Amphetamine Decreases α2C-Adrenoceptor Binding of [11C]ORM-13070: A PET Study in the Primate Brain

Background:

The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands.

Methods:

We explored the use of the novel α_2C-adrenoceptor antagonist PET tracer [¹¹C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [¹¹C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys.

Results:

Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [¹¹C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [¹¹C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [¹¹C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP _ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP _ND values by 31–50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata.

Conclusions:

Together, these results indicate that [¹¹C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.     

Shiga toxin-producing Escherichia coli serotype O78:H(-) in family, Finland, 2009

Shiga toxin-producing Escherichia coli (STEC) is a pathogen that causes gastroenteritis and bloody diarrhea but can lead to severe disease, such as hemolytic uremic syndrome (HUS). STEC serotype O78:H(-) is rare among humans, and infections are often asymptomatic. We detected a sorbitol-fermenting STEC O78:H(-):stx(1c):hlyA in blood and fecal samples of a 2-week-old boy who had bacteremia and HUS and in fecal samples of his asymptomatic family members. The phenotypic and genotypic characteristics and the virulence properties of this invasive STEC were investigated. Our findings demonstrate that contrary to earlier suggestions, STEC under certain conditions can invade the human bloodstream. Moreover, this study highlights the need to implement appropriate diagnostic methods for identifying the whole spectrum of STEC strains associated with HUS.     

11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism,plasma pharmacokinetics,whole-body distribution and radiation dosimetry in healthy men

Purpose

¹¹C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine (¹¹C-ORM-13070) is a novel PET tracer for imaging of α_2C-adrenoceptors in the human brain. Brain α_2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer’s disease. To validate the use of ¹¹C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose.

Methods

Radiometabolism was studied in a test–retest setting in six healthy men. After intravenous injection of ¹¹C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time–activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of ¹¹C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling.

Results

Two radioactive metabolites of ¹¹C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged ¹¹C-ORM-13070 decreased from 81?±?4 % of total radioactivity at 4 min after tracer injection to 23?±?4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged ¹¹C-ORM-13070 in arterial plasma were 0.0117?±?0.0056 min^?1 and 73.6?±?35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 – 4.2 μSv/MBq.

Conclusion

¹¹C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of ¹¹C-ORM-13070 was in the same range as that of other ¹¹C-labelled brain receptor tracers. An injection of 500 MBq of ¹¹C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of ¹¹C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.     

Visual assessment of [11C]PIB PET in patients with cognitive impairment

Purpose

The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia.

Methods

We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects.

Results

The evaluation of visual classification as “normal” or “abnormal” showed good interobserver agreement (κ?=?0.90). There was a clear correlation between visual and quantitative analysis (r?=?0.47–0.79, p?<?0.001). The most difficult visually assessed brain area was the putamen (κ?=?0.11; correlation with quantitative analysis: reader A r?=?0.22; reader B r?=?0.60).

Conclusion

Our study shows that visual evaluation of [¹¹C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings.     

N-ras gene mutations in acute myeloid leukemia: accurate detection by solid-phase minisequencing.

Mutations in the N-ras gene are found in one-third of patients with acute myeloid leukemia. The N-ras mutations could serve as markers for residual cells, if a highly sensitive method for detecting the mutations was available. We applied a new method, solid-phase minisequencing, to analyze bone-marrow cells from 16 patients with acute myeloid leukemia for mutations in codon 12, 13 and 61 of the N-ras gene. In the solid-phase minisequencing technique the mutations are identified by a primer extension reaction, in which a single labelled nucleoside triphosphate is incorporated into an immobilized DNA fragment previously amplified by the polymerase chain reaction. We identified N-ras mutations in 5 of the patients (30%). In one patient, we observed 2 mutations that were shown to be located in different alleles. With the solid-phase minisequencing method, we were able to determine the proportion of mutated cells in the samples. We found that in 4 of the samples only a fraction (7-64%) of the blasts carried an N-ras mutation, and in one sample practically all blast cells were mutated. The method was highly sensitive, allowing us to identify N-ras mutations even when the sample consisted of 99.7% normal cells and only 0.3% mutated blasts.     

