Biomedical subjects
Publications and source records attributed to G Oz.
Metastatic tumour spread to the mandible is quite rare. We report a case of distant metastasis of pulmonary adenocarcinoma in the mandibular bone. The patient had pain in his left mandibular premolar-molar area caused by a mandibular metastasis from a previously undiagnosed pulmonary adenocarcinoma.
The brain uses glucose as a primary fuel for energy generation. Glucose gains entry into the brain by facilitated diffusion across the blood-brain barrier. Glucose transport may adapt during changes in cerebral glucose metabolism, neural activation and changes in plasma glucose levels. Within the brain, glucose is either oxidized to produce ATP or used to synthesize glycogen. To ensure the delivery of a continuous supply of glucose to maintain normal cellular function, the brain has developed a complex regulatory system to preserve its supply. Gluco-sensing neurons have been demonstrated in various regions of the brain and they appear to play an important role in not only detecting changes in brain glucose levels but also in initiating responses to maintain constant brain glucose levels. In this review, we will discuss the regulation of brain glucose metabolism (CMR(gluc)) and how it adapts to chronic changes in glycemia, like that seen in hyperglycemic patients with diabetes mellitus or patients with type 1 diabetes, recurrent hypoglycemia, and hypoglycemia unawareness. We will also consider the role of brain glycogen in providing fuel for energy under conditions of stress.
BACKGROUND: Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. OBJECTIVE: To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. METHODS: The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. RESULTS: Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. CONCLUSIONS: The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.
Cerebral rates of anaplerosis are known to be significant, yet the rates measured in vivo have been debated. In order to track glutamate metabolism in brain glutamatergic neurons and brain glia, for the first time unrestrained awake rats were continuously infused with a combination of H14CO3- and [1 - 13C]glucose in over 50 infusions ranging from 5 to 60 min. In whole-brain extracts from these animals, the appearance of 14C in brain glutamate and glutamine and appearance of 13C in the C-4 position of glutamate and glutamine were measured as a function of time. The rate of total neuronal glutamate turnover, the anaplerotic rate of synthesis of glutamine and glutamate from H14CO3-, flux through the glutamate/glutamine cycle, and a minimum estimate of whole-brain anaplerosis was obtained. The rate of synthesis of 14C-glutamate from H14CO3- was 1.29 +/- 0.11 nmoles/min/mg protein, whereas the rate of synthesis of 14C-glutamine was 1.48 +/- 0.10 nmoles/min/mg protein compared to total glutamate turnover of 9.39 +/- 0.73 nmoles/min/mg protein. From the turnover rate of glutamine, an upper limit for flux through the glutamate/glutamine cycle was estimated at 4.6 nmoles/min/mg protein. Synthesis of glutamine from H14CO3- was substantial, amounting to 32% of the glutamate/glutamine cycle. These rates were not significantly affected by a single injection of 100 mg/kg of the antiepileptic drug gabapentin. In contrast, acute administration of gabapentin significantly lowered incorporation of H14CO3- into glutamate and glutamine in excised rat retinas, suggesting metabolic effects of gabapentin may require chronic treatment and/or are restricted to brain areas enriched in target enzymes such as the cytosolic branched chain aminotransferase. We conclude that the brain has a high anaplerotic activity and that the combination of two tracers with different precursors affords unique insights into the compartmentation of cerebral metabolism.
OBJECTIVE: To assess whether a relationship existed between the T102C polymorphism of 5-HT2A receptor gene and temporomandibular dysfunction. METHODS: Sixty-three patients with temporomandibular dysfunction, and 54 healthy volunteer controls were included in the study. Molecular analysis of the T102C polymorphism of the 5-HT2A receptor gene was performed using PCR technique. RESULTS: The C/C genotype was over represented in the patients whereas T/T genotype was over represented in the controls (P < 0.05). The genotype distribution of the patients who had temporomandibular dysfunction was not different than those who did not have temporomandibular dysfunction (P > 0.05). CONCLUSION: The T102C polymorphism may be involved in the etiology of temporomandibular dysfunction. The overrepresentation of the C/C variant of 5-HT2A receptor gene in temporomandibular dysfunction suggests a possible role of the serotonergic system in this disease, particularly at the receptor level.
MRI reconstruction using super-resolution is presented and shown to improve spatial resolution in cases when spatially-selective RF pulses are used for localization. In 2-D multislice MRI, the resolution in the slice direction is often lower than the in-plane resolution. For certain diagnostic imaging applications, isotropic resolution is necessary but true 3-D acquisition methods are not practical. In this case, if the imaging volume is acquired two or more times, with small spatial shifts between acquisitions, combination of the data sets using an iterative super-resolution algorithm gives improved resolution and better edge definition in the slice-select direction. Resolution augmentation in MRI is important for visualization and early diagnosis. The method also improves the signal-to-noise efficiency of the data acquisition.
