Biomedical subjects

J M Hoffman

Publications and source records attributed to J M Hoffman.

At least 91 records · Page 5Linked to original sources

PubMed1993

Lysophosphatidic acid mimics serum-induced sensitization of cyclic AMP accumulation.

Pretreatment of 1321N1 human astrocytoma cells with serum induces a pronounced increase in subsequent stimulation by forskolin and other agents of intracellular cyclic AMP accumulation, a phenomenon referred to as sensitization (Mol. Pharmacol. 39, 399-406, 1991). Pretreatment of these cells with lysophosphatidic acid induced sensitization to a similar extent as that with serum (approximately fivefold for forskolin stimulation and twofold for isoproterenol and prostaglandin E1 stimulation), with half-maximal effects at approximately 30 nM lysophosphatidic acid. Phosphatidic acid was effective but less potent whereas other lipids were ineffective. Sensitization by serum and by lysophosphatidic acid were almost completely inhibited by pertussis toxin pretreatment and partially inhibited by prolonged phorbol ester exposure to induce protein kinase C down-regulation. Among nine cell lines tested, those that exhibited sensitization with serum showed comparable sensitization with lysophosphatidic acid. The effects of both lysophosphatidic acid and serum were markedly inhibited by treatment with phospholipase B but only minimally altered with phospholipases A2, D, and C. Exposure of cells to phospholipase C alone induced approximately threefold sensitization, but both serum and lysophosphatidic acid were able to induce further three- to fourfold sensitization above that induced by phospholipase C alone. In contrast, the effects of serum and lysophosphatidic acid were not additive with each other. Together these results suggest that lysophosphatidic acid or a closely related compound present in serum is the factor responsible for sensitization of the cyclic AMP pathway.

Alprostadil↗

PubMed1993

Normal brain F-18 FDG-PET and MRI anatomy.

Image registration techniques will become increasingly important in correlative multimodality imaging. In the case of PET, a structural imaging study can be invaluable in correlating structure metabolism relationships. A registered brain atlas of PET and MRI has been developed by the authors that allows clinicians, residents, fellows, and others to refer to a structural abnormality on MRI or metabolic abnormality on PET and correlate it neuro-anatomically.

Brain↗

PubMed1993

A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency virus type 1 isolates resistant to related inhibitors.

Pyridinone derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and HIV-1 replication in cell culture. However, the potential clinical usefulness of these compounds as monotherapeutic agents may be limited by the selection of inhibitor-resistant viral variants. Resistance in cell culture is due primarily to mutational alterations at RT amino acid residues 103 and 181. A recombinant HIV-1 RT containing both of these mutations was used to screen a panel of pyridinone analogs for inhibitory activity. L-696,229 and L-697,661, pyridinones currently undergoing clinical evaluation, were more than 4,000-fold weaker against the mutant enzyme than against the wild-type enzyme. In contrast, one derivative of L-696,229, L-702,019 (3-[2-(4,7-dichlorobenzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyrid in-2(1H)-thione), showed only three-fold different potencies against the two enzymes. L-702,019 was also a potent inhibitor of the replication of mutant HIV-1 containing the individual mutations at amino acid 103 or 181 as well as of clinical isolates resistant to L-697,661 and L-696,229. Isolation and analysis of resistant viral variants in cell culture showed that significant resistance to L-702,019 could be engendered only by multiple amino acid substitutions in RT. Accordingly, these studies demonstrated the potential of identifying second-generation specific HIV-1 RT inhibitors that can overcome the viral resistance selected by the first generation of inhibitors.

Antiviral Agents↗

PubMed1993

Focal pulmonary abnormalities: evaluation with F-18 fluorodeoxyglucose PET scanning.

The authors assessed the role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in differentiation of benign from malignant focal pulmonary abnormalities seen on chest radiographs. Fifty-one patients underwent FDG PET scanning. Focal abnormalities at radiography included solitary pulmonary nodules (n = 38), pulmonary masses (n = 5), and poorly marginated infiltrates or opacities (n = 8). Proof of diagnosis was obtained by means of transbronchial biopsy (n = 21), open lung biopsy (n = 14), percutaneous needle biopsy (n = 14), or cytologic evaluation of sputum (n = 1). A nodule in one patient had been radiographically stable for at least 8 years. Quantitative analysis was performed by calculation of a standardized uptake ratio (SUR). Thirty-three malignant lesions had a mean SUR (+/- 1 standard deviation) of 6.5 +/- 2.9. Eighteen benign lesions had a mean SUR of 1.7 +/- 1.2. For a benign lesion with SUR of 2.5 or less, specificity of FDG PET was 100%, while sensitivity was 89%. These results suggest that FDG PET is accurate in differentiation of benign from malignant focal pulmonary abnormalities.

