Geospatial analysis of household spread of Ebola virus in a quarantined village - Sierra Leone, 2014.

We performed a spatial-temporal analysis to assess household risk factors for Ebola virus disease (Ebola) in a remote, severely-affected village. We defined a household as a family's shared living space and a case-household as a household with at least one resident who became a suspect, probable, or confirmed Ebola case from 1 August 2014 to 10 October 2014. We used Geographic Information System (GIS) software to calculate inter-household distances, performed space-time cluster analyses, and developed Generalized Estimating Equations (GEE). Village X consisted of 64 households; 42% of households became case-households over the observation period. Two significant space-time clusters occurred among households in the village; temporal effects outweighed spatial effects. GEE demonstrated that the odds of becoming a case-household increased by 4·0% for each additional person per household (P < 0·02) and 2·6% per day (P < 0·07). An increasing number of persons per household, and to a lesser extent, the passage of time after onset of the outbreak were risk factors for household Ebola acquisition, emphasizing the importance of prompt public health interventions that prioritize the most populated households. Using GIS with GEE can reveal complex spatial-temporal risk factors, which can inform prioritization of response activities in future outbreaks.

Unexpected Mass Decoupling for 3He-4He Films on a Solid Hydrogen Substrate.

Quartz oscillator measurements reveal new behavior in 3He-4He mixture films on a H2 substrate. For mixture films of total coverage greater than one monolayer, in addition to the expected Kosterlitz-Thouless transition, a second mass decoupling event is observed, which behaves differently from the Kosterlitz-Thouless transition.

6-[18F]Fluoro-A-85380: an in vivo tracer for the nicotinic acetylcholine receptor.

6-[18F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[18F]fluoro-A-85380 or 6-[18F]FA), a new tracer for positron emission tomography, was synthesized by no-carrier-added [18F] fluorination of 6-iodo-3-((1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy)pyridine followed by acidic deprotection. 6-[18F]FA followed the regional densities of brain nicotinic acetylcholine receptors (nAChRs) reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands as well as with unlabeled 6-FA. A preliminary toxicology study of the 6-FA showed a relatively low biological effect.

Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors.

ABSTRACT. [(18)F] SR144385 and [(18)F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [(18)F] SR147963 and 2.5 for [(18)F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.

[11C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1- piperazinecarboxylate ([11C]GR89696): synthesis and in vivo binding to kappa opiate receptors.

GR89696, racemic methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate, a kappa opioid receptor ligand, was labeled with [11C]methyl chloroformate. The radiochemical yield was 20% with an observed specific radioactivity of 75.5 GBq/micromol at end of synthesis (2,040 mCi/micromol). Five minutes after intravenous administration, 5.4% of the injected dose accumulated in mouse whole brain. Brain region to cerebellar ratios increased over time with ratios at 90 min of 7.8, 5.6, and 4.5 for the hypothalamus, olfactory tubercle, and striatum, respectively. The uptake of [11C]GR89696 correlated with known kappa opioid receptor densities and was inhibited by kappa opioid selective drugs.

2-[18F]Fluoro-A-85380, an in vivo tracer for the nicotinic acetylcholine receptors.

The in vivo brain regional distribution of 2-[18F]fluoro-A-85380, a novel tracer for positron emission tomographic (PET) studies, followed the regional densities of brain nAChRs reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands as well as with unlabeled 2-fluoro-A-85380. A preliminary toxicology study of the 2-fluoro-A-85380 showed a relatively low biological effect. 2-[18F]Fluoro-A-85380 holds promise as a useful radiotracer for imaging of nAChRs with PET.

Synthesis and evaluation of N-[11C]methylated analogues of epibatidine as tracers for positron emission tomographic studies of nicotinic acetylcholine receptors.

