166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.

166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.     

PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements.

18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.     

Additive Effects of Sevoflurane and Propofol on γ-Aminobutyric Acid Receptor Function

Background: Previous studies have shown that propofol and sevoflurane enhance the function of [gamma]-aminobutyric acid type A (GABAA) receptors. However, it is not known whether these two drugs modulate the same molecular pathways. In addition, little is known about receptor function in the presence of both propofol and sevoflurane. The aim of this study was to better understand the interactions of propofol and sevoflurane with the GABAA receptor.

Methods: Wild-type [alpha]1, [beta]2, [gamma]2s GABAA receptor subunit complementary DNAs were transfected into human embryonic kidney cells grown on glass coverslips using a calcium phosphate transfection method. After transfection (36-72 h), cells were whole cell patch clamped and exposed to combinations of the following: 0.3-1,000 [mu]m [gamma]-aminobutyric acid (GABA), 0-10 [mu]m propofol, and 0-1,650 [mu]m sevoflurane. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger.

Results: Both propofol and sevoflurane alone enhanced the amplitude of GABAA receptor responses to submaximal concentrations of GABA in a dose-dependent manner. The enhancement was underpinned by an increase in the apparent affinity of the receptor for GABA. Coapplication of both anesthetics further enhanced the apparent affinity of the receptor for GABA.     

Report of a National Conference on Donation after Cardiac Death

A national conference on organ donation after cardiac death (DCD) was convened to expand the practice of DCD in the continuum of quality end-of-life care. This national conference affirmed the ethical propriety of DCD as not violating the dead donor rule. Further, by new developments not previously reported, the conference resolved controversy regarding the period of circulatory cessation that determines death and allows administration of pre-recovery pharmacologic agents, it established conditions of DCD eligibility, it presented current data regarding the successful transplantation of organs from DCD, it proposed a new framework of data reporting regarding ischemic events, it made specific recommendations to agencies and organizations to remove barriers to DCD, it brought guidance regarding organ allocation and the process of informed consent and it set an action plan to address media issues. When a consensual decision is made to withdraw life support by the attending physician and patient or by the attending physician and a family member or surrogate (particularly in an intensive care unit), a routine opportunity for DCD should be available to honor the deceased donor's wishes in every donor service area (DSA) of the United States.     

Influence of Short‐term Confinement and Exercise on Tibia Development in Growing Pigs

The influence of short‐term confinement and moderate exercise on tibia development was investigated in growing pigs (36–41 kg, 10 weeks at the beginning of the study). Animals were kept for 2 weeks either in individual crates of 0.8 m² (‘confinement’, n = 4) or kept in groups of four animals in large crates of 5.6 m² without (‘control’) or with additional exercise (30 min walking at 5 days/week; ‘exercise’). Bone density and morphological parameters were evaluated by computer tomography (CT). Periosteal apposition and longitudinal growth were determined after polychrome sequential labelling in weekly intervals. Cortical areas of the cross sections at the mid‐shaft and at 75% of the length of the bone measured distal to the carpus by CT were significantly correlated to each other (r = 0.70) and revealed a significant reduction in confined animals. This difference was explained by lower periosteal apposition rates in these animals compared with exercised and group‐housed pigs. Similarly longitudinal growth and the formation and calcification of spongiosa of the tibiae were inhibited by confinement. Thus, 2 weeks of confinement led to significant differences in bone growth and metabolism in young growing piglets when compared with animals with moderate activity.     

Electroencephalographic and imaging profile in a subacute sclerosing panencephalitis (SSPE) cohort: a correlative study.

OBJECTIVE: There are only a few studies correlating diverse radiological and EEG features of subacute sclerosing panencephalitis (SSPE). The objective of the study was to (a) describe EEG profile and (b) correlate it with the clinical and imaging data of patients with confirmed SSPE. METHODS: This study was conducted at a University teaching hospital in south India and involved 58 patients (M:F=37:21, age: 12.3, SD 4.8 years) of SSPE. Diagnosis of SSPE was based on the characteristic clinical manifestations, and raised IgG (1:625) anti-measles antibody in cerebrospinal fluid (CSF) by ELISA in all the patients. Scalp EEGs were recorded on 16 channel machines using standard parameters and procedures. The EEG, clinical and imaging data were reviewed. RESULTS: EEGs were frequently abnormal: typical (37) and atypical (21). Diffuse slowing of background activity (BGA) was noted in 46 records being asymmetrical in six. Periodic complexes were periodic (32), quasi-periodic (21) or a-periodic (4). Periodic complexes (PC) (amplitude: 370.7, SD 171.2 microV; duration - 1.7, SD 2.0 s; inter-complex interval: 8.4, SD 9.2s) were symmetrical in 39 and asymmetrical in 19. CT (32) and MRI (23) scans were normal in 16 patients while others had white matter (15), cerebral edema (8), cerebral atrophy (8), basal ganglia (2), and thalamic (2) changes. There was an independent association of frontally dominant slowing of BGA (p=0.04) and typical PCs (p=0.03) with the diffuse cerebral edema on imaging. White matter changes correlated with slowing of BGA (p=0.04), but not with typical PC (p=0.16). CONCLUSIONS: This study provides valuable insight into the structural and clinical correlates of EEG changes in SSPE. SIGNIFICANCE: Irrespective of the incidence of occurrence of SSPE in a community, a clinician should be aware of the wide spectra of EEG findings. This study also discusses the possible underlying structural and clinical correlates.     

Malignancy larynx presenting solely as pharyngo-cutaneous fistula

Malignancy larynx usually presents early, the common symptoms being hoarseness, pain thorat, cough and irritation of throat. An advanced malignancy is likely to be complicated by a pharyngo-cutaneous fistula. However it is an occurrence towards the end stage of the disease. Here we present a case of malignancy larynx primarily presenting as pharyngo-cutaneous fistula without any other symptoms.