A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human.

Type 2 diabetes mellitus is the result of a combination of impaired insulin secretion with reduced insulin sensitivity of target tissues. There are an estimated 150 million affected individuals worldwide, of whom a large proportion remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. In this study, NMR-based metabolomic analysis in conjunction with multivariate statistics was applied to examine the urinary metabolic changes in two rodent models of type 2 diabetes mellitus as well as unmedicated human sufferers. The db/db mouse and obese Zucker (fa/fa) rat have autosomal recessive defects in the leptin receptor gene, causing type 2 diabetes. 1H-NMR spectra of urine were used in conjunction with uni- and multivariate statistics to identify disease-related metabolic changes in these two animal models and human sufferers. This study demonstrates metabolic similarities between the three species examined, including metabolic responses associated with general systemic stress, changes in the TCA cycle, and perturbations in nucleotide metabolism and in methylamine metabolism. All three species demonstrated profound changes in nucleotide metabolism, including that of N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide, which may provide unique biomarkers for following type 2 diabetes mellitus progression.

Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats.

Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.

Neurophysical modeling of brain dynamics.

A recent neurophysical model of brain electrical activity is outlined and applied to EEG phenomena. It incorporates single-neuron physiology and the large-scale anatomy of corticocortical and corticothalamic pathways, including synaptic strengths, dendritic propagation, nonlinear firing responses, and axonal conduction. Small perturbations from steady states account for observed EEGs as functions of arousal. Evoked response potentials (ERPs), correlation, and coherence functions are also reproduced. Feedback via thalamic nuclei is critical in determining the forms of these quantities, the transition between sleep and waking, and stability against seizures. Many disorders correspond to significant changes in EEGs, which can potentially be quantified in terms of the underlying physiology using this theory. In the nonlinear regime, limit cycles are often seen, including a regime in which they have the characteristic petit mal 3 Hz spike-and-wave form.

Meckel's diverticulum: demonstration of heterotopic gastric mucosa with technetium-99m-pertechnetate SPECT.

Demonstration of functioning heterotopic gastric mucosa with 99mTc-pertechnetate SPECT is reported. Abnormal tracer uptake was shown conclusively with SPECT but not with planar imaging. When a Meckel's diverticulum is suspected, we suggest SPECT be performed if the results of planar scintigraphy are equivocal and that it be considered if there is a high clinical suspicion and planar imaging is normal.

Individual sympathetic varicosities possess different sensitivities to alpha 2 and P2 receptor agonists and antagonists in mouse vas deferens.

1. The diversity of alpha(2) and purinergic autoreceptor actions on action potential evoked calcium transients in single varicosities has been investigated using the calcium indicator Oregon Green 488 BAPTA-1. 2. During long trains of impulses (10 Hz for 30 s), the change in calcium concentration in varicosities from its resting level (Delta[Ca(2+)](v)) increased in many varicosities during the first 3 s of stimulation before reaching a plateau. 3. The alpha(2) adrenoceptor agonist clonidine (1 microM) decreased Delta[Ca(2+)](v) by over 40% during short trains (five impulses at 5 Hz) in most varicosities, although some were unaffected. The alpha(2) adrenoceptor antagonist idazoxan (2 microM) increased the Delta[Ca(2+)](v) plateau following long trains in most varicosities. Hence, most varicosities possess alpha(2) adrenoceptors which are activated when noradrenaline accumulates extracellularly. 4. During long trains of impulses, the P(2y)-purinergic receptor agonist 2-methyl-thio-ATP (100 microM) decreased Delta[Ca(2+)](v) plateau by about 50% in most varicosities; alpha,beta-methylene ATP (100 microM) decreased it by about 50% in a minority of varicosities; adenosine (200 microM) had no significant effect. Suramin (100 microM) increased the Delta[Ca(2+)](v) during all stimulus protocols in most varicosities, suggesting that ambient ATP modulates Delta[Ca(2+)](v) responses. The P(2y) receptor antagonist reactive blue (100 microM) affected a minority of varicosities. Given that most varicosities respond to suramin, other P(2) receptor subtypes are probably present. 5. The ATP ectoenzyme antagonist ARL67157 (50 microM) decreased the plateau Delta[Ca(2+)](v) during long trains in complete strings of varicosities but not in others. 6. The present technique indicates that varicosities have diverse autoreceptor utilization.

Fewer metabolites of dietary choline reach the blood of rats after treatment with lithium.

Choline is an important precursor for the biosynthesis of acetylcholine, phosphatidylcholine and sphingomyelin. It is also a major source of labile methyl groups. Lithium is an important component of the treatment of bipolar affective illness, and it inhibits choline transport across membranes. We studied the effect of lithium treatment upon the appearance in blood, liver and intestine of metabolites formed from dietary choline. Rats were treated for 9 days with 2 mEq/kg lithium carbonate or water. Animals were fasted overnight, and on the 10th day were fed with a solution containing radiolabeled choline chloride. The lithium-treated groups also received 2.0 mEq/kg lithium as part of this solution. After an oral dose of 1 ml of a 1 mM choline solution, the lithium-treated animals had significantly lower levels of choline-derived radiolabel in blood than did controls at 30, 60, 120, and 180 minutes (47% (+/- 5%; SEM), 51% (+/- 7%), 59% (+/- 4%) and 74% (+/- 9%), respectively). We observed similar decreases of the accumulation in blood, at 180 minutes after the dose, of choline-derived radiolabel when choline was administered at lower or higher concentrations. After an oral treatment containing 0.1, 1 or 10 mM choline, lithium treated animals accumulated 69% (+/- 6%; SEM), 66% (+/- 11%) and 72% (+/- 7%) as much radiolabel in serum as did controls. Most of the radiolabel found in blood at 180 minutes was in metabolites of choline which are formed within liver (betaine and phosphatidylcholine). The diminished accumulation of radiolabel in serum after lithium treatment was not due to increased accumulation of label by erythrocytes, liver or gut wall. We suggest that lithium influences the release by liver of betaine and phosphatidylcholine.