Four halogen-substituted analogues of N-methylepibatidine, a nicotinic acetylcholine receptor (nAChR) ligand, were synthesized. They were (+/-)-exo-N-methyl-2-(2-halogeno-5-pyridyl)-7-azabicyclo[2. 2.1]heptanes, where halogeno = F (1a), Cl (2a), Br (3a), I (4a). (+/-)-N-Ethylepibatidine (2b) also was synthesized. The compounds 1a, 2a, 3a, and 4a and their corresponding normethyl analogues 1, 2, 3, and 4 inhibited the in vitro binding of [3H]epibatidine to nAChRs to a similar degree, with affinities in the 27-50 pM range. The binding affinity of N-ethylepibatidine (2b), however, was substantially lower. The N-[11C]methyl derivatives of 1, 2, and 3 were synthesized from high-specific radioactivity [11C]methyl iodide using a high-temperature/high-pressure technique. The corresponding radiolabeled compounds [11C]1a, [11C]2a, and [11C]3a were administrated to mice intravenously. The pattern of regional distribution of the three tracers in the mouse brain following intravenous administration matched those of [3H]epibatidine, [3H]norchloroepibatidine, and (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), which are highly specific nAChR probes. The initial brain uptake of the 11C analogues and the acute toxicity of the corresponding authentic nonlabeled compounds appeared to be related to their lipophilicity.

Nicotine induced up-regulation of nicotinic receptors in CD-1 mice demonstrated with an in vivo radiotracer: gender differences.

Up-regulation of brain nicotinic receptors (nAChRs) by chronic nicotine treatment has chiefly been demonstrated by in vitro binding assays. Here, we report that up-regulation of nAChRs in CD-1 mice can be detected using a specific in vivo radioligand for nAChRs, [125I]IPH. After 10 days of (-)-nicotine administration, male and female mice demonstrated a significant elevation of [125I]IPH binding in all brain regions studied. [125I]IPH uptake also displayed significant gender differences with male animals showing a more pronounced increase in [125I]IPH accumulation.

5-[I-125/123]lodo-3(2(S)-azetidinylmethoxy)pyridine, a radioiodinated analog of A-85380 for in vivo studies of central nicotinic acetylcholine receptors.

The in vivo biodistribution profile of the novel nicotinic acetylcholine receptor (nAChR) radioligand 5-[I-125/123]Iodo-3(2(S)-azetidinylmethoxy)pyridine, [I-125/123]-5-IA, in mouse brain was examined. This radiotracer displayed good brain penetration (3.1% of the injected dose (ID) in whole brain at 15 min post-radioligand injection). Radioligand distribution was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus (14.9 %ID/g at 60 min), moderate uptake in cortex (8.5 %ID/g at 60 min), and lowest uptake in the cerebellum (2.4 %ID/g at 60 min). Pretreatment with several different nAChR agonists (A-85380, (-)-nicotine, cytisine) significantly inhibited [I-125]-5-IA binding in all brain regions studied (P < 0.01) demonstrating the high specificity of the radioligand for nAChRs. Blocking doses of the muscarinic antagonist scopolamine and the non-competitive nAChR channel blocker mecamylamine had no significant effect on radioactive uptake supporting the in vitro selectivity of [I-125]-5-IA for the nAChR component of the cholinergic system. [I-125]-5-IA binding sites were shown to be saturable with unlabeled 5-IA. With a relatively low acute toxicity (LD50 > 3 mg/kg via intravenous injection in mice) and high in vivo specificity and selectivity, 5-IA labeled with the imaging radionuclide I-123 may prove useful for single photon emission computed tomography (SPECT) studies of nAChRs in human subjects.

Autoradiographic and SPECT imaging of cerebral opioid receptors with an iodine-123 labeled analogue of diprenorphine.

