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Biomedical subjects

L Garrett

Publications and source records attributed to L Garrett.

At least 19 recordsLinked to original sources
PubMed2005

Lineage differentiation of canine lymphoma/leukemias and aberrant expression of CD molecules.

Multiparameter flow cytometry analysis and specific cluster differentiation (CD) molecules were used to determine the expression profiles of B- and T-cell antigens on lymph node preparations from 59 dogs with generalized or multisystemic lymphoma. Lymph node samples from 11 healthy dogs were labeled to validate the specificity of antibodies and to formulate guidelines for interpretation of the results obtained from lymphoma samples. In normal lymph nodes, T-lymphocytes expressing CD3, CD4, or CD8 beta represented 59+/-11%, 43+/-8%, or 16+/-5% of the total cells, whereas B-lymphocytes expressing either CD21 or surface IgM (IgM) represented 37+/-9% or 14+/-5%, respectively. Small lymphocytes could be distinguished from large lymphocytes by forward light scatter. Of the patient samples 29 different breeds were represented with Golden and Labrador retriever being the most common. The lymphoma samples segregated into three groups based on CD antigen expression. Thirty cases predominantly expressed one or more combinations of CD79a, IgM, and CD21 representing a B-cell lineage. Three B-cell cases also expressed the stem cell antigen, CD34. Sixteen cases expressed one or more combinations of CD3, CD4, and CD8 consistent with a T-cell lineage and CD3+CD4+CD8--phenotype was the most common. Thirteen cases showed a mixed expression profile for T- and B-cell antigens and in three cases CD14 was highly expressed. Clinical response was poorest for T-cell lymphomas. Leukemic states occurred in all three phenotypes; but mixed cell cases had the greatest proportion. Dual immunofluorescence staining confirmed co-expression of T-cell (CD3) and B-cell antigens (CD79a or CD21) on neoplastic lymphocytes of six mixed cell cases. In one mixed cell case, dual immunostaining identified lymphocyte populations that stained mutually exclusive for CD79a and CD3. Six mixed cell lymphomas tested by PCR showed clonality for rearranged antigen receptor. Four cases that were CD79a+CD3+ had TCRgamma chain gene rearrangements, whereas two cases that were CD3+CD8+CD21+ had Ig heavy chain rearrangement. One case expressing multiple CD molecules (CD3+CD8+CD21+CD14+) was PCR negative for both Ig and TCRgamma gene rearrangement and could not be classified into a B- or T-cell lineage. We show for the first time co-expression of B- and T-cell markers on lymphoma cells that had specific T- or B-cell gene rearrangements. These findings suggest that aberrant CD molecule expression is not an uncommon finding in canine lymphomas and is a useful diagnostic marker for malignancy.

Animals↗
PubMed2005

Multiple dose pharmacokinetics and acute safety of piroxicam and cimetidine in the cat.

The purpose of this study was to evaluate the multiple dose pharmacokinetics and acute safety of piroxicam and cimetidine alone and in combination in cats. Seven healthy cats were included in this randomized-crossover study. The cats were assigned to groups designated to receive cimetidine alone (15 mg/kg, p.o., q12 h), piroxicam alone (0.3 mg/kg, p.o., q24 h), and piroxicam combined with cimetidine (both at aforementioned doses). The cats were dosed for 10 days followed by at least a 2-week washout period between trials. Serial blood samples were collected following the first and last doses and analyzed utilizing a high-performance liquid chromatography with mass spectrometry detection (LC/MS) assay. Pharmacokinetic parameters were determined using noncompartmental analysis. Endoscopic evaluation of the gastric mucosa was performed and serum urea nitrogen (SUN), creatinine, alkaline phosphatase (ALP), and alanine transaminase (ALT) activities were evaluated. There were not a clinically relevant difference between the pharmacokinetic parameters of piroxicam administered alone or in combination with cimetidine after either the first or last dose. Gastric ulcers were not observed in any cats although gastric erosions were. The SUN, creatinine, ALP, and ALT activities remained within reference ranges for all cats. It appears that once daily, short-term use of piroxicam alone and in combination with cimetidine in cats is relatively safe based on the parameters evaluated in this study. However, further studies are necessary to determine the long-term gastrointestinal safety of piroxicam.

Administration, Oral↗
PubMed2004

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia.

Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.

Acute Disease↗
PubMed2001

Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion.

