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Biomedical subjects

R Myers

Publications and source records attributed to R Myers.

At least 19 recordsLinked to original sources
PubMed2006

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders.

Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders.

Antidepressive Agents↗
PubMed2006

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model.

Because of their ability to replicate, the dose-response relationships of oncolytic viruses cannot easily be predicted. To better understand the pharmacokinetics of virotherapy in relation to viral dose and schedule, we administered MV-CEA intraperitoneally in an orthotopic mouse model of ovarian cancer. MV-CEA is an attenuated oncolytic measles virus engineered to express soluble human carcinoembryonic antigen (CEA), and the virus is currently undergoing phase I clinical testing in patients with ovarian cancer. Plasma CEA levels correlate with numbers of virus-infected tumor cells at a given time, and were used as a surrogate to monitor the profiles of viral gene expression over time. The antineoplastic activity of single- or multiple-dose MV-CEA was apparent over a wide range of virus doses (10(3)-10(8) TCID(50)), with little reduction in observed antitumor efficacy, even at the lowest tested dose. However, analysis of CEA profiles of treated mice was highly informative, illustrating the variability in virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice.

Animals↗
PubMed2005

Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41.

The objective of this study was to track the evolution of sequence changes in both the heptad region 1 (HR1) and HR2 domains of gp41 associated with resistance to enfuvirtide (ENF) in a patient cohort receiving long-term ENF treatment. We studied 17 highly antiretroviral agent-experienced patients receiving long-term ENF treatment with virological rebound or a lack of suppression. Sixty-two samples obtained after between 5 and 107 weeks of ENF therapy were analyzed. Baseline samples from 15 of these 17 patients were available for analysis. Viruses from five samples from four patients were also sequenced after the cessation of ENF therapy. Drug susceptibilities were assessed by a pseudotype virus reporter assay. We identified HR1 and HR2 sequence changes over time in relation to the baseline sequences. Mutations in HR1 (amino acids 36 to 45) were noted in all cases, including previously unreported changes N42Q/H and N43Q. In addition to a range of HR2 sequence changes at polymorphic sites, isolates from 6 of 17 (35%) patients developed an S138A substitution in the HR2 domain at least 8 weeks after the start of ENF treatment and also subsequent to the first emergence of HR1 mutations. In most, but not all, cases the S138A mutation accompanied HR1 mutations at position 43. Molecular modeling demonstrates the close proximity of S138A with amino acids 40 and 45 in HR1. Of note, isolates in samples available from four patients demonstrated the loss of both the HR1 and the S138A HR2 mutations following the cessation of therapy. We show that the S138A HR2 mutation increased the level of resistance by approximately threefold over that conferred by the HR1 mutation N43D. Continual evolution of HR1 in the domain from amino acids 36 to 45 was observed during long-term ENF therapy. We have identified, for the first time, an ENF resistance-associated HR2 mutation, S138A, which appeared in isolates from 6 of 17 patients with virological failure and demonstrated its potential to contribute to drug resistance. We propose that this represents a possible secondary and/or compensatory mutation, particularly when it coexists with mutations at position 43 in HR-1.

Amino Acid Sequence↗
PubMed2003

[11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy.

Microglia, the brain's intrinsic macrophages, bind (R)-PK11195 when activated by neuronal injury. The authors used [11C](R)-PK11195 PET to localize in vivo microglial activation in patients with multiple system atrophy (MSA). Increased [11C](R)-PK11195 binding was primarily found in the dorsolateral prefrontal cortex, putamen, pallidum, pons, and substantia nigra, reflecting the known distribution of neuropathologic changes in MSA. Providing an indicator of disease activity, [11C](R)-PK11195 PET can thus be used to characterize the in vivo neuropathology of MSA.

Aged↗
PubMed2003

Use of cancer susceptibility testing among primary care physicians.

