Biomedical subjects

M R Palmer

Publications and source records attributed to M R Palmer.

At least 19 recordsLinked to original sources

PubMed2004

Preliminary treatment planning and dosimetry for a clinical trial of neutron capture therapy using a fission converter epithermal neutron beam.

A Phase I/II clinical trial of neutron capture therapy (NCT) was conducted at Harvard-MIT using a fission converter epithermal neutron beam. This epithermal neutron beam has nearly ideal performance characteristics (high intensity and purity) and is well-suited for clinical use. Six glioblastoma multiforme (GBM) patients were treated with NCT by infusion of the tumor-selective amino acid boronophenylalanine-fructose (BPA-F) at a dose of 14.0 g/m(2) body surface area over 90 min followed by irradiation with epithermal neutrons. Treatments were planned using NCTPlan and an accelerated version of the Monte Carlo radiation transport code MCNP 4B. Treatments were delivered in two fractions with two or three fields. Field order was reversed between fractions to equalize the average blood boron concentration between fields. The initial dose in the dose escalation study was 7.0 RBEGy, prescribed as the mean dose to the whole brain volume. This prescription dose was increased by 10% to 7.7 RBEGy in the second cohort of patients. A pharmacokinetic model was used to predict the blood boron concentration for determination of the required beam monitor units with good accuracy; differences between prescribed and delivered doses were 1.5% or less. Estimates of average tumor doses ranged from 33.7 to 83.4 RBEGy (median 57.8 RBEGy), a substantial improvement over our previous trial where the median value of the average tumor dose was 25.8 RBEGy.

Aged↗

PubMed2004

Development and application of an unconstrained technique for patient positioning in fixed radiation beams.

A flexible technique for positioning patients in fixed orientation radiation fields such as those used in neutron capture therapy (NCT) has been developed. The positioning technique employs reference points marked on the patient in combination with a 3D digitizer to determine the beam entry point and a template fitted to the patient's head is used to determine the proper beam orientation. A coordinate transformation between the CT image data and reference points on the patient determined by a least squares algorithm based on singular value decomposition is used to map the beam entry point from the planning system onto the patient. The technique was validated in a phantom study where the mean error in entry point placement was 1.3 mm. Five glioblastoma multiforme patients have been treated with NCT using this positioning technique.

Algorithms↗

PubMed2004

Variable fitness effects of Wolbachia infection in Drosophila melanogaster.

Maternally inherited Wolbachia bacteria are extremely widespread among insects and their presence is usually associated with parasitic modifications of host fitness. Wolbachia pipientis infects Drosophila melanogaster populations from all continents, but their persistence in this species occurs despite any strong parasitic effects. Here, we have investigated the symbiosis between Wolbachia and D. melanogaster and found that Wolbachia infection can have significant survival and fecundity effects. Relative to uninfected flies, infected females from three fly strains showed enhanced survival or fecundity associated with Wolbachia infection, one strain showed both and one strain responded positively to Wolbachia removal. We found no difference in egg hatch rates (cytoplasmic incompatibility) for crosses between infected males and uninfected females, although there were fecundity differences. Females from this cross consistently produced fewer eggs than infected females and these fecundity differences could promote the spread of infection just like cytoplasmic incompatibility. More surprising, we found that infected females often had the greatest fecundity when mated to uninfected males. This could also promote the spread of Wolbachia infection, though here the fitness benefits would also help to spread infection when Wolbachia are rare. We suggest that variable fitness effects, in both sexes, and which interact strongly with the genetic background of the host, could increase cytoplasmic drive rates in some genotypes and help explain the widespread persistence of Wolbachia bacteria in D. melanogaster populations. These interactions may further explain why many D. melanogaster populations are polymorphic for Wolbachia infection. We discuss our results in the context of host-symbiont co-evolution.

Animals↗

PubMed2003

A 23,000-year record of surface water pH and PCO2 in the western equatorial Pacific Ocean.

The oceans play a major role in defining atmospheric carbon dioxide (CO2) levels, and although the geographical distribution of CO2 uptake and release in the modern ocean is understood, little is known about past distributions. Boron isotope studies of planktonic foraminifera from the western equatorial Pacific show that this area was a strong source of CO2 to the atmosphere between approximately 13,800 and 15,600 years ago. This observation is most compatible with increased frequency of La Niña conditions during this interval. Hence, increased upwelling in the eastern equatorial Pacific may have played an important role in the rise in atmospheric CO2 during the last deglaciation.

Journal Article↗

PubMed2002

A theoretical model for the microdosimetry of discontinuous distributions of heavy particle tracks.

