The effects of the novel anti-hypertensive agent BRL 34915, (+/-) 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-b enzo[b]pyran-3-ol, have been compared with those of verapamil on rat isolated portal vein. BRL 34915 produced a concentration-dependent reduction in mechanical responses to noradrenaline but had relatively little inhibitory effect on K+-induced contractions. Verapamil reduced the magnitude of both noradrenaline and K+-induced mechanical responses. BRL 34915 delayed the appearance of the reduced noradrenaline contractions, a property not shared by verapamil. BRL 34915 abolished spontaneous electrical and mechanical discharges and hyperpolarized the portal vein cells close to their calculated potassium equilibrium potential. Verapamil inhibited spontaneous electrical and mechanical discharges, effects associated with a small depolarization. BRL 34915 produced a significant increase in the 86Rb efflux rate coefficient whilst verapamil was without effect on this parameter. The inhibitory effects of BRL 34915 were rapid in onset and readily reversible by washing, whilst those of verapamil were slower in onset and only slowly reversible. It is concluded that the inhibitory effects of BRL 34915 in rat portal vein are produced by the opening of potassium channels in the smooth muscle cells. This inhibits spike activity and in sufficient concentration holds the membrane potential at or close to the potassium equilibrium potential, thereby reducing the effects of excitatory agents.

Tonic GABAA receptor-mediated inhibition is typically generated by delta subunit-containing extrasynaptic receptors. Because the delta subunit is highly expressed in the thalamus, we tested whether thalamocortical (TC) neurons of the dorsal lateral geniculate nucleus (dLGN) and ventrobasal complex exhibit tonic inhibition. Focal application of gabazine (GBZ) (50 microM) revealed the presence of a 20 pA tonic current in 75 and 63% of TC neurons from both nuclei, respectively. No tonic current was observed in GABAergic neurons of the nucleus reticularis thalami (NRT). Bath application of 1 microM GABA increased tonic current amplitude to approximately 70 pA in 100% of TC neurons, but it was still not observed in NRT neurons. In dLGN TC neurons, the tonic current was sensitive to low concentrations of the delta subunit-specific receptor agonists allotetrahydrodeoxycorticosterone (100 nM) and 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol (THIP) (100 nM) but insensitive to the benzodiazepine flurazepam (5 microM). Bath application of low concentrations of GBZ (25-200 nM) preferentially blocked the tonic current, whereas phasic synaptic inhibition was primarily maintained. Under intracellular current-clamp conditions, the preferential block of the tonic current with GBZ led to a small depolarization and increase in input resistance. Using extracellular single-unit recordings, block of the tonic current caused the cessation of low-threshold burst firing and promoted tonic firing. Enhancement of the tonic current by THIP hyperpolarized TC neurons and promoted burst firing. Thus, tonic current in TC neurons generates an inhibitory tone. Its modulation contributes to the shift between different firing modes, promotes the transition between different behavioral states, and predisposes to absence seizures.

A volatile kairomone emitted from lima bean plants (Phaseolus lunatus) infested with the spider miteTetranychus urticae, was collected on Tenax-TA and analyzed with GC-MS. Two components were identified as the methylene monoterpene (3E)-4,8-dimethyl-1,3,7-nonatriene and the methylene sesquiterpene (3E,7E)-4,8,12-dimethyl-1,3,7,11-tridecatetraene, respectively, after purification by preparative GC on a megabore column and recording of UV, IR, and [(1)H]NMR spectra. The response of two species of predatory mites towards the identified chemicals was tested in a Y-tube olfactometer. Four of the compounds tested, linalool (3,7-dimethyl-1,6-octadien-3-ol), (E)-β-ocimene [(3E)-3,7-dimethyl-1,3,6-octatriene], (3E)-4,8-dimethyI-1,3,7-nonatriene, and methyl salicylate attracted females ofPhytoseiulus persimilis. Linalool and methyl salicylate attracted females ofAmblyseius potentillae. The response ofA. potentillae to these two kairomone components was affected by the rearing diet of the predators in the same way as was reported for the response to the natural kairomone blend: when reared on a carotenoid-deficient diet, the predators responded to the volatile kairomone ofT. urticae, but when reared on a carotenoid-containing diet they did not. The identified kairomone components are all known from the plant kingdom. They are not known to be produced by animals de novo. In addition to biological evidence, this chemical evidence suggests that the plant is involved in production of the kairomone. Based on the present study and literature data on the response ofT. urticae to infochemicals, it is concluded that the kairomone component linalool is also a component of a volatile spider-mite dispersing pheromone.