Primary care physicians (PCPs) are assuming greater roles in cancer risk assessment and susceptibility testing of patients. The objective of this study was to assess the beliefs and practices of PCPs relative to genetic susceptibility testing for cancer. A cross-sectional survey was mailed to 726 PCPs in community-based practices in southeastern Pennsylvania and southern New Jersey. Data were collected on physician background, cognitive and psychosocial factors, practice environment, and patient factors. The main outcome measure was physician self-reported recommendation or referral of patients for cancer genetic susceptibility testing in a 12-month period prior to the survey. Of those surveyed, 475 (65%) PCPs responded. Complete survey data were available for 433 PCPs. Multivariable analyses show that factors positively associated with PCP recommendation/referral included: patient inquiry about their need for genetic testing for cancer (p < 0.001); PCP belief that patient age is the best predictor of cancer risk (p = 0.01); PCP self-reported frequency of collecting patient diet information (p = 0.01) and medical history information (p = 0.01); and PCP participation in an integrated health system (p = 0.01). PCP use of cancer genetic susceptibility testing may be influenced by patient inquiry, provider beliefs about factors that affect cancer risk, provider collection of risk-assessment data, and provider practice environment.

Cross-Sectional Studies↗
PubMed2003

Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Gemcitabine (difluorodeoxycytidine) is active as a single agent in Hodgkin's disease and has been used successfully in combination with cisplatin to treat a variety of solid tumors. PATIENTS AND METHODS: We evaluated the combination of gemcitabine/dexamethasone/cisplatin (GDP) as salvage chemotherapy in 23 patients with relapsed or refractory Hodgkin's disease (median age 36 years, range 19-57). Treatment consisted of gemcitabine 1000 mg/m(2) intravenously on days 1 and 8, dexamethasone 40 mg orally days 1-4 and cisplatin 75 mg/m(2) on day 1, every 21 days as an outpatient. Response was assessed following two cycles of treatment. RESULTS: There were four complete responses and 12 partial responses for a response rate of 69.5% (95% confidence interval 52% to 87%); the remaining seven patients had stable disease and no patient progressed on treatment. All patients had successful stem cell mobilization and underwent transplantation with a median 10.6 x 10(6) CD34+ cells/kg. Hematological toxicity from GDP was mild (grade 3 neutropenia 8.6%, grade 3 thrombocytopenia 13%). CONCLUSIONS: In summary, GDP is an active regimen for patients with relapsed or refractory Hodgkin's disease. The response rate is similar to the rates of other current salvage regimens, it can be given to outpatients with tolerable toxicity and it does not inhibit the mobilization of autologous stem cells.

Administration, Oral↗
PubMed2002

Genome scan for quantity of hand osteoarthritis: the Framingham Study.

OBJECTIVE: To search for markers linked to quantity of radiographic hand osteoarthritis (OA) in the Framingham Heart Study. METHODS: The sample included 684 original cohort members and 793 offspring in 296 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence (K/L) score, osteophytes, and joint space narrowing (0-3 scale). Four quantitative phenotypes were computed from these measurements: sum of K/L scores across hand joints, sum of osteophyte scores, sum of joint space narrowing scores, and proportion of affected joints. Prior to linkage analysis, these phenotypes were adjusted for age using a linear regression analysis from which standardized residuals were computed. The regression analysis was performed separately for each sex and each generation. The variance component model (SOLAR) was then applied to the normalized scores of the residuals. RESULTS: The average age was 62 years for the original cohort and 54 years for the offspring. Fifty percent of the original cohort and 30% of their offspring had at least 1 affected joint (K/L score >or=2). Heritability ranged from 28% (proportion of joints affected with OA) to 34% (sum of K/L scores). Eight chromosomal regions indicated suggestive linkage (multipoint logarithm of odds [LOD] score >1.5) for at least 1 phenotype; LOD scores were highest for joint space narrowing, with a multipoint LOD score = 2.96 on chromosome 1p at D1S1665. Chromosomes 7, 9, 13, and 19 indicated consistent LOD score elevation for multiple OA phenotypes. CONCLUSION: There are several chromosomes that may harbor OA susceptibility genes. Further investigation of these regions using larger studies and finer maps will be important to confirm linkage.

Adult↗
PubMed2002

Dedicated small animal scanners: a new tool for drug development?

