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J D McDonald

Publications and source records attributed to J D McDonald.

At least 19 recordsLinked to original sources
PubMed2006

Large neutral amino acids in the treatment of phenylketonuria (PKU).

Large neutral amino acids (LNAAs) have been used on a limited number of patients with phenylketonuria (PKU) with the purpose of decreasing the influx of phenylalanine (Phe) to the brain. In earlier studies on mice with PKU (ENU(2)/ENU(2)), LNAAs were given and a surprising decline in blood Phe concentrations was observed. The formula used in the mouse experiment (PreKUnil) lacked lysine. Therefore, a new formulation of LNAAs (NeoPhe) was developed, introducing changes in the concentration of some amino acids and adding lysine, so that such a mixture could be used in humans. The new formula was found to be effective in reducing blood Phe concentration in mice by about 50% of the elevated levels. Patients with PKU were given LNAAs and blood Phe concentrations were determined in an open-label study. Three centers--in Russia, the Ukraine and the USA--took part in the study. NeoPhe was given at 0.5 g/kg per day in three divided doses to eight subjects with PKU and at 1.0 g/kg per day to three patients, for one week. The NeoPhe resulted in decrease of elevated blood Phe by 50% in both groups. The preliminary data from this study are encouraging and a double blind placebo-controlled trial will be required to show long-term efficacy and tolerance of LNAAs in the treatment of PKU.

Adolescent↗
PubMed2006

Health effects of subchronic exposure to environmental levels of hardwood smoke.

Hardwood smoke is a contributor to both ambient and indoor air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center, a series of health assays was conducted on rodents exposed to environmentally relevant levels of hardwood smoke. This article summarizes the study design and exposures, and reports findings on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential. Hardwood smoke was generated from an uncertified wood stove, burning wood of mixed oak species. Animals were exposed to clean air (control) or dilutions of whole emissions based on particulate (30, 100, 300, and 1000 micromg/m3). F344 rats, SHR rats, strain A/J mice, and C57BL/6 mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Effects of exposure on general indicators of toxicity, bacterial clearance, cardiac function, and carcinogenic potential were mild. Exposure-related effects included increases in platelets and decreases in blood urea nitrogen and serum alanine aminotransferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Pulmonary histopathology revealed very little accumulation of hardwood smoke particulate matter. Parallel studies demonstrated mild exposure effects on bronchoalveolar lavage parameters and in a mouse model of asthma. In summary, the results reported here show few and only modest health hazards from short-term to subchronic exposures to realistic concentrations of hardwood smoke.

Air Pollutants↗
PubMed2006

Health effects of subchronic exposure to diesel-water-methanol emulsion emission.

The U.S. Environmental Protection Agency's National Ambient Air Quality Standards for ozone and particulate matter (PM) require urban non-attainment areas to implement pollution-reduction strategies for anthropogenic source emissions. The type of fuel shown to decrease combustion emissions components versus traditional diesel fuel, is the diesel emulsion. The Lubrizol Corporation, in conjunction with Lovelace Respiratory Research Institute and several subcontracting laboratories, recently conducted a health assessment of the combustion emissions of PuriNOx diesel fuel emulsion (diesel-water-methanol) in rodents. Combustion emissions from either of two, 2002 model Cummins 5.9L ISB engines, were diluted with charcoal-filtered air to exposure concentrations of 125, 250 and 500 microg total PM/m3. The engines were operated on a continuous, repeating, heavy-duty certification cycle (U.S. Code of Federal Regulations, Title 40, Chapter I) using Rotella-T 15W-40 engine oil. Nitrogen oxide (NO) and PM were reduced when engines were operated on PuriNOx versus California Air Resources Board diesel fuel under these conditions. Male and female F344 rats were housed in Hazleton H2000 exposure chambers and exposed to exhaust atmospheres 6 h/day, five days/week for the first 11 weeks and seven days/week thereafter. Exposures ranged from 61 to 73 days depending on the treatment group. Indicators of general toxicity (body weight, organ weight, clinical pathology and histopathology), neurotoxicity (glial fibrillary acidic protein assay), genotoxicity (Ames assay, micronucleus, sister chromatid exchange), and reproduction and development were measured. Overall, effects observed were mild. Emulsion combustion emissions were not associated with neurotoxicity, reproductive/developmental toxicity, or in vivo genotoxicity. Small decreases in serum cholesterol in the 500-microg/m3 exposure group were observed. PM accumulation within alveolar macrophages was evident in all exposure groups. The latter findings are consistent with normal physiological responses to particle inhalation. Other statistically significant effects were present in some measured parameters of other exposed groups, but were not clearly attributed to emissions exposure. Positive mutagenic responses in several strains of Salmonella typhimurium were observed subsequent to treatment with emulsion emissions subfractions. Based on the cholesterol results, it can be concluded that the 250-microg/m3 exposure level was the no observed effect level. In general, biological findings in exposed rats and bacteria were consistent with exposure to petroleum diesel exhaust in the F344 rat and Ames assays.

