Promising clinical performance of pretargeted immuno-PET with anti-CEA bispecific antibody and gallium-68-labelled IMP-288 peptide for imaging colorectal cancer metastases: a pilot study.

INTRODUCTION: This pilot study evaluated the imaging performance of pretargeted immunological positron emission tomography (immuno-PET) using an anti-carcinoembryonic antigen (CEA) recombinant bispecific monoclonal antibody (BsMAb), TF2 and the [68Ga]Ga-labelled HSG peptide, IMP288, in patients with metastatic colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients requiring diagnostic workup of CRC metastases or in case of elevated CEA for surveillance were prospectively studied. They had to present with elevated CEA serum titre or positive CEA tumour staining by immunohistochemistry of a previous biopsy or surgical specimen. All patients underwent endoscopic ultrasound (EUS), chest-abdominal-pelvic computed tomography (CT), abdominal magnetic resonance imaging (MRI) and positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET). For immuno-PET, patients received intravenously 120 nmol of TF2 followed 30 h later by 150 MBq of [68Ga]Ga-labelled IMP288, both I.V. The gold standard was histology and imaging after 6-month follow-up. RESULTS: Eleven patients were included. No adverse effects were reported after BsMAb and peptide injections. In a per-patient analysis, immuno-PET was positive in 9/11 patients. On a per-lesion analysis, 12 of 14 lesions were positive with immuno-PET. Median SUVmax, MTV and TLG were 7.65 [3.98-13.94, SD 3.37], 8.63 cm3 [1.98-46.64; SD 14.83] and 37.90 cm3 [8.07-127.5; SD 43.47] respectively for immuno-PET lesions. Based on a per-lesion analysis, the sensitivity, specificity, positive-predictive value and negative-predictive value were, respectively, 82%, 25%, 82% and 25% for the combination of EUS/CT/MRI; 76%, 67%, 87% and 33% for FDG-PET; and 88%, 100%, 100% and 67% for immuno-PET. Immuno-PET had an impact on management in 2 patients. CONCLUSION: This pilot study showed that pretargeted immuno-PET using anti-CEA/anti-IMP288 BsMAb and a [68Ga]Ga-labelled hapten was safe and feasible, with promising diagnostic performance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02587247 Registered 27 October 2015.

Disparate effects of adalimumab and fumaric acid esters on cardiovascular risk factors in psoriasis patients: results from a prospective, randomized, observer-blinded head-to-head trial.

BACKGROUND: The effect of adalimumab and fumaric acid esters (FAE) on the cardiovascular risk associated with psoriasis has only been investigated scarcely in randomized controlled studies. OBJECTIVE: The aim of this prospective, randomized controlled head-to-head trial was to compare the influence of adalimumab and FAE on cardiovascular disease markers in psoriasis patients. METHODS: Sixty-five patients with moderate to severe plaque psoriasis were randomly assigned to adalimumab or FAE treatment for 6 months. Cardiovascular haemodynamic parameters [flow-mediated dilation (FMD), nitro-glycerine mediated dilation (NMD) and carotid intima-media thickness (CIMT), blood pressure] were assessed at baseline (v0) and after 6 months (v6). Cutaneous disease severity, inflammatory and lipid cardiovascular risk markers were analysed at baseline(v0), after 3 (v3) and 6 months (v6). RESULTS: After 6 months of treatment FMD in the adalimumab group increased significantly [v0 5.9% (6.4% SD), v6 8.0% (4.8% SD), P = 0.048) but not in the FAE group. (v0 7.0% (4.1% SD), v6 8.4% (6.1% SD), P = 0.753]. This was paralleled by a significant decrease of high sensitive C-reactive protein (hsCRP) in the adalimumab group in comparison to the FAE group (v0: 0.39 mg/dL (0.38 SD), v6: 0.39 mg/dL (0.48 SD), P = 0.043). No significant changes were observed in any other haemodynamic parameters. FAE, however, additionally decreased total cholesterol (P = 0.046) and apolipoprotein B (P = 0.041) levels compared to adalimumab. Mean Psoriasis Area and Severity Index (psoriasis area severity score) reduction was greater but not significant (P = 0.116) under adalimumab treatment compared to FAE treatment [-71.1% (29.9 SD) vs. -54.6% (45.7%)]. CONCLUSION: In our study, both treatments were documented to exert effects on the cardiovascular system. While adalimumab showed anti-inflammatory effects and improved FMD, FAE interacted favourably with the cholesterol metabolism.