The feasibility of imaging cerebral opioid receptors by single photon emission computed tomography (SPECT) has been established in baboon using a novel analog of diprenorphine (DPN) radiolabeled with iodine-123. The radioligand, [123I]-O-IA-DPN (C6-O-[123I]iodoallyl-DPN), was prepared in good yield (80%) with high radiochemical purity (>97%) and high specific radioactivity (>2,400 mCi/micromol). In ex vivo autoradiographic studies, with and without naltrexone blockade, [123I]-O-IA-DPN specifically labeled opioid receptors throughout the mouse brain. Nonmetabolized radioligand accounted for >90% of the signal observed in extracts of whole mouse brain. SPECT imaging trials showed that [123I]-O-IA-DPN selectively localized in regions of baboon brain known to have high densities of opioid receptors, such as striatum, thalamus, and temporal cortex. A much lower level of radioligand uptake and retention was noted for cerebellum, a region with few opioid binding sites. Pretreatment with naltrexone (6.5 pmol/kg) blocked [123I]-O-IA-DPN binding in all brain regions. Using naltrexone blockade to define the nonspecific component for a given region of interest, total to nonspecific binding ratios increased linearly (r > or = 0.98) over the SPECT study with maximal values for striatum (9.8), thalamus (7.1), and temporal cortex (6.9) reached at the last time point investigated (3.5 h). Specific binding for these regions, assessed as the difference between regional SPECT activity for the control and blocked states, proved irreversible over the observation period. By the end of the time course, specific [123I]-O-IA-DPN binding was >85% of total radioactivity in regions rich in opioid receptors and 62% of total radioactivity in cerebellum. The aggregate data are consistent with visualization of multiple opioid receptor types. Thus, [123I]-O-IA-DPN should prove useful for SPECT studies within the constraints imposed by a lack of innate selectivity for a single type of brain opioid receptor.

In vivo detection of short- and long-term MDMA neurotoxicity--a positron emission tomography study in the living baboon brain.

The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [11C](+)McN 5652, a potent 5-HT transporter ligand, as well as [11C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [11C](+)McN5652, [11C](-)McN5652 (the inactive enantiomer of the active enantiomer [11C](+)McN5652) and [11C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [11C](+)McN 5652, but not with [11C](-)McN5652 or [11C]RTI-55. Reductions in specific [11C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (-)[11C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [11C](+)McN5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [11C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects.

Risperidone: clinical outcome predictors and cost-effectiveness in a naturalistic setting.

Although risperidone seems to be a safe and effective treatment for the management of psychotic symptoms, its acquisition cost is considerably higher than that of conventional antipsychotics, and its precise role in managing psychiatric illnesses has yet to be defined. The purpose of this investigation was to examine the relationship of patient demographic variables to therapeutic outcomes and to analyze the financial impact of risperidone on the treatment of psychotic symptoms. Subjects included in this 2-year, retrospective cohort, intent-to-treat analysis were all patients initiated on risperidone therapy at an inpatient psychiatric treatment facility. Clinical outcomes were assessed from the absolute change in hospitalized days, total number of psychotropic medications prescribed, and historic Clinical Global Impression severity scores. Logistic regression analysis was conducted to analyze the potential relationship to certain demographic variables to therapeutic response. The cost-benefit analysis compared the direct treatment costs incurred by the institution before and after risperidone initiation. Of the 66 patients originally started on risperidone, 57 completed a therapeutic trial. A clinical response was evident in 54 percent of these patients overall. Logistic regression analysis identified previous treatment intolerance and a negative history of substance abuse as predictive of therapeutic success with risperidone (p = .0006 and p = .01, respectively). Hospitalization rates declined by 43 percent among treatment responders and by 1.3 percent among nonresponders resulting in a net annual savings of $147,962. Risperidone may be efficacious in many patients who had previously failed antipsychotic trials. Patients who had been unable to tolerate traditional antipsychotics and those who lacked a documented history of substance abuse were uniquely responsive to risperidone treatment. The significant decline in hospitalized days that was observed among responsive patients seems to indicate that risperidone may be a cost-effective approach to the management of psychotic symptoms.

High-affinity no-carrier-added 99mTc-labeled chemotactic peptides for studies of inflammation in vivo.

