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Biomedical subjects

J M Links

Publications and source records attributed to J M Links.

At least 19 recordsLinked to original sources
PubMed2001

Characterization of toxicokinetics and toxicodynamics with linear systems theory: application to lead-associated cognitive decline.

We present a theoretical approach to analysis of toxicokinetics and toxicodynamics using linear systems theory. In our approach, we define two impulse response functions that characterize the kinetic behavior of an environmental agent in the body and the dynamic time-course behavior of its effect on the body. This approach provides a formalism for understanding the relation among exposure, dose, and cumulative biologically effective dose and for understanding the implications of an effect time-course on cross-sectional and longitudinal data analyses. We use lead-associated cognitive decline as a specific example where the approach may be applied.

Cognition Disorders↗
PubMed2000

Past adult lead exposure is associated with longitudinal decline in cognitive function.

OBJECTIVE: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. METHODS: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. "Peak" tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. RESULTS: In former lead workers, peak tibia lead ranged from -2.2 to 98.7 microg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 microg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. CONCLUSIONS: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

Adult↗
PubMed2000

6-[18F]fluoro-A-85380, a novel radioligand for in vivo imaging of central nicotinic acetylcholine receptors.

A novel positron emission tomography (PET) radiotracer, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[18F]fluoro-A-85380, 6-[18F]FA) was synthesized by a no-carrier-added fluorination. In vitro 6-[18F]FA bound to nicotinic acetylcholine receptors (nAChRs), with very high affinity (Kd 28 pM). In PET studies, 6-[18F]FA specifically labeled central nAChRs in the brain of the Rhesus monkey and demonstrated highest levels of accumulation of radioactivity in brain regions enriched with the alpha4beta2 subtype of nAChR. 6-[18F]FA exhibited a target-to-non-target ratio (estimated as radioactivity in the thalamus to that in the cerebellum) of binding in primate brain similar to that previously determined for a labeled analog of epibatidine, [18F]FPH. In contrast to [18F]FPH, the novel tracer is expected to exhibit substantially less toxicity. Thus, the novel radioligand, 6-[18F]FA, appears to be a suitable candidate for imaging nAChRs in human brain.

Animals↗
PubMed2000

Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers.

We evaluated associations of tibial lead levels with polymorphisms in the vitamin D receptor (VDR) in 504 former organolead manufacturing workers with past exposure to lead. In this cross-sectional study, we measured tibial lead by (109)Cd K-shell X-ray fluorescence. Tibial lead was evaluated in subjects with different VDR genotypes defined using the BsmI restriction enzyme, adjusting for confounding variables. Study participants had a mean age +/- SD of 57.4 +/- 7.6 years. A total of 169 (33.5%) subjects were homozygous for the BsmI restriction site (designated bb), 251 (49.8%) were heterozygous (Bb), and 84 (16.7%) were homozygous for the absence of the restriction site (BB). Among all of the study subjects, tibial lead concentrations were low, with a mean +/- SD of 14.4 +/- 9.3 microg Pb/g bone mineral. There were only small differences in tibial lead concentrations by VDR genotype, with mean +/- SD tibial lead concentrations of 13.9 +/- 7.9, 14.3 +/- 9.5, and 15.5 +/- 11.1 in subjects with bb, Bb, and BB, respectively. In a multiple linear regression model of tibial lead concentrations, the VDR genotype modified the relation between age and tibial lead concentrations; subjects with the B allele had larger increases in tibial lead concentrations with increasing age (0.37, 0.48, and 0.67 microg/g per year of age in subjects with bb, Bb, and BB, respectively; the adjusted p-value for trend in slopes = 0.04). The VDR genotype also modified the relation between years since last exposure to lead and tibial lead concentrations. Subjects with bb evidenced an average decline in tibial lead concentrations of 0.10 microg/g per year since their last exposure to lead, whereas subjects with Bb and BB evidenced average increases of 0.03 and 0.11 microg/g per year, respectively (the adjusted p-value for trend in slopes = 0.01). Polymorphisms in the vitamin D receptor modified the relations of age and years since the last exposure to lead with tibial lead concentrations. Although controversy remains on the influence of the VDR genotype on bone mineral density, the data suggest that variant VDR alleles modify lead concentrations in bone, either by influencing lead content or calcium content or both.