There are two broad classes of models used to address the econometric problems caused by skewness in data commonly encountered in health care applications: (1) transformation to deal with skewness (e.g., ordinary least square (OLS) on ln(y)); and (2) alternative weighting approaches based on exponential conditional models (ECM) and generalized linear model (GLM) approaches. In this paper, we encompass these two classes of models using the three parameter generalized Gamma (GGM) distribution, which includes several of the standard alternatives as special cases-OLS with a normal error, OLS for the log-normal, the standard Gamma and exponential with a log link, and the Weibull. Using simulation methods, we find the tests of identifying distributions to be robust. The GGM also provides a potentially more robust alternative estimator to the standard alternatives. An example using inpatient expenditures is also analyzed.

Death of oligodendrocyte (OL) precursors can be triggered in vitro by cystine deprivation, a form of oxidative stress that involves depletion of intracellular glutathione. We report here that OLs demonstrate maturation-dependent differences in survival when subjected to free radical-mediated injury induced by glutathione depletion. Using immunopanning to isolate rat preoligodendrocytes (preOLs), we generated highly enriched populations of preOLs and mature OLs under chemically defined conditions. Cystine deprivation caused a similar decrease in glutathione levels in OLs at both stages. However, preOLs were completely killed by cystine deprivation, whereas mature OLs remained viable. Although the glutathione-depleting agents buthionine sulfoximine and diethylmaleate were more potent in depleting glutathione in mature OLs, both agents were significantly more toxic to preOLs. Glutathione depletion markedly increased intracellular free radical generation in preOLs, but not in mature OLs, as indicated by oxidation of the redox-sensitive probe dihydrorhodamine 123. The antioxidants alpha-tocopherol, idebenone, and glutathione monoethylester prevented the oxidation of dihydrorhodamine in cystine-depleted preOLs and markedly protected against cell death. When the intracellular glutathione level was not manipulated, preOLs were also more vulnerable than mature OLs to exogenous free radical toxicity generated by a xanthine-xanthine oxidase system. Ultrastructural features of free radical-mediated injury in glutathione-depleted preOLs included nuclear condensation, margination of chromatin, and mitochondrial swelling. These observations indicate that preOLs are significantly more sensitive to the toxic effects of glutathione depletion and that oligodendroglial maturation is associated with decreased susceptibility to oxidative stress.

To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cells in vitro. By comparing gene expression in these OLs to OLs generated in vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell-cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.

We report a reparameterization of the glycosidic torsion χ of the Cornell et al. AMBER force field for RNA, χ(OL). The parameters remove destabilization of the anti region found in the ff99 force field and thus prevent formation of spurious ladder-like structural distortions in RNA simulations. They also improve the description of the syn region and the syn-anti balance as well as enhance MD simulations of various RNA structures. Although χ(OL) can be combined with both ff99 and ff99bsc0, we recommend the latter. We do not recommend using χ(OL) for B-DNA because it does not improve upon ff99bsc0 for canonical structures. However, it might be useful in simulations of DNA molecules containing syn nucleotides. Our parametrization is based on high-level QM calculations and differs from conventional parametrization approaches in that it incorporates some previously neglected solvation-related effects (which appear to be essential for obtaining correct anti/high-anti balance). Our χ(OL) force field is compared with several previous glycosidic torsion parametrizations.

