Sub-cellular localisation of fukutin related protein in different cell lines and in the muscle of patients with MDC1C and LGMD2I

MDC1C and LGMD2I are two allelic forms of muscular dystrophies caused by mutations in the gene encoding for fukutin related protein (FKRP). FKRP encodes for a putative glycosyltransferase, the precise function of which is unknown. However, the marked reduction of -dystroglycan glycosylation in the muscle of MDC1C and LGMD2I patients suggests a role for FKRP in dystroglycan processing. Using a polyclonal antibody raised against FKRP we now show that endogenous FKRP locates to the Golgi apparatus of neuronal, oligodendroglial, and the cardiac muscle cell line H9c2. In differentiated C2C12 myotubes and in transverse sections of normal skeletal and cardiac muscle, endogenous FKRP surrounded the myonuclei. This localisation was unaffected in the skeletal muscle of patients with MDC1C and LGMD2I carrying various FKRP mutations. These observations imply a specific role for FKRP during striated muscle, neuronal and glial development and suggest that protein mis-localisation is not a common mechanism of disease in FKRP-related dystrophies.     

PET imaging in the assessment of normal and impaired cognitive function

PET has been used to directly quantify several processes relevant to the status of cerebral health and function, including cerebral blood flow, cerebral blood volume, cerebral rate of oxygen metabolism, and cerebral glucose use. Clinically, the most commonly performed PET studies of the brain are performed with fluorine-18-fluorodeoxyglucose as the imaged radiopharmaceutical. Such scans have demonstrated diagnostic and prognostic use in evaluating patients who have cognitive impairment, and in distinguishing among primary neurodegenerative dementias and other causes of cognitive decline. In certain pathologic circumstances, the normal coupling between blood flow and metabolic needs may be disturbed, and changes in oxygen extraction fraction can have significant prognostic value.     

Hyperpolarized helium-3 MR imaging of pulmonary function

Recent advances in HP MR imaging contrast agents have led to novel tests of pulmonary function. Many of these tests show promise in the clinical arena.     

FDG-PET imaging in primary bilateral adrenal lymphoma: a case report and review of the literature

Primary adrenal lymphoma is an extremely rare entity. Only 70 cases have been reported in the English literature. Most of the patients are elderly men with bilateral adrenal masses without extraadrenal involvement. The most common presenting symptoms are fever, weight loss, lumbar pain, and/or symptoms of adrenal insufficiency. Of the cases reported, CT, ultrasound, and MRI were the imaging modalities used to describe the lesions. FDG PET has been used successfully to differentiate benign and malignant adrenal masses. The authors report a 67-year-old man diagnosed as having primary bilateral adrenal lymphoma and having no evidence of extraadrenal spread who was evaluated from the time of diagnosis to complete remission with FDG PET scanning. The literature of this unusual neoplasm is reviewed in detail.     

Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography (PET)

18F-labeled non-sulfonylurea hypoglycemic agent (S)-2-(2-[(18)F]fluoroethoxy)-4-((3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl)-benzoic acid ([(18)F]repaglinide), a derivative of the sulfonylurea-receptor (SUR) ligand repaglinide, was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. [(18)F]Repaglinide could be obtained in an overall radiochemical yield (RCY) of 20% after 135 min with a radiochemical purity higher than 98% applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate. Specific activity was in the range of 50-60 GBq/micromol. Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group. To characterize the properties of fluorinated repaglinide, the affinity of the analogous non-radioactive (19)F-compound for binding to the human SUR1 isoform was assessed. [(19)F]Repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (K(D)) of 134 nM. Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide. Finally, biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection. Pancreatic tissue displayed a stable accumulation of approximately 0.12% of the injected dose from 10 min to 30 min p.i. 50% of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide, indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET.     

Akt stimulates aerobic glycolysis in cancer cells

Cancer cells frequently display high rates of aerobic glycolysis in comparison to their nontransformed counterparts, although the molecular basis of this phenomenon remains poorly understood. Constitutive activity of the serine/threonine kinase Akt is a common perturbation observed in malignant cells. Surprisingly, although Akt activity is sufficient to promote leukemogenesis in nontransformed hematopoietic precursors and maintenance of Akt activity was required for rapid disease progression, the expression of activated Akt did not increase the proliferation of the premalignant or malignant cells in culture. However, Akt stimulated glucose consumption in transformed cells without affecting the rate of oxidative phosphorylation. High rates of aerobic glycolysis were also identified in human glioblastoma cells possessing but not those lacking constitutive Akt activity. Akt-expressing cells were more susceptible than control cells to death after glucose withdrawal. These data suggest that activation of the Akt oncogene is sufficient to stimulate the switch to aerobic glycolysis characteristic of cancer cells and that Akt activity renders cancer cells dependent on aerobic glycolysis for continued growth and survival.     

Utility of fluorodeoxyglucose-PET imaging in the management of patients with Hodgkin's and non-Hodgkin's lymphomas

FDG-PET imaging has a number of advantages in the management of patients with lymphoma. PET shows a functional metabolic status and gives quantitative information. In addition, PET provides whole-body images that give a comprehensive assessment of disease extent during the staging and followup. Based on the present literature, FDG-PET is at least equivalent to CT for the initial staging of lymphomas. The impact of new technologies of combined PET/CT and fast-scanning CT with contrast has yet to be evaluated in the management of lymphoma patients, however. At this point, FDG-PET and CT must be considered as giving complementary staging information. FDG-PET also has high diagnostic accuracy for restaging lymphoma after initial treatment. FDG-PET has shown high accuracy in the early prediction of response to chemotherapy and in the evaluation of residual masses after chemotherapy or radiation therapy. Therefore, PET is likely to play a major role in tailoring the intensity of the treatment to the individual patient. A pretreatment FDG-PET study is essential for accurate assessment of residual masses and early monitoring of response to the treatment. In addition, a baseline PET scan will help detect relapse or residual disease, because relapse occurs most often in the region of previous disease.