Biomedical subjects
Publications and source records attributed to M D Wilson.
Unfractionated heparin infusion may be a more suitable choice of anticoagulant treatment in patients with venous thromboembolism in the immediate postoperative period.
Chromosome 7q22 has been the focus of many cytogenetic and molecular studies aimed at delineating regions commonly deleted in myeloid leukemias and myelodysplastic syndromes. We have compared a gene-dense, GC-rich sub-region of 7q22 with the orthologous region on mouse chromosome 5. A physical map of 640 kb of genomic DNA from mouse chromosome 5 was derived from a series of overlapping bacterial artificial chromosomes. A 296 kb segment from the physical map, spanning ACHE: to Tfr2, was compared with 267 kb of human sequence. We identified a conserved linkage of 12 genes including an open reading frame flanked by ACHE: and Asr2, a novel cation-chloride cotransporter interacting protein Cip1, Ephb4, Zan and Perq1. While some of these genes have been previously described, in each case we present new data derived from our comparative sequence analysis. Adjacent unfinished sequence data from the mouse contains an orthologous block of 10 additional genes including three novel cDNA sequences that we subsequently mapped to human 7q22. Methods for displaying comparative genomic information, including unfinished sequence data, are becoming increasingly important. We supplement our printed comparative analysis with a new, Web-based program called Laj (local alignments with java). Laj provides interactive access to archived pairwise sequence alignments via the WWW. It displays synchronized views of a dot-plot, a percent identity plot, a nucleotide-level local alignment and a variety of relevant annotations. Our mouse-human comparison can be viewed at http://web.uvic.ca/~bioweb/laj.html. Laj is available at http://bio.cse.psu.edu/, along with online documentation and additional examples of annotated genomic regions.
ERCC1 plays an essential role in the nucleotide excision repair (NER) of DNA. We compare 37 kb of sequence from the ERCC1 region on human chromosome 19q13.3 to the orthologous region on mouse chromosome 7. In addition to showing the conserved gene structure between ERCC1, ASE-1, and their murine counterparts, this genomic comparison reveals a highly conserved 497 bp segment found 5 kb upstream of ERCC1 exon 1 that contains a CpG island and previously unidentified "classical" promoter elements. Additional putative regulatory elements are also found within a conserved LINE-1 (long interspersed nuclear element) sequence 800 bp upstream of exon 1 in both human and mouse. Expressed sequence tag (EST) assemblies for human ERCC1 identified numerous splice variants involving exons 1, 2, 3, 7, 8, and 9 that could affect DNA repair efficiencies of ERCC1. A previously undescribed transcript that reads through exon 9 and utilizes the polyadenylation signal of a neighboring Alu element accounts for nearly half of the total splice variants identified in the human EST database. This transcript would theoretically translate to a larger ERCC1 protein product containing a novel C-terminal end. Overall, approximately 18% of publicly available ERCC1 cDNA sequences were determined to be splice variants, while no variants were found in the mouse. The ability to assess novel transcripts and identify candidate regulatory regions demonstrates the potential utility for a catalogue archiving comparative analyses for all genes involved in DNA repair. Our comparative genomic analysis of ERCC1 can be viewed at http://web.uvic.ca/-bioweb/laj.html.
Splanchnic ischaemia is an important problem in patients with large burns. This reports the case of an 11-year-old boy with 70% full-thickness TBSA burns who sustained multiple episodes of severe gastrointestinal haemorrhage due to both extensive ischaemic enterocolitis and severe gastric ulceration which required surgical intervention on several occasions. Causative mechanisms of splanchnic ischaemia in this patient including increased mesenteric vascular resistance, abdominal compartment syndrome and enteric feeding, are considered.