Nuclear imaging techniques can provide information about the time course of uptake, the spatial distribution, and the functional effects of a drug in the human body. Recently, PET has also acquired the potential to affect the drug development process during a very early stage, when a drug is undergoing animal testing. The development of dedicated small animal scanners with high resolution has made it possible to assess the time course of uptake of a drug within a single animal, providing that the drug is labelled with a positron-emitting isotope. Dedicated small animal scanners may therefore prove to be very useful, especially in those parts of the drug development process that require a longitudinal study design. However, in the case of receptor and enzyme studies, there may be pharmacological constraints and specific radioactivity of the radiopharmaceuticals may become an important issue. This paper will assess the potential and also the limitations of high-resolution PET in animal testing of therapeutic drugs.

Animals↗
PubMed2001

Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury.

Limb denervation leads to reorganization of the representational zones of the somatosensory cortex. Using [11C](R)-PK11195, a sensitive in vivo marker of glial cell activation, and PET, we provide first evidence that limb denervation induces a trans-synaptic increase in [11C](R)-PK11195 binding in the human thalamus but not somatosensory cortex: these brain structures appeared morphologically normal on magnetic resonance imaging (MRI). The increased thalamic signal was detectable many years after nerve injury, indicating persistent reorganization of the thalamus. This glial activation, beyond the first-order projection area of the injured neurons, may reflect continually altered afferent activity. Our findings support the view that long-term rearrangement of cortical representational maps is significantly determined within the thalamus.

Adult↗
PubMed2001

Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511).

OBJECTIVE: To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients. DESIGN: Phase III, multicenter, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid). Data were analyzed on an intent-to-treat basis. RESULTS: Sixty-seven percent of patients receiving nelfinavir 750 mg tid, and 50% receiving nelfinavir 500 mg tid in combination with ZDV/3TC achieved HIV RNA < 400 copies/ml compared to 7% receiving ZDV/3TC plus placebo (P < 0.001); 55% and 30% of patients in the nelfinavir-containing arms achieved HIV RNA < 50 copies/ml at week 24. This compared with 4% in the placebo-containing arm. For patients continuing nelfinavir treatment (750 mg or 500 mg tid as treated) for a further 6 months, the proportions achieving < 400 copies/ml at week 48 were 75% and 54% (P = 0.001) and < 50 copies/ml 61% and 37%, respectively (P = 0.004). The mean increases from baseline in CD4 cell counts were also durable in patients receiving the triple combination nelfinavir therapy. The range and incidence of adverse events was similar for the two nelfinavir-containing arms, with diarrhea being the most common adverse event. CONCLUSIONS: Nelfinavir plus ZDV/3TC was superior to ZDV/3TC/placebo. In addition, the 750 mg tid nelfinavir dose was better than the 500 mg tid dose. Virologic responses were sustained over 12 months.

Adult↗
PubMed2001

In-vivo measurement of activated microglia in dementia.

BACKGROUND: Activated microglia have a key role in the brain's immune response to neuronal degeneration. The transition of microglia from the normal resting state to the activated state is associated with an increased expression of receptors known as peripheral benzodiazepine binding sites, which are abundant on cells of mononuclear phagocyte lineage. We used brain imaging to study expression of these sites in healthy individuals and patients with Alzheimer's disease. METHODS: We studied 15 normal individuals (age 32-80 years), eight patients with Alzheimer's disease, and one patient with minimal cognitive impairment. Quantitative in-vivo measurements of glial activation were obtained with positron emission tomography (PET) and carbon-11-labelled (R)-PK11195, a specific ligand for the peripheral benzodiazepine binding site. FINDINGS: In normal individuals, regional [11C](R)-PK11195 binding did not significantly change with age, except in the thalamus, where an age-dependent increase was found. By contrast, patients with Alzheimer's disease showed significantly increased regional [11C](R)-PK11195 binding in the entorhinal, temporoparietal, and cingulate cortex. INTERPRETATION: In-vivo detection of increased [11C](R)-PK11195 binding in Alzheimer-type dementia, including mild and early forms, suggests that microglial activation is an early event in the pathogenesis of the disease.

Adult↗
PubMed2001

Some applications of near-ultraviolet laser-induced fluorescence detection in nanomolar- and subnanomolar-range high-performance liquid chromatography or micro-high-performance liquid chromatography.

