Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons.

Stable wakefulness requires orexin/hypocretin neurons (OHNs) and OHR2 receptors. OHNs sense diverse environmental cues and control arousal accordingly. For unknown reasons, OHNs contain multiple excitatory transmitters, including OH peptides and glutamate. To analyze their cotransmission within computational frameworks for control, we optogenetically stimulated OHNs and examined resulting outputs (spike patterns) in a downstream arousal regulator, the histamine neurons (HANs). OHR2s were essential for sustained HAN outputs. OHR2-dependent HAN output increased linearly during constant OHN input, suggesting that the OHN→HAN(OHR2) module may function as an integral controller. OHN stimulation evoked OHR2-dependent slow postsynaptic currents, similar to midnanomolar OH concentrations. Conversely, glutamate-dependent output transiently communicated OHN input onset, peaking rapidly then decaying alongside OHN→HAN glutamate currents. Blocking glutamate-driven spiking did not affect OH-driven spiking and vice versa, suggesting isolation (low cross-modulation) of outputs. Therefore, in arousal regulators, cotransmitters may translate distinct features of OHN activity into parallel, nonredundant control signals for downstream effectors.

Elevated CSF histamine levels in multiple sclerosis patients.

BACKGROUND Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis. FINDINGS CSF HISTAMINE LEVELS IN MS PATIENT SAMPLES WERE SIGNIFICANTLY HIGHER (MEDIAN: 35.6 pg/ml) than in controls (median: 5.5 pg/ml; Beta = 0.525, p < 0.001). In addition, histamine increased with age (Pearson's correlation, p < 0.003). CONCLUSIONS Histamine may be an important factor for both the initiation and maintenance of chronic inflammatory diseases of the central nervous system. Our observation encourages a deeper investigation of the role of histamine in MS.

Deoxynucleoside triphosphates bearing histamine, carboxylic acid, and hydroxyl residues--synthesis and biochemical characterization.

Modified nucleoside triphosphates (dA(Hs)TP, dU(POH)TP, and dC(Val)TP) bearing imidazole, hydroxyl, and carboxylic acid residues connected to the purine and pyrimidine bases through alkyne linkers were prepared. These modified dN*TPs were excellent substrates for various DNA polymerases in primer extension reactions. Moreover, the combined use of terminal deoxynucleotidyl transferase (TdT) and the modified dNTPs led to efficient tailing reactions that rival those of natural counterparts. Finally, the triphosphates were tolerated by polymerases under PCR conditions, and the ensuing modified oligonucleotides served as templates for the regeneration of unmodified DNA. Thus, these modified dN*TPs are fully compatible with in vitro selection methods and can be used to develop artificial peptidases based on DNA.

Liberation of hope: An ethnographic study of community-based initiatives in Houston, Texas

This is an ethnographic study about the worldview of community-based initiatives in Houston, Texas, and the people who work in them. People who participated in this study recognize that their direct constructive action is at the heart of authentic social change in their minority communities. Through qualitative data analysis, a constellation of relationships and process patterns were found to constitute themselves into the system of the community-based initiative. The predominant patterns identified from the findings in this study are: the pervasiveness of place, the importance of people, unique initiatory patterns, the concrete local sustainability, the ever-present action orientation, the resourceful use of networks and inter-relationships, the significance of church influence, the core sense of spirituality and the essence of hope. These patterns emerged out of the local knowledge, which is acutely sensitive to the elements of history and lived experience, embedded in the distinctive moral and visionary patterns of meaning and expression. Findings from the research reveal that these community-based initiatives are not programs--they are people--people who keep hope alive in their communities and who, by their daily practice, liberate others. ^

Impact of consciousness raising and social liberation on readiness to engage in regular physical activity among adults in Magnolia Park/Lawndale-Wayside, Houston, TX

According to the transtheoretical model, consciousness raising and social liberation are processes used to help individuals progress through the stages of change for a given behavior. This study assessed the impact of these two processes on readiness to engage in regular physical activity among a convenience sample of 35 adults in the Magnolia Park/Lawndale-Wayside area of Houston, TX. The duration of the study was approximately 4 weeks. All pre/post-test data were collected via self-administered surveys available in English or Spanish. Baseline data were used to determine the culturally relevant content of a one-dose intervention consisting of a presentation and dissemination of educational materials as well as a list of local physical activity opportunities. Although the intervention did not improve progression through the stages of change, significant increases were evident among 5 out of 6 processes of change. Based on these results and qualitative data, this study recommended that the Houston Parks and Recreation Department incorporate cultural competency into the design and publication of materials and revise the schedule of available programs (i.e.: increase the number of walking programs) in order to reflect the physical activity preferences of Magnolia Park/Lawndale-Wayside residents.^

Impaired locomotor activity and exploratory behavior in mice lacking histamine H1 receptors

From pharmacological studies using histamine antagonists and agonists, it has been demonstrated that histamine modulates many physiological functions of the hypothalamus, such as arousal state, locomotor activity, feeding, and drinking. Three kinds of receptors (H1, H2, and H3) mediate these actions. To define the contribution of the histamine H1 receptors (H1R) to behavior, mutant mice lacking the H1R were generated by homologous recombination. In brains of homozygous mutant mice, no specific binding of [3H]pyrilamine was seen. [3H]Doxepin has two saturable binding sites with higher and lower affinities in brains of wild-type mice, but H1R-deficient mice showed only the weak labeling of [3H]doxepin that corresponds to lower-affinity binding sites. Mutant mice develop normally, but absence of H1R significantly increased the ratio of ambulation during the light period to the total ambulation for 24 hr in an accustomed environment. In addition, mutant mice significantly reduced exploratory behavior of ambulation and rearings in a new environment. These results indicate that through H1R, histamine is involved in circadian rhythm of locomotor activity and exploratory behavior as a neurotransmitter.

IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils

IL-18 is a proinflammatory cytokine that plays an important role in natural killer cell activation and T helper 1 (Th1) cell responses. Mast cells and basophils are major inducers and effectors of allergic inflammation. Here we show that basophils and mast cells derived by culture of bone marrow cells with IL-3 for 10 days express IL-18Rα chain and that basophils produce large amounts of IL-4 and IL-13 in response to stimulation with IL-3 and IL-18. Injection of IL-12 and IL-18 inhibits IgE production in helminth-infected wild-type mice and abolishes the capacity of their basophils to produce IL-4 and IL-13 in response to stimulation either with IL-3 and IL-18 or with FcɛR cross-linkage. By contrast, this combination of cytokines actually increases IgE levels in helminth-infected IFN-γ−/− mice and enhances IL-4 and IL-13 production by their basophils. Furthermore, injection of IL-18 alone enhances basophil production of IL-4 and histamine both in wild-type and IFN-γ−/− mice. Thus, IL-18 has the potential to stimulate basophils but, when given with IL-12, exhibits an antiallergic action in vivo.

Differential quantal release of histamine and 5-hydroxytryptamine from mast cells of vesicular monoamine transporter 2 knockout mice

The recent availability of mice lacking the neuronal form of the vesicular monoamine transporter 2 (VMAT2) affords the opportunity to study its roles in storage and release. Carbon fiber microelectrodes were used to measure individual secretory events of histamine and 5-hydroxytryptamine (5-HT) from VMAT2-expressing mast cells as a model system for quantal release. VMAT2 is indispensable for monoamine storage because mast cells from homozygous (VMAT2−/−) mice, while undergoing granule-cell fusion, do not release monoamines. Cells from heterozygous animals (VMAT2+/−) secrete lower amounts of monoamine per granule than cells from wild-type controls. Investigation of corelease of histamine and 5-HT from granules in VMAT2+/− cells revealed 5-HT quantal size was reduced more than that of histamine. Thus, although vesicular transport is the limiting factor determining quantal size of 5-HT and histamine release, intragranular association with the heparin matrix also plays a significant role.

Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia

In myocardial ischemia, adrenergic nerves release excessive amounts of norepinephrine (NE), causing dysfunction and arrhythmias. With anoxia and the concomitant ATP depletion, vesicular storage of NE is impaired, resulting in accumulation of free NE in the axoplasm of sympathetic nerves. Intraneuronal acidosis activates the Na+/H+ exchanger (NHE), leading to increased Na+ entry in the nerve terminals. These conditions favor availability of the NE transporter to the axoplasmic side of the membrane, causing massive carrier-mediated efflux of free NE. Neuronal NHE activation is pivotal in this process; NHE inhibitors attenuate carrier-mediated NE release. We previously reported that activation of histamine H3 receptors (H3R) on cardiac sympathetic nerves also reduces carrier-mediated NE release and alleviates arrhythmias. Thus, H3R activation may be negatively coupled to NHE. We tested this hypothesis in individual human SKNMC neuroblastoma cells stably transfected with H3R cDNA, loaded with the intracellular pH (pHi) indicator BCECF. These cells possess amiloride-sensitive NHE. NHE activity was measured as the rate of Na+-dependent pHi recovery in response to an acute acid pulse (NH4Cl). We found that the selective H3R-agonist imetit markedly diminished NHE activity, and so did the amiloride derivative EIPA. The selective H3R antagonist thioperamide abolished the imetit-induced NHE attenuation. Thus, our results provide a link between H3R and NHE, which may limit the excessive release of NE during protracted myocardial ischemia. Our previous and present findings uncover a novel mechanism of cardioprotection: NHE inhibition in cardiac adrenergic neurons as a means to prevent ischemic arrhythmias associated with carrier-mediated NE release.

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.

Adding Color to Feminism: White Privilege Within the Women's Liberation Movement.

This paper will explore how white privilege has been intertwined with the women's liberation movement in the United States. Feminism and its goals are described briefly and linked to an evaluation of white privilege within the movement. The feminist movement is explored throughout its three waves, including a class and race analysis of each separate period. In addition, this analysis focuses on how Black and Chicana women have been excluded from the mainstream, White, middle-class movement. Through the use of Social Dominance Theory (Sidanius & Pratto, 1999), the prevalence and impact of oppression and hierarchy are explored. The implications of oppression and exclusion in the current political climate are followed by suggestions for aligning the goals and direction of feminism with social justice.

Becoming a State: Zionist and Palestinian Movements for National Liberation

This study examines the road to statehood for the Zionist and Palestinian movements. There are three components which frame this investigation: 1. social movements and the practices in which they engage that are aimed at establishing statehood for a people; 2. distinctive configurations of the international system and the manner in which both the material and ideational foundations of that system pulls units towards conformity and predictable behavior; and finally, 3. the role of agency, that is, the way in which instrumentally rational individuals attempt to push the structure in which they are embedded towards a configuration that is better suited to their interests and objectives The most influential factor guiding these struggles for national liberation are those forces which emanate from the prevailing structure of the international system. Not only was it demonstrated that the established material and ideational preferences of existing states have strong bearing on a movement’s ideological orientation and by consequence its chosen course of struggle, but hegemonic order configurations also define political cleavages and in so doing present movement leaders with both tactical and strategic opportunities by harnessing or exploiting those cleavages. From the agency perspective, the cases showed that the leadership of each movement was highly influential in the determination of a movement’s success or failure.