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T2 decay data.

Multi-compartment T2 mapping has gained particular relevance for the study of myelin water in the brain. As a facilitator of rapid saltatory axonal signal transmission, myelin is a cornerstone indicator of white matter development and function. Regularized non-negative least squares fitting of multi-echo T2 data has been widely employed for the computation of the myelin water fraction (MWF), and the obtained MWF maps have been histopathologically validated. MWF measurements depend upon the quality of the data acquisition, B1+ homogeneity and a range of fitting parameters. In this special issue article, we discuss the relevance of these factors for the accurate computation of multi-compartment T2 and MWF maps. We generated multi-echo spin-echo T2 decay curves following the Carr-Purcell-Meiboom-Gill approach for various myelin concentrations and myelin T2 scenarios by simulating the evolution of the magnetization vector between echoes based on the Bloch equations. We demonstrated that noise and imperfect refocusing flip angles yield systematic underestimations in MWF and intra-/extracellular water geometric mean T2 (gmT2 ). MWF estimates were more stable than myelin water gmT2 time across different settings of the T2 analysis. We observed that the lower limit of the T2 distribution grid should be slightly shorter than TE1 . Both TE1 and the acquisition echo spacing also have to be sufficiently short to capture the rapidly decaying myelin water T2 signal. Among all parameters of interest, the estimated MWF and intra-/extracellular water gmT2 differed by approximately 0.13-4 percentage points and 3-4 ms, respectively, from the true values, with larger deviations observed in the presence of greater B1+ inhomogeneities and at lower signal-to-noise ratio. Tailoring acquisition strategies may allow us to better characterize the T2 distribution, including the myelin water, in vivo.

Different from the Beginning: WM Maturity of Female and Male Extremely Preterm Neonates-A Quantitative MRI Study.

BACKGROUND AND PURPOSE: Former preterm born males are at higher risk for neurodevelopmental disabilities compared with female infants born at the same gestational age. This retrospective study investigated sex-related differences in the maturity of early myelinating brain regions in infants born <28 weeks' gestational age using diffusion tensor- and relaxometry-based MR imaging. MATERIALS AND METHODS: Quantitative MR imaging sequence acquisitions were analyzed in a sample of 35 extremely preterm neonates imaged at term-equivalent ages. Quantitative MR imaging metrics (fractional anisotropy; ADC [10-3mm2/s]; and T1-/T2-relaxation times [ms]) of the medulla oblongata, pontine tegmentum, midbrain, and the right/left posterior limbs of the internal capsule were determined on diffusion tensor- and multidynamic, multiecho sequence-based imaging data. ANCOVA and a paired t test were used to compare female and male infants and to detect hemispheric developmental asymmetries. RESULTS: Seventeen female (mean gestational age at birth: 26 + 0 [SD, 1 + 4] weeks+days) and 18 male (mean gestational age at birth: 26 + 1 [SD, 1 + 3] weeks+days) infants were enrolled in this study. Significant differences were observed in the T2-relaxation time (P = .014) of the pontine tegmentum, T1-relaxation time (P = .011)/T2-relaxation time (P = .024) of the midbrain, and T1-relaxation time (P = .032) of the left posterior limb of the internal capsule. In both sexes, fractional anisotropy (P [♀] < .001/P [♂] < .001) and ADC (P [♀] = .017/P [♂] = .028) differed significantly between the right and left posterior limbs of the internal capsule. CONCLUSIONS: The combined use of various quantitative MR imaging metrics detects sex-related and interhemispheric differences of WM maturity. The brainstem and the left posterior limb of the internal capsule of male preterm neonates are more immature compared with those of female infants at term-equivalent ages. Sex differences in WM maturation need further attention for the personalization of neonatal brain imaging.

Quantitative Susceptibility Mapping of Venous Vessels in Neonates with Perinatal Asphyxia.