Administration, Inhalation↗
PubMed2005

Health effects of subchronic exposure to diesel-water emulsion emission.

The U.S. Environmental Protection Agency (EPA) National Ambient Air Quality Standards for ozone and particulate matter are requiring urban nonattainment areas to implement pollution-reduction strategies for anthropogenic source emissions. A type of fuel shown to decrease combustion emissions components versus traditional diesel fuels is the diesel-water emulsion. The Lubrizol Corporation in conjunction with Lovelace Respiratory Research Institute and several subcontracting laboratories recently conducted a rodent health assessment of inhaled combustion emissions of PuriNO(x) diesel fuel emulsion. Combustion emissions from either of two 2001 model Cummins 5.9-L ISB engines were diluted with charcoal-filtered air to exposure concentrations of 100, 200, and 400 microg total particulate matter/m(3). The engines were operated on a continuously repeating, heavy-duty certification cycle (U.S. Code of Federal Regulations, Title 40, Chapter I) using Rotella-T 15W-40 engine oil. Nitrogen oxide and particulate matter were reduced when engines were operated on PuriNO(x) versus California Air Resources Board diesel fuel under these conditions. Male and female F344 rats were housed in Hazleton H2000 exposure chambers and exposed to exhaust atmospheres 6 h/day, 5 days/wk for the first 11 wk and 7 days/wk threafter. Exposures ranged from 58 to 70 days, depending on the treatment group. Indicators of general toxicity (body weight, organ weight, clinical pathology, and histopathology), neurotoxicity (glial fibrillary acidic protein assay), genotoxicity (Ames assay, micronucleus, sister chromatid exchange), and reproduction and development were measured. Overall, effects observed were mild. Emulsion combustion emissions were not associated with neurotoxicity, reproductive/developmental toxicity, or in vivo genotoxicity. Small decreases in serum cholesterol and small increases in platelet values in some groups of exposed animals were observed. Particulate matter accumulation within alveolar macrophages was evident in all exposure groups. These findings are consistent with normal physiological responses to particle inhalation. Other statistically significant effects were present in some measured parameters of other exposed groups but were not clearly attributed to emissions exposure. Positive mutagenic responses in several strains of Salmonella typhimurium were observed subsequent to treatment with emulsion emissions subfractions. Based on the cholesterol and platelet results, it can be concluded that the 100 microg/m(3) exposure level was the no-observed-effect level. In general, biological findings in diesel emulsion emission-exposed animals and bacteria were consistent with exposure to petroleum diesel exhaust in the F344 rat and Ames assays.

Administration, Inhalation↗
PubMed2005

Evaluation of nebulizer performance under various humidity conditions.

Jet nebulizers are a drug delivery tool commonly used for treating respiratory diseases. When a nebulizer generates aerosols, the rate at which droplets evaporate depends on humidity conditions around the nebulizer outlet. Because the relative humidity (RH) of the air affects the evaporation rate, the aerosol distribution and drug delivery dose is also affected by RH. Four nebulizers were chosen for comparison in this study: PARI LC Plus (PARI Respiratory Equipment, Inc., Midlothian, VA), SideStream (Medic-Aid Ltd., UK), VixOne (Westmed, Inc., Tucson, AZ), and Micromist (Hudson Respiratory Care Inc., Temecula, CA). Two different formulations were used: albuterol (liquid solution) and budesonide (suspension). Particle distribution (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]), nebulizer efficiency (total efficiency and respirable fraction [RF] efficiency for particles less than 4.7 microm), and dead volume (the amount of solution remaining after nebulization) were compared at the RH of 5%, 50%, and 80%. Our results showed that the MMAD increased (p value varied from <0.001 to 0.016) with the increase in RH, except for with the VixOne unit with albuterol (p = 0.24). The MMAD from the budesonide always appeared higher than from the albuterol. The RF (and thus, the inhalation dose) was lower with a higher RH. Except for the PARI LC Plus with budesonide, the RF decreased approximately 15-27% when the RH rose from 5% to 50%. For the PARI LC Plus nebulizer, the lower dead volume (0.22 mL) with higher residual drugs (62.3% of total drug) was obtained at an RH of 5% comparing the RH of 50% and 80% because of the unit's unique design.

