Faculty Bibliography

INTRODUCTION: We examined pulmonary diffusing capacity (D(LCO)) and its partition in pulmonary vascular diseases without evident parenchymal disease to assess the pattern and proportionality of change in membrane diffusion (D(m)) and capillary blood volume (V(c)). Disproportionate reduction in D(m) relative to V(c) (low D(m)/V(c)) in these diseases has been attributed to associated alveolar membrane/parenchymal disease, thus providing a potentially important diagnostic tool. METHODS: Diseases included: idiopathic pulmonary arterial hypertension (n=6), chronic thromboembolic disease (n=5), and intravenous drug use (n=14), providing a spectrum of pulmonary vascular diseases. V(c) and D(m) were determined as described by Roughton and Forster. RESULTS: All diseases showed a reduced V(c) (59+/-10, 69+/-14, 71+/-21 % predicted, respectively) and D(m) (76+/-22, 53+/-19, 63+/-16 % predicted, respectively) with no differences between groups (p>0.05). Disproportionate reduction of D(m) (D(m)/V(c) % predicted <1) was seen in all diseases (range 0.36-1.89). A mathematical analysis is presented to illustrate that changes in vascular geometry may additionally influence the proportionality of changes in D(m) and V(c). The mathematical analysis suggests that when reduction in patency of some vessels co-exits with compensatory dilatation of the remaining vasculature, a disproportionate reduction in D(m) relative to V(c) may result. CONCLUSIONS: The balance between vascular curtailment and compensatory dilatation may contribute to the variability of the D(m)/V(c) relationship seen in pulmonary vascular disease. Disproportionate reduction in D(m) relative to V(c) may result from this imbalance and need not imply subclinical alveolar membrane and/or parenchymal disease.

Coronary MR angiography (CMRA) is generally confined to the acquisition of multiple targeted slabs with coverage dictated by the competing constraints of signal-to-noise ratio (SNR), physiological motion, and scan time. This work addresses these obstacles by demonstrating the technical feasibility of using a 32-channel coil array and receiver system for highly accelerated volumetric breath-hold CMRA. The use of the 32-element array in unaccelerated CMRA studies provided a baseline SNR increase of as much as 40% over conventional cardiac-optimized phased array coils, which resulted in substantially enhanced image quality and improved delineation of the coronary arteries. Modest accelerations were used to reduce breath-hold durations for tailored coverage of the coronary arteries using targeted multi-oblique slabs to as little as 10 s. Finally, high net accelerations were combined with the SNR advantages of a 3D steady-state free precession (SSFP) technique to achieve previously unattainable comprehensive volumetric coverage of the coronary arteries in a single breath-hold. The merits and limitations of this simplified volumetric imaging approach are discussed and its implications for coronary MRA are considered

OBJECTIVE: The purpose of the study was to quantify the fat fraction in nine fat-water phantoms containing 0-80% fat using opposed-phase imaging with the qualitative guidance of 1H MR spectroscopy (MRS), which was used by observer 1 to visually assess the sizes of the water and fat peaks to apply two alternative mathematic formulas for the calculation of the fat fraction. In addition, the fat fraction was also quantified directly with 1H MRS as an independent method by two observers (observers 2 and 3). CONCLUSION: The fat fraction calculated with opposed-phase imaging (FF(OPI)) and that calculated with 1H MRS (FF(MRS)) correlated well with the known fat fractions of the phantoms (FF(P)): r = 0.99 for FF(OPI); p < 0.0001 and r = 0.96-0.98 for FF(MRS); p < 0.001, for observers 2 and 3, respectively. Opposed-phase imaging should be combined with 1H MRS to ensure accurate quantification of the fat fraction

The biological changes that occur in the brains of Alzheimer's disease (AD) patients are thought to begin long before the onset of clinical symptoms. Although current therapeutic agents have been approved only for patients with mild to moderate AD, Alzheimer-type pathology in patients with mild to moderate AD is already quite advanced. One impetus for the development of the concept of mild cognitive impairment (MCI) was the attempt to recognize AD early in its clinical expression and to determine whether it is possible through therapeutic interventions to improve the memory impairment at this stage or delay further progression to dementia. To this end, several clinical trials have been conducted in patients with MCI. On September 8 and 9, 2004 a meeting of the Alzheimer's Association Research Roundtable was held at which experts in the field of MCI convened to review the collective experience from these trials and to consider potential approaches that might improve MCI clinical trials in the future. This article summarizes the presentations and discussions of that meeting