BACKGROUND AND PURPOSE: Cerebral venous oxygen saturation can be used as an indirect measure of brain health, yet it often requires either an invasive procedure or a noninvasive technique with poor sensitivity. We aimed to test whether cerebral venous oxygen saturation could be measured using quantitative susceptibility mapping, an MR imaging technique, in 3 distinct groups: healthy term neonates, injured term neonates, and preterm neonates. MATERIALS AND METHODS: We acquired multiecho gradient-echo MR imaging data in 16 neonates with perinatal asphyxia and moderate or severe hypoxic-ischemic encephalopathy (8 term age: average, 40.0 [SD, 0.8] weeks' gestational age; 8 preterm, 33.5 [SD, 2.0] weeks' gestational age) and in 8 healthy term-age controls (39.3 [SD, 0.6] weeks, for a total of n = 24. Data were postprocessed as quantitative susceptibility mapping images, and magnetic susceptibility was measured in cerebral veins by thesholding out 99.95% of lower magnetic susceptibility values. RESULTS: The mean magnetic susceptibility value of the cerebral veins was found to be 0.36 (SD, 0.04) ppm in healthy term neonates, 0.36 (SD, 0.06) ppm in term injured neonates, and 0.29 (SD, 0.04) ppm in preterm injured neonates. Correspondingly, the derived cerebral venous oxygen saturation values were 73.6% (SD, 2.8%), 71.5% (SD, 7.4%), and 72.2% (SD, 5.9%). There was no statistically significant difference in cerebral venous oxygen saturation among the 3 groups (P = .751). CONCLUSIONS: Quantitative susceptibility mapping-derived oxygen saturation values in preterm and term neonates agreed well with values in past literature. Cerebral venous oxygen saturation in preterm and term neonates with hypoxic-ischemic encephalopathy, however, was not found to be significantly different between neonates or healthy controls.

MR relaxation in multiple sclerosis.

This article provides an overview of relaxation times and their application to normal brain and brain and cord affected by multiple sclerosis. The goal is to provide readers with an intuitive understanding of what influences relaxation times, how relaxation times can be accurately measured, and how they provide specific information about the pathology of MS. The article summarizes significant results from relaxation time studies in the normal human brain and cord and from people who have multiple sclerosis. It also reports on studies that have compared relaxation time results with results from other MR techniques.

Quantitative Analysis of Punctate White Matter Lesions in Neonates Using Quantitative Susceptibility Mapping and R2* Relaxation.

BACKGROUND AND PURPOSE: It is difficult to distinguish punctate white matter lesions from focal hemorrhagic lesions in neonates on conventional MR imaging because both kinds of lesions show increased signal intensity on T1-weighted images and, frequently, decreased signal intensity on T2-weighted images. Our aim was to distinguish punctate white matter lesions and focal hemorrhagic lesions using quantitative measures. MATERIALS AND METHODS: In the current study, we acquired multiecho gradient recalled-echo MR imaging data from 24 neonates with hypoxic-ischemic encephalopathy and postprocessed them as R2* relaxation maps and quantitative susceptibility maps. Seven subjects who were found to have multifocal punctate white matter lesions and/or focal hemorrhagic lesions on R2* maps were included (mean gestational age at birth, 33 ± 4.28 weeks; mean gestational age at scanning, 38 ± 2 weeks). Manually drawing ROIs on R2* maps, we measured R2* and magnetic susceptibility values of the lesions, along with white matter regions within the corpus callosum as healthy comparison tissue. RESULTS: R2* and magnetic susceptibility values were both found to easily distinguish punctate white matter lesions, focal hemorrhagic lesions, and healthy white matter tissue from each other (P < .05), with a large Hedge g. R2* and magnetic susceptibility values were significantly increased in focal hemorrhagic lesions compared with punctate white matter lesions and healthy white matter tissue. Punctate white matter lesions were also found to have significantly increased values over healthy white matter tissue. CONCLUSIONS: R2* and quantitative susceptibility maps can be used to help clinicians distinguish and measure focal hemorrhages, punctate white matter lesions, and healthy white matter tissue.

FLAIR2 improves LesionTOADS automatic segmentation of multiple sclerosis lesions in non-homogenized, multi-center, 2D clinical magnetic resonance images.