Adult↗

PubMed1993

Temporal lobe hypometabolism on PET: predictor of seizure control after temporal lobectomy.

To investigate the relationship of temporal lobe hypometabolism demonstrated on PET to surgical outcome and underlying pathology, we reviewed 30 consecutive epilepsy patients who underwent interictal PET studies with 18F fluorodeoxyglucose before temporal lobectomy. Two interpreters blindly reviewed the PET studies and graded them for degree, extent, and location of temporal lobe hypometabolism. Pathologic analysis of en bloc resected tissue showed mesial temporal sclerosis (n = 22), astrocytoma (n = 2), and no pathologic diagnosis (n = 6). Outcome (24 to 40 months' follow-up) was rated as seizure-free (21 patients), significantly improved (five patients), and not significantly improved (four patients). Both the degree and extent of the temporal lobe hypometabolism demonstrated on PET were strongly associated with subsequent seizure control. Pathologic findings, however, did not correlate with degree of PET hypometabolism or subsequent outcome. These data demonstrate that in patients judged to have temporal lobe epilepsy, the presence of temporal lobe hypometabolism is associated with a positive outcome after ipsilateral temporal lobectomy.

Adolescent↗

PubMed1993

An interactive, computer-based atlas of neurologic positron emission tomographic studies for use in teaching.

Recent developments in personal computer hardware and software allow the manipulation of radiologic images. We developed an interactive, computer-based atlas of clinical neurologic positron emission tomographic studies for use as an educational resource. A personal computer and multimedia software were used to assemble the clinical case studies. For each clinical case, the user had available the clinical history, positron emission tomographic and correlative anatomic images, study interpretation, discussion, and references. The clinical cases were selected for their educational value, either as a representative example of an abnormality or for their ability to illustrate a common pitfall in positron emission tomographic imaging of the brain.

Central Nervous System Diseases↗

PubMed1993

Clinical positron emission tomography imaging.

Positron emission tomography (PET) is assuming increasing importance as an imaging modality in evaluation of neurologic, oncologic, and cardiac disease. Its unique ability to provide cross-sectional physiologic information makes it very useful in the evaluation of human disease in which structural anatomy remains unchanged but the metabolism or function of the tissue is affected by the disease process. We provide an overview of the present status of clinical PET in the United States.

Brain Diseases↗

PubMed1993

Accuracy of registration of PET, SPECT and MR images of a brain phantom.

Accuracy of a surface-fitting algorithm for three-dimensional image registration of single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance (MR) images was tested using a three-dimensional, water-fillable brain phantom. Multislice or volume image sets were acquired for each modality. Small fiducial markers were attached to assess accuracy of surface fitting and provide an alternate fitting technique. A maximum gradient technique was found to work well for SPECT and PET edge detection. Transformation parameters for translation, rotation and scaling were determined by surface fit to match each SPECT and PET scan with MR images. Using the markers, overall translation errors were found to be < 2 mm in each direction and rotational errors < 2 degrees in every case. Errors for specific internal regions were also determined to be < 2 mm for most regions, with only a few fits resulting in errors > 3 mm for some cortical regions. Results indicate surface fitting to be sufficiently accurate for visual comparison of registered images and for enhanced SPECT and PET region of interest (ROI) determination and image reconstruction.

Algorithms↗

PubMed1993

Human pathologic correlation with PET in ischemic and nonischemic cardiomyopathy.

To assess the correlation between myocardial perfusion, metabolism and histologic findings in patients with cardiomyopathy, we evaluated myocardial perfusion and metabolism using positron emission tomography (PET) with 13NH3 (ammonia) and 18FDG (fluoro-2-deoxy-glucose) in nine patients prior to undergoing orthotopic cardiac transplantation. Four patients had ischemic cardiomyopathy (ISCM) and five had nonischemic cardiomyopathy (NISCM). Normalized circumferential profile analyses of representative mid-ventricular perfusion and metabolism PET images were performed for each patient. A corresponding mid-ventricular transaxial slice was obtained from the formalin fixed explanted heart and processed for routine histology. Hematoxylin-eosin stained and Masson trichrome stained sections were evaluated and the percentage of the slice occupied by infarct was determined planimetrically at 10-degree intervals in a circumferential manner. A significant correlation was found between circumferential normalized PET count density profile of perfusion and metabolism in both the ischemic and nonischemic groups (ISCM range r = 0.65-0.75; NISCM range, r = 0.70-0.87). Furthermore, there was a correlation in the ISCM group between the extent of matched perfusion/metabolism defects and transmural infarct involvement (r = 0.66-0.88). PET perfusion and metabolic data closely correlate with pathologic infarction in human hearts of ischemic cardiomyopathy patients.

