PET Studies of Cerebral Levodopa Metabolism: A Review of Clinical Findings and Modeling Approaches

[18F]Fluoro-3,4-dihydroxyphenyl-l-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson’s disease. Following intravenous FDOPA injection, the decarboxylated metabolite [18F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons; reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood samples are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [18F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson’s disease and schizophrenia

The Problem of Universal Salvation in the Theology of Emil Brunner

This article examines the approach of the twentieth-century dialectical theologian, Emil Brunner (1889–1966), to the perennial theological problem of the possibility of universal salvation, a topic which has occupied the reflections of Christopher Morse, whose scholarship we honor in the present volume

Monoamine Oxidase Inhibition by Plant-Derived β-Carbolines; Implications for the Psychopharmacology of Tobacco and Ayahuasca

The monoamine oxidases (MAOs) are flavin-containing amine oxidoreductases responsible for metabolism of many biogenic amine molecules in the brain and peripheral tissues. Whereas serotonin is the preferred substrate of MAO-A, phenylethylamine is metabolized by MAO-B, and dopamine and tyramine are nearly ambivalent with respect to the two isozymes. β-Carboline alkaloids such as harmine, harman(e), and norharman(e) are MAO inhibitors present in many plant materials, including foodstuffs, medicinal plants, and intoxicants, notably in tobacco (Nicotiana spp.) and in Banisteriopsis caapi, a vine used in the Amazonian ayahuasca brew. The β-carbolines present in B. caapi may have effects on neurogenesis and intrinsic antidepressant properties, in addition to potentiating the bioavailability of the hallucinogen N,N-dimethyltryptamine (DMT), which is often present in admixture plants of ayahuasca such as Psychotria viridis. Tobacco also contains physiologically relevant concentrations of β-carbolines, which potentially contribute to its psychopharmacology. However, in both cases, the threshold of MAO inhibition sufficient to interact with biogenic amine neurotransmission remains to be established. An important class of antidepressant medications provoke a complete and irreversible inhibition of MAO-A/B, and such complete inhibition is almost unattainable with reversible and competitive inhibitors such as β-carbolines. However, the preclinical and clinical observations with synthetic MAO inhibitors present a background for obtaining a better understanding of the polypharmacologies of tobacco and ayahuasca. Furthermore, MAO inhibitors of diverse structures are present in a wide variety of medicinal plants, but their pharmacological relevance in many instances remains to be established. Keywords: Banisteriopsis caapi; Nicotiana; ayahuasca; dimethyltryptamine (DMT); harmine; monoamine oxidase (MAO); tobacco; β-carbolines

Effectiveness of hand removal for small-scale management of Japanese beetles (Coleoptera: Scarabaeidae)

Hand removal is often recommended as a method for small-scale control of Japanese beetles (Popillia japonica Newman). In this study, we investigated the effectiveness of daily hand removal for controlling damage by Japanese beetles on grape plants. We also investigated whether the timing of the removal (at 0800, 1400, or 1900 hours, or at all 3 periods) inßuenced the effectiveness of the technique. We found that hand removal signiÞcantly lowered the number of beetles on, and consequently the damage to, grape plants relative to nonremoval controls. Of the single removal treatments, removal of beetles at 1900 hours was most effective, with results similar to removing beetles three times per day. The majority of beetles removed from plants during the experiment were female, a pattern that matches our understanding of aggregation formation behavior in the species, and which may serve to enhance the beneÞts of hand removal. Hand removal seems to work by decreasing the number of feeding beetles, which in turn reduces the release of aggregation kairomones from the plant, and subsequently decreases the attractiveness of the plant to future beetles

Magnetohydrodynamical torsional oscillations from thermo-resistive instability in hot jupiters