Short-term synaptic plasticity (STP) is an important mechanism for modifying neural circuits during computation. Although STP is much studied, its role in the processing of complex natural spike patterns is unknown. Here we analyze the responses of excitatory and inhibitory hippocampal synapses to natural spike trains at near-physiological temperatures. Our results show that excitatory and inhibitory synapses express complementary sets of STP components that selectively change synaptic strength during epochs of high-frequency discharge associated with hippocampal place fields. In both types of synapses, synaptic strength rapidly alternates between a near-constant level during low activity and another near-constant, but elevated (for excitatory synapses) or reduced (for inhibitory synapses) level during high-frequency epochs. These history-dependent changes in synaptic strength are largely independent of the particular temporal pattern within the discharges, and occur concomitantly in the two types of synapses. When excitatory and feed-forward inhibitory synapses are co-activated within the hippocampal feed-forward circuit unit, the net effect of their complementary STP is an additional increase in the gain of excitatory synapses during high-frequency discharges via selective disinhibition. Thus, excitatory and feed-forward inhibitory hippocampal synapses in vitro act synergistically as an adaptive filter that operates in a switch-like manner and is selective for high-frequency epochs

Mechanisms that function to regulate the rate of de novo phosphatidylinositol (PtdIns) synthesis in mammalian cells have not been elucidated. In this study, we characterize the effect of phorbol ester treatment on de novo PtdIns synthesis in C3A human hepatoma cells. Incubation of cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA) initially (1-6 h) results in a decrease in precursor incorporation into PtdIns; however, at later times (18-24 h), a marked increase is observed. TPA-induced glucose uptake from the medium is not required for observation of the stimulation of PtdIns synthesis, because the effect is apparent in glucose-free medium. Inhibition of the activation of arachidonic acid substantially blocks the synthesis of PtdIns but has no effect on the synthesis of phosphatidylcholine (PtdCho). Increasing the concentration of cellular phosphatidic acid by blocking its conversion to diacylglycerol, on the other hand, enhances the synthesis of PtdIns and inhibits the synthesis of PtdCho. The TPA-induced stimulation of PtdIns synthesis is not the result of the concomitant TPA-induced G1 arrest, because G1 arrest induced by mevastatin has no effect on PtdIns synthesis. Inhibition of protein kinase C activity blocks the stimulatory action of TPA on de novo synthesis of PtdIns but has no effect on TPA-induced inhibition. Potential sites of enzymatic regulation are discussed

Studies of short-term plasticity (STP) in the hippocampus, performed mostly at room temperature, have shown that small central synapses rapidly depress in response to high-frequency stimulation. This decrease in synaptic strength with synapse use places constraints on the use of STP as a dynamic filter for processing of natural high-frequency input. Here we report that, because of a strong but differential temperature dependence of STP components, the properties of STP in excitatory hippocampal synapses change dramatically with temperature. By separating the contributions of various STP processes during spike trains at different temperatures, we found a shift from dominating depression at 23 degrees C to prevailing facilitation and augmentation at 33-38 degrees C. This shift of balance among STP components resulted from a large increase in amplitudes of facilitation and augmentation (Q10 approximately 2.6 and approximately 5.1, respectively) and little change in the amplitude of depression (Q10 approximately 1.1) with temperature. These changes were accompanied by the accelerated decay of all three processes (Q10 = 3.2, 6.6, and 2.1, respectively). The balance of STP components achieved at higher temperatures greatly improved the maintenance of synaptic strength during prolonged synaptic use and had a strong effect on the processing of natural spike trains: a variable mixture of facilitated and depressed responses at 23 degrees C changed into a significantly more reproducible and depression-free filtering pattern at 33-38 degrees C. This filtering pattern was highly conserved among cells, slices, and animals, and under various physiological conditions, arguing for its physiological significance. Therefore, the fine balance among STP components, achieved only at near body temperatures, is required for the robust function of STP as a dynamic filter during natural stimulation