In this work we present some applications of near-UV laser-induced fluorescence (LIF) with micro-HPLC (microHPLC) and HPLC. To test the sensitivity of the detection, we used pyrene and aflatoxins, because both of these molecules exhibit native fluorescence. Then we studied catecholamines derivatized with 1,2-diphenylethylenediamine. The results show that we were able to reach better sensitivity levels than previously described in LIF studies. For catecholamines, a 50-fold increase in sensitivity compared to conventional fluorescence was obtained. These results indicate that LIF detection associated with HPLC or microHPLC can be used to detect very low concentrations of substances that can be excited in the near-UV range after labeling at nanomolar concentrations.

Aflatoxins↗
PubMed2001

Comparative biodistribution and metabolism of carbon-11-labeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and DNA-intercalating analogues.

The tricyclic carboxamide N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a DNA-intercalating agent capable of inhibiting both topoisomerases I and II and is currently in Phase II clinical trial. Many related analogues have been developed, but despite their potent in vitro cytotoxicities, they exhibit poor extravascular distribution. As part of an ongoing drug development program to obtain related "minimal intercalators" with lower DNA association constants, we have compared the biodistribution and metabolite profiles of the prototype compound, DACA, with three analogues to aid rational drug selection. All of these compounds share a common structural feature, N-dimethyl side chain, which was radiolabeled with the positron-emitting radioisotope, carbon-11. This strategy was selected because it allows promising candidates emerging from preclinical studies in animals to be evaluated rapidly in humans using positron emission tomography (PET). The acridine DACA, the phenazine SN 23490, the pyridoquinoline SN 23719, and the dibenzodioxin SN 23935 were found to be cytotoxic in in vitro assays with an IC50 of 1.4-1.8 microM, 0.4-0.6 microM, 1.3-1.6 microM, and 24-36 microM, respectively, in HT29, U87MG, and A375M cell lines. Ex vivo biodistribution studies with carbon-11 radiolabeled compounds in mice bearing human tumor xenografts showed rapid clearance of 11C-radioactivity (parent drug and metabolites) from blood and the major organs. Rapid hepatobiliary clearance and renal excretion were also observed. There was low [<5% of injected dose/gram (%ID/g)] and variable uptake of 11C-radioactivity in three tumor types for all of the compounds. Tumor (U87MG) to blood 11C-radioactivity for [11C]DACA, [11C](9-methoxyphenazine-1-carboxamide (SN 23490), [11C]2-(4-pyridyl)quinoline-8-carboxamide (SN 23719), and [11C]dibenzo[1,4]dioxin-1-carboxamide (SN 23935) at 30 min were 2.9 +/- 1.1, 2.3 +/- 0.6, 2.6 +/- 0.6, and 0.7 +/- 0.2, respectively. For SN 23719, the distribution of 11C-radioactivity in normal tissues and tumors determined ex vivo was in broad agreement with that determined in vivo by whole body PET scanning. [11C]DACA was rapidly and extensively metabolized to several plasma metabolites and a major tumor metabolite. In contrast, [11C]SN 23935, [11C]SN 23490, and [11C]SN 23719 showed less extensive metabolism. In the tumor samples, the parent [11C]DACA and [11C]SN 23935 represented between 0.3 and 1.5%ID/g, whereas [11C]SN 23490 and [11C]SN 23719 represented between 1.5 and 2.8%ID/g. In conclusion, by using a strategy with 11C-labeling, we have determined the tissue distribution and metabolic stability of novel tricyclic carboxamides with the view of selecting analogues with potentially better in vivo activity against solid tumors. SN 23490 and SN 23719 had more favorable distribution and metabolic stability compared with DACA and SN 23935 and may warrant further development. The radiolabeling strategy used allows ex vivo and in vivo evaluation of promising anticancer agents in animals and offers the potential of rapid translation to studies in humans using PET.

Acridines↗
PubMed2001

Effect of 5-HT on binding of [(11)C] WAY 100635 to 5-HT(IA) receptors in rat brain, assessed using in vivo microdialysis nd PET after fenfluramine.