Wave-number spectrum of electrocorticographic signals.

A physiologically based continuum model of corticothalamic electrodynamics is generalized and used to derive the theoretical form of the electrocorticographic (ECoG) wave-number spectrum. A one-dimensional projection of the spectrum is derived, as is the azimuthally averaged two-dimensional spectrum for isotropic and anisotropic cortices. The predicted spectra are found to consist of a low-k plateau followed by three regions of power-law decrease, which result from filtering of the electrical activity through physical structures at different scales in the cortex. The magnitude of the maximum theoretical power-law exponent is larger for the two-dimensional (2D) spectrum than for its 1D counterpart. The predicted spectra agree well with experimental data obtained from 1D and 2D recording arrays on the cortical surface, enabling the structures in the brain that are important in determining spatial cortical dynamics to be identified. The cortical dispersion relation predicted by our model is also investigated, providing insight into the relationships between temporal and spatial brain dynamics.

Spatially uniform and nonuniform analyses of electroencephalographic dynamics,with application to the topography of the alpha rhythm.

Corticothalamic dynamics are investigated using a model in which spatial nonuniformities are incorporated via the coupling of spatial eigenmodes. Comparison of spectra generated using the nonuniform analysis with those generated using a uniform one demonstrates that, for most frequencies, local activity is only weakly dependent on activity elsewhere in the cortex; however, dispersion of low-wave-number activity ensures that distant dynamics influence local dynamics at low frequencies (below approximately 2 Hz ), and at the alpha frequency (approximately 10 Hz ), where propagating signals are inherently weakly damped, and wavelengths are large. When certain model parameters have similar spatial profiles, as is expected from physiology, the low-frequency discrepancies tend to cancel, and the uniform analysis with local parameter values is an adequate approximation to the full nonuniform one across the whole spectrum, at least for large-scale nonuniformities. After comparing the uniform and nonuniform analyses, we consider one possible application of the nonuniform analysis: studying the phenomenon of occipital alpha dominance, whereby the alpha frequency and power are greater at the back of the head (occipitally) than at the front. In order to infer realistic nonuniformities in the model parameters, the uniform version of the model is first fitted to data recorded from 98 normal subjects in a waking, eyes-closed state. This yields a set of parameters at each of five electrode sites along the midline. The inferred parameter nonuniformities are consistent with anatomical and physiological constraints. Introducing these spatial profiles into the full nonuniform model then quantitatively reproduces observed site-dependent variations in the alpha power and frequency. The results confirm that the frequency shift is mainly due to a decrease in the corticothalamic propagation delay, but indicate that the delay nonuniformity cannot account for the observed occipital increase in alpha power; the occipital alpha dominance is due to decreased cortical gains and increased thalamic gains in occipital regions compared to frontal ones.

Wave-number spectrum of electroencephalographic signals.

A recently developed, physiologically based continuum model of corticothalamic electrodynamics is used to derive the theoretical form of the electroencephalographic wave-number spectrum and its projection onto a one-dimensional recording array. The projected spectrum is found to consist of a plateau followed by regions of power-law decrease with various exponents, which are dependent on both model parameters and temporal frequency. The theoretical spectrum is compared with experimental results obtained in other studies, showing good agreement. The model provides a framework for understanding the nature of the spatial power spectrum by linking the underlying physiology with the large-scale dynamics of the brain.

Modal analysis of corticothalamic dynamics, electroencephalographic spectra, and evoked potentials.

The effects of cortical boundary conditions and resulting modal aspects of continuum corticothalamic electrodynamics are explored, including feedbacks. Dispersion relations, electroencephalographic spectra, and stimulus response functions are calculated from the underlying physiology, and the effects of discrete mode structure are determined. Conditions under which modal effects are important are obtained, along with estimates of the point at which modal series can be truncated, and the limit in which only a single globally uniform mode need be retained. It is found that for physiologically plausible parameters only the lowest cortical spatial eigenmode together with the set of next-lowest modes can produce distinct modal structure in spectra and response functions, and then only at frequencies where corticothalamic resonances reduce dissipation to the point where the spatial eigenmodes are weakly damped. The continuum limit is found to be a good approximation, except at very low frequencies and, under some circumstances, near the alpha resonance. It is argued that the major electroencephalographic rhythms result from corticothalamic feedback resonances, but that cortical modal effects can contribute to weak substructure in the alpha resonance. This mechanism is compared and contrasted with purely cortical and pacemaker-based alternatives and testable predictions are formulated to enable experimental discrimination between these possibilities.