Hot jupiter atmospheres may be subject to a thermo-resistive instability where an increase in the electrical conductivity due to ohmic heating results in runaway of the atmospheric temperature. We introduce a simplified one-dimensional model of the equatorial sub-stellar region of a hot jupiter which includes the temperature-dependence and time-dependence of the electrical conductivity, as well as the dynamical back-reaction of the magnetic field on the flow. This model extends our previous one-zone model to include the radial structure of the atmosphere. Spatial gradients of electrical conductivity strongly modify the radial profile of Alfv\'en oscillations, leading to steepening and downwards transport of magnetic field, enhancing dissipation at depth. We find unstable solutions that lead to self-sustained oscillations for equilibrium temperatures in the range $T_\mathrm{eq}\approx 1000$--$1200$~K, and magnetic field in the range $\approx 10$--$100$~G. For a given set of parameters, self-sustained oscillations occur in a narrow range of equilibrium temperatures which allow the magnetic Reynolds number to alternate between large and small values during an oscillation cycle. Outside of this temperature window, the system reaches a steady state in which the effect of the magnetic field can be approximated as a magnetic drag term. Our results show that thermo-resistive instability is a possible source of variability in magnetized hot jupiters at colder temperatures, and emphasize the importance of including the temperature-dependence of electrical conductivity in models of atmospheric dynamics.Comment: Submitted to The Astrophysical Journa

Monoamine Oxidase Inhibition by Plant-Derived β-Carbolines; Implications for the Psychopharmacology of Tobacco and Ayahuasca.

The monoamine oxidases (MAOs) are flavin-containing amine oxidoreductases responsible for metabolism of many biogenic amine molecules in the brain and peripheral tissues. Whereas serotonin is the preferred substrate of MAO-A, phenylethylamine is metabolized by MAO-B, and dopamine and tyramine are nearly ambivalent with respect to the two isozymes. β-Carboline alkaloids such as harmine, harman(e), and norharman(e) are MAO inhibitors present in many plant materials, including foodstuffs, medicinal plants, and intoxicants, notably in tobacco (Nicotiana spp.) and in Banisteriopsis caapi, a vine used in the Amazonian ayahuasca brew. The β-carbolines present in B. caapi may have effects on neurogenesis and intrinsic antidepressant properties, in addition to potentiating the bioavailability of the hallucinogen N,N-dimethyltryptamine (DMT), which is often present in admixture plants of ayahuasca such as Psychotria viridis. Tobacco also contains physiologically relevant concentrations of β-carbolines, which potentially contribute to its psychopharmacology. However, in both cases, the threshold of MAO inhibition sufficient to interact with biogenic amine neurotransmission remains to be established. An important class of antidepressant medications provoke a complete and irreversible inhibition of MAO-A/B, and such complete inhibition is almost unattainable with reversible and competitive inhibitors such as β-carbolines. However, the preclinical and clinical observations with synthetic MAO inhibitors present a background for obtaining a better understanding of the polypharmacologies of tobacco and ayahuasca. Furthermore, MAO inhibitors of diverse structures are present in a wide variety of medicinal plants, but their pharmacological relevance in many instances remains to be established

Effectiveness of hand removal for small-scale management of Japanese beetles (Coleoptera: Scarabaeidae)

Hand removal is often recommended as a method for small-scale control of Japanese beetles (Popillia japonica Newman). In this study, we investigated the effectiveness of daily hand removal for controlling damage by Japanese beetles on grape plants. We also investigated whether the timing of the removal (at 0800, 1400, or 1900 hours, or at all 3 periods) inßuenced the effectiveness of the technique. We found that hand removal signiÞcantly lowered the number of beetles on, and consequently the damage to, grape plants relative to nonremoval controls. Of the single removal treatments, removal of beetles at 1900 hours was most effective, with results similar to removing beetles three times per day. The majority of beetles removed from plants during the experiment were female, a pattern that matches our understanding of aggregation formation behavior in the species, and which may serve to enhance the beneÞts of hand removal. Hand removal seems to work by decreasing the number of feeding beetles, which in turn reduces the release of aggregation kairomones from the plant, and subsequently decreases the attractiveness of the plant to future beetles

What is the impact of water sanitation and hygiene in healthcare facilities on care seeking behaviour and patient satisfaction? A systematic review of the evidence from low-income and middle-income countries