The Smad family of intracellular signaling intermediates transduce signals downstream from the transforming growth factor beta (TGF-beta) family of receptor serine threonine kinases. The original member of this family, Smad1, has been shown to mediate signals from receptors for the bone morphogenetic proteins (BMPs), a large group of ligands in the TGF-beta superfamily that mediate important developmental events. We have targeted the Smad1 gene in mice and created mutants null at this locus. Smad1 mutant mice die at approximately 9.5 days postcoitum due to defects in allantois formation. In Smad1 mutant mice, the allantois fails to fuse to the chorion, resulting in a lack of placenta and failure to establish a definitive embryonic circulation. Although vasculogenesis is initiated in the mutant allantois, the vessels formed are disorganized, and VCAM-1 protein, a marker for distal allantois development, is not expressed. Smad1 null fibroblasts are still able to respond to BMP2, however, suggesting that the defect observed in the developing extraembryonic tissue is caused by a very specific loss of transcriptional activity regulated by Smad1. Our data further demonstrate that although highly similar structurally, Smad proteins are not functionally homologous.

Allantoin↗
PubMed2001

Safety profile and tolerability of amprenavir in patients enrolled in an early access program.

BACKGROUND: The amprenavir (APV) early or expanded access program was designed to provide open-label APV to patients who would potentially receive benefit beyond that expected from currently available protease inhibitors (PIs) and who were at risk of disease progression before the drug's expected time of regulatory approval. OBJECTIVE: This study was conducted as part of an early access program to assess the safety profile and tolerability of APV in adults and children (> or =4 years of age) who were either intolerant to or, in the opinion of the patient's physician, virologically failing a previous PI-containing antiretroviral regimen. Specific CD4+ cell count and viral load limits were not imposed by this early access protocol. METHODS: This open-label, nonrandomized study was conducted at multiple sites throughout the United States. Adults received APV at a dosage of 1200 mg BID. Patients weighing <50 kg received APV at a dosage of 20 mg/kg BID for the solid formulation or 1.5 mL/kg BID for the liquid formulation. RESULTS: A total of 489 physicians registered for this program; 364 (74.4%) enrolled patients. The safety population of 2217 patients (2048 males [92.4%] and 169 females [7.6%] aged 2 to 74 years) received APV for a median duration of 85 days (range, 2-218 days). Patients in the intent-to-treat population (n = 1427) had extensive experience with antiretroviral therapy. Drug-related treatment-emergent adverse events reported in >3% of patients in the safety population were nausea in 279 patients (12.6%), diarrhea in 197 patients (8.9%), rash in 177 patients (8.0%), vomiting in 148 patients (6.7%), and fatigue in 89 patients (4.0%). Adverse events and laboratory test abnormalities were graded for severity on a scale of 1 to 4 in accordance with AIDS Clinical Trials Group guidelines. Grade 3 treatment-emergent abnormal laboratory values regardless of causality occurring in >3% of patients were neutropenia in 69 of 1887 patients (3.7%; grade 3 toxicity = 500-749/mm3) and elevated triglycerides in 80 of 1593 patients (5.0%; grade 3 toxicity = 751-1200 mg/dL). Most common grade 4 treatment-emergent laboratory abnormalities were elevated serum creatine phosphokinase levels in 36 of 1266 patients (2.8%; grade 4 = >6 times upper normal limit), elevated triglycerides in 39 of 1593 patients (2.4%), and neutropenia in 41 of 1887 patients (2.2%). CONCLUSIONS: The results of this large cohort of patients support the data from the phase II/III clinical development program and suggest that APV has an acceptable safety profile and is generally well tolerated when used in combination with other antiretroviral drugs in a heavily treatment-experienced, heterogeneous patient population.

Adolescent↗
PubMed2001

Targeted disruption of the methionine synthase gene in mice.

Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2000

Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone.

Patients with mutations in the thyroid hormone receptor beta (TRbeta) gene manifest resistance to thyroid hormone (RTH), resulting in a constellation of variable phenotypic abnormalities. To understand the molecular basis underlying the action of mutant TRbeta in vivo, we generated mice with a targeted mutation in the TRbeta gene (TRbetaPV; PV, mutant thyroid hormone receptor kindred PV) by using homologous recombination and the Cre/loxP system. Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with RTH. Homozygous PV mice exhibit severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype is distinct from that seen in mice with a null mutation in the TRbeta gene. Importantly, we identified abnormal expression patterns of several genes in tissues of TRbetaPV mice, demonstrating the interference of the mutant TR with the gene regulatory functions of the wild-type TR in vivo. These results show that the actions of mutant and wild-type TRbeta in vivo are distinct. This model allows further study of the molecular action of mutant TR in vivo, which could lead to better treatment for RTH patients.

Alleles↗
PubMed2000

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

Allosteric Site↗
PubMed2000

Bcl-x and Bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis.