BACKGROUND: Accurate segmentation of MS lesions on MRI is difficult and, if performed manually, time consuming. Automatic segmentations rely strongly on the image contrast and signal-to-noise ratio. Literature examining segmentation tool performances in real-world multi-site data acquisition settings is scarce. OBJECTIVE: FLAIR2, a combination of T2-weighted and fluid attenuated inversion recovery (FLAIR) images, improves tissue contrast while suppressing CSF. We compared the use of FLAIR and FLAIR2 in LesionTOADS, OASIS and the lesion segmentation toolbox (LST) when applied to non-homogenized, multi-center 2D-imaging data. METHODS: Lesions were segmented on 47 MS patient data sets obtained from 34 sites using LesionTOADS, OASIS and LST, and compared to a semi-automatically generated reference. The performance of FLAIR and FLAIR2 was assessed using the relative lesion volume difference (LVD), Dice coefficient (DSC), sensitivity (SEN) and symmetric surface distance (SSD). Performance improvements related to lesion volumes (LVs) were evaluated for all tools. For comparison, LesionTOADS was also used to segment lesions from 3 T single-center MR data of 40 clinically isolated syndrome (CIS) patients. RESULTS: Compared to FLAIR, the use of FLAIR2 in LesionTOADS led to improvements of 31.6% (LVD), 14.0% (DSC), 25.1% (SEN), and 47.0% (SSD) in the multi-center study. DSC and SSD significantly improved for larger LVs, while LVD and SEN were enhanced independent of LV. OASIS showed little difference between FLAIR and FLAIR2, likely due to its inherent use of T2w and FLAIR. LST replicated the benefits of FLAIR2 only in part, indicating that further optimization, particularly at low LVs is needed. In the CIS study, LesionTOADS did not benefit from the use of FLAIR2 as the segmentation performance for both FLAIR and FLAIR2 was heterogeneous. CONCLUSIONS: In this real-world, multi-center experiment, FLAIR2 outperformed FLAIR in its ability to segment MS lesions with LesionTOADS. The computation of FLAIR2 enhanced lesion detection, at minimally increased computational time or cost, even retrospectively. Further work is needed to determine how LesionTOADS and other tools, such as LST, can optimally benefit from the improved FLAIR2 contrast.

What Have We Learned from Perfusion MRI in Multiple Sclerosis?

Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.

Hippocampal volume and vasculature before and after exercise in treatment-resistant schizophrenia.

BACKGROUND: Schizophrenia is associated with poor cognitive function and elevated cardiometabolic disease risk. These health concerns may exacerbate neurocognitive dysfunction associated with hippocampal abnormalities, particularly hippocampal volume reductions. Regular exercise is thought to improve symptom severity, reduce depression, and improve cognition in schizophrenia, and may trigger exercise-mediated hippocampal growth. The potential for the benefits of exercise for treatment-resistant schizophrenia patients has not been clearly assessed. This study aims to assess the effect of exercise on hippocampal plasticity and clinical outcomes in chronic schizophrenia. METHODS: Seventeen DSM-IV criteria schizophrenia or schizoaffective disorder patients completed a customized moderate intensity 12-week aerobic or weight-bearing exercise program. Adherence rates were 83% ±â€¯9.4%) with 70% of participants completing the entire exercise program. Concomitant neuroimaging, clinical and cognitive assessments were obtained at baseline and 12-weeks. RESULTS: At follow-up, symptom severity scores (t(16) = -16.8, p. ≤ 0.0001) and social functioning (t(16) = 4.4, p. = 0.0004) improved. A trend for improved depression scores (t(16) = -2.0, p. = 0.06) with no change in anxiety, or extrapyramidal symptoms were seen. Hippocampal volume increased (t(16) = -2.54, p. = 0.02), specifically in the left CA-1 field (F(16) = -2.33, p. = 0.03). Hippocampal vascular volume was unchanged. Change in hippocampal volume and vascular volume was not significantly correlated with change in symptom severity or affect scores. CONCLUSIONS: Adjunct exercise may accelerate symptom improvement in treatment-resistant psychosis patients. While the underlying mechanism remains unclear, these results indicate that chronic schizophrenia patients experience hippocampal plasticity in response to exercise. STUDY REGISTRATION: Clinical Trials.govNCT01392885.

Prevalence of Brain Microbleeds in Alzheimer Disease: A Systematic Review and Meta-Analysis on the Influence of Neuroimaging Techniques.