A survey of Plasmodium falciparum infection and clone multiplicity in Ghanaian children was carried out to study the effect of the onset of the malaria transmission season on disease incidence. Fortnightly blood samples were collected from 40 children living in the rural town of Dodowa, between February and August 1998. P. falciparum parasite densities were calculated and PCR genotyping was carried out using the polymorphic MSP-1 and MSP-2 genes as target loci for the estimation of the number of parasite clones in each sample. The average clone number was estimated using maximum likelihood techniques and the minimum number of clones per patient was analysed for the effects of age, sex, season, minimum number of clones per child, level of parasitaemia and parasite genotype. The statistical analysis indicated that the more clones a child carried, the more likely they were to have a clinical malaria episode. This was true after adjusting for age and season effects and for the measured circulating parasitaemia. The probability of clinical disease also increased if the MSP-1 MAD 20 and the MSP-2 FC 27 alleles were present. This longitudinal analysis thus indicates that the probability of a Ghanaian child having a symptomatic malaria episode is positively associated with both increasing numbers and novel types of P. falciparum clones.
Larvae of the Simulium damnosum Theobald complex (Diptera: Simuliidae) were sampled in June 1996 from two sites in south-west Ghana where larviciding has not been applied: Sutri Rapids on the Tano river (05 degrees 23 minutes N 02 degrees 38 minures W) and Sekyere-Heman on the Pra river (05 degrees 11 minutes N 01 degrees 35 minutes W). All specimens were identified as Simulium sanctipauli Vajime & Dunbar sensu stricto (Diptera: Simuliidae). Bioassays with temephos (organophosphorus larvicide employed by the Onchocerciasis Programme for systematic treatment of most rivers across West Africa since the 1970s) showed about five-fold resistance in the Tano population (LC95 2.37-3.14 mg/L) and slight tolerance to temephos in the Pra population (LC95 0.67-0.76 mg/L), vs. the diagnostic concentration of 0.625 mg/L. Larval salivary polytene chromosomes of S. sanctipauli showed fixed inversions 1S-24/24, standard IIL-6 and a new inversion IL/36 polymorphism at Sutri on the Tano. These karyotype characteristics differ from those of temephos-resistant S. sanctipauli in rivers of C te d'Ivoire and other sites on the Tano in Ghana. Thus, temephos resistance in S. sanctipauli at Sutri is associated with distinct chromosomal configurations, showing that immigration was unlikely. This resistance could have been locally selected by exposure of S. sanctipauli larval populations to agrochemicals run-off from cocoa, coffee and oil plantations flanking the rivers.
We conducted an entomological study to document the effect of irrigation on the vectors and transmission dynamics of lymphatic filariasis in the Upper East Region of Ghana. Mosquitoes were collected by indoor spraying of houses in a cluster of communities located around irrigation projects (Tono and Vea) and others without reservoirs (Azoka). Anopheles gambiae s.s. was the dominant species and major vector, followed by An. funestus. Anopheles arabiensis constituted 9--14% of the An. gambiae complex but none were infective. Culex quinquefasciatus was also not infective in these communities. Chromosomal examinations showed that >60% (n=280--386) of the An. gambiae s.s. in irrigated communities were Mopti forms whilst 73% (n=224) in the non-irrigated area were Savannah forms. Infectivity rates (2.3--2.8 vs. 0.25), worm load (1.62--2.04 vs. 1.0), annual bites per person (6.50--8.83 vs. 0.47) and annual transmission potential (13.26--14.30 vs. 0.47) were significantly higher in irrigated communities.
Williams syndrome (WS) is a complex neurodevelopmental disorder arising from a microdeletion at Chr band 7q11.23, which results in a hemizygous condition for a number of genes. Within this region we have completely characterized 200 kb containing the genes LIMK1, WBSCR1, and RFC2. Evidence was also found for WBSCR5 in this region, but not the previously proposed genes WSCR2 and WSCR6. The syntenic region in mouse was also sequenced (115 kb) and characterized, and a comparative sequence analysis with a percent identity plot (PIP) easily allowed us to identify coding exons. This genomic region is GC rich (50.1% human, 49.9% mouse) and contains an unusually high abundance of repetitive elements consisting primarily of Alu (45.4%, one of the highest levels identified to date) in human, and the B family of SINES (30.6% of the total sequence) in mouse. WBSCR1 corresponds to eukaryotic initiation factor 4H, identified in rabbit, and is herein found to be constitutively expressed in both human and mouse, with two RNA and protein products formed (exon 5 is alternatively spliced). The transcription pattern of WBSCR5 was also examined and discussed along with its putative amino acid sequence.