Adult↗

PubMed1993

FDG-PET in differentiating lymphoma from nonmalignant central nervous system lesions in patients with AIDS.

Structural imaging studies such as CT or MRI are not able to accurately differentiate infectious from malignant cerebral lesions in patients with AIDS. We studied 11 individuals with AIDS and central nervous system (CNS) lesions with 18F-fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). FDG-PET was able to accurately differentiate between a malignant (lymphoma) and nonmalignant etiology for the CNS lesions. Both qualitative visual inspection of the images as well as semiquantitative analysis using count ratios was performed and revealed similar results. FDG-PET may be useful in the management of AIDS patients with CNS lesions since high FDG uptake most likely represents a malignant process which should be biopsied for confirmation rather than treated presumptively as infectious.

AIDS-Related Opportunistic Infections↗

PubMed1992

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1 specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and -alkylamino analogues.

A potent (IC50 = 30 nM), specific nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor 3-[N-(phthalimidomethyl)amino]-5-ethyl-6-methylpyridin-2(1H) -one (1), was discovered through an in vitro screening program. This compound did not inhibit (IC50 > 300 microns) other DNA and RNA polymerases, including HIV-2 RT and SIV-RT. Unfortunately, hydrolytic instability of this (aminomethyl)phthalimide precluded use as an antiviral agent. In the first paper of this series, preliminary development efforts are described which produced ethylphthalimide 20, a hydrolytically stable compound with reduced (100-fold) HIV-1 RT inhibitory activity and weak (CIC95 = 40 microM) antiviral activity in H9 cells. Structure-activity studies demonstrated the importance of the 5-ethyl, 6-methyl substituent pattern on the pyridinone ring and the need for a flexible two-atom linker between the pyridinone and phthalimide heterocycles. These leads, 1 and 20, provided a basis for the further development of this structural class of inhibitors from which several compounds, the subject of accompanying reports, were selected for clinical evaluation.

Antiviral Agents↗

PubMed1992

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one.

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.

Aminopyridines↗

PubMed1992

Cerebral glucose utilization in motor neuron disease.

Positron emission tomography with fluorodeoxyglucose F 18 (18F-fluorodeoxyglucose) was used to examine regional cerebral glucose metabolism in individuals with motor neuron disease. Motor neuron disease involves selective loss of motor neurons, large pyramidal cells in the motor cortex, and corticospinal tract degeneration. We postulated that the local cerebral metabolic rate of glucose should correlate with this regional neuronal cell loss. Glucose metabolism values in patients with motor neuron disease were reduced compared with those of controls in several regions; however, when corrected for multiple comparisons, no significant difference was observed between patients with motor neuron disease and age-matched controls. No correlation was noted between the local cerebral metabolic rate of glucose and duration or severity of illness. Correlation between metabolic changes with objective findings on neurologic examination, including motor weakness and tendon reflexes, provided interesting results, including a decline in glucose metabolism with progressive weakness and upper motor neuron dysfunction. Moreover, in supplementary motor areas, there appears to be an increase in regional glucose metabolism as the neurologic condition deteriorates, possibly representing increased metabolic activity of the motor association cortex in response to primary loss of pyramidal cells.

Adult↗

PubMed1992

Serial changes of cerebral glucose metabolism and caudate size in persons at risk for Huntington's disease.

