post-regulatory element and polyadenylation signal. Changes in these elements led to transgene expression varying by over three orders of magnitude. In experiments conducted in primary cell culture and in >100 stereotactically injected rats, we observed highly efficient and stable (>15 months) gene expression in neurons and limited expression in glia; the highest expression occurred with endogenous, nonviral promoters such as neuron-specific enolase and beta-actin. The packaging size of AAV-2 was maximized at 5.7 kb without impairing gene expression, as judged by direct comparison with a number of smaller AAV-2 constructs. The genomic insert size and titer were confirmed by Southern blot and quantitative PCR, and infectivity was tested by particle titer using ELISA with a conformation-dependent epitope that requires the full intact capsid. A packaging and purification protocol we describe allows for high-titer, high-capacity AAV-2 vectors that can transduce over 2 x 10(5) neurons in vivo per microliter of vector, using the strongest expression cassette.

Animals↗
PubMed2001

A potentially improved approach to methylene blue virus inactivation of plasma: the Maco Pharma Maco-Tronic system.

Plasma was subjected to methylene blue (MB) photochemical virus inactivation using the Maco Pharma Maco-Tronic system which allows three units to be illuminated together, thus reducing processing time. The plasma bag system used incorporates an integral membrane plasma filter and a dry MB pill which dissolves in the plasma to give a 1-microM concentration. There is computer-controlled processing and datalogging. In an assessment of 10 pools of Group A plasma, the losses of coagulation factors, following MB/light treatment, were 23% fibrinogen, 10% FV, 26% FVIII, 11% FIX and 13% FXI. Group O, Group B and Group AB plasmas were not tested. Von Willebrand factor (vWf) multimers showed no substantial change when treated with MB, and no losses were seen for antithrombin III (ATIII), protein C and vWf:Ag. Measurements of C3a, C5a, prothrombin fragment 1+2 and FXIIa indicated that there was no activation as a result of filtration.

Antithrombin III↗
PubMed2001

Coronin is involved in uptake of Mycobacterium bovis BCG in human macrophages but not in phagosome maintenance.

By applying density gradient electrophoresis (DGE) to human macrophages infected with Mycobacterium bovis BCG, we were able to separate three different bacterial fractions representing arrested phagosomes, phagolysosomes and mycobacterial clumps. After further purification of the phagosomal population, we found that isolated phagosomes containing live BCG were arrested in maturation as they exhibited only low amounts of the lysosomal glycoprotein LAMP-1 and processing of the lysosomal hydrolase cathepsin D was blocked. In addition, low amounts of MHC class I and class II molecules and the absence of HLA-DM suggest sequestration of mycobacterial phagosomes from antigen-processing pathways. We further investigated the involvement of the actin-binding protein coronin in intracellular survival of mycobacteria and showed that human coronin, as well as F-actin, were associated with early stages of mycobacterial phagocytosis but not with phagosome maintenance. Therefore, we conclude that the unique DGE migration pattern of arrested phagosomes is not as a result of retention of coronin, but that there are other proteins or lipids responsible for the block in maturation in human macrophages.

Bacterial Proteins↗
PubMed2001

Long-term follow-up on an intensified treatment regimen for advanced resectable head and neck squamous cell carcinomas.

From February 1993 through July 1994, 37 patients with stage III-IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx (stage II-IV) were registered to a treatment regimen consisting of preoperative continuous infusion cisplatin (80 mg/m2/80 hours) with hyperfractionated external beam radiotherapy (9.1 Gy/7 fractions of 1.3 Gy BID), surgical resection, intraoperative radiotherapy (7.5 Gy), and postoperative radiotherapy (40 Gy) with concurrent cisplatin (100 mg/m2 x 2 courses). The objectives of the regimen were to improve patient compliance while also increasing treatment intensity. The purpose of this article is to report the local, regional (nodal), and distant disease control of these patients after an extended time at risk (median 40 months). Overall compliance (73%), local control at primary site (97%), and regional nodal control (95%) were excellent. The rate of distant metastasis was 19%. Absolute survival at 48 months was 45.9%.

Carcinoma, Squamous Cell↗