Upon storage under aerobic conditions metallothioneins (MTs) form a new species, which is characterized by a molecular mass approximately twice the size of monomeric MT and shifted (113/111)Cd- and (1)H-NMR resonances. The investigation of this oxidative dimerization process by NMR spectroscopy allowed us to structurally characterize this MT species that has been described to occur in vivo and might be synthesized under conditions of oxidative stress. The oxidative dimer was characterized by the formation of an intermolecular cysteine disulphide bond involving the alpha-domain, and a detailed analysis of chemical shift changes and intermolecular nuclear Overhauser effects points towards a disulphide bond involving Cys(36). In contrast to the metal-bridged (non-oxidative) dimerization, the metal-cysteine cluster structures in both MT domains remain intact and no conformational exchange or metal-metal exchange was observed. Also in contrast to the many recently reported oxidative processes which involve the beta-domain cysteine groups and result in the increased dynamics of the bound metal ions in this N-terminal domain, we found no evidence for any increased dynamics in the alpha-domain metals following this oxidation. Therefore these findings provide additional corroboration that metal binding in the C-terminal alpha-domain is rather tight, even under conditions of a changing cellular oxidation potential, compared with the more labile/dynamic nature of the metals in the N-terminal beta-domain cluster under similar conditions.
The brain specific member of the metallothionein (MT) family of proteins, metallothionein-3, inhibits the growth and survival of neurons, in contrast to the ubiquitous mammalian MT isoforms, MT-1 and MT-2, that are found in most tissues and are thought to function in metal ion homeostasis and detoxification. Solution NMR was utilized to determine the structural and dynamic differences of MT-3 from MT-1 and 2. The high-resolution solution structure of the C-terminal alpha-domain of recombinant mouse MT-3 revealed a tertiary fold very similar to MT-1 and 2, except for a loop that accommodates an acidic insertion relative to these isoforms. This loop was distinguished from the rest of the domain by dynamics of the backbone on the nano- to picosecond time-scale shown by (15)N relaxation studies and was identified as a possible interaction site with other proteins. The N-terminal beta-domain contains the region responsible for the growth inhibitory activity, a CPCP tetrapeptide close to the N-terminus. Because of exchange broadening of a large number of the NMR signals from this domain, homology modeling was utilized to calculate models for the beta-domain and suggested that while the backbone fold of the MT-3 beta-domain is identical to MT-1 and 2, the second proline responsible for the activity, Pro9, may show structural heterogeneity. (15)N relaxation analyses implied fast internal motions for the beta-domain. On the basis of these observations, we conclude that the growth inhibitory activity exhibited by MT-3 is a result of a combination of local structural differences and global dynamics in the beta-domain.
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In a recent paper Jiang et al. (Jiang, L. J., Maret, W. & Vallee, B. L. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 9146-9149) reported that metallothionein interacts with adenosine triphosphate (ATP) to form a 1:1 complex with a dissociation constant of K(d) = 176 +/- 33 microM at pH 7.4. In an effort to characterize further this interaction using nuclear magnetic resonance spectroscopy, titration calorimetry, gel-filtration chromatography, affinity chromatography, and ultrafiltration, we were unable to find any evidence for the binding of ATP to metallothionein.
Sequential 1H-NMR assignments of mouse [Cd7]-metallothionein-1 (MT1) have been carried out by standard homonuclear NMR methods and the use of an accordion-heteronuclear multiple quantum correlation (HMQC) experiment for establishing the metal, 113Cd2+, to cysteine connectivities. The three-dimensional structure was then calculated using the distance constraints from two-dimensional nuclear Overhauser effect (NOE) spectroscopy spectra and the Cys-Cd connectivities as input for a distance geometry-dynamical simulated annealing protocol in X-PLOR 3.851. Similar to the mammalian MT2 isoforms, the homologous primary structure of MT1 suggested two separate domains, each containing one metal cluster. Because there were no interdomain constraints, the structure calculation for the N-terminal beta- and the C-terminal alpha-domain were carried out separately. The structures are based on 409 NMR constraints, consisting of 381 NOEs and 28 cysteine-metal connectivities. The only elements of regular secondary structure found were two short stretches of 3(10) helices along with some half-turns in the alpha-domain. Structural comparison with rat liver MT2 showed high similarity, with the beta-domain structure in mouse MT1 showing evidence of increased flexibility compared to the same domain in MT2. The latter was reflected by the presence of fewer interresidue NOEs, no slowly exchanging backbone amide protons, and enhanced cadmium-cadmium exchange rates found in the beta-domain of MT1.
This article reviews the use of nuclear magnetic resonance methods of spin 1/2 metal nuclei to probe the metal binding site(s) in a variety of metalloproteins. The majority of the studies have involved native Zn(II) and Ca(II) metalloproteins where there has been isostructural substitution of these metal ions with the I = 1/2 (111/113)Cd(II) ion. Also included are recent studies that have utilized the 109Ag(I) ion to probe Cu(I) sites in yeast metallothionein and 199Hg(II) as a probe of the metal binding sites in mercury resistance proteins. Pertinent aspects for the optimal execution of these experiments along with the procedures for the metal substitution reactions are discussed together with the presentation of a 113Cd chemical shift correlation map with ligand type and coordination number. Specific examples of protein systems studied using the (111/113)Cd and 109Ag nuclei include the metallothionein superfamily of Zn(II)- and Cu(I)-binding proteins from mammalian, invertebrate, and yeast systems. In addition to the structural features revealed by these metal ion nuclear magnetic resonance studies, important new information is frequently provided about the dynamics at the active-site metal ion. In an effort for completeness, other less frequently used spin 1/2 metal nuclei are mentioned.
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