Adult↗
PubMed2000

Validation of an analytic method of calculating cerebral glucose metabolism using PET.

UNLABELLED: Quantitative modeling of cerebral metabolic rate for glucose (CMRglc) using PET with the FDG method requires calculation of the integral of the time course of radioactivity in arterial plasma. Numeric integration has typically been used but requires 30 or more blood samples taken between 15 s and 100 min after injection of the radiotracer. Our laboratory has developed an alternative integration method that fits the values of the plasma samples to an analytically integrable function using only 4-6 samples taken between 40 and 110 min after radiotracer injection. METHODS: The plasma integrals were calculated by both the analytic and the numeric methods with data from FDG PET studies that were not used in the development of the analytic method. In 39 PET studies from 22 healthy volunteers, 30 plasma samples were taken over 110 min. RESULTS: The plasma integrals determined by the analytic and numeric methods yielded a within-subject correlation coefficient of >0.95 and differences of <10%. CONCLUSION: Because the analytic method requires less blood sampling and does not require sampling immediately after radiotracer injection, the experimental procedure is simplified without loss of accuracy in CMRglc computation, and the effect of missing or incorrect samples is reduced.

Adult↗
PubMed1999

2-[18F]F-A-85380: a PET radioligand for alpha4beta2 nicotinic acetylcholine receptors.

2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380), a ligand for nicotinic acetylcholine receptors (nAChRs) was evaluated in an in vitro binding assay with membranes of rat brain and in vivo by PET in Rhesus monkey brain. The ligand has high affinity for alpha4beta2 nAChRs (K(D)=50 pM), crosses the blood-brain barrier, and distributes in the monkey brain in a pattern consistent with that of alpha4beta2 nAChRs. The specific/non-specific binding ratio increased steadily, reaching a value of 3.3 in the thalamus at 4 h. The specific binding of 2-[18F]F-A-85380 was reversed by cytisine. These results, in combination with the data demonstrating low toxicity of 2-[18F]F-A-85380, indicate that this ligand shows promise for use with PET in human subjects.

Alkaloids↗
PubMed1999

Predictors of dimercaptosuccinic acid chelatable lead and tibial lead in former organolead manufacturing workers.

OBJECTIVES: To identify predictors of tibial and dimercaptosuccinic acid (DMSA) chelatable lead in 543 organolead manufacturing workers with past exposure to organic and inorganic lead. METHODS: In this cross sectional study, tibial lead (by 109Cd K-shell x ray fluorescence), DMSA chelatable lead (4 hour urinary lead excretion after oral administration of 10 mg/kg), and several exposure measures were obtained on study participants, mean (SD) age 57.6 (7.6) years. RESULTS: Tibial lead concentrations ranged from -1.6 to 52.0 micrograms lead/g bone mineral, with a mean (SD) of 14.4 (9.3) micrograms/g. DMSA chelatable lead ranged from 1.2 to 136 micrograms, with a mean (SD) of 19.3 (17.2) micrograms. In a multiple linear regression model of tibial lead, age (p < 0.01), duration of exposure (p < 0.01), current (p < 0.01) and past (p = 0.05) cigarette smoking, and diabetes (p = 0.01) were all independent positive predictors, whereas height (p = 0.03), and exercise inducing sweating (p = 0.04) were both negative predictors. The final regression model accounted for 31% of the variance in tibial lead concentrations; 27% was explained by age and duration of exposure alone. DMSA chelatable lead was directly associated with tibial lead (p = 0.01), cumulative exposure to inorganic lead (y.microgram/m3, p = 0.01), current smoking (p < 0.01), and weight (p < 0.01), and negatively associated with diabetes (p = 0.02). The final model accounted for 11% of the variance in chelatable lead. When blood lead was added to this model of DMSA chelatable lead, tibial lead, cumulative exposure to inorganic lead, and diabetes were no longer significant; blood lead accounted for the largest proportion of variance (p < 0.001); and the total model r2 increased to 19%. CONCLUSIONS: The low proportions of variance explained in models of both tibial and chelatable lead suggest that other factors are involved in the deposition of lead in bone and soft tissue. In epidemiological studies of the health effects of lead, evaluation of associations with both these measures may allow inferences to be made about whether health effects are likely to be recent, and thus potentially reversible, or chronic, and thus possibly irreversible. The data also provide direct evidence that in men the total amount of lead in the body that is bioavailable declines with age.