Aerosols↗
PubMed2004

Health effects of subchronic exposure to environmental levels of diesel exhaust.

Diesel exhaust is a public health concern and contributor to both ambient and occupational air pollution. As part of a general health assessment of multiple anthropogenic source emissions conducted by the National Environmental Respiratory Center (NERC), a series of health assays was conducted on rats and mice exposed to environmentally relevant levels of diesel exhaust. This article summarizes the study design and exposures, and reports findings on several general indicators of toxicity and carcinogenic potential. Diesel exhaust was generated from a commonly used 2000 model 5.9-L, 6-cylinder turbo diesel engine operated on a variable-load heavy-duty test cycle burning national average certification fuel. Animals were exposed to clean air (control) or four dilutions of whole emissions based on particulate matter concentration (30, 100, 300, and 1000 microg/m(3)). Male and female F344 rats and A/J mice were exposed by whole-body inhalation 6 h/day, 7 days/wk, for either 1 wk or 6 mo. Exposures were characterized in detail. Effects of exposure on clinical observations, body and organ weights, serum chemistry, hematology, histopathology, bronchoalveolar lavage, and serum clotting factors were mild. Significant exposure-related effects occurring in both male and female rats included decreases in serum cholesterol and clotting Factor VII and slight increases in serum gamma-glutamyl transferase. Several other responses met screening criteria for significant exposure effects but were not consistent between genders or exposure times and were not corroborated by related parameters. Carcinogenic potential as determined by micronucleated reticulocyte counts and proliferation of adenomas in A/J mice were unaffected by 6 mo of exposure. Parallel studies demonstrated effects on cardiac function and resistance to viral infection; however, the results reported here show few and only modest health hazards from subchronic or shorter exposures to realistic concentrations of contemporary diesel emissions.

Adenoma↗
PubMed2001

Characterization of the mouse phenylalanine hydroxylase mutation Pah(enu3).

Phenylketonuria (PKU) is an inborn error of metabolism that is inherited in an autosomal recessive manner. It arises from a deficiency of phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine and thereby hastening its catabolism. To produce mouse models for the study of PKU, male mice were mutagenized with ethylnitrosourea and their progeny were screened for the elevated phenylalanine levels characteristic of phenylalanine hydroxylase deficiency. Of three mutant alleles recovered, two (Pah(enu1) and Pah(enu2)) were characterized previously and shown to be missense mutations. Sequencing of phenylalanine hydroxylase cDNA from the third mutant allele, Pah(enu3), revealed that two differently sized transcripts were being produced. These transcripts contained either a 5-nucleotide insertion or a 5-nucleotide deletion and both of these modifications occurred at the same location, the exon 11-exon 12 junction. Sequencing of the exon 11-intron 11 boundary revealed a T --> G transversion in the invariant GT dinucleotide of the wild-type 5' splice donor site. The analogous human Pah mutation would be called c.1199 + 2T > G. Sequence analysis also revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site, that appear to be used when the wild type is ablated and to thereby yield the observed differently sized transcripts. The 5-nucleotide insertion and the 5-nucleotide deletion are both predicted to cause frame shifting in exon 12 and exon 13, leading to premature termination.

Alleles↗
PubMed2001

Effect of maternal blood phenylalanine level on mouse maternal phenylketonuria offspring.

The genetic mouse model BTBR-Pah(enu2) was used to more thoroughly investigate the pathogenesis of maternal phenylketonuria (MPKU). More specifically, it was used to examine the effect of maternal blood phenylalanine (PHE) level on the pregnancy outcome of MPKU offspring as determined by certain key measures of development at birth (i.e., head circumference, weight, and crown-rump length of offspring). In this study, we clearly observed that elevated maternal blood PHE levels, whether they were caused by the maternal diet or the maternal genotype, were responsible for fetal abnormalities. As in human MPKU, significant reductions (P < 0.0001) in birth weight, crown-rump length, and head circumference were seen in offspring gestated under the condition of high maternal blood PHE levels. These findings strongly suggest that there are sufficient similarities between human MPKU and MPKU in this mouse model to establish it as a very promising model for future studies designed to characterize human MPKU more thoroughly.

Abortion, Spontaneous↗
PubMed2000

A heteroallelic mutant mouse model: A new orthologue for human hyperphenylalaninemia.