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Dietary intake of soy protein is associated with reductions in plasma cholesterol. Isoflavones are thought to be active components of soy and responsible for the beneficial effects because of their structural similarities to estrogen. The purposes of this study were to determine if i) soy protein or a semipurified soy extract, rich in isoflavones, is responsible for improving the lipid profile and ii) altered intestinal cholesterol metabolism is one mechanism for hypocholesterolemic effects. Ovariectomized adult female cynomolgus monkeys (40) were assigned to groups fed diets containing i) casein-lactalbumin (CAS) ii) intact soy protein (SOY), iii) CAS plus an isoflavone-rich semipurified soy extract similar in isoflavone content as SOY (ISO) or iv) CAS plus conjugated equine estrogen (CEE) for 20 wk. Cholesterol absorption was determined using the fecal isotope ratio method. Bile acid excretion was measured using the 3alpha-hydroxysteroid dehydrogenase assay. The SOY group had significantly lower total- and VLDL + LDL-cholesterol compared to the other three groups and significantly higher HDL-cholesterol compared to the CAS and CEE groups. Cholesterol absorption was significantly lower in the SOY group compared to the other groups, but bile acid excretion was not significantly affected. The hypocholesterolemic effect of soy protein appears to be mediated in part by decreased cholesterol absorption. The semipurified soy extract, rich in isoflavones, added to casein protein did not have lipid-lowering effects. Other components of soy such as saponins, phytic acid or the amino acid composition may be involved in the hypocholesterolemic effects seen in this study.
Apo-E-deficient apo-B100-only mice (APOE:(-/-)APOB:(100/100)) and LDL receptor-deficient apo-B100-only mice (LDLR:(-/-)APOB:(100/100)) have similar total plasma cholesterol levels, but nearly all of the plasma cholesterol in the former animals is packaged in VLDL particles, whereas, in the latter, plasma cholesterol is found in smaller LDL particles. We compared the apo-B100-containing lipoprotein populations in these mice to determine their relation to susceptibility to atherosclerosis. The median size of the apo-B100-containing lipoprotein particles in APOE:(-/-)APOB:(100/100) plasma was 53.4 nm versus only 22.1 nm in LDLR:(-/-)APOB:(100/100) plasma. The plasma levels of apo-B100 were three- to fourfold higher in LDLR:(-/-)APOB:(100/100) mice than in APOE:(-/-)APOB:(100/100) mice. After 40 weeks on a chow diet, the LDLR:(-/-)APOB:(100/100) mice had more extensive atherosclerotic lesions than APOE:(-/-)APOB:(100/100) mice. The aortic DNA synthesis rate and the aortic free and esterified cholesterol contents were also higher in the LDLR:(-/-)APOB:(100/100) mice. These findings challenge the notion that all non-HDL lipoproteins are equally atherogenic and suggest that at a given cholesterol level, large numbers of small apo-B100-containing lipoproteins are more atherogenic than lower numbers of large apo-B100-containing lipoproteins.