Adult↗
PubMed1998

Advances in nuclear medicine instrumentation: considerations in the design and selection of an imaging system.

Nuclear medicine remains a vibrant and dynamic medical specialty because it so adeptly marries advances in basic science research, technology, and medical practice in attempting to solve patients' problems. As a physicist, it is my responsibility to identify or design new instrumentation and techniques, and to implement, validate, and help apply these new approaches in the practice of nuclear medicine. At Johns Hopkins, we are currently in the process of purchasing both a single-photon/coincidence tomographic imaging system and a dedicated positron emission tomography (PET) scanner. Given the exciting advances that have been made, but the conflicting opinions of manufacturers and colleagues alike regarding "best" choices, it seemed useful to review what is new now, and what is on the horizon, to help identify all of the important considerations in the design and selection of an imaging system. It is important to note that many of the "advances" described here are in an early stage of development, and may never make it to routine clinical practice. Further, not all of the advances are of equal importance, or have the same degree of general clinical applicability. Please also note that the references contained herein are for illustrative purposes and are not all-inclusive; no implication that those chosen are "better" than others not mentioned is intended.

Diagnostic Imaging↗
PubMed1998

In vivo imaging of brain nicotinic acetylcholine receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography.

The distribution and kinetics of 5-[123I]iodo-A-85380, a novel ligand for brain nicotinic acetylcholine receptors (nAChRs), were evaluated in the Rhesus monkey using single photon emission computed tomography (SPECT). Peak levels of radioactivity were measured in brain at 90 min after injection of the tracer. Accumulation of radioactivity was highest in the thalamus, intermediate in the frontal cortex and basal ganglia, and lowest in the cerebellum. The ratio of specific to nonspecific binding (V3") in the thalamus, estimated from the (thalamic-cerebellar)/cerebellar radioactivity ratio, reached a value of 6 at 4 h post-injection. Specific binding was reduced by subcutaneous injection of 1 mg/kg cytisine at 2.25 h after injection of radiotracer. At 2.5 h after cytisine administration, radioactivity in the thalamus was reduced by 84%, in the frontal cortex, by 76%, and in the basal ganglia, by 57% of the level measured at the time of cytisine administration, demonstrating that the binding was reversible. On the basis of these findings, together with other data indicating high affinity, receptor subtype selectivity, low nonspecific binding and lack of toxicity in animals, 5-[123I]iodo-A-85380 appears to be a promising ligand for SPECT imaging of nAChRs in the human brain.

Animals↗
PubMed1998

Special issues in quantitation of brain receptors and related markers by emission computed tomography.

Emission computed tomography provides an opportunity to quantify neurotransmitter-neuroreceptor systems in vivo. In order to do so, very high image quality and quantitative accuracy are required. Quantitation of receptor systems involves considerations of physical effects (such as finite spatial resolution, scatter, and attenuation), instrumentation design (such as spatial sampling), image processing (such as filtering), and data analysis (such as kinetic modeling). Appropriate application of these considerations can lead to useful results, but emerging approaches promise even greater levels of accuracy and precision.

Brain↗
PubMed1997

Theoretical analysis of error propagation in triple-energy absorptiometry: application to measurement of lead in bone in vivo.