Hyperphenylalaninemias (HPA) are Mendelian disorders resulting from deficiencies in the conversion of phenylalanine to tyrosine. The vast majority are explained by a primary deficiency of phenylalanine hydroxylase (PAH) activity. The majority of untreated patients experience irreversible impairment of cognitive development. Although it is one of the best known hereditary metabolic disorders, mechanisms underlying the pathophysiology of the disease are still not fully understood; to this end, the availability of an orthologous animal model is relevant. Various mutant hyperphenylalaninemic mouse models with an HPA phenotype, generated by N-ethyl-N'-nitrosourea (ENU) mutagenesis at the Pah locus, have become available. Here we report a new hybrid strain, ENU1/2, with primary enzyme deficiency, produced by cross breeding. The ENU1, ENU1/2, and ENU2 strains display mild, moderate, and severe phenotypes, respectively, relative to the control strain (BTBR/Pas). The Pah enzyme activities of the various models correlate inversely with the corresponding phenylalanine levels in plasma and brain and the delay in plasma clearance response following a phenylalanine challenge. The maternal HPA effect on the fetus correlates directly with the degree of hyperphenylalaninemia, but only the ENU2 strain has impaired learning.

Alleles↗
PubMed2000

Postnatal growth in a mouse genetic model of classical phenylketonuria.

Because of the ethical problems of withholding dietary treatment from patients with phenylketonuria, effectively studying long-term effects such as postnatal growth rates is difficult or impossible. The only literature available on the growth rate of phenylketonurics dates from the era before effective dietary treatment regimens were instituted routinely. Although some of these studies suggest that these patients have a reduced growth rate, whether this is a consistent feature of the untreated phenylketonuric is unclear. The mutant mouse line BTBR-Pahenu, a genetic model for human phenylketonuria, provides an opportunity to conduct studies that will clarify this issue. In this study, the weights of newborn mice were monitored from about 7 to 40 days after birth. Comparison to heterozygous, sex-matched littermates revealed a reduction in the size of homozygous mutants throughout the study. Therefore, reduced postnatal growth is an abiding feature of phenylketonuria in this mouse model. This finding not only helps to document the association between size reduction and untreated phenylketonuria but also sets the stage for studies designed to investigate the means by which size reduction occurs.

Animals↗
PubMed1999

Linkage analysis of the hph-1 mutation and the GTP cyclohydrolase I structural gene.

Our research establishes genetic linkage between the hph-1 mutation and the GTP-CH I structural gene. Our results indicate that these two loci are within an 8 cM region with 95% confidence. This finding lends additional support for the use of the hph-1 mouse mutant as a bona fide model system for the human disorder GTP-CH I to further our understanding of the molecular mechanisms involved in the disease pathology of GTP-CH I deficiency.

Alleles↗
PubMed1999

Integration of preoperative and intraoperative functional brain mapping in a frameless stereotactic environment for lesions near eloquent cortex. Technical note.

The authors present a method of incorporating preoperative noninvasive functional brain mapping data into the frameless stereotactic magnetic resonance (MR) imaging dataset used for image-guided resection of brain lesions located near eloquent cortex. They report the use of functional (f)MR imaging and magnetic source (MS) imaging for preoperative mapping of eloquent cortex in difficult cases of brain tumor resection such as those in which there are large expansive masses or in which reoperations are required and the anatomy is distorted from prior treatments. To correlate methods of preoperative and intraoperative mapping localization directly, the authors have developed techniques of importing preoperative MS and fMR imaging data into an image-guided frameless stereotactic computer workstation. The data appear as a seamless overlay on the same preoperative volumetric MR imaging dataset used for stereotactic guidance during the operation. Intraoperatively identified functional locations mapped by cortical stimulation are recorded as digitally registered points. This approach should prove useful in assessing the accuracy and reliability of various preoperative functional brain mapping techniques.

Adult↗
PubMed1997

Characterization of mutations at the mouse phenylalanine hydroxylase locus.

Two genetic mouse models for human phenylketonuria have been characterized by DNA sequence analysis. For each, a distinct mutation was identified within the protein coding sequence of the phenylalanine hydroxylase gene. This establishes that the mutated locus is the same as that causing human phenylketonuria and allows a comparison between these mouse phenylketonuria models and the human disease. A genotype/phenotype relationship that is strikingly similar to the human disease emerges, underscoring the similarity of phenylketonuria in mouse and man. In PAHENU1, the phenotype is mild. The Pahenu1 mutation predicts a conservative valine to alanine amino acid substitution and is located in exon 3, a gene region where serious mutations are rare in humans. In PAHENU2, the phenotype is severe. The Pahenu2 mutation predicts a radical phenylalanine to serine substitution and is located in exon 7, a gene region where serious mutations are common in humans. In PAHENU2, the sequence information was used to devise a direct genotyping system based on the creation of a new Alw26I restriction endonuclease site.