BACKGROUND AND PURPOSE: The literature on the prevalence of Alzheimer disease-associated cerebral microbleeds assessed with MR imaging shows considerable heterogeneity in terms of imaging techniques and parameters. Our aim was to perform a meta-analysis of the role of imaging techniques, including image acquisition, field strength and scanner type, and clinical and demographic factors on the reported prevalence of microbleeds in Alzheimer disease. MATERIALS AND METHODS: The prevalence of microbleeds was examined with respect to a priori-selected moderating variables via meta-analytic tools of literature reports. RESULTS: Fourteen unique studies providing 15 microbleed prevalence rates met the selection criteria for inclusion. The aggregate prevalence of microbleeds was 24% (95% CI, 19%-28%). Scan (SWI = 40%, gradient echo = 18%, EPI = 19%) and field strength (slope = 0.39; standard error = 15, P < .01) influenced the prevalence of microbleeds. The associations between microbleeds and age, sex, and global cognitive status were not significant. After updating the literature, the aggregate prevalence remained in the 95% CI range. CONCLUSIONS: Imaging technique and field strength are strongly associated with the prevalence of microbleeds over the global aggregate. Standardized imaging protocols for identification of microbleeds are recommended to minimize confounds.

FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection.

BACKGROUND AND PURPOSE: FLAIR and double inversion recovery are important MR imaging scans for MS. The suppression of signal from CSF in FLAIR and the additional suppression of WM signal in double inversion recovery improve contrast between lesions, WM and GM, albeit at a reduced SNR. However, whether the acquisition of double inversion recovery is necessary is still debated. Here, we present an approach that allows obtaining CSF-suppressed images with improved contrast between lesions, WM and GM without strongly penalizing SNR. MATERIALS AND METHODS: 3D T2-weighted and 3D-FLAIR data acquired from September 2014 to April 2015 in healthy volunteers (23.4 ± 2.4 years of age; female/male ratio, 3:2) and patients (44.1 ± 14.0 years of age; female/male ratio, 4:5) with MS were coregistered and multiplied (FLAIR(2)). SNR and contrast-to-noise measurements were performed for focal lesions and GM and WM. Furthermore, data from 24 subjects with relapsing-remitting and progressive MS were analyzed retrospectively (52.7 ± 8.1 years of age; female/male ratio, 14:10). RESULTS: The GM-WM contrast-to-noise ratio was by 133% higher in FLAIR(2) than in FLAIR and improved between lesions and WM by 31%, 93%, and 158% compared with T2, DIR, and FLAIR, respectively. Cortical and juxtacortical lesions were more conspicuous in FLAIR(2). Furthermore, the 3D nature of FLAIR(2) allowed reliable visualization of callosal and infratentorial lesions. CONCLUSIONS: We present a simple approach for obtaining CSF suppression with an improved contrast-to-noise ratio compared with conventional FLAIR and double inversion recovery without the acquisition of additional data. FLAIR(2) can be computed retrospectively if T2 and FLAIR scans are available.

Reduced Myelin Water in the White Matter Tracts of Patients with Niemann-Pick Disease Type C.

Previous studies using diffusion tensor imaging to examine white matter in Niemann-Pick disease type C have produced mixed results. However, diffusion tensor imaging does not directly measure myelin and may be affected by other structural changes. We used myelin water imaging to more directly examine demyelination in 2 patients with Niemann-Pick disease type C. The results suggest that this technique may be useful for identifying regional changes in myelination in this condition.

High-Field High-Repetition-Rate Sources for the Coherent THz Control of Matter.

Ultrashort flashes of THz light with low photon energies of a few meV, but strong electric or magnetic field transients have recently been employed to prepare various fascinating nonequilibrium states in matter. Here we present a new class of sources based on superradiant enhancement of radiation from relativistic electron bunches in a compact electron accelerator that we believe will revolutionize experiments in this field. Our prototype source generates high-field THz pulses at unprecedented quasi-continuous-wave repetition rates up to the MHz regime. We demonstrate parameters that exceed state-of-the-art laser-based sources by more than 2 orders of magnitude. The peak fields and the repetition rates are highly scalable and once fully operational this type of sources will routinely provide 1 MV/cm electric fields and 0.3 T magnetic fields at repetition rates of few 100 kHz. We benchmark the unique properties by performing a resonant coherent THz control experiment with few 10 fs resolution.

Similar effects of electroporational stress and treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate on vimentin expression in mouse plasmacytoma cells.