A novel approach to solving microdosimetry problems using conditional probabilities and geometric concepts has been developed. This approach is valid for cases where a convex site is immersed in uniform or discontinuous distributions of heavy charged particle tracks and assumes no restrictions in site geometry or the kind of randomness. These conditions are relevant to the study of microdosimetry in applications such as neutron capture therapy (NCT), irradiation experiments using heavy ion particle beams, environmental radon, or occupational exposure to radioactive materials. Expressions applicable to the case of surface-distributed sources of tracks are presented that may represent situations such as NCT, where boron compounds are bound to the membranes of cellular nuclei. Microdosimetric spectra, specific energy averages, and mean number of 10B capture reactions for cell inactivation are calculated, showing their dependence on 10B localisation.

Alpha Particles↗

PubMed2001

Intranigral transplantation of solid tissue ventral mesencephalon or striatal grafts induces behavioral recovery in 6-OHDA-lesioned rats.

Parkinson's disease (PD) is characterized by a degeneration of the dopamine (DA) pathway from the substantia nigra (SN) to the basal forebrain. Prior studies in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats have primarily concentrated on the implantation of fetal ventral mesencephalon (VM) into the striatum in attempts to restore DA function in the target. We implanted solid blocks of fetal VM or fetal striatal tissue into the SN to investigate whether intra-nigral grafts would restore motor function in unilaterally 6-OHDA-lesioned rats. Intra-nigral fetal striatal and VM grafts elicited a significant and long-lasting reduction in apomorphine-induced rotational behavior. Lesioned animals with ectopic grafts or sham surgery as well as animals that received intra-nigral grafts of fetal cerebellar cortex showed no recovery of motor symmetry. Subsequent immunohistochemical studies demonstrated that VM grafts, but not cerebellar grafted tissue expressed tyrosine hydroxylase (TH)-positive cell bodies and were associated with the innervation by TH-positive fibers into the lesioned SN as well as adjacent brain areas. Striatal grafts were also associated with the expression of TH-positive cell bodies and fibers extending into the lesioned SN and an induction of TH-immunolabeling in endogenous SN cell bodies. This finding suggests that trophic influences of transplanted fetal striatal tissue can stimulate the re-expression of dopaminergic phenotype in SN neurons following a 6-OHDA lesion. Our data support the hypothesis that a dopaminergic re-innervation of the SN and surrounding tissue by a single solid tissue graft is sufficient to improve motor asymmetry in unilateral 6-OHDA-lesioned rats.

Animals↗

PubMed2001

A theoretical model for event statistics in microdosimetry. I: Uniform distribution of heavy ion tracks.

In this work we describe a novel approach to solving microdosimetry problems using conditional probabilities and geometric concepts. The intersection of a convex site with a field of randomly oriented straight track segments is formulated in terms of the relative overlap between the chord associated with the action line of the track and the track itself. This results in a general formulation that predicts the contribution of crossers, stoppers, starters, and insiders in terms of two separate functions: the chord length distribution (characteristic of the site geometry and the type of randomness) and an independent set of conditional probabilities. A Monte Carlo code was written in order to validate the proposed approach. The code can represent the intersection between an isotropic field of charged particle tracks and a general ellipsoid of unrestricted geometry. This code was used to calculate the event distribution for a sphere as well as the expected mean value and variance of the track length distribution and to compare these against the deterministic calculations. The observed agreement was shown to be very good, within the precision of the Monte Carlo approach. The formulation is used to calculate the event frequency, lineal energy, and frequency mean specific energy for several monoenergetic and isotropic proton fields in a spherical site, as a function of the site diameter, proton energy, and the event type.

Biophysical Phenomena↗

PubMed2001

A theoretical model for event statistics in microdosimetry. II: Nonuniform distribution of heavy ion tracks.

A microdosimetry model, described in Part I, applies to the case of a convex site immersed in a uniform distribution of heavy particle tracks, and assumes no restrictions in site geometry or the kind of randomness. In Part II, this model is extended to include nonuniform distributions of particle tracks. This situation is relevant to the study of microdosimetry, for example, in boron neutron capture, in irradiation experiments using heavy ion particle beams, where the sources of particle tracks are external to the cell, or in irradiation from internally incorporated particle-emitting radionuclides, such as environmental radon or occupational exposure to radioactive materials. The formalism developed permits the calculation of statistical properties, track length distributions, and microdosimetric spectra for convex sites where the "inner" and "outer" concentrations of sources may be different, or for tracks originating on the surface of a convex site. Expressions applicable to the case of surface-distributed sources of tracks are presented that may represent situations such as boron compounds bound to the membrane of a cellular nucleus in boron neutron capture. A series of Monte Carlo calculations and analytical solutions, illustrating the case of spherical site geometry, are presented and compared. Finally, microdosimetric spectra and specific energy averages are calculated for alpha and lithium particles originating from thermal neutron capture in 10B, showing their dependence on 10B localization (extra-site, uniform, intra-site, or surface-distributed).