Nalpha-for-Nle-Leu-Phe-Nle-Tyr-Lys, a chemotactic peptide that binds with high affinity to the chemoattractant receptor on granulocytes and monocytes, was labeled with 99mTc using the diaminedithiol (DADT) chelating system to coordinate the Tc. 99mTc labeling of the DADT-coupled peptide was accomplished in 84% overall yield (room temperature for 10 min) using [99mTc]glucoheptonate as the donor of prereduced Tc. HPLC analysis showed two major 99mTc-labeled peptide peaks, 99mTc-DADT-Pep-I and 99mTc-DADT-Pep-II, were obtained in a ratio of 1:0.85. Using an iodoacetamide-derivatized gel to remove unlabeled peptide from the 99mTc labeling mixtures, essentially no-carrier-added (nca) high-specific activity 99mTc-labeled chemotactic peptides were obtained. The 99Tc analogues of the peptides were synthesized (72% yield) in a similar fashion and correlated with 99mTc complexes I and II by HPLC. In vitro competitive receptor binding assays of the isolated 99Tc analogues were performed against the tritiated chemotactic peptide [3H]N-for-Met-Leu-Phe ([3H]fMLF) using isolated granulocytes. The 99Tc-derivatized peptides showed similar binding affinities to the chemoattractant receptor as the unlabeled Nalpha-for-Nle-Leu-Phe-Nle-Tyr-Lys. The nca 99mTc-labeled peptides gave high contrast images of experimental inflammation in rabbits without causing neutropenia. Thus, it is feasible to attach the Tc-DADT chelate to low-molecular weight receptor binding chemotactic peptides and retain substantial binding to the receptor. Chemotactic peptides labeled with 99mTc via the DADT ligand system have the potential for imaging focal sites of inflammation without toxic effects, an important consideration in the successful utilization of chemotactic peptide agonists.

Design, synthesis, and initial evaluation of high-affinity technetium bombesin analogues.

Potent antagonists of bombesin-like peptides have shown great potential for applications in cancer therapy. A 99mTc-labeled agent capable of identifying patients who could benefit from these emerging therapies would have a great impact on patient management. This study involves the synthesis and initial evaluation of technetium diaminedithiolate analogues derived from the potent bombesin analogue Pyr-Gln-Lys-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (Lys3-bombesin). We coupled two diaminedithiol (DADT) bifunctional chelating agents (BCAs 1 and 2) to the Lys3 residue at the N-terminal region that is not required for binding to the receptor. 99mTc labeling was performed by ligand exchange on addition of [99mTc]glucoheptonate to a solution of the adduct at room temperature. Two products were obtained from each adduct on analysis by HPLC. The major to minor product ratios of the 99mTc-labeled analogues were 3:1 for products from BCA 1 and 9:1 for the products from BCA 2. Macroscopic amounts of the 99Tc analogues were similarly prepared using [99Tc]glucoheptonate. In this case, the major to minor ratios were 2:1 for the products from both BCAs. For initial evaluation of the binding of the Tc-labeled peptides to bombesin receptors, the 99Tc analogues were used in vitro in competitive binding assays in rat brain cortex membranes against [125I-Tyr4]bombesin. Results of the in vitro assays showed that the inhibition constants (Ki) of the major and minor products were 3.5+/-0.7 and 3.9+/-1.5 nM, respectively, for the products from BCA 1; and 7.4+/-2.0 and 5.2+/-1.5 nM for the products derived from BCA 2, respectively. The high affinity exhibited by these technetium analogues is an indication of their potential for use in non-invasive in vivo biochemical characterization of cancers that possess receptors for bombesin.

Imaging nicotinic acetylcholine receptors with fluorine-18-FPH, an epibatidine analog.