We propose a three component tissue decomposition for quantifying lead in bone from a mixture of bone and muscle in vivo using a triple-energy absorptiometric method. The theoretical optimization of this method, by relating signal uncertainty to radiation dose, requires an expression of the signal variance. The error propagation was therefore theoretically modeled for a counting detector, assuming noise dominance by quantum statistics and neglecting covariance between energy levels. A final expression for the lead signal variance at each energy level was obtained via a Jacobian matrix. The Jacobian was maximized by choosing the first energy as low as permissible by dose constraints below the lead K edge. A second optimum was achieved when the upper energy was just above and the middle energy was just below the lead K edge. While the signal-to-noise ratio (SNR) had similar behavior to that of the Jacobian as a function of middle and upper energies, the SNR was almost constant as a function of lower energy in the 40-60 keV range. Hence, dose could be reduced without SNR loss. A simulated clinical measurement on an adult tibia using a 50 mCi 155Eu source and a 10 min acquisition time resulted in a standard deviation of 4 micrograms Pb/g bone mass. This approach can be applied to other systems containing three components, provided there is a K edge within the counting energy range.

Absorptiometry, Photon↗
PubMed1996

MR-based correction of brain PET measurements for heterogeneous gray matter radioactivity distribution.

Partial volume and mixed tissue sampling errors can cause significant inaccuracy in quantitative positron emission tomographic (PET) measurements. We previously described a method of correcting PET data for the effects of partial volume averaging on gray matter (GM) quantitation; however, this method may incompletely correct GM structures when local tissue concentrations are highly heterogeneous. We have extended this three-compartment algorithm to include a fourth compartment: a GM volume of interest (VOI) that can be delineated on magnetic resonance (MR) imaging. Computer simulations of PET images created from human MR data demonstrated errors of up to 120% in assigned activity values in small brain structures in uncorrected data. Four-compartment correction achieved full recovery of a wide range of coded activity in GM VOIs such as the amygdala, caudate, and thalamus. Further validation was performed in an agarose brain phantom in actual PET acquisitions. Implementation of this partial volume correction approach in [18F]fluorodeoxyglucose and [11C]-carfentanil PET data acquired in a healthy elderly human subject was also performed. This newly developed MR-based partial volume correction algorithm permits the accurate determination of the true radioactivity concentration in specific structures that can be defined by MR by accounting for the influence of heterogeneity of GM radioactivity.

Aged↗
PubMed1995

In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder.

BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.

Adult↗
PubMed1995

Cardiac single-photon emission tomography with a 90 degrees dual-head system.

Dual-head single-photon emission tomography (SPET) systems which permit a 90 degrees orientation of the heads provide a twofold increase in sensitivity for 180 degrees SPET compared with single-head systems. Since such systems have additional mechanical and electrical alignment and stability requirements, clinical equivalency for myocardial perfusion SPET must be demonstrated. Accordingly, we studied 26 subjects who underwent exercise thallium scintigraphy consecutively with both single-head and dual-head systems. Image acquisition was similar, except that the dual-head study took one-half the time. Image reconstruction was identical. Images were interpreted in a blinded fashion, and rated for technical quality. All 26 studies were equivalently interpreted for the presence or absence of perfusion defects. Fourteen of the studies were judged to be technically equivalent; seven were judged to be slightly better with the single-head system; three were judged to be slightly better with the dual-head system; and two were judged to be definitely better with the dual-head system. We conclude that dual-head 90 degrees systems provide equivalent clinical performance in half the acquisition time.

Aging↗
PubMed1995

Molecular epidemiology and human risk monitoring.

Molecular epidemiologic research involves the identification of relations between previous exposure to some putative causative agent and subsequent biological effects in a cluster of individuals in populations. There is intensive current research in the field of molecular epidemiology, and this research has a direct impact on risk assessment processes. Many of the challenges facing risk assessors today can be addressed by research focused on developing a better understanding of (a) exposure characteristics or assessment, (b) the relationship between exposure and dose, and (c) the ultimate exposure/dose effect response relationship. Results from this research can be used to design and implement preventive interventions in at risk populations. Thus, the application of research in exposure assessment and molecular epidemiology to risk assessment and preventive interventions makes this a core program for public health.

Animals↗