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Biomedical subjects

Philip Lee

Publications and source records attributed to Philip Lee.

11 recordsLinked to original sources
PubMed2004

Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder.

Hartnup disorder, an autosomal recessive defect named after an English family described in 1956 (ref. 1), results from impaired transport of neutral amino acids across epithelial cells in renal proximal tubules and intestinal mucosa. Symptoms include transient manifestations of pellagra (rashes), cerebellar ataxia and psychosis. Using homozygosity mapping in the original family in whom Hartnup disorder was discovered, we confirmed that the critical region for one causative gene was located on chromosome 5p15 (ref. 3). This region is homologous to the area of mouse chromosome 13 that encodes the sodium-dependent amino acid transporter B(0)AT1 (ref. 4). We isolated the human homolog of B(0)AT1, called SLC6A19, and determined its size and molecular organization. We then identified mutations in SLC6A19 in members of the original family in whom Hartnup disorder was discovered and of three Japanese families. The protein product of SLC6A19, the Hartnup transporter, is expressed primarily in intestine and renal proximal tubule and functions as a neutral amino acid transporter.

Amino Acid Sequence↗
PubMed2004

Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.

Elsewhere, we reported the safety and efficacy results of a multicenter phase 3 trial of recombinant human alpha -galactosidase A (rh-alpha GalA) replacement in patients with Fabry disease. All 58 patients who were enrolled in the 20-wk phase 3 double-blind, randomized, and placebo-controlled study received subsequently 1 mg/kg of rh-alpha GalA (agalsidase beta, Fabrazyme, Genzyme Corporation) biweekly in an ongoing open-label extension study. Evidence of long-term efficacy, even in patients who developed IgG antibodies against rh- alpha GalA, included the continuously normal mean plasma globotriaosylceramide (GL-3) levels during 30 mo of the extension study and the sustained capillary endothelial GL-3 clearance in 98% (39/40) of patients who had a skin biopsy taken after treatment for 30 mo (original placebo group) or 36 mo (original enzyme-treated group). The mean serum creatinine level and estimated glomerular filtration rate also remained stable after 30-36 mo of treatment. Infusion-associated reactions decreased over time, as did anti-rh- alpha GalA IgG antibody titers. Among seroconverted patients, after 30-36 mo of treatment, seven patients tolerized (no detectable IgG antibody), and 59% had > or =4-fold reductions in antibody titers. As of 30 mo into the extension trial, three patients were withdrawn from the study because of positive serum IgE or skin tests; however, all have been rechallenged successfully at the time of this report. Thus, enzyme replacement therapy for 30-36 mo with agalsidase beta resulted in continuously decreased plasma GL-3 levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile.

Adult↗
PubMed2004

Autosomal recessive hypercholesterolaemia: long-term follow up and response to treatment.

Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in ARH on chromosome 1p35-36, encoding a putative adaptor protein. Mutations in the gene prevent normal internalisation of the low density lipoprotein (LDL) receptor by cultured lymphocytes and monocyte-derived macrophages, but not skin fibroblasts. This newly identified disorder is characterised by severe hypercholesterolaemia, large tendon, tuberous and planar xanthomas and premature atherosclerosis. We describe long-term (9-23 years) follow up and response to treatment of eight subjects with ARH from four families (Turkish/Lebanese, Indian-Asian, English and Italian). The clinical phenotype of ARH is similar to that of classical homozygous familial hypercholesterolaemia (FH) caused by mutations in the LDL-receptor gene but is more variable, less severe and is more responsive to lipid-lowering therapy with bile acid sequestrants and/or HMG-CoA reductase inhibitors. The latter reduced total serum cholesterol by up to 60% and the former by 20-35%. The cardiovascular complications of premature atherosclerosis seem to be delayed in some individuals and the involvement of the aortic root and valve are rarer in comparison with homozygous FH.

Adult↗
PubMed2004

Quantitative review of riparian buffer width guidelines from Canada and the United States.