While specific antagonists of the beta 1-adrenoceptor, such as atenolol and betaxolol, are widely available, a potent specific antagonist selective for the beta 2-adrenoceptor has yet to be described. Previously described beta 2-selective antagonists such as butoxamine, H 35/25, and IPS 339 are lacking in potency, specificity, or appropriate beta 2-selectivity. ICI 118,551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol] possesses a high degree of selectivity and specificity for the beta 2-adrenoceptor. The affinity of propranolol and ICI 118,551 for beta-adrenoceptors has been determined by comparing their antagonist potencies, expressed as pA2 values, against the actions of isoproterenol on the guinea pig atrium and uterus. ICI 118,551 had a higher affinity for the uterine beta 2-receptor than did propranolol (pA2 9.26 and 8.64, respectively) but a lower affinity for the atrial beta 1-receptor (pA2 7.17 and 8.30, respectively). Thus, the beta 2/ beta 1-selectivity ratios, in vitro, were 123 for ICI 118,551 and 2.2 for propranolol. The potency and selectivity of ICI 118,551 and atenolol on the chronotropic and vasodilator actions of isoproterenol were compared in anaesthetised dogs. The apparent K' B values at the vascular beta-adrenoceptor were 2.1 micrograms/kg for ICI 118,551 and 253 micrograms/kg for atenolol, and the potency ratio for antagonism of vascular versus atrial actions of isoproterenol was greater than 250:1. In regard to ancillary pharmacological properties, ICI 118,551 has no partial agonist activity but has a membrane-stabilising action similar to that of propranolol.

Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB(1) or CB(2) receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB(1), but not a CB(2), receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(-/-) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endo-cannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.

SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) possesses pharmacologic effects similar to standard antipsychotics, including selective supression of conditioned avoidance responding in rats and squirrel monkeys, blockade of apomorphine-induced stereotypy in rats and blockade of methamphetamine-induced lethality in aggregated mice. At effective doses in these tests, no changes in gross behavior, neurological or autonomic function were observed. In contrast to the standards tested, SCH 23390 blocked dopamine-stimulated adenylate cyclase at concentrations (IC50 = 0.01 microM) about 2000 times lower than those needed to block spiperone binding (IC50 = 24 microM). This suggests specific D1-receptor antagonism. Inability of SCH 23390 to cause hyperprolactinemia, considered to be a D2-receptor effect, is consistent with this hypothesis. SCH 23390 showed lower increases in dopamine turnover suggesting that the blockade of SCH 23390 may be more specific for post- than presynaptic sites. Additional evidence for the selectivity of SCH 23390 among putative postsynaptic dopamine sites includes its lack of effect on apomorphine-induced hypothermia or emesis. Based on these results, it is postulated that SCH 23390 is a selective D1-receptor antagonist.

Bone morphogenetic protein (BMP) signaling inhibits the generation of oligodendroglia and enhances generation of astrocytes by neural progenitor cells both in vitro and in vivo. This study examined the mechanisms underlying the effects of BMP signaling on glial lineage commitment. Treatment of cultured neural progenitor cells with BMP4 induced expression of all four members of the inhibitor of differentiation (ID) family of helix-loop-helix transcriptional inhibitors and blocked oligodendrocyte (OL) lineage commitment. Overexpression of Id4 or Id2 but not Id1 or Id3 in cultured progenitor cells reproduced both the inhibitory effects of BMP4 treatment on OL lineage commitment and the stimulatory effects on astrogliogenesis. Conversely, decreasing the levels of Id4 mRNA by RNA interference enhanced OL differentiation and inhibited the effects of BMP4 on glial lineage commitment. This suggests that induction of Id4 expression mediates effects of BMP signaling. Bacterial two-hybrid and co-immunoprecipitation studies demonstrated that ID4, and to a lesser extent ID2, complexed with the basic-helix-loop-helix transcription (bHLH) factors OLIG1 and OLIG2, which are required for the generation of OLs. By contrast, ID1 and ID3 did not complex with the OLIG proteins. In addition, the OLIG and ID proteins both interacted with the E2A proteins E12 and E47. Further, exposure of cultured progenitor cells to BMP4 changed the intracellular localization of OLIG1 and OLIG2 from a predominantly nuclear to a predominantly cytoplasmic localization. These observations suggest that the induction of ID4 and ID2, and their sequestration of both OLIG proteins and E2A proteins mediate the inhibitory effects of BMP signaling on OL lineage commitment and contribute to the generation of astrocytes.