Patient satisfaction with healthcare has clear implications on service use and health outcomes. Barriers to care seeking are complex and multiple and delays in seeking care are associated with significant morbidity and mortality. We sought to assess the relationship between water, sanitation and hygiene (WASH) provision in healthcare facilities (HCF) and patient satisfaction/care seeking behaviour in low-income and middle-income countries. Pubmed and Medline Ovid were searched using a combination of search terms. 984 papers were retrieved and only 21 had a WASH component warranting inclusion. WASH was not identified as a driver of patient satisfaction but poor WASH provision was associated with significant patient dissatisfaction with infrastructure and quality of care. However, this dissatisfaction was not sufficient to stop patients from seeking care in these poorly served facilities. With specific regard to maternal health services, poor WASH provision was the reason for women choosing home delivery, although providers’ attitudes and interpersonal behaviours were the main drivers of patient dissatisfaction with maternal health services. Patient satisfaction was mainly assessed via questionnaires and studies reported a high risk of courtesy bias, potentially leading to an overestimation of patient satisfaction. Patient satisfaction was also found to be significantly affected by expectation, which was strongly influenced by patients’ socioeconomic status and education. This systematic review also highlighted a paucity of research to describe and evaluate interventions to improve WASH conditions in HCF in low-income setting with a high burden of healthcare-associated infections. Our review suggests that improving WASH conditions will decrease patience dissatisfaction, which may increase care seeking behaviour and improve health outcomes but that more rigorous research is needed

From impact to recovery: tracking mild traumatic brain injury with MRI-a pilot study and case series.

BACKGROUND Diagnosis and recovery tracking of mild traumatic brain injury (mTBI) is often challenging due to the lack of clear findings on routine imaging techniques. This also complicates defining safe points for returning to activities. HYPOTHESIS/PURPOSE Quantitative susceptibility mapping (QSM) can provide information about cerebral venous oxygen saturation (CSvO2) in the context of brain injury. We tested the prediction that these imaging modalities would enable the detection of changes and recovery patterns in the brains of patients with mTBI. STUDY DESIGN In a case-control study, we recruited a cohort of 24 contact sport athletes for baseline QSM and resting-state functional MRI (rs-fMRI) scanning. Two of those who subsequently experienced head impact with significant post-injury symptoms underwent scans at 3, 7, 14 and 28 days post-injury; one had a boxing match without classical mTBI symptoms were also followed-up on. RESULTS The cohort baseline QSM measurements of the straight sinus were established. The two injured athletes with post-impact symptoms consistent with mTBI had susceptibility results at days 3 and 7 post-impact that fell below the 25th percentile of the baseline values. The per cent amplitude fluctuation quantified from rs-fMRI agreed with the susceptibility trends in the straight sinus. CONCLUSION QSM holds promise as a diagnostic tool for tracking mTBI progression or recovery in contact sport head injury

Dopamine and Addiction: The medium is the message

A large variety of addictive substances and behaviors has been linked to changes in brain dopamine neurons, which are connected to pathways intimately involved in motivation and reward. Indeed, it has been claimed that all addictions, including nicotine, amphetamine, cocaine, alcohol, and perhaps gambling converge on dopamine mechanisms in parts of the brain subserving reward or reinforcement. However, physiological studies suggest that this simple model may confuse the message (mediated by dopamine) that a reward has taken place, with the reward itself. Dopamine may in fact subserve the education of the brain to anticipate strategies for obtaining rewards in the future, but some drugs may hi-jack this normal motivational and adaptive process and become an end in themselves. Many addictive drugs produce short term changes in receptors for dopamine and other neurotransmitters. While these temporary changes may account for the unpleasant aspects of the acute phase of withdrawal, other factors must underlie craving and the risk of relapse in drug addiction. It is coming to be understood that these long term changes are mediated by intracellular proteins under the control of dopamine receptors, which ultimately serve to alter gene expression, thus inducing longlasting changes in neuronal activity. While many biochemical studies of addiction have been carried out in experimental animals, the advent of positron emission tomography (PET) has made possible the investigation of dopamine systems in living humans. Short term and chronic changes in brain dopamine have been noted in PET studies of nicotine, cocaine, alcohol and amphetamine addicts. It is hoped that a more complete biochemical understanding of the nature of addiction will ultimately lead to improved treatments