UNLABELLED: Nicotinic acetylcholine receptors (nAChRs) have been implicated in a variety of central processes, such as learning and memory and analgesia. These receptors also mediate the reinforcing properties of nicotine in tobacco products and are increased in postmortem samples of brains of smokers. On the other hand, brains of individuals who have died from dementia of the Alzheimer type show abnormally low densities of nAChRs. In this study, the distribution and kinetics of [(+/-)-exo-2-(2-[18F] fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (18F-FPH), a high-affinity nAChR agonist, was evaluated in a baboon using PET. METHODS: After intravenous injection of 5 mCi [185 MBq] 18F-FPH into a 25-kg anesthetized baboon, sequential quantitative tomographic data were acquired over a period of 150 min. Regions of interest were placed and time-activity curves were generated. Brain kinetics of the radiotracer were calculated, and the in vivo regional binding in the baboon brain was compared with the known in vitro regional distribution of nAChRs in the rat and human brain. RESULTS: Brain activity reached a plateau within 60 min after injection of the tracer, and the binding was reversible. Elimination of 18F-FPH was relatively rapid from the cerebellum (clearance t[1/2] = 3 hr), intermediate from the hypothalamus/midbrain (t[1/2] = 7 hr) and slow from the thalamus (t[1/2] = 16 hr). Radioactivity due to 18F-FPH at 130 min postinjection was highest in the thalamus and hypothalamus/midbrain, intermediate in the neocortex and hippocampus and lowest in the cerebellum. Subcutaneous injection of 1 mg/kg cytisine 45 min after injection of the radiotracer reduced brain activity at 130 min by 67%, 64%, 56% and 52% of control values in the thalamus, hypothalamus/midbrain, hippocampus and cerebellum, respectively. The regional binding of 18F-FPH at 130 min was highly correlated with the known densities of nAChR measured in vitro in human (r = 0.81) and rat brain (r = 0.90). CONCLUSION: These results demonstrate the feasibility of imaging nAChRs in vivo. Fluorine-18-FPH appears to be a suitable tracer to study nAChRs in the human brain.

[125/123I]IPH: a radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors.

Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [(125)I] or [(123)I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [(125)I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi >> cerebellum). [(125)I]IPH binding sites were shown to be saturable with unlabeled IPH (ED50 approximately 1 microg/kg). The uptake of [(125)I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (-)-nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on [(125)I]IPH binding. A preliminary SPECT imaging study with [(123)I]IPH in a baboon showed [(123)I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [(123)I]IPH binding in baboon brain was also displaced (35-45% displacement) by a challenge dose of cytisine showing that a well-characterized nicotinic agonist effectively competes for [(123)I]IPH binding sites. [(123)I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain.

Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors.

UNLABELLED: Visualization of central nicotinic acetylcholine receptors (nAChRs) with modern PET or SPECT imaging techniques has been hampered by the lack of a radioligand with suitable in vivo binding characteristics (i.e., high target-to-nontarget ratios and kinetics appropriate for the half-life of the tracer and imaging modality used). This paper describes in vivo binding, kinetics and pharmacology of a highly potent 18F-labeled analog of epibatidine, (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), in the mouse brain with the view towards application of this tracer for PET imaging of nAChR in human brain. METHODS: Fluorine-18-FPH was administered intravenously to mice, and time-activity curves were determined for several regions in the brain and other organs. Saturation and pharmacology of [18F]FPH binding was demonstrated in vivo by preinjecting unlabeled FPH or other drugs with known pharmacological action before [18F]FPH was injected. The effect of the drugs on [18F]FPH accumulation was evaluated. RESULTS: [18F]FPH was rapidly incorporated into the mouse brain; peak activity (2.4% of the injected dose) was measured at 5 min after intravenous administration, followed by washout to 1.1% injected dose (ID) at 60 min. Highest concentrations of 18F occurred at 15 min in areas known to contain high densities of nAChR ¿e.g., thalamus [9.7% of injected dose per gram tissue (ID/g¿] and superior colliculus (8.3% ID/g)]. Accumulation of the 18F tracer in hippocampus, striatum, hypothalamus and cortical areas was intermediate (5.0, 5.6, 4.2 and 5.6% ID/g, respectively) and low in the cerebellum (2.8% ID/g). The distribution of [18F]FPH in the mouse brain matched that of other in vivo nAChR probes such as 3H-labeled epibatidine or norchloroepibatidine, [3H](-)-nicotine and [3H]cytisine and that of nAChR densities determined in postmortem autoradiographic studies in rodents. Preinjection of blocking doses of unlabeled epibatidine, (-)-nicotine, lobeline and cytisine significantly inhibited [18F]FPH binding in thalamus and superior colliculus, but not in cerebellum, whereas drugs that interact with binding sites other than acetylcholine recognition sites of nAChR (e.g., mecamylamine, scopolamine, N-methylspiperone and ketanserin) had no effect on [18F]FPH accumulation in any of the brain regions examined. CONCLUSION: Fluorine-18-FPH labels nAChR in vivo in the mouse brain. Because of its high uptake into the brain and high ratios of specific-to-nonspecific binding, this radioligand appears to be ideally suited for PET imaging of nAChR in the mammalian brain.

