Neighborhood socioeconomic status and coronary heart disease risk prediction in a nationally representative sample.

OBJECTIVES: Test the association between coronary heart disease (CHD) risk scores and neighborhood socioeconomic status (NSES) in a US nationally-representative sample and describe whether the association varies by gender and race/ethnicity. STUDY DESIGN: Cross-sectional study. METHODS: We use Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 linked with Census tract data. Multivariable regression models and propensity score adjusted models are employed to test the association between NSES and 10-year risk of CHD based on the Framingham Risk Score (FRS), adjusting for individual-level characteristics. RESULTS: An individual living in a neighborhood at the 75th percentile of NSES (high NSES) has, on average, a 10-year CHD risk that is 0.16 percentage points lower (95% Confidence Interval 0.16, 0.17) than a similar person residing in a neighborhood at the 25th percentile of NSES (low NSES). Race/ethnicity and gender were found to significantly modify the association between NSES and CHD risk: the association is larger in men than women and in whites than minorities. Propensity score models showed that findings on the main effects of NSES were robust to self-selection into neighborhoods. Similar results were observed between NSES and risk of cardiovascular disease events. CONCLUSIONS: NSES is significantly associated with CHD risk, and the relationship varies by gender and race/ethnicity.

2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research.

Information processing in the vertebrate retina occurs in two separate channels known as ON and OFF channels. When intracellular electrophysiological recordings were obtained from the perfused retina-eyecup preparation of the mud-puppy (Necturus maculosus), the addition of 2-amino-4-phosphonobutyric acid to the bathing medium blocked all responses in the ON channel but left intact the OFF responses including OFF ganglion cell discharge. 2-Amino-4-phosphonobutyric acid blocks the light response of the ON bipolar cell by mimicking the endogenous photoreceptor transmitter.

An excitatory amino acid antagonist blocks cone input to sign-conserving second-order retinal neurons.

cis-2,3-Piperidinedicarboxylic acid (PDA), an excitatory amino acid antagonist, reversibly blocked cone input to OFF bipolars and horizontal cells, whereas ON bipolars were relatively unaffected. Kainic acid effects were also blocked, indicating a postsynaptic mechanism of action. The use of PDA helps to characterize one of two classes of excitatory amino acid synaptic receptors that mediate cone influence in the outer retina.

Intensity-dependent, rapid activation of presynaptic metabotropic glutamate receptors at a central synapse.

Synaptic signals from retinal bipolar cells were monitored by measuring EPSCs in ganglion cells voltage-clamped at -70 mV. Spontaneous EPSCs were strongly suppressed by l-2-amino-4-phosphonobutyrate (AP-4), an agonist at group III metabotropic glutamate receptors (mGluRs). Agonists of group I or II mGluRs were ineffective. AP-4 also suppressed ganglion cell EPSCs evoked by bipolar cell stimulation using potassium puffs, sucrose puffs, or zaps of current (0.5-1 microA). In addition, AP-4 suppressed Off EPSCs evoked by dim-light stimuli. This indicates that group III mGluRs mediate a direct suppression of bipolar cell transmitter release. An mGluR antagonist, (RS)-alpha-cyclopropyl-4-phosphonophenylyglycine (CPPG), blocked the action of AP-4. When bipolar cells were weakly stimulated, AP-4 produced a large suppression of the EPSC, but CPPG alone had little effect. Conversely, when bipolar cells were strongly stimulated, CPPG produced an enhancement of the EPSC, but AP-4 alone had little effect. This indicates that endogenous feedback regulates bipolar cell transmitter release and that the dynamic range of the presynaptic metabotropic autoreceptor is similar to that of the postsynaptic ionotropic receptor. Furthermore, the feedback is rapid and intensity-dependent. Hence, concomitant activation of presynaptic and postsynaptic glutamate receptors shapes the responses of ganglion cells.

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.

B-wave of the electroretinogram. A reflection of ON bipolar cell activity.

Light-evoked intraretinal field potentials (electroretinogram, ERG) have been measured simultaneously with extracellular potassium fluxes in the amphibian retina. The application of highly selective pharmacologic agents permitted us to functionally isolate various classes of retinal neurons. It was found that: (a) application of APB (2-amino-4-phosphonobutyrate), which has previously been shown to selectively abolish the light responsiveness of ON bipolar cells, causes a concomitant loss of the ERG b-wave and ON potassium flux. (b) Conversely, PDA (cis 2,3-piperidine-dicarboxylic acid) or KYN (kynurenic acid), which have been reported to suppress the light responses of OFF bipolar, horizontal, and third-order retinal neurons, causes a loss of the ERG d-wave as well as OFF potassium fluxes. The b-wave and ON potassium fluxes, however, remain undiminished. (c) NMA (N-methyl-DL-aspartate) or GLY (glycine), which have been reported to suppress the responses of third-order neurons, do not diminish the b- or d-waves, nor the potassium fluxes at ON or OFF. This leads to the conclusion that the b-wave of the ERG is a result of the light-evoked depolarization of the ON bipolar neurons. This experimental approach has resulted in two further conclusions: (a) that the d-wave is an expression of OFF bipolar and/or horizontal cell depolarization at the termination of illumination and (b) that light-induced increases in extracellular potassium concentration in both the inner (proximal) and outer (distal) retina are the result of ON bipolar cell depolarization.