Sex differences and estrous cycle variations in anxiolytic-like behaviors and progestin concentrations were examined. Proestrous (n=22), estrous (n=19), diestrous (n=20), and male (n=18) Long-Evans rats were tested in horizontal crossing, open field, elevated plus-maze, emergence, holeboard, social interaction, tailflick, pawlick, and defensive burying tasks. Concentrations of plasma and hippocampal progesterone and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) were measured by radioimmunoassay in behaviorally tested (proestrus n=11, estrus n=8, diestrus n=9, male n=7) and yoked non-tested rats (proestrus n=11, estrus n=8, diestrus n=10, male n=8). Proestrous females exhibited more anxiolytic-like behavior than all other groups on the elevated plus-maze, social interaction, and defensive burying tasks. Proestrous females had significantly shorter latencies to emerge from a cylinder than did estrous and diestrous females, but not males. Proestrous and estrous females entered significantly more peripheral and total squares in a brightly-lit open field than did males. While proestrous females had a tendency to make more beam breaks than did males in the horizontal crossing task, there were no differences between groups on the holeboard task. There was a tendency for proestrous females to have longer tailflick latencies than diestrous and male rats; however, on the pawlick task there were no differences among the groups. Plasma and central progesterone and 3alpha,5alpha-THP of tested and non-tested rats were not different. Proestrous females had significantly higher plasma and hippocampal progesterone and 3alpha,5alpha-THP levels than all other groups. These data demonstrate that proestrous increases in anxiolytic-like behavior coincide with elevated circulating and hippocampal progestin concentrations.

The Minimum Evolution (ME) approach to phylogeny estimation has been shown to be statistically consistent when it is used in conjunction with ordinary least-squares (OLS) fitting of a metric to a tree structure. The traditional approach to using ME has been to start with the Neighbor Joining (NJ) topology for a given matrix and then do a topological search from that starting point. The first stage requires O(n(3)) time, where n is the number of taxa, while the current implementations of the second are in O(p n(3)) or more, where p is the number of swaps performed by the program. In this paper, we examine a greedy approach to minimum evolution which produces a starting topology in O(n(2)) time. Moreover, we provide an algorithm that searches for the best topology using nearest neighbor interchanges (NNIs), where the cost of doing p NNIs is O(n(2) + p n), i.e., O(n(2)) in practice because p is always much smaller than n. The Greedy Minimum Evolution (GME) algorithm, when used in combination with NNIs, produces trees which are fairly close to NJ trees in terms of topological accuracy. We also examine ME under a balanced weighting scheme, where sibling subtrees have equal weight, as opposed to the standard "unweighted" OLS, where all taxa have the same weight so that the weight of a subtree is equal to the number of its taxa. The balanced minimum evolution scheme (BME) runs slower than the OLS version, requiring O(n(2) x diam(T)) operations to build the starting tree and O(p n x diam(T)) to perform the NNIs, where diam(T) is the topological diameter of the output tree. In the usual Yule-Harding distribution on phylogenetic trees, the diameter expectation is in log(n), so our algorithms are in practice faster that NJ. Moreover, this BME scheme yields a very significant improvement over NJ and other distance-based algorithms, especially with large trees, in terms of topological accuracy.

Oligodendrocytes (OLs) are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal signaling. The embryonic lineage and postnatal development of OLs have been well-studied and many features of the process have been described, including the origin, migration, proliferation, and differentiation of precursor cells. Less clear is the extent to which OLs and damaged/dysfunctional myelin are replaced following injury to the adult CNS. OLs and their precursors are very vulnerable to conditions common to CNS injury and disease sites, such as inflammation, oxidative stress, and elevated glutamate levels leading to excitotoxicity. Thus, these cells become dysfunctional or die in multiple pathologies, including Alzheimer's disease, spinal cord injury, Parkinson's disease, ischemia, and hypoxia. However, studies of certain conditions to date have detected spontaneous OL replacement. This review will summarize current information on adult OL progenitors, mechanisms that contribute to OL death, the consequences of their loss and the pathological conditions in which spontaneous oligodendrogenesis from endogenous precursors has been observed in the adult CNS.