In mouse plasmacytoma cells (MPC-11), an activation of the normally repressed vimentin gene was observed as a response to transfectional stress. Effects of electroporation on vimentin gene expression were compared at the cellular and chromatin level to those caused by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). At the cellular level, similar changes in vimentin gene activity and cell-cycle distribution were observed by flow cytometry, whereas at the chromatin level similar changes in patterns of hypersensitive regions were detected by DNase I mapping. Additionally, a region located 700 bp upstream of the transcriptional start became hypersensitive to DNase I digestion upon electroporation and TPA treatment. This region overlaps two adjacent AP-1-like binding elements and generates specific DNA/AP-1 complexes in bandshift experiments. Therefore, the transcription factor AP-1 seems to play a central role in the activation of vimentin gene expression induced by these 2 different forms of stress.

High resolution susceptibility weighted MR-imaging of brain tumors during the application of a gaseous agent.

PURPOSE: To employ a high resolution blood oxygenation level dependent (BOLD) method called susceptibility weighted imaging (SWI) together with the breathing of carbogen to investigate the response of cerebral tumors to this breathing gas and to assess tumor anatomy at high resolution. METHODS: Five patients with cerebral tumors (four glioblastoma multiforme, one astrocytoma [WHO grade II]) were studied using a susceptibility weighted 3D gradient echo, first order velocity compensated sequence (TE = 45 ms, TR = 67 ms, alpha = 25 degrees , FOV = 256 x 192 x 64 mm(3), typical matrix = 512 x 192 x 64), on a 1.5 T MR scanner while they were breathing air and carbogen. Signal changes between the two breathing conditions were investigated. RESULTS: The glioblastomas showed strong but heterogeneous signal changes between carbogen and air breathing, with changes between + 22.4 +/- 4.9 % at the perimeter of the tumors and - 5.0 +/- 0.4 % in peritumoral areas that appeared hyperintense on T (2)-weighted images. The astrocytoma displayed a signal decrease during carbogen breathing (- 4.1 +/- 0.1 % to - 6.8 +/- 0.3 % in peritumoral areas that correspond to hyperintense regions on T (2)-weighted images, and - 3.1 +/- 0.1 % in the tumor-center). CONCLUSIONS: SWI provides high resolution images of cerebral anatomy and venous vascularization. Combined with hypercapnia it allows for regional assessment of tumor activity.

Can a double isotope method be used to measure fractional zinc absorption from urinary samples?

OBJECTIVE: This study was designed to test whether fractional absorption calculated from urinary enrichment of stable isotopes of zinc accurately reflects true absorption measured by faecal monitoring. DESIGN: The two techniques were directly compared in volunteers, whereby each subject acted as his/her own control. SETTING: Volunteers were healthy adults, living at home, who were taking part in a larger study on zinc. They attended the local hospital for isotope administration. SUBJECTS: Fifteen volunteers were recruited, seven of whom had non-insulin dependent diabetes mellitus. All completed the study, but five did not carry out a complete faecal collection. INTERVENTIONS: Each subject received an oral and i.v. dose of different stable isotopes of zinc with breakfast. Faecal and urinary enrichment with the isotopes was measured. RESULTS: There was no significant correlation between the two measures of absorption. CONCLUSIONS: The double label stable isotope technique for determining zinc absorption from measurements of urinary enrichment does not reliably predict true zinc absorption (measured by faecal and urinary monitoring) in a heterogenous group of adults given relatively low doses of stable isotopes of zinc.

Zinc metabolism in non-insulin dependent diabetes mellitus.

Low plasma zinc concentrations and increased zinc excretion have been reported in patients with non-insulin dependent diabetes mellitus (NIDDM). This study was designed to compare zinc metabolism in ten NIDDM patients with ten healthy controls, using stable isotopes of zinc. Zinc absorption from a standard breakfast labelled extrinsically with 3 mg 67Zn was measured using a fecal monitoring technique and thermal ionization quadrupole mass spectrometry. One hour after the test meal each volunteer was given 0.5 mg 70Zn (as citrate) intravenously and blood samples taken at intervals for up to 6 days. Isotopic enrichment was measured and the data entered into a simple kinetic model to estimate the size and rate of turnover of exchangeable pools of zinc. Urinary zinc excretion was higher in the male diabetics than controls (p < 0.05), but not in females. Since the efficiency of absorption and endogenous losses of zinc were very variable between individuals, and there was only a limited amount of data, it was not possible to draw conclusion about the effect of NIDDM on zinc absorption and excretion. However, the fact that there were no differences in exchangeable zinc pool sizes suggests that zinc metabolism is not altered in NIDDM.