Rat pups must learn maternal odor to support attachment behaviors, including nursing and orientation toward the mother. Neonates have a sensitive period for rapid, robust odor learning characterized by increased ability to learn odor preferences and decreased ability to learn odor aversions. Specifically, odor-0.5 mA shock association paradoxically causes an odor preference and coincident failure of amygdala activation in pups until postnatal day 10 (P10). Because sensitive-period termination coincides with a declining 'stress hyporesponsive period' when corticosterone release is attenuated, we explored the role of corticosterone in sensitive-period termination. Odor was paired with 0.5 mA shock in either sensitive-period (P8) or postsensitive-period (P12) pups while manipulating corticosterone. We then assessed preference/aversion learning and the olfactory neural circuitry underlying its acquisition. Although sensitive-period control paired odor-shock pups learned an odor preference without amygdala participation, systemic (3 mg/kg, i.p.; 24 h and 30 min before training) or intra-amygdala corticosterone (50 or 100 ng; during training) permitted precocious odor-aversion learning and evoked amygdala neural activity similar to that expressed by older pups. In postsensitive-period (P12) pups, control paired odor-shock pups showed an odor aversion and amygdala activation, whereas corticosterone-depleted (adrenalectomized) paired odor-shock pups showed odor-preference learning and activation of an odor learning circuit characteristic of the sensitive period. Intra-amygdala corticosterone receptor antagonist (0.3 ng; during training) infused into postsensitive-period (P12) paired odor-shock pups also showed odor-preference learning. These results suggest corticosterone is important in sensitive-period termination and developmental emergence of olfactory fear conditioning, acting via the amygdala as a switch between fear and attraction. Because maternal stimulation of pups modulates the pups' endogenous corticosterone, this suggests maternal care quality may alter sensitive-period duration

The Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac1 and Epac2) mediate stimulatory actions of the second messenger cAMP on insulin secretion from pancreatic beta cells. Because Epac2 is reported to interact in vitro with the isolated nucleotide-binding fold-1 (NBF-1) of the beta cell sulfonylurea receptor-1 (SUR1), we hypothesized that cAMP might act via Epac1 and/or Epac2 to inhibit beta cell ATP-sensitive K+ channels (KATP channels; a hetero-octomer of SUR1 and Kir6.2). If so, Epac-mediated inhibition of KATP channels might explain prior reports that cAMP-elevating agents promote beta cell depolarization, Ca2+ influx, and insulin secretion. Here we report that Epac-selective cAMP analogs (2'-O-Me- cAMP; 8-pCPT-2'-O-Me-cAMP; 8-pMeOPT-2'-O-Me-cAMP), but not a cGMP analog (2'-O-Me-cGMP), inhibit the function of KATP channels in human beta cells and rat INS-1 insulin-secreting cells. Inhibition of KATP channels is also observed when cAMP, itself, is administered intracellularly, whereas no such effect is observed upon administration N6-Bnz-cAMP, a cAMP analog that activates protein kinase A (PKA) but not Epac. The inhibitory actions of Epac-selective cAMP analogs at KATP channels are mimicked by a cAMP agonist (Sp-8-Br-cAMPS), but not a cAMP antagonist (Rp-8-Br-cAMPS), and are abrogated following transfection of INS-1 cells with a dominant- negative Epac1 that fails to bind cAMP. Because both Epac1 and Epac2 co-immunoprecipitate with full-length SUR1 in HEK cell lysates, such findings delineate a novel mechanism of second messenger signal transduction in which cAMP acts via Epac to modulate ion channel function, an effect measurable as the inhibition of KATP channel activity in pancreatic beta cells

Natural odorants are complex mixtures of diverse chemical compounds. Monomolecular odorants are represented in the main olfactory bulb by distinct spatial patterns of activated glomeruli. However, it remains unclear how individual compounds contribute to population representations of natural stimuli, which appear to be unexpectedly sparse. We combined gas chromatography and intrinsic signal imaging to visualize glomerular responses to natural stimuli and their fractionated components. While whole stimuli activated up to 20 visible glomeruli, each fractionated component activated only one or few glomeruli, and most glomeruli were activated by only one component. Thus, responses to complex mixtures reflected activation by multiple components, with each contributing only a small part of the overall representation. We conclude that the population response to a complex stimulus is largely the sum of the responses to its individual components, and activation of an individual glomerulus independently signals the presence of a specific component.