The effects of agonists at mu and delta opioid receptors were compared by measuring membrane currents under voltage clamp from neurons of the rat nucleus locus coeruleus and guinea pig submucous plexus. In each tissue, the appropriate selective agonist (Tyr-D-Ala-Gly-MePhe-Gly-ol for mu receptors in locus coeruleus or Tyr-D-Pen-Gly-Phe-D-Pen for delta receptors in submucous plexus) increased the conductance of an inwardly rectifying potassium conductance and strongly hyperpolarized the membrane. The properties of the potassium conductance affected by the two opioids could not be distinguished. Experiments with intracellular application of guanosine 5'-[gamma-thio]triphosphate indicated that a guanine nucleotide-binding regulatory protein was involved in the coupling between opioid receptor and potassium channel, but there was no evidence for activation of either cAMP-dependent protein kinase or protein kinase C. It is noted that a number of vertebrate neurotransmitter receptors are coupled to potassium channels. The potassium conductance associated with these channels has properties similar to the conductance activated by mu and delta opioids; this family includes the following receptors: acetylcholine M2, norepinephrine alpha 2, dopamine D2, 5-hydroxytryptamine 5-HT1, adenosine A1, gamma-aminobutyric acid GABAB, and somatostatin. It is suggested that this conductance is a conserved neuronal effector coupled to one of the receptor types that mediates the effects of each of several major transmitters. The mu and delta opioid receptors appear to be unusual in that both utilize this same effector mechanism.

Robust regression techniques are a class of estimators that are relatively insensitive to the presence of one or more outliers in the data. They are especially well suited to data that require large numbers of statistical tests and may contain outliers due to factors not of experimental interest. Both these issues apply particularly to neuroimaging data analysis. We use simulations to compare several robust techniques against ordinary least squares (OLS) regression, and we apply robust regression to second-level (group "random effects") analyses in three fMRI datasets. Our results show that robust iteratively reweighted least squares (IRLS) at the 2nd level is a computationally efficient technique that both increases statistical power and decreases false positive rates in the presence of outliers. The benefits of IRLS are apparent with small samples (n = 10) and increase with larger sample sizes (n = 40) in the typical range of group neuroimaging experiments. When no true effects are present, IRLS controls false positive rates at an appropriate level. We show that IRLS can have substantial benefits in analysis of group data and in estimating hemodynamic response shapes from time series data. We provide software to implement IRLS in group neuroimaging analyses.

Marital and family researchers often study infrequent behaviors. These powerful psychological variables, such as abuse, criticism, and drug use, have important ramifications for families and society as well as for the statistical models used to study them. Most researchers continue to rely on ordinary least-squares (OLS) regression for these types of data, but estimates and inferences from OLS regression can be seriously biased for count data such as these. This article presents a tutorial on statistical methods for positively skewed event data, including Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial regression models. These statistical methods are introduced through a marital commitment example, and the data and computer code to run the example analyses in R, SAS, SPSS, and Mplus are included in the online supplemental material. Extensions and practical advice are given to assist researchers in using these tools with their data.

Reactive microglia in the CNS have been implicated in the pathogenesis of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, the mechanism by which activated microglia kill oligodendrocytes (OLs) remains elusive. Here we show that lipopolysaccharide (LPS)-induced death of developing OLs is caused by microglia-derived peroxynitrite, the reaction product of nitric oxide (NO) and superoxide anion. Blocking peroxynitrite formation with nitric oxide synthase inhibitors, superoxide dismutase mimics, or a decomposition catalyst abrogated the cytotoxicity. Only microglia, but not OLs, expressed inducible NO synthase (iNOS) after LPS challenge; microglia from iNOS knockout mice were not cytotoxic upon activation. The molecular source for superoxide was identified as the superoxide-generating enzyme NADPH oxidase. The oxidase was activated upon LPS exposure, and its inhibition prevented microglial toxicity toward OLs. Furthermore, microglia isolated from mice deficient in the catalytic component of the oxidase, gp91(phox), failed to induce cell death. Our results reveal a role for NADPH oxidase in LPS-induced OL death and suggest that peroxynitrite produced by iNOS and NADPH oxidase in activated microglia may play an important role in the pathogenesis of white matter disorders.