Restricted germ cell loss through apoptosis is initiated in the fetal gonad around embryonic day 13.5 (E13.5) as part of normal germ cell development. The mechanism of this germ cell attrition is unknown. We show that Bcl-x plays a crucial role in maintaining the survival of mouse germ cells during gonadogenesis. A bcl-x hypomorphic mouse was generated through the introduction of a neomycin (neo) gene into the promoter of the bcl-x gene by homologous recombination. Mice that contained two copies of the hypomorphic allele had severe reproductive defects attributed to compromised germ cell development. Males with two mutant alleles lacked spermatogonia and were sterile; females showed a severely reduced population of primordial and primary follicles and exhibited greatly impaired fertility. Primordial germ cells (PGCs) in bcl-x hypomorph mice migrated to the genital ridge by E12.5 but were depleted by E15.5, a time when Bcl-x and Bax were present. Two additional bcl-x transcripts were identified in fetal germ cells more than 300 bp upstream of previously reported start sites. Insertion of a neo cassette led to a down-regulation of the bcl-x gene at E12.5 in the hypomorph. Bax was detected by immunohistochemistry in germ cells from bcl-x hypomorph and control testes at E12.5 and E13.5. Bcl-x function was restored, and animals of both genders were fertile after removal of the neo selection cassette using Cre-mediated recombination. Alternatively, the loss of Bcl-x function in the hypomorph was corrected by the deletion of both copies of the bax gene, resulting in a restoration of germ cell survival. These findings demonstrate that the balance of Bcl-x and Bax control PGC survival and apoptosis.

Animals↗
PubMed1999

Effects of providing hospital-based doulas in health maintenance organization hospitals.

OBJECTIVE: To evaluate whether providing doulas during hospital-based labor affects mode of delivery, epidural use, breast-feeding, and postpartum perceptions of the birth, self-esteem, and depression. METHODS: This was a randomized study of nullipara enrollees in a group-model health maintenance organization who delivered in one of three health maintenance organization-managed hospitals; 149 had doulas, and 165 had usual care. Study data were obtained from the mothers' medical charts, study intake forms, and phone interviews conducted 4-6 weeks postpartum. RESULTS: Women who had doulas had significantly less epidural use (54.4% versus 66.1%, P < .05) than women in the usual-care group. They also were significantly (P < .05) more likely to rate the birth experience as good (82.5% versus 67.4%), to feel they coped very well with labor (46.8% versus 28.3%), and to feel labor had a very positive effect on their feelings as women (58.0% versus 43.7%) and perception of their bodies' strength and performance (58.0% versus 41.0%). The two groups did not differ significantly in rates of cesarean, vaginal, forceps, or vacuum delivery, oxytocin administration; or breast-feeding, nor did they differ on the postpartum depression or self-esteem measures. CONCLUSION: For this population and setting, labor support from doulas had a desirable effect on epidural use and women's perceptions of birth, but did not alter need for operative deliveries.

Adolescent↗
PubMed1998

Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA.

Huntington disease (HD) is an adult-onset, autosomal dominant inherited human neurodegenerative disorder characterized by hyperkinetic involuntary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus and hippocampus are well recognized as neuropathological correlates for the clinical manifestations of HD. The underlying genetic mutation is the expansion of CAG trinucleotide repeats (coding for polyglutamines) to 36-121 copies in exon 1 of the HD gene. The HD mRNA and protein product (huntingtin) show widespread distribution, and thus much remains to be understood about the selective and progressive neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of full-length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus and hippocampus. These animals represent clinically relevant models for HD pathogenesis, and may provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.

Animals↗
PubMed1998

Economic outcomes associated with the use of risperidone in a naturalistic group practice setting.

The purpose of this cohort pilot study was to compare the resource utilization and economic outcomes associated with the use of risperidone versus haloperidol in a naturalistic setting. Patient charts from a large psychiatric group practice were reviewed, and hospital billing data were obtained. Patients meeting the inclusion criteria were placed into one of two cohorts depending on their medication history. Thirty patients treated with risperidone met the selection criteria, and a random quota sampling technique was used to allow for a matched control cohort of 30 patients treated with haloperidol. In the haloperidol and risperidone cohorts, 24 and 28 patients, respectively, were evaluated statistically. Mean utilization rates and costs per patient per month for each service were estimated by using regression analysis. Patients in the risperidone cohort had significantly fewer hospitalizations than did those in the haloperidol cohort (P = 0.004). Likewise, risperidone patients had significantly lower hospitalization costs than haloperidol patients (P = 0.005). Conversely, patients treated with risperidone visited the physician more frequently than did those treated with haloperidol (P = 0.0005). Estimated mean total monthly costs were $123.34 lower (95% confidence interval = $464, $217) per patient in the risperidone cohort than in the haloperidol cohort ($1,636.11 vs $1759.45; P = 0.4693). Significant reductions in hospital costs in the risperidone cohort offset higher medication and physician costs. Overall, total monthly costs were similar for the two cohorts.

Antipsychotic Agents↗