Animals↗
PubMed1997

Cardiovascular defects among the progeny of mouse phenylketonuria females.

In a genetic mouse model of human phenylketonuria we have examined the offspring of hyperphenylalaninemic mothers for the presence of cardiovascular defects, an important feature of the pathology of the human maternal phenylketonuria syndrome. Beginning at 14.5 d after conception (75% through gestation), a variety of cardiovascular defects became apparent among the progeny of the hyperphenylalaninemic females. These defects ranged from mild to serious and correlated with the maternal but not the fetal Pah genotype. Nearly all of the defects were vascular, however, whereas the most reported in humans so far have been cardiac. The predisposing biochemical condition in this mouse disease model seems to be the same as in the human disease; elevated maternal blood phenylalanine levels concentrated across the placental barrier to produce a teratogenic developmental environment. This model for congenital cardiovascular defects should enhance two related areas of research. 1) It should allow a more thorough investigation of the relationship between maternal diet and maternal phenylketonuria birth defects, and 2) it should provide an experimental tool to gain insight into the normal process of cardiovascular development.

Animals↗
PubMed1996

Tumor suppressor genes and medulloblastoma.

Although primary intracranial neoplasms are the most common type of solid cancer in children, little is known about their etiology at the molecular genetic level. Recently, studies have shown that a class of genes known as tumor suppressors play an important role in the origin of several different types of human tumors, including those located in the central nervous system (CNS). Using a variety of techniques, selective loss of DNA sequences has been identified in tissue specimens from children with medulloblastoma, one of the most common pediatric brain tumors. The most consistent losses to date have been shown for probes located on distal chromosome arm 17p. Although the known tumor suppressor p53 is located on this chromosome, and deletion and mutation of the p53 gene are the most common genetic events in human cancers of many types, such alterations have been infrequently detected in medulloblastoma specimens. These results suggest that inactivation of another tumor suppressor gene or genes located on 17p is important in medulloblastoma tumorigenesis. Deletion of 17p has also been shown to have implications for clinical management, as the loss of DNA sequences located on this chromosome arm is strongly associated with a negative prognosis for these patients. The identification and cloning of this tumor suppressor gene or genes will aid in understanding of the pathogenesis of medulloblastoma, as well as guiding the development of novel and more effective strategies for a cure.

Cerebellar Neoplasms↗
PubMed1996

Correlation of chromosome 17p loss with clinical outcome in medulloblastoma.

Medulloblastomas are primitive neuroectodermal tumors that arise in the cerebella of children. Cytogenetic and loss of heterozygosity (LOH) studies have shown that deletions on the short arm of chromosome 17 occur in 25-50% of cases, suggesting that loss of a tumor suppressor gene located on 17p plays a role in the genesis or progression of medulloblastoma. We report here on an LOH analysis of 21 patients with medulloblastoma using markers for 15 polymorphic loci previously ordered on chromosome 17 by meiotic break point mapping. Although the frequency of LOH in our patients (48%) was consistent with previous reports, our maps showed much larger deletions, the smallest spanning a 38-cM genetic distance distal to marker UT49 (D17S731). Survival analysis did not show a significant association between LOH on 17p and survival, although the sample size was too small to rule out a difference of less than 10-fold. Clinical risk factors were better prognostic indicators than LOH, with significantly prolonged survival in patients free of craniospinal metastasis following gross total tumor resection.

Adolescent↗
PubMed1995

Using high-efficiency mouse germline mutagenesis to investigate complex biological phenomena: genetic diseases, behavior, and development.

A valuable approach to investigating a biological process is to study the effect of mutations in the involved genes. By studying a diverse set of such mutations, one can gain important insights into the roles that the given gene product plays in the biological process. Although this approach has long been recognized, the scarcity of mammalian mutations has largely limited such investigations to simple organisms. It has recently been shown that highly efficient mutagenesis of the mouse germline with a random point mutagen can produce mutations that are valuable in several important ways. First, it can produce numerous different types of mutations. Second, it can be used to mutate genes that have yet to be cloned or characterized. Genes that have been marked by mutation can ultimately yield molecular access after mapping to high resolution and cloning from map position. Such new investigative capabilities will ultimately allow one to gain intimate knowledge of the molecular basis of complex biological processes like behavior and development. Third, mutations can be induced that yield animal models of human heritable diseases. Such disease models allow for intensive research into the etiology of the given disease and also permit the facile evaluation of new therapeutic regimens.

Animals↗