Estimating flavonoid intake is a first step toward documenting the protective effects of flavonoids against risk of chronic diseases. Although flavonoids are important dietary sources of antioxidants, insufficient data on the comprehensive food composition of flavonoids have delayed the assessment of dietary intake in a population. We aimed to estimate the dietary flavonoid intake in U.S. adults and its sociodemographic subgroups and to document major dietary sources of flavonoids. We expanded the recently released USDA Flavonoid Database to increase its correspondence with the 24-h dietary recall (DR) of the NHANES 1999-2002. We systematically assigned a particular food code to all foods that were prepared or processed similarly. This expanded database included 87% of fruits and fruit juices, 86% of vegetables, 75% of legumes, and, overall, 45% of all foods reported by the 24-h DR of the NHANES 1999-2002. Estimated mean daily total flavonoid intake, 189.7 mg/d, was mainly from flavan-3-ols (83.5%), followed by flavanones (7.6%), flavonols (6.8%), anthocyanidins (1.6%), flavones (0.8%), and isoflavones (0.6%). The flavonoid density of diets increased with age (P < 0.001) and income (P < 0.05). It was higher in women (P < 0.001), Caucasians (P < 0.001), and vitamin supplement users (P < 0.001) and lower in adults with high levels of nonleisure time physical activity (P < 0.01) compared with their counterparts. The greatest daily mean intake of flavonoids was from the following foods: tea (157 mg), citrus fruit juices (8 mg), wine (4 mg), and citrus fruits (3 mg). The proposed relation between flavonoid intake and the prevention of chronic diseases needs further investigation using the estimates introduced in this study.

BACKGROUND

The variability in preferences used in quality-adjusted life-years estimation jeopardizes the comparability of cost-effectiveness analyses and has led the Panel on Cost-Effectiveness in Health and Medicine (the PCEHM) to call for a catalog of "off-the-shelf" preference weights associated with conditions that can be used by health researchers without the burden of collecting primary data.

OBJECTIVE

The current research responds to the call by developing a nationally representative catalog of preference-based scores for chronic conditions and associated sociodemographic characteristics.

METHODS

The authors report the EQ-5Dindex scores of chronic conditions and associated sociodemographic characteristics in the nationally representative Medical Expenditure Panel Survey (MEPS). Chronic conditions were coded using "quality priority conditions" (QPC) and clinical classification categories (CCC). OLS, Tobit, and censored least absolute deviations (CLAD) regression models were used to provide condition estimates adjusted for age, comorbidity, gender, race, ethnicity, income, and education.

RESULTS

Unadjusted and adjusted EQ-5Dindex scores for each QPC and CCC code are presented. EQ-5Dindex scores for older age categories were lower than younger categories, female scores were lower than males, certain racial groups had lower scores than others, and EQ-5Dindex scores were higher for individuals with higher education and income levels.

CONCLUSIONS

The preference-based chronic condition scores reported in this research are nationally representative and may be useful to researchers to calculate quality-adjusted life-years for cost-effectiveness analyses and population-based burden of illness studies without the difficulty of primary data collection. Further research is necessary to validate these scores in condition-specific studies.

A method based on isotope dilution-mass spectrometry was developed for the determination of nine cholesterol oxidation products in human plasma. The cholesterol oxidation products determined were cholest-5-ene-3 beta,7 alpha-diol, cholest-5-ene-3 beta,7 beta-diol (7 alpha- and 7 beta-hydroxycholesterol, respectively), 3 beta-hydroxycholest-5-en-7-one(7-oxocholesterol),5,6 alpha-epoxy-5 alpha- cholestan-3 beta-ol (cholesterol-5 alpha,6 alpha-epoxide),5,6 beta-epoxy-5 beta-cholestan-3 beta-ol (cholesterol-5 beta,6 beta-epoxide), (cholesterol-5 beta,6 beta-epoxide), cholestane-3 beta,5 alpha,6 beta-triol, cholest-5-ene-3 beta,24-diol (24-hydroxycholesterol), cholest-5-ene-3 beta,25-diol (25-hydroxycholesterol), and cholest-5-ene-3 beta,27-diol (27-hydroxycholesterol). A corresponding deuterium-labeled internal standard, containing 3 to 6 deuterium atoms, was synthesized for each cholesterol oxidation product except 5 beta,6 beta-epoxycholesterol which was determined using the internal standard for 5 alpha,6 alpha-epoxycholesterol. Plasma from 31 healthy volunteers was analyzed by the new method and 27-, 24-, and 7 alpha-hydroxycholesterol were the most abundant cholesterol oxidation products (mean values 154, 64, and 43 ng/ml, respectively). The other oxysterols determined were present in concentrations lower than 30 ng/ml. Males had higher 27-hydroxycholesterol concentrations in plasma than females. The 5,6-oxygenated products were present mainly unesterified while the other oxidation products were mostly in esterified form.

