Synthesis of [ 18 F]GBR 12909, a dopamine reuptake inhibitor

Preparation of no‐carrier‐added fluorine‐18 labeled GBR 12909 (1‐[2‐(bis(4‐fluorophenyl)methoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine), a specific and high affinity inhibitor of dopamine reuptake, is described. 4‐Fluoro‐4′‐[ 18 F]fluorobenzophenone was prepared by [ 18 F]fluoride ion substitution of the corresponding trimethylammonium trifluoromethanesulfonate salt. The [ 18 F]benzophenone was reduced to the benzhydrol, chlorinated, then used to alkylate 1‐(2‐hydroxyethyl)‐4‐(3‐phenyl‐propyl)piperazine to yield [ 18 F]GBR 12909 in high specific activity (≥2000 Ci/mmol) and overall yields of 10–16% (corrected, 140 min synthesis).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90171/1/2580280708_ftp.pd

Development of in vivo Raman spectroscopy for the diagnosis of breast cancer and intra-operative margin assessment

Thesis (Ph. D.)--Harvard University--MIT Division of Health Sciences and Technology, 2005.Includes bibliographical references.Breast cancer is the most commonly diagnosed cancer among women in the United States. It is the most common cause of death in women ages 45-55. Optical techniques can potentially play a diagnostic role in several aspects of breast cancer evaluation and treatment. This thesis outlines progress on the use of Raman spectroscopy to diagnose breast cancer. Laboratory studies on fresh-frozen tissues are used to demonstrate that the detailed information provided by Raman spectroscopy yields accurate breast disease diagnosis. A Raman spectroscopic-based diagnostic algorithm was developed which classifies samples into four categories according to specific pathological diagnoses: normal, fibrocystic change, fibroadenoma, and infiltrating carcinoma. Cancerous lesions were separated from non- cancerous tissues with a sensitivity of 94% and a specificity of 95%. Further, use of a spectral model based on the morphological structures that comprise breast tissue allows increased understanding of the relationship between a Raman spectrum and tissue disease state. Based on the excellent results of our laboratory work, two clinical studies were undertaken. These studies translate Raman spectroscopy from a laboratory technique into a clinically useful tool. The first study tests the diagnostic algorithm in a prospective manner on freshly excised tissue. Preliminary results are promising. The second study is the first demonstration of in vivo data acquisition of Raman spectra of breast tissue. The culmination of this research is the demonstration of accurate intra-operative margin status assessment during partial mastectomy surgeries.(cont.) Application of our previously developed diagnostic algorithm resulted in perfect sensitivity and specificity in this small in vivo data set. These preliminary findings indicate that Raman spectroscopy has the potential to lessen the need for re-excision surgeries resulting from positive margins and thereby reduce the recurrence rate of breast cancer following partial mastectomy surgeries. The experiments and theory presented throughout this thesis demonstrate that Raman spectroscopy is a viable clinical tool that can be used to accurately diagnosis breast cancer and breast disease.by Abigail Susan Haka.Ph.D

Collapse of the hyperfine magnetic field at the Ru site in ferromagnetic rare earth intermetallics

The M\"{o}ssbauer Effect(ME) is frequently used to investigate magnetically ordered systems. One usually assumes that the magnetic order induces a hyperfine magnetic field, $B_{hyperfine}$, at the ME active site. This is the case in the ruthenates, where the temperature dependence of $B_{hyperfine}$ at $^{99}$Ru sites tracks the temperature dependence of the ferromagnetic or antiferromagnetic order. However this does not happen in the rare-earth intermetallics, GdRu$_2$ and HoRu$_2$. Specific heat, magnetization, magnetic susceptibility, M\"{o}ssbauer effect, and neutron diffraction have been used to study the nature of the magnetic order in these materials. Both materials are found to order ferromagnetically at 82.3 and 15.3 K, respectively. Despite the ferromagnetic order of the rare earth moments in both systems, there is no evidence of a correspondingly large $B_{hyperfine}$ in the M\"{o}ssbauer spectrum at the Ru site. Instead the measured spectra consist of a narrow peak at all temperatures which points to the absence of magnetic order. To understand the surprising absence of a transferred hyperfine magnetic field, we carried out {\it ab initio} calculations which show that spin polarization is present only on the rare-earth site. The electron spin at the Ru sites is effectively unpolarized and, as a result, $B_{hyperfine}$ is very small at those sites. This occurs because the 4$d$ Ru electrons form broad conduction bands rather than localized moments. These 4$d$ conduction bands are polarized in the region of the Fermi energy and mediate the interaction between the localized rare earth moments.Comment: 34 pages -Revtex + 17 ps figure

A review of neurocognitive functioning of children with sex chromosome trisomies: identifying targets for early intervention