By using a combination of positron emission tomography (PET) and postmortem tissue dissection, the effect of increased endogenous serotonin on specific binding of [(11)C]WAY 100635 to the 5-HT(1A) receptor was investigated in rat brain in vivo. The binding studies were complemented by in vivo microdialysis to monitor 5-HT levels in similarly treated isoflurane-anaesthetised rats, with the dialysis probe locations corresponding to two of the tissues sampled for specific binding of the radioligand. Fenfluramine treatment (10 mg/kg i.p.) resulted in a approximately 5-fold increase in extracellular 5-HT in medial prefrontal cortex and a approximately 15-fold increase in lateral hippocampus, maximal at approximately 40 min after injection. PET scan duration was either 60 or 90 min, beginning 30 min after fenfluramine injection. The specific binding of [(11)C]WAY 100635 was reduced by 10-20% in hippocampus, which showed highest binding in control animals. Specific binding, however, was unaffected in both prefrontal cortex and midbrain raphe, each additional high binding regions. The minimal effects are consistent with a low baseline occupancy of the 5-HT(1A) receptor by 5-HT in vivo, so that only a large change in endogenous agonist concentration will affect radioligand binding. This implies that utilisation of [(11)C]WAY 100635 in human PET to quantify 5-HT(1A) receptor expression can be extended to pathology where synaptic 5-HT levels are altered as a consequence of the disease state.

Animals↗
PubMed2001

Growth and recombination of phage lambda in the presence of exonuclease V from Bacillus subtilis.

When expressed in Escherichia coli, the AddAB exonuclease/recombinase from Bacillus subtilis blocks the growth of phage lambda. Mutants of lambda that are deleted for ea47, a gene of unknown function which is expressed early in the lytic cycle, are not blocked for growth. The blocked-growth phenotype of lambda ea47+ in the presence of AddAB is expressed only when phage DNA replication is permitted.

Bacillus subtilis↗
PubMed2001

Experimental increase in accommodative potential after neodymium: yttrium-aluminum-garnet laser photodisruption of paired cadaver lenses.

PURPOSE: Loss of lens elasticity is one of several proposed mechanisms responsible for the decline in accommodation with age and is the most accepted explanation for presbyopia. We wish to confirm the lens elasticity premise and attempt to experimentally reverse the age-dependent loss of accommodative potential as measured by polar strain. DESIGN: Experimental human autopsy eye study. PARTICIPANTS AND CONTROLS: Thirty-six cadaver lenses were tested to determine the age-dependent polar strain. Eleven lens pairs were then tested with one lens treated with neodymium:yttrium-aluminum-garnet (Nd:YAG) laser and the other left untreated before rotation as an age control. TESTING: Using a custom-made rotational apparatus (described by Fisher, 1971), freshly excised cadaver lenses (<48 hours postmortem) were rotated at 1000 rpm on a 9-mm diameter pedestal to simulate the physiologic pull of the zonules. Lenses were initially tested to determine the age-dependent polar strain. One lens in a pair was then treated with an Nd:YAG laser and the other left untreated before testing. Treatment consisted of 100 suprathreshold pulse placed in a central annular pattern of 2- to 4-mm diameter. Treatment energies varied from 2.5 to 7.0 mJ/pulse, depending on the relative clarity of the lenses. Polar strain was both microscopically measured and calculated from projected photographs before and after rotation of both lased and unlased lenses. Statistically significant differences were determined by paired t test. MAIN OUTCOME MEASURES: Polar strain (decrease in axial thickness with rotation) of the lens. RESULTS: An age-dependent decrease in polar strain was observed that paralleled the findings of Fisher. Both measured and projected polar strain were greater in the lased than unlased lens, and this difference was highly significant by paired t test (P = 0.001 and P = 0.004, respectively). CONCLUSIONS: Age-dependent loss of lens elasticity (polar strain) can be experimentally reversed (increased) by selective intralenticular photodisruption.

Accommodation, Ocular↗
PubMed2001

The biological application of small animal PET imaging.

The short history of small animal PET is reviewed in the context of its application in the laboratory. Early work has demonstrated a role for the technique in both drug development and in the in vivo monitoring of neuroreceptor function with time. As spatial resolution approaches 1 mm, challenges in quantification remain. However, the ability to carry out animal PET studies that are analogous to human PET will form an important bridge between laboratory and clinical sciences.

Animals↗