The widely accepted model of G protein-coupled receptor (GPCR) regulation describes a system where the agonist-activated receptors couple to G proteins to induce a cellular response, and are subsequently phosphorylated by a family of kinases called the G protein-coupled receptor kinases (GRKs). The GRK-phosphorylated receptor then acts as a substrate for the binding of a family of proteins called arrestins, which uncouple the receptor and G protein so desensitizing the agonist-induced response. Other kinases, principally the second messenger-dependent protein kinases, are also known to play a role in the desensitization of many GPCR responses. It is now clear that there are subtle and complex interactions between GRKs and second messenger-dependent protein kinases in the regulation of GPCR function. Functional selectivity describes the ability of agonists to stabilize different active conformations of the same GPCR. With regard to desensitization, distinct agonist-activated conformations of a GPCR could undergo different molecular mechanisms of desensitization. An example of this is the mu opioid receptor (MOPr), where the agonists morphine and [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) induce desensitization of the MOPr by different mechanisms, largely protein kinase C (PKC)- or GRK-dependent, respectively. This can be best explained by supposing that these two agonists stabilize distinct conformations of the MOPr, which are nevertheless able to couple to the relevant G-proteins and produce similar responses, yet are sufficiently different to trigger different regulatory processes. There is evidence that other GPCRs also undergo agonist-selective desensitization, but the full therapeutic consequences of this phenomenon await further detailed study.

1. Methane mono-oxygenase of Methylococcus capsulatus (Bath) catalyses the oxidation of various substituted methane derivatives including methanol. 2. It is a very non-specific oxygenase and, in some of its catalytic properties, apparently resembles the analogous enzyme from Methylomonas methanica but differs from those found in Methylosinus trichosporium and Methylomonas albus. 3. CO is oxidized to CO2. 4. C1-C8 n-alkanes are hydroxylated, yielding mixtures of the corresponding 1- and 2-alcohols; no 3- or 4-alcohols are formed. 5. Terminal alkenes yield the corresponding 1,2-epoxides. cis- or trans-but-2-ene are each oxidized to a mixture of 2,3-epoxybutane and but-2-en-1-ol with retention of the cis or trans configuration in both products; 2-butanone is also formed from cis-but-2-ene only. 6. Dimethyl ether is oxidized. Diethyl ether undergoes sub-terminal oxidation, yielding ethanol and ethanal in equimolar amounts. 7. Methane mono-oxygenase also hydroxylates cyclic alkanes and aromatic compounds. However, styrene yields only styrene epoxide and pyridine yields only pyridine N-oxide. 8. Of those compounds tested, only NADPH can replace NADH as electron donor.

BACKGROUND

Data from mechanistic studies support a beneficial effect of specific flavonoids on insulin sensitivity. However, few studies have evaluated the relation between intakes of different flavonoid subclasses and type 2 diabetes.

OBJECTIVE

The objective was to evaluate whether dietary intakes of major flavonoid subclasses (ie, flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) are associated with the risk of type 2 diabetes in US adults.

METHODS

We followed up a total of 70,359 women in the Nurses' Health Study (NHS; 1984-2008), 89,201 women in the NHS II (1991-2007), and 41,334 men in the Health Professionals Follow-Up Study (1986-2006) who were free of diabetes, cardiovascular disease, and cancer at baseline.

RESULTS

During 3,645,585 person-years of follow-up, we documented 12,611 incident cases of type 2 diabetes. Higher intakes of anthocyanins were significantly associated with a lower risk of type 2 diabetes (pooled HR for the 3 cohorts from a comparison of extreme quintiles: 0.85; 95% CI: 0.80, 0.91; P-trend < 0.001) after multivariate adjustment for age, BMI, and lifestyle and dietary factors. Consumption of anthocyanin-rich foods, particularly blueberries (pooled HR: 0.77 from a comparison of ≥2 servings/wk with <1 serving/mo; 95% CI: 0.68, 0.87; P-trend < 0.001) and apples/pears (pooled HR: 0.77 from a comparison of ≥5 servings/wk with <1 serving/mo; 95% CI: 0.65, 0.83; P-trend < 0.001), was also associated with a lower risk of type 2 diabetes. No significant associations were found for total flavonoid intake or other flavonoid subclasses.

CONCLUSIONS

A higher consumption of anthocyanins and anthocyanin-rich fruit was associated with a lower risk of type 2 diabetes.