Influence of pegylation and hapten location at the surface of radiolabelled liposomes on tumour immunotargeting using bispecific antibody.

INTRODUCTION: This paper proposes liposomes as a potential new tool for radioimmunotherapy in solid tumours with a two step targeting system. Tumour pretargeting is obtained by using a monoclonal bispecific antibody (BsmAb, anti CEA x anti-DTPA-In) and pegylated liposomes containing lipid-hapten (DSPE-DTPA-In or DSPE-PEG-DTPA-In). To optimise at the same time in vivo behaviour and specific targeting, the study focuses on the liposome formulation in order to determine more precisely the role of pegylation on both the blood half-life and the specific recognition with the BsmAb. METHODS: Different liposome formulations containing two PEG length (1000 and 2000) in varying amount (1.5-6 mol%) were prepared with DTPA directly coupled to DSPE or at the end of the PEG chain (DSPE-DTPA or DSPE-PEG-DTPA). Liposomes were immobilized on an L1 chip to measure by SPR (Surface Plasmon Resonance) the effect of pegylation on the BsmAb recognition of the DTPA-In hapten. Pharmacokinetic studies were performed in mice. Tumour targeting was studied in nude mice xenografted with human colorectal adenocarcinoma cells that express CEA, and doubly radiolabelled liposomes (with (111)In and (125)I) injected 24h after the BsmAb. RESULTS: The best in vitro apparent dissociation constant was obtained with liposomes bearing DTPA at the end of the PEG chain (KD=6.3 nM), which showed significant specific tumour uptake after BsmAb injection (8.6 ± 2.4% ID/g at 24h versus 4.5 ± 0.5%ID/g for passive targeting, α=0.01). All tumour/organ ratios were superior to 1 at 24h for this formulation, except for the spleen. CONCLUSION: The feasibility of specific tumour targeting in mice with a BsmAb and radiolabelled liposomes was demonstrated and the interest of SPR to predict their targeting performance in vivo was highlighted. This original and new approach provides promising prospects for the radioimmunotherapy of solid tumours.

Evaluation of white matter myelin water fraction in chronic stroke.

Multi-component T2 relaxation imaging (MCRI) provides specific in vivo measurement of myelin water content and tissue water environments through myelin water fraction (MWF), intra/extra-cellular water fraction (I/EWF) and intra/extracellular and global geometric mean T2 (GMT2) times. Quantitative MCRI assessment of tissue water environments has provided new insights into the progression and underlying white matter pathology in neural disorders such as multiple sclerosis. It has not previously been applied to investigate changes in white matter in the stroke-affected brain. Thus, the purposes of this study were to 1) use MCRI to index myelin water content and tissue water environments in the brain after stroke 2) evaluate relationships between MWF and diffusion behavior indexed by diffusion tensor imaging-based metrics and 3) examine the relationship between white matter status (MWF and fractional anisotropy) and motor behavior in the chronic phase of stroke recovery. Twenty individuals with ischemic stroke and 12 matched healthy controls participated. Excellent to good test/re-test and inter-rater reliability was observed for region of interest-based voxelwise MWF data. Reduced MWF was observed in whole-cerebrum white matter (p < 0.001) and in the ipsilesional (p = 0.017) and contralesional (p = 0.037) posterior limb of internal capsule (PLIC) after stroke compared to whole-cerebrum and bilateral PLIC MWF in healthy controls. The stroke group also demonstrated increased I/EWF, I/E GMT2 and global GMT2 times for whole-cerebrum white matter. Measures of diffusion behavior were also significantly different in the stroke group across each region investigated (p < 0.001). MWF was not significantly correlated with specific tensor-based measures of diffusion in the PLIC for either group. Fractional anisotropy in the ipsilesional PLIC correlated with motor behavior in chronic stroke. These results provide novel insights into tissue-specific changes within white matter after stroke that may have important applications for the understanding of the neuropathology of stroke.