OBJECTIVE: To determine the rate of change of glucose metabolism and caudate size in persons at risk for Huntington's disease. DESIGN: Eighteen persons at risk for Huntington's disease had two positron emission tomographic glucose metabolic studies and two magnetic resonance imaging scans separated by 42 (+/- 9) months. SETTING: Ambulatory research subjects at a teaching hospital with magnetic resonance imaging and positron emission tomographic technology. SUBJECTS: Seven of the individuals were Huntington' disease gene negative by testing at the polymorphic DNA loci D4S10, D4S43, and D4S125; the remainder were gene positive by genetic testing or onset of chorea after study entry. INTERVENTIONS: None. OUTCOME MEASURES: Onset of chorea and imaging results. RESULTS: The gene-positive group demonstrated a significant 3.1% loss of glucose metabolic rate per year in the caudate nucleus (95% confidence interval [CI], -4.64, -1.48) compared with the gene-negative group. There was a 3.6% per year increase in the magnetic resonance imaging bicaudate ratio (95% CI, 1.81, 5.37), a linear measure of caudate atrophy. The rate of change in caudate size did not correlate with the rate of change in caudate metabolism, suggesting that metabolic loss and atrophy may develop independently. CONCLUSIONS: The results suggest that a reduction in caudate glucose metabolism and atrophy develop rapidly in Huntington's disease. The findings establish a strategy for using serial positron emission tomographic imaging to monitor experimental pharmacologic interventions in presymptomatic individuals who have developed caudate hypometabolism.

Adult↗

PubMed1992

Perfusion quantitation using positron emission tomography.

Positron emission tomography (PET) is assuming increasing importance as a clinical and investigative functional imaging modality. Cerebral blood flow determination with PET is now more easily performed due to improvement in tomography design, increased speed and ease of data analysis, and improvement in radiopharmaceutical synthesis and delivery. This article reviews the historic development of the PET, the evolution of cerebral blood flow measurement techniques with PET, technical considerations in PET imaging, radiopharmaceuticals for cerebral blood flow determination, and tracer kinetic models used for cerebral blood flow determination. Representative examples of PET cerebral blood flow imaging are shown and the evolving applications to brain mapping are discussed.

Animals↗

PubMed1992

Positron emission tomography and familial Alzheimer's disease: a pilot study.

OBJECTIVE: Local cerebral metabolic rates for glucose were compared between patients with familial Alzheimer's disease (FAD), sporadic Alzheimer's Disease (SAD), and normal controls (NC) to determine if FAD is associated with a unique pattern of brain metabolism. DESIGN: Case-control study matched to convenience sample of FAD. METHODS: Subjects in the three diagnostic groups were scanned using fluorodeoxyglucose and the Positron Emission Tomographic (PET) technique. The criterion standard of a detailed clinical history and examination were compared to scan results. SETTING: Patients in a university hospital. SUBJECTS: Ambulatory controls and Alzheimer's patients, both sporadic (n = 8) and familial (n = 7). The two groups were similar in severity of cognitive dysfunction. RESULTS: FAD and SAD patients did not significantly differ in terms of local cerebral metabolic rates for glucose.

Aged↗

PubMed1992

Nontraumatic final impressions for fixed partial dentures.

A nontraumatic, nonretraction impression technique is presented which uses the fabrication of an acrylic resin shell from an interocclusal wax impression. A crucial step in the procedure is obtaining the complete finish line of the preparation within the resin. This tray, which is filled with an elastomeric impression material, is combined with a triple tray of the same material to provide all the necessary relationships to construct a crown or coping. This procedure is especially efficient for multiple abutments during fixed partial denture construction.

Acrylic Resins↗

PubMed1992

L-696,229 specifically inhibits human immunodeficiency virus type 1 reverse transcriptase and possesses antiviral activity in vitro.

L-696,229 (3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-pyridin-2 (1H)-one) is a specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity that possesses antiviral activity in cell culture (W.S. Saari, J.M. Hoffman, J.S. Wai, T.E. Fisher, C.S. Rooney, A.M. Smith, C.M. Thomas, M. E. Goldman, J. A. O'Brien, J. H. Nunberg, J. C. Quintero, W. A. Schleif, E. A. Emini, and P. S. Anderson, J. Med. Chem. 34:2922-2925, 1991). In the present study, the RT-inhibitory activity and antiviral properties were characterized in detail. The inhibition of RT activity was template-primer dependent with 50% inhibitory concentrations of 0.018 to 0.50 microM and was noncompetitive with respect to deoxynucleoside triphosphates. L-696,229 inhibited RT activity in a mutually exclusive manner with respect to either phosphonoformate or azidothymidine triphosphate and was a weak partial inhibitor of the RNase H activity associated with HIV-1 RT. The compound did not significantly inhibit other retroviral or cellular polymerases at 300 microM.L-696,229 inhibited the spread of HIV-1 infection in cell cultures with all cell types and viral isolates tested, including human peripheral blood mononuclear cells and a virus isolate resistant to azidothymidine.

Benzoxazoles↗