The northernmost focus for Onchocerca volvulus Leuckhart (Nematoda: Onchocercidae), the causative agent of human onchocerciasis, is found along the Nile near the town of Abu Hamed in Sudan. The vector for O. volvulus at this focus is a single monomorphic population of Simulium (Edwardsellum) damnosum Theobald. This black fly population is limited to a small area between the fourth and fifth cataracts of the Nile River that is isolated geographically from all other populations of S. damnosum sensu lato. Phylogenies produced from cytological analyses and sequence data derived from the NADH dehydrogenase subunit 4 and 16S rRNA genes indicate that Abu Hamed black flies are similar to, but distinct from, the savanna-dwelling sibling species of S. damnosum s.l., Simulium (Edwardsellum) damnosum sensu strictu Theobald, and S. (Edwardsellum) sirbanum Vajime & Dunbar. The DNA sequence and the cytological data support the hypothesis that the black fly population present in Abu Hamed may represent a new sibling species of S. damnosum s.l. We propose that this population be informally designated as the hamedense form of the Simulium damnosum complex.
Retrieval analyses disclosed in vivo dissociation of HA in orthopaedic acetabular components, but excellent bone ingrowth into intact HA coatings on dental retrievals. Initial healing and the bone interface between HA-coated and non-coated implants in the posterior maxilla (Mx) and mandible (Md) was assessed in an animal model using light microscopy (LM), including confocal (CM) and Nomarski (NM) microscopy. Seventy-two implants (36 HA-coated; 36 non-coated) were placed into jaws of six dogs; half after extraction, half after 3 months healing. Animals were euthanized 3 months postimplantation. All implants osseointegrated; however, preliminary morphometry showed higher BCL for HA-coated (51%) than non-coated implants (44%) in the Mx (p < 0.05). BCL for HA-coated Md implants was not significantly higher (64%) than non-coated implants (62%). Bone closely apposed both implant types; however, LM suggested a more intimate association with HA coatings. Serial sections disclosed a reddish coating on the HA, possibly analogous to oral tissue proteoglycans, which was not visible with non-coated implants. This material was continuous with similar material coating endosteum, osteoid regions, and osteocyte (Os) lacunae close to the implant. An interdigitating canaliculi network allowed communication between interfacial Os and Os deeper within the bone. Data suggest HA offers enhanced initial bone fixation in the Mx, and that adequate bone exists for non-coated implant stability in the Md. No HA dissociation was seen with implants in the animal study, which was consistent with retrieved human HA dental implants.
BACKGROUND AND OBJECTIVE: Liposomes as photosensitizer carriers may enhance the photodynamic effect on tumors. STUDY DESIGN/MATERIALS AND METHODS: To test this hypothesis, we treated U87 human glioma in rat brain with photodynamic therapy (PDT) using Photofrin encapsulated in a liposome carrier or Photofrin in dextrose. Nontumored brain was also treated and Photofrin content ratios were measured in tumor and nontumored brain. RESULTS: PDT using the liposome encapsulated photosensitizer significantly increased tumor destruction compared to PDT with Photofrin in dextrose (P = 0.007), whereas no difference in tissue damage was detected in nontumored brain with or without liposome carrier. Photofrin uptake was also significantly elevated in the liposome vehicle group compared to the dextrose (P < 0.05) group. CONCLUSIONS: Our data suggest that Photofrin encapsulated in a liposome may enhance the PDT treatment of human brain tumors.
Onchocerciasis is endemic on the island of Bioko, Equatorial Guinea, where it is transmitted by the 'Bioko form' of the Simulium damnosum complex, a cytospecies unique to the island. To determine the distribution of vector breeding, three dry season and two wet season expeditions were made in 1989, 1996 and 1997, and 226 of the island's 247 rivers (91.5%) were visited. Of these 226 rivers, 130 (58%) were flowing during the dry season, forty-five (20%) supported aquatic stages of Simuliidae of any species and twenty-five (11%) contained larvae or pupae of the S. damnosum complex. The twenty-one rivers not prospected were in the mountainous south of the island, where an additional seventeen rivers were reached but not satisfactorily prospected. Of these thirty-eight rivers, twenty-nine were considered highly likely to support vector breeding, bringing the total number of rivers which could harbour the vector during the dry season to fifty-four (21.9% of the island's total). Breeding was believed to be limited to river stretches below 1000 m altitude, and during the dry season the total length of those stretches which could support breeding on Bioko was estimated to be 1020 km. A combination of factors, including low river discharges during the dry season, the relatively low water temperature on Bioko, the suitability of limited stretches of most rivers as vector breeding sites and the close proximity of many rivers within a small geographical area, render the vector vulnerable to eradication by aerial treatment of rivers with insecticide. The isolation of the Bioko form of the S. damnosum complex suggests that reinvasion following treatment would be unlikely, and eradication of the vector might be achieved by a dry season larviciding programme in one or two years.