Sex chromosome trisomies (SCT) are among the most common chromosomal duplicationsin humans. Due to recent technological advances in non-invasive screening, SCTcan already be detected during pregnancy. This calls for more knowledge about thedevelopment of (young) children with SCT. This review focused on neurocognitivefunctioning of children with SCT between 0 and 18 years, on domains of global intellectualfunctioning, language, executive functioning, and social cognition, in order toidentify targets that could benefit from early treatment.Online databases were used to identify peer-reviewed scientific articles using specificsearch terms. In total 18 studies were included. When applicable, effect sizes werecalculated to indicate clinical significance.Results of the reviewed studies show that although traditionally, the focus has been onlanguage and intelligence (IQ) in this population, recent studies suggest that executivefunctioning and social cognition may also be significantly affected already in childhood.These findings suggest that neuropsychological screening of children diagnosed withSCT should be extended, to also include executive functioning and social cognition.Knowledge about these neurocognitive risks is important to improve clinical care andhelp identify targets for early support and intervention programs to accommodatefor the needs of individuals with SCT.NWO016.165.397Education and Child Studie

Regional brain distribution of [18F]GBR 13119, a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice

We have examines the regional brain distribution of [18F]GBR 13119 (18F: [beta]+, T1/2 = 110 min), a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice. High levels of binding are observed in the striatum of both species, with striatum/cerebellum ratios of 3-4 at 60 min after injection of the radiotracer. Striatum radioactivity and striatum/cerebellum ratios are more than 50% reduced in C57BL/6 mice treated chronically with the neurotoxin MPTP. We conclude mice are an appropriate model for the in vivo study of the dopamine uptake system, and that [18F]GBR 13119 may be a suitable in vivo marker for degeneration of striatal dopaminergic neurons.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27847/1/0000258.pd

Mouse brain distribution of a carbon-11 labeled vesamicol derivative: Presynaptic marker of cholinergic neurons

The regional mouse brain distribution of a new carbon-11 labeled derivative of vesamicol, [11C]-5-(N-methylamino)benzovesamicol ([11C]MABV) is reported. Radiotracer concentrations in vivo are in the rank order of striatum>cortex>hippocampus>hypothalamus> cerebellum, consistent with reported distributions of other presynaptic cholinergic neuronal markers. In time course studies, striatum/cerebellum and cortex/cerebellum ratios for (-)-[11C]MABV continue to increase to values of 13 and 5, respectively, 75 min after i.v. injection of [11C]MABV. The specific binding in striatum and cortex is lowered by pretreatment with (+/-)-vesamicol, and shows stereoselectivity with lower uptake and lower ratios for the (+)-enantiomer. (-)-[11C]MABV is proposed as a positron-emitting radioligand for the in vivo study of presynaptic cholinergic neurons.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28961/1/0000798.pd

Changes in capital allocation practices – ERM and organisational change

This paper aims to study changes in capital allocation routines following the introduction of a new risk management system, enterprise risk management (ERM). Based on an institutional framework and empirical evidence from multiple sources in a large UK insurance company, we evaluated the extent and nature of organisational change. ERM was seen as an external driver to the change in the existing routines, which in turn led to internal changes in new capital allocation routines. The change was extreme, which signifies that existing capital allocation routines were not strong enough to deal with ERM as a key driver of change

In vivo binding of the dopamine uptake inhibitor [18F]GBR 13119 in MPTP-treated C57BL/6 mice

The in vivo regional distribution of [18F]GBR 13119 (1-[(4-[18F]fluorophenyl(phenyl)methoxy)ethyl]-4-(3-phenylpropyl) piperazine), a specific dopamine reuptake inhibitor, was examined in brains of C57BL/6 mice after MPTP treatment. At 2 weeks post MPTP the in vivo specific binding of [18F]GBR 13119 in striatum was decreased 63% relative to age and sex-matched controls. Animals studied at 6 and 8 weeks after MPTP treatment showed a gradual recovery of specific [18F]GBR 13119 binding in the striatum. No significant changes were observed in binding of radiotracer to cerebellum or cortex after MPTP treatment, nor were age-related changes observed in control mice. In vivo radiotracer studies thus appear useful for following gradual changes in the dopamine uptake system of mouse brain after neurotoxin treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29646/1/0000735.pd

13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis

This work was supported by funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (Grant 677542), a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 107613/Z/15/Z), and the Barts Charity (Grant MGU0343). This work was also funded, in part, by Medical Research Council Advance Course Masters (Grant MR/J015741/1). The authors declare no conflicts of interest

Raman spectroscopy: elucidation of biochemical changes in carcinogenesis of oesophagus

Several techniques are under development to diagnose oesophageal adenocarcinoma at an earlier stage. We have demonstrated the potential of Raman spectroscopy, an optical diagnostic technique, for the identification and classification of malignant changes. However, there is no clear recognition of the biochemical changes that distinguish between the different stages of disease. Our aim is to understand these changes through Raman mapping studies. Raman spectral mapping was used to analyse 20-μm sections of tissue from 29 snap-frozen oesophageal biopsies. Contiguous haematoxylin and eosin sections were reviewed by a consultant pathologist. Principal component analysis was used to identify the major differences between the spectra across each map. Pseudocolour score maps were generated and the peaks of corresponding loads identified enabling visualisation of the biochemical changes associated with malignancy. Changes were noted in the distribution of DNA, glycogen, lipids and proteins. The mean spectra obtained from selected regions demonstrate increased levels of glycogen in the squamous area compared with increased DNA levels in the abnormal region. Raman spectroscopy is a highly sensitive and specific technique for demonstration of biochemical changes in the carcinogenesis of Barrett's oesophagus. There is potential for in vivo application for real-time endoscopic optical diagnosis