Rectal <Emphasis Type="Italic">E. coli</Emphasis> above ciprofloxacin ECOFF associate with infectious complications following prostate biopsy

Transrectal prostate biopsies carry the risk of infection. By using non-selective culture plates, instead of commonly used ciprofloxacin (CIP)-containing plates, we analyzed the association between Escherichia coli CIP minimal inhibitory concentration (MIC) and post-biopsy infectious complications. A pre-biopsy rectal swab was taken from 207 consecutive men, scheduled for transrectal 12-core prostate biopsy with CIP 750 mg as the mostly used prophylaxis. CIP MIC of rectal Gram-negative bacilli was determined from a chromogenic agar. Rectal E. coli were categorized to resistant (R) and intermediate (I) isolates together (R + I, MIC >?0.25 mg/l) and to sensitive (S, MIC ≤?0.25 mg/l) using EUCAST clinical breakpoints. In addition, epidemiological cutoff (ECOFF R, MIC >?0.064 mg/l) was used for categorization. Eighteen (8.7%) men showed CIP R + I E. coli by the EUCAST breakpoints and 41 (19.8%) using the ECOFF R criteria. During follow-up, 15 (7.2%) men had infectious symptoms, of which 9 (4.3%) were culture-confirmed infections. Only 4 (26.7%) of these 15 patients showed R + I E. coli in the rectal swab according to EUCAST, but 10 (66.7%) using the ECOFF cutoff. Rectal E. coli CIP R + I by the EUCAST clinical breakpoints associated with infectious complications with OR 5.7 (95% CI 1.5–21.8, P?=?0.005) and ECOFF R E. coli by OR 10.7 (95% CI 3.0–37.6, P?<?0.001). Men carrying rectal E. coli with moderately lowered CIP susceptibility (MIC > ECOFF 0.064 mg/l) were identified and, interestingly, they showed a high risk of developing infectious symptoms after the biopsy. This explains why some men develop infectious complications despite appropriate antibiotics before prostatic biopsies. Trial registration: NCT02140502     

Peer Reviewed: Pedometer Use Among Adults at High Risk of Type 2 Diabetes,Finland, 2007-2008

Introduction

A pedometer helps adults exercise more, but sedentary adults need instruction and advice to be motivated to use one. We conducted this qualitative study to describe the experiences of participants at high risk of type 2 diabetes who began using a pedometer.

Methods

A total of 74 people at high risk of type 2 diabetes participated in 6 months of group counseling. From April 2007 to April 2008, we collected data through questionnaires, theme interviews (n = 22) and video recordings of counseling sessions. From October 2007 through June 2008, we analyzed the data.

Results

Pedometers were useful tools for observing levels of exercise, setting personal goals for walking, and helping evaluate whether daily goals were met. Negative experiences were associated with functional failures, pedometers'' unsuitability for exercise other than walking, and the goal of 10,000 steps, which some participants considered too high.

Conclusions

Sedentary adults can be motivated to use a pedometer if we inform them that regular users find it a useful instrument for increasing their level of exercise. These adults should set realistic goals for walking and receive adequate instructions for using pedometers.     

Modic changes in vertebral endplates: a comparison of MR imaging and multislice CT

OBJECTIVE: This paper aims to evaluate the presence of endplate sclerosis in different types of Modic changes and to assess the capability of MRI in detecting endplate sclerosis within these changes. MATERIALS AND METHODS: The lumbar spines (L3-S1) of 70 patients were retrospectively reviewed to determine Modic changes and disc degeneration from MRI and endplate sclerosis from CT. T1- and T2-weighted signal intensity and Hounsfield unit (HU) measurements of type I and II Modic changes were recorded and the association of both Modic types I and II with endplate sclerosis was analyzed with a Mann-Whitney test. RESULTS: Altogether 82 Modic changes in 36 subjects were recorded: 13% were type I, 12% mixed type I/II, 65% type II, 9% mixed type II/III, and 1% type III. Thirty-eight percent of the endplates with Modic changes had sclerosis in CT. Of specific Modic types, mixed I/II and II/III associated significantly with endplate sclerosis. Endplate sclerosis was not detected in MRI in a quantitative analysis. CONCLUSION: Endplate sclerosis exists in all types of Modic changes, especially in mixed Modic types, and not only in type III changes, as previously assumed. Endplate sclerosis was not detected in MRI, which may depend on the amount of mineralization of the bone marrow.