Biophysical Phenomena↗

PubMed2001

A pharmacokinetic model for the concentration of 10B in blood after boronophenylalanine-fructose administration in humans.

An open two-compartment model has been developed for predicting (10)B concentrations in blood after intravenous infusion of the l-p-boronophenylalanine-fructose complex (BPA-F) in humans and derived from studies of pharmacokinetics in 24 patients in the Harvard-MIT Phase I clinical trials of BNCT. The (10)B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of approximately 32 microg/g (for infusion of 350 mg/kg over 90 min) followed by a biphasic exponential clearance profile with half-lives of 0.34 +/- 0.12 and 9.0 +/- 2.7 h, due to redistribution and primarily renal elimination, respectively. The model rate constants k(1), k(2) and k(3) are 0.0227 +/- 0.0064, 0.0099 +/- 0.0027 and 0.0052 +/- 0.0016 min(-1), respectively, and the central compartment volume of distribution, V(1), is 0.235 +/- 0.042 kg/kg. The validity of this model was demonstrated by successfully predicting the average pharmacokinetic response for a cohort of patients who were administered BPA-F using an infusion schedule different from those used to derive the parameters of the model. Furthermore, the mean parameters of the model do not differ for cohorts of patients infused using different schedules.

Adult↗

PubMed2001

Biological dosimetry for epithermal neutron beams.

The radiobiological effectiveness of an epithermal neutron beam is described using cell survival as the end point. The M67 epithermal neutron beam at the Nuclear Reactor Laboratory, Massachusetts Institute of Technology, that was used for clinical trials of boron neutron capture therapy was used to irradiate Chinese hamster ovary cells at seven depths in a water-filled phantom that simulated healthy tissue. No boron was added to the samples. Therefore, this experiment evaluates the biological effectiveness of the neutron and photon components, which comprise 80-95% of the dose to healthy tissue. Cell survival was dependent upon the depth in the phantom, as a result of moderation and attenuation of the epithermal neutron beam components by the overlying water. The results were compared with 250 kVp X irradiations to determine relative biological effectiveness values. Cell survival as a function of the dose delivered was lowest at the most shallow depth of 0.5 cm, and increased at depths of 1.5, 3, 4, 5.6, 6.6 and 8.1 cm. The gradual increase in cell survival with increasing depth in the phantom is due to the exponential drop of the fast-neutron intensity of the beam. These results are applicable to clinical boron neutron capture therapy Phase I/II trials in which healthy tissue toxicity was an end point.

Animals↗

PubMed2000

Atmospheric carbon dioxide concentrations over the past 60 million years.

Knowledge of the evolution of atmospheric carbon dioxide concentrations throughout the Earth's history is important for a reconstruction of the links between climate and radiative forcing of the Earth's surface temperatures. Although atmospheric carbon dioxide concentrations in the early Cenozoic era (about 60 Myr ago) are widely believed to have been higher than at present, there is disagreement regarding the exact carbon dioxide levels, the timing of the decline and the mechanisms that are most important for the control of CO2 concentrations over geological timescales. Here we use the boron-isotope ratios of ancient planktonic foraminifer shells to estimate the pH of surface-layer sea water throughout the past 60 million years, which can be used to reconstruct atmospheric CO2 concentrations. We estimate CO2 concentrations of more than 2,000 p.p.m. for the late Palaeocene and earliest Eocene periods (from about 60 to 52 Myr ago), and find an erratic decline between 55 and 40 Myr ago that may have been caused by reduced CO2 outgassing from ocean ridges, volcanoes and metamorphic belts and increased carbon burial. Since the early Miocene (about 24 Myr ago), atmospheric CO2 concentrations appear to have remained below 500 p.p.m. and were more stable than before, although transient intervals of CO2 reduction may have occurred during periods of rapid cooling approximately 15 and 3 Myr ago.

Animals↗

PubMed2000

Changes in the proportions of peripheral blood lymphocytes in patients with worn implants.