Two metabotropic gamma-aminobutyric acid receptors differentially modulate calcium currents in retinal ganglion cells.

Metabotropic gamma-aminobutyric acid (GABA) receptors were studied in amphibian retinal ganglion cells using whole cell current and voltage clamp techniques. The aim was to identify the types of receptor present and their mechanisms of action and modulation. Previous results indicated that ganglion cells possess two ionotropic GABA receptors: GABAAR and GABACR. This study demonstrates that they also possess two types of metabotropic GABAB receptor: one sensitive to baclofen and another to cis-aminocrotonic acid (CACA). The effects of these selective agonists were blocked by GDP-beta-S. Baclofen suppressed an omega-conotoxin-GVIA-sensitive barium current, and this action was reversed by prepulse facilitation, indicative of a direct G-protein pathway. The effect of baclofen was also partially occluded by agents that influence the protein kinase A (PKA) pathway. But the effect of PKA activation was unaffected by prepulse facilitation, indicating PKA acted through a parallel pathway. Calmodulin antagonists reduced the action of baclofen, whereas inhibitors of calmodulin phosphatase enhanced it. Antagonists of internal calcium release, such as heparin and ruthenium red; did not affect the baclofen response. Thus, the baclofen-sensitive receptor may respond to influx of calcium. The CACA-sensitive GABA receptor reduced current through dihydropyridine-sensitive channels. Sodium nitroprusside and 8-bromo-cGMP enhanced the action of CACA, indicating that a nitric oxide system can up-regulate this receptor pathway. CACA-sensitive and baclofen-sensitive GABAB receptors reduced spike activity in ganglion cells. Overall, retinal ganglion cells possess four types of GABA receptor, two ionotropic and two metabotropic. Each has a unique electrogenic profile, providing a wide range of neural integration at the final stage of retinal information processing.

Structural studies of cytochrome reductase. Improved membrane crystals of the enzyme complex and crystallization of a subcomplex.

Membrane crystals of mitochondrial ubiquinol: cytochrome c reductase of improved size and long-range order and of the cytochrome bc1 subcomplex have been obtained by a dialysis method. The enzyme--Triton X-100 complex was mixed with Triton phospholipid micelles and the Triton slowly removed by dialysis for 48 hours at pH 5.5 at room temperature or above. The effect of varying the pH and temperature on the shape, size and order of the crystals is described.

Characterization of serine's inhibitory action on neurons in the mudpuppy retina.

Experiments were performed in the superfused retina-eyecup of mudpuppies using intracellular electrophysiological techniques to evaluate the effects of serine on amacrine and ganglion cells. Serine was found to have a dose-dependent inhibitory effect mediated by the opening of chloride channels. Serine appears to act on a glycine receptor based on the observations that: (1) serine's effect is blocked by strychnine but not by bicuculline or picrotoxin, (2) in the presence of saturating glycine concentrations serine had no effect on membrane voltage or conductance, and (3) cells inhibited by serine were always sensitive to glycine, but not always sensitive to GABA. High pressure liquid chromatography measurements disclose that there is a high concentration of extracellular serine in the retina. The data indicate that serine could act as an inhibitory neurotransmitter.

Comparison of the actions of glycine and related amino acids on isolated third order neurons from the tiger salamander retina.

Whole cell voltage and current clamp recordings were obtained from third order neurons isolated from the salamander retina. Using cross desensitization, the structure-function relationship of short chain amino acids on the glycine receptor were examined. L-Serine, L-alanine, beta-alanine and taurine all cross desensitized with glycine, but did not show significant cross desensitization with GABA. This indicates that these amino acids act at the glycine receptor. The order of potency was glycine >> beta-alanine > taurine >> L-alanine > L-serine. TAG, a reputed selective taurine antagonist, was equally effective in blocking taurine and glycine currents. There is no evidence for distinct receptors for taurine. Amino acids with larger moieties at the alpha carbon, such as threonine and valine, produced inactive ligands. Placing a methyl group on the amine of glycine or esterification of the carboxyl group also greatly reduced activity. Based on these modifications of the glycine molecule, it appears that selectivity at the glycine receptor results in part from steric restrictions at all three sites in the glycine chain. The steric interference is most critical at the carboxyl and amino ends, and less limiting at the alpha carbon. Doses of L-serine that had only slight effects in voltage clamp experiments, nevertheless produced large effects in current clamp experiments. This indicates that several endogenous amino acids can have significant effects on membrane voltage, even when their shunting activity may be small. High concentrations of agonists produced desensitization in the voltage clamp records, but there was little evidence of desensitization in the current clamp experiments. These results indicate that several endogenous amino acids can activate the glycine receptor, but there is no evidence for a discrete receptor for taurine, beta-alanine, L-alanine or L-serine. Since all these endogenous amino acids have similar amino and acid terminals, reduction in potency results from steric interference around the alpha carbon. This graded potency may have functional significance in mediating inhibition.