Fenfluramine-induced loss of serotonin transporters in baboon brain visualized with PET.

The present study sought to determine whether or not Positron Emission Tomography (PET) with the newly developed positron emitting serotonin (5-HT) transporter ligand, (+)[11C]McN-5652, could be used to detect fenfluramine-induced 5-HT neurotoxicity in the brain of living primates (baboons). Six PET imaging studies were performed: three before treatment with fenfluramine (5 mg/kg, s.c., twice daily for 4 days) and three after (18, 45, and 81 days after treatment). The dose of fenfluramine used in this study (5 mg/kg) is known to produce 5-HT neurotoxicity in primates, and to be approximately two times higher than a dose of fenfluramine reported to produce small and inconsistent weight loss in baboons (2 mg/kg). Following fenfluramine treatment, marked lasting reductions in regional brain specific binding of (+)[11C]McN-5652 were found by means of PET. Findings with PET corresponded well with post-mortem neurochemical findings indicative of serotonergic neurotoxicity (lasting depletions of regional brain 5-HT, 5-HIAA, and 5-HT uptake sites). These results suggest that PET imaging with (+)[11C]McN-5652 will be useful for evaluating the 5-HT neurotoxic potential of fenfluramine and related drugs in living humans.

Functional outcome measures for knee dysfunction assessment.

Maximizing the functional abilities of the individual is the primary objective of any therapeutic intervention. Functional outcome data are valuable to those involved in the care of the athlete because such data provides information that helps facilitate the clinical decision-making process and, therefore, helps insure a safe and efficient return to athletics. Functional outcome measures also provide useful data for assessing therapeutic intervention efficacy. The clinician/researcher must consider various factors when selecting an appropriate outcome measure, such as: the patient population, pathology, specific test parameters, psychometric properties, and practicality of the measure. The primary purpose of this paper is to provide the reader with guidelines for either assessing existing measures or developing new measures of functional outcomes for use in clinical practice and research.

Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction.

The potential interaction between lithium and angiotensin-converting enzyme (ACE) inhibitors was investigated in a retrospective, longitudinal, case-control study of 20 hypertensive patients previously stabilized on lithium therapy. The objective of the study was to determine the impact of ACE inhibition on steady-state lithium concentrations and to evaluate the potential association of altered lithium clearance with age, renal function, and electrolyte balance. After initiation of the ACE inhibitor, steady-state lithium concentrations increased by 36.1%, lithium clearance was reduced by 25.5% (p < 0.0001), and four patients presented with symptoms suggestive of lithium toxicity. Significant bivariate correlations were observed for lithium clearance change and age (r = -0.45; p < 0.05) and for lithium clearance change and serum creatinine (r = -0.52; p < 0.02). Multiple regression analysis indicated that 25% of the change in lithium clearance was associated with a change in serum creatinine. This percentage was increased to 35% by the inclusion of age in the regression model. None of the other variables (age, height, weight, or change in serum sodium/potassium) made a significant contribution to this model. The authors concluded that a clinically important increase in lithium concentrations can occur in patients started on ACE inhibitor therapy. As elderly patients may be uniquely predisposed to this interaction, avoidance of this medication combination in older populations should be considered.