We compared the peripheral blood and periprosthetic tissues of 53 patients at revision arthroplasty with those of 30 patients at primary arthroplasty to determine whether there is a systemic difference in lymphocytes in patients with worn hip implants. The absolute number and relative proportion of lymphocytes bearing CD2, CD3, CD4, CD8, CD16, CD19, HLA-DR, kappa and lambda antigens were compared with the levels of IL-1beta, IL-6 and PGE2 in the pseudosynovial membrane as well as with a semiquantitative estimate of metal and polyethylene particles, necrosis and chronic inflammation and the total concentration of metals within the periprosthetic tissues. There was a significant increase in the relative proportion of CD2-positive T-cells and CD16-positive natural killer cells in the peripheral blood at revision arthroplasty compared with primary arthroplasty and an increased proportion of CD8-positive T-cells and a decreased ratio of CD4 to CD8 (helper inducer/suppressor cytotoxic cells). Three control patients, who went on to have revision surgery, had values at primary arthroplasty which were similar to those of patients at the time of revision surgery. These differences did not correlate with the local concentration of metal, plastic or cement or inflammatory response or the type of prosthesis. An inverse correlation was noted between the necrosis in the periprosthetic tissue and both the local production of IL-6 and the absolute numbers of T-cells in peripheral blood. We conclude that there may be several cell-mediated systemic immune responses to aseptic loosening, at least one of which may be directly related to events in the periprosthetic tissues. We cannot exclude the possibility that the changes in the proportion of CD8-positive cells reflected a predisposition, rather than a reaction, to loosening of the implant.

Aged↗

PubMed1999

Multiple single-unit recordings in the striatum of freely moving animals: effects of apomorphine and D-amphetamine in normal and unilateral 6-hydroxydopamine-lesioned rats.

Ensembles of striatal neurons were recorded in freely moving normal and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats using chronically implanted electrode arrays. Animals received bilateral striatal implants of two 16-microwire arrays 1 week before recordings. Identified striatal neurons were categorized as medium spiny-like and large aspiny-like based on a combination of their activity autocorrelations and firing rates. Baseline firing rates of medium spiny-like neurons in the 6-OHDA-lesioned striata were significantly faster than were firing rates of the same neurons in the intact hemispheres of 6-OHDA-lesioned rats or normal animals. However, firing rates of large aspiny-like neurons were faster in both hemispheres of the 6-OHDA-lesioned rats as compared to normal animals. Interestingly, firing rates of neurons in all groups decreased by fivefold or greater under urethane anesthesia, although the relative firing rates between hemispheres were unchanged. d-Amphetamine (5.0 mg/kg, s.c.) increased the firing rates of both types of striatal neurons by twofold or greater in normal rats and in the intact hemispheres of 6-OHDA-lesioned animals. By contrast, this treatment did not alter neuron firing in the 6-OHDA-lesioned striata. Apomorphine (0.05 mg/kg, s.c.) did not affect neuronal firing rates either in normal rat striatum or in the unlesioned hemispheres of 6-OHDA-lesioned animals. However, it did significantly increase the firing rate of the medium spiny-like neurons in 6-OHDA-lesioned striata. These results demonstrate that the dopaminergic innervation of the striatum differentially influences two electrophysiologically distinct sets of striatal neurons in freely moving rats.

Anesthesia↗

PubMed1999

Potentiation of ethanol effects in cerebellum by activation of endogenous noradrenergic inputs.

We previously found that beta adrenergic agonists such as norepinephrine and isoproterenol potentiate the depressant actions of ethanol (EtOH) on cerebellar Purkinje neurons. Furthermore, antagonism of the beta adrenergic effects of endogenously released catecholamines with timolol reduced EtOH-induced depressions of neuronal activity in that brain area. In the present study, we further investigated the hypothesis that activity of the endogenous noradrenergic innervation to the cerebellar cortex can potentiate this EtOH action. We investigated the interaction of synaptically released catecholamines on EtOH-induced depressions of cerebellar Purkinje neurons in three different experiments: (1) endogenous catecholamine release was facilitated by applying the catecholamine uptake inhibitor desmethylimipramine, (2) activity of the noradrenergic innervation of the cerebellar cortex from locus ceruleus was increased by causing acute withdrawal from 7 days of chronic morphine treatment with the opiate antagonist naloxone, and (3) the noradrenergic innervation of the cerebellum was activated directly by electrical stimulation of the locus ceruleus. We found that all three conditions potentiated EtOH-induced depressions in the cerebellum and that this potentiation of ethanol effects could be antagonized by the systemic administration of the beta adrenergic antagonist propranolol. Furthermore, morphine withdrawal also caused potentiation of the depressant effects of phencyclidine, which are known to be regulated by the endogenous catecholamine innervation in this brain area. Taken together with our previous data demonstrating a beta adrenergic facilitation of EtOH actions in this brain area, the present results suggest that the activity of endogenous noradrenergic synapses can regulate the depressant effects of EtOH on cerebellar Purkinje neurons.