This paper reviewed the provincial, territorial, and state guidelines for the retention of treed riparian buffers after timber harvest in Canada and the United States. Comparisons amongst jurisdictions were facilitated through the use of a standardized template for the classification of waterbodies. Mean buffer widths varied from 15.1 to 29.0 m for different waterbody types when both countries were combined. However, Canadian jurisdictions had wider buffers (except for intermittent streams). In part, this was due to the high percentage of Boreal jurisdictions in Canada and Southeast jurisdictions in the United States. The Boreal region had the widest buffers while Southeastern jurisdictions had the narrowest buffers. Just under half (approximately 44%) of the jurisdictions investigated had three or more modifying factors in the guidelines. Of these, waterbody type, shoreline slope, waterbody size, and presence of fish were the most common. Boreal and Pacific jurisdictions tended to have a more diverse set of waterbody size classes, waterbody types, and other modifying factors. Jurisdictions from the Midwest, Northeast, and Southeast maintained relatively simple 'one-size-fits-all' guidelines. Jurisdictions without modifying factors for slope or presence of fish applied wider baseline buffers than jurisdictions with these factors. A large percentage of jurisdictions (approximately 80%) allowed some selective harvest in buffers. However, these were often accompanied by relatively restrictive prescriptions. In comparison to the ecological recommendations, buffer widths for most jurisdictions were adequate to protect the aquatic biota and habitats but were, generally, less than recommended widths for terrestrial communities. In the future, two management trends are likely to continue, the shift towards more complicated guidelines and the expansion to larger-scale, watershed planning of riparian areas.

Animals↗
PubMed2004

Executive functioning, memory, and learning in phenylketonuria.

The executive deficit hypothesis of treated phenylketonuria (PKU) suggests that dopaminergic depletion in the lateral prefrontal cortex leads to selective executive impairment. This was examined by comparing adults with PKU on a lifelong diet with a matched healthy control group. Those with PKU were impaired on selective and sustained attention, working memory (Self-Ordered Pointing), and letter fluency. However, they failed to show differential sensitivity to increased cognitive load on the attentional and working memory tasks, and they did not differ significantly on the remaining executive tasks (rule finding, inhibition, and multitasking). Nor did they differ significantly on recall or recognition memory. Overall, the findings provided little support for the executive deficit hypothesis. A possible explanation in terms of slowed information processing speed is explored.

Adolescent↗
PubMed2004

Phage shock protein PspA of Escherichia coli relieves saturation of protein export via the Tat pathway.

Overexpression of either heterologous or homologous proteins that are routed to the periplasm via the twin-arginine translocation (Tat) pathway results in a block of export and concomitant accumulation of the respective protein precursor in the cytoplasm. Screening of a plasmid-encoded genomic library for mutants that confer enhanced export of a TorA signal sequence (ssTorA)-GFP-SsrA fusion protein, and thus result in higher cell fluorescence, yielded the pspA gene encoding phage shock protein A. Coexpression of pspA relieved the secretion block observed with ssTorA-GFP-SsrA or upon overexpression of the native Tat proteins SufI and CueO. A similar effect was observed with the Synechocystis sp. strain PCC6803 PspA homologue, VIPP1, indicating that the role of PspA in Tat export may be phylogenetically conserved. Mutations in Tat components that completely abolish export result in a marked induction of PspA protein synthesis, consistent with its proposed role in enhancing protein translocation via Tat.

Arabidopsis Proteins↗
PubMed2002

Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.

Familial hypercholesterolemia is an autosomal dominant disorder with a gene-dosage effect that is usually caused by mutations in the LDL receptor gene that disrupt normal clearance of LDL. In the homozygous form, it results in a distinctive clinical phenotype, characterized by inherited hypercholesterolemia, cholesterol deposition in tendons, and severe premature coronary disease. We described previously two families with autosomal recessive hypercholesterolemia that is not due to mutations in the LDL receptor gene but is characterized by defective LDL receptor-dependent internalization and degradation of LDL by transformed lymphocytes from the patients. We mapped the defective gene to chromosome 1p36 and now show that the disorder in these and a third English family is due to novel mutations in ARH1, a newly identified gene encoding an adaptor-like protein. Cultured skin fibroblasts from affected individuals exhibit normal LDL receptor activity, but their monocyte-derived macrophages are similar to transformed lymphocytes, being unable to internalize and degrade LDL. Retroviral expression of normal human ARH1 restores LDL receptor internalization in transformed lymphocytes from an affected individual, as demonstrated by uptake and degradation of (125)I-labeled LDL and confocal microscopy of cells labeled with anti-LDL-receptor Ab.

Adaptor Proteins, Signal Transducing↗