In mice with genetically engineered high levels of plasma low density lipoprotein (LDL), we tested the hypothesis that an increase in the dietary content of monounsaturated fatty acids but not of polyunsaturated fatty acids would promote atherosclerosis. The mouse model used was an LDL receptor-null, human apoB100-overexpressing strain. Six experimental groups of 19 to 38 mice of both sexes were established when the animals had reached 8 weeks of age. For the next 16 weeks, individual groups were fed either a commercial diet or prepared diets including fat as 10% of energy, with 5 different fatty acid enrichment patterns including the following: saturated (sat), cis and trans monounsaturated (mono), and n-3 and n-6 polyunsaturated (poly). Highly significant differences (ANOVA, P<0. 0001) in LDL cholesterol (in mg/dL) were found, with the rank order at 16 weeks being trans mono (mean, 1390)>sat (922)=cis mono (869)=n-6 poly (868)>n-3 poly (652)>commercial diet (526). Significant elevations in very low density lipoprotein cholesterol were also found in the trans and cis mono and sat groups, and triacylglycerol concentrations were also elevated in all groups. High density lipoprotein cholesterol concentrations were consistently low (20 to 50 mg/dL) in all groups. Highly significant differences (ANOVA, P<0.0001) in atherosclerosis, quantified by measurement of aortic cholesteryl ester concentration (mg/g protein) among dietary fatty acid groups were found, with the order being trans mono (mean, 50.4)>sat (35.6)=cis mono (34.6)>n-6 poly (18. 3)=n-3 poly (9.7)=commercial diet (7.8). Therefore, in this mouse model of hypercholesterolemia, dietary cis or trans monounsaturated fat did not protect against atherosclerosis development, whereas aortic atherosclerosis in either of the polyunsaturated fat groups was significantly less than in the saturated fat group.
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OBJECTIVES: To assess pediatric residents' self-reported skills and satisfaction with providing sexuality-related health care to teenagers and to examine differences by resident and patient gender. DESIGN: Cross-sectional survey. PARTICIPANTS: Forty second-year (PGY2) and 17 third-year (PGY3) pediatric residents at one training program who completed a self-administered questionnaire. MAIN OUTCOME MEASURES: Residents rated their skills with taking a history from, performing a physical examination on, developing a diagnosis for, and counseling both male and female teenagers. Skills with providing health care to male and female teenagers were assessed separately. Scales were constructed for skills with performing a physical examination and providing a diagnosis and counseling. Residents also rated their satisfaction with providing health care to male and female teenagers. Skills and satisfaction with providing health care to male vs female teenagers were analyzed. RESULTS: Female residents rated their skills with providing health care to male teenagers significantly lower than their skills with providing health care to female teenagers as follows: taking a history of pubertal development (PGY2, P = .001; PGY3, P = .02), taking a sexual history (PGY2, P = .004), asking about sexual preference (PGY2, P = .02), examination and diagnosis scale (PGY2, P < .001; PGY3, P = .008), and counseling scale (PGY2, P = .003). For male residents, there were no significant differences in skills with providing health care to male vs female teenagers. Second-year, but not third-year, female residents reported significantly lower (P < .005) satisfaction with providing health care to male vs female teenagers. CONCLUSIONS: Among female residents, discrepancies were found when comparing self-assessed competencies and, for PGY2 residents, level of satisfaction with providing health care to male vs female patients. If other research confirms these findings, educational interventions related to sexuality-related health care for teenagers should be designed with consideration to gender-specific learner needs.