Adrenergic Uptake Inhibitors↗

PubMed1998

Characterization of wear debris associated with aseptic loosening of a canine hip prosthesis.

A 12-month-old Golden Retriever bitch underwent unilateral hip arthroplasty following a diagnosis of coxofemoral osteoarthritis secondary to hip dysplasia. The hip prosthesis underwent aseptic loosening and was removed 6 months after implantation. Synovial biopsies taken at that time revealed scattered foci of granulomatous inflammation associated with intra-cytoplasmic and extracellular particulate material. Electron microscopical analyses demonstrated that this material contained cobalt, chromium, titanium and zirconium, which was probably wear debris from the loosened prosthesis. In human patients with hip arthroplasty, widespread dissemination of wear debris from loosened prostheses occasionally occurs, with an increased prevalence of neoplasia. A similar phenomenon may be predicted to occur with the increasing use of hip arthroplasty in the dog.

Animals↗

PubMed1998

Electrophysiological characterization of cerebellar neurons from adult rats exposed to ethanol during development.

The purpose of this study was to investigate the spontaneous activity of mature rat cerebellar neurons that had been exposed to ethanol (EtOH) during postnatal days 4 to 10, which corresponds to the third trimester in humans. Newborn Sprague-Dawley rats were implanted with gastric feeding tubes and were artificially reared from postnatal days 4 to 10 with two different diets. The experimental group received 4.5 g/kg/day of EtOH delivered in a milk solution. Controls received similar feeding with an isocaloric supplement replacing the EtOH. Electrophysiological evaluations were performed after an EtOH-free rearing period. Although lobules IX and X of the cerebellar vermis appeared morphologically smaller in the animals neonatally exposed to EtOH, compared with controls, extracellular recordings from both Purkinje cells and Golgi interneurons in adult rats showed no differences in spontaneous activity or firing pattern between the control and EtOH-exposed animals. Similarly, excitations and inhibitions of Purkinje neuron activity evoked by parallel pathway stimulation appeared unaffected by the developmental EtOH exposure. However, we did observe a significant decrease in the proportion of Purkinje neurons generating complex spike bursts in the group exposed to EtOH neonatally. These data suggest that, although fewer Purkinje neurons may survive the brain growth spurt if exposed to EtOH during this critical period of development, those that do survive appear to function normally. The observed abnormality in complex spike production may result from EtOH effects on developing neurons in the inferior olive that give rise to the climbing fibers that cause this bursting pattern in Purkinje neurons.

Animals↗

PubMed1997

Effects of ethanol and nomifensine on NE clearance in the cerebellum of young and aged Fischer 344 rats.

Rapid chronoamperometric recordings coupled with local application of drugs by pressure ejection were used to investigate the effects of nomifensine and ethanol (EtOH) on exogenous norepinephrine (NE) clearance in the cerebellum of young (5-month-old) and aged (24-26-month-old) male Fischer 344 rats. In the young rats, local nomifensine application prolonged exogenous NE clearance, indicating transporter mediated uptake inhibition. NE clearance was modestly but significantly prolonged in the aged rats as compared to the young rats, suggesting less efficient uptake. Consistent with this, there was little effect of nomifensine on NE clearance in the aged rats. In contrast to the effect of nomifensine, EtOH inhibited NE clearance in both young and aged rats. These data further support the hypothesis that one effect of EtOH in cerebellar NE systems is inhibition of NE uptake into NE-containing nerve terminals, and they also demonstrate that the effect of nomifensine on exogenous NE clearance in vivo in the cerebellum is altered by the aging process, while the effect of EtOH is not.

Aging↗

PubMed1997

Ethanol depression of cerebellar Purkinje neuron firing involves nicotinic acetylcholine receptors.

Local application of ethanol (EtOH) has been reported to inhibit Purkinje neuron firing. EtOH-induced depressions can be antagonized by bicuculline, suggesting involvement of GABAA receptors. Since there is evidence from other studies indicating that nicotine may interact with EtOH responses, in this study we investigated whether nicotinic acetylcholine receptors (nAChR's) might be also involved in EtOH-induced depressions of these neurons in urethane-anesthetized Sprague-Dawley rats. Using local application (micropressure ejection) of drugs onto cerebellar Purkinje neurons while recording extracellular firing rates, we found that depressant responses to EtOH could be potentiated by subdepressant doses of nicotine. Furthermore, EtOH-induced depressions of firing could be antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist. Results from the present study indicate that EtOH-induced depressions may involve nAChRs in the cerebellum.

Action Potentials↗