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Detection of errors during speech production: a review of speech monitoring models.

In this paper three theories of speech monitoring are evaluated. The perception-based approach proposes that the same mechanism employed in understanding other-produced language, the speech comprehension system, is also used to monitor one's own speech production. A conceptual, an inner, and an auditory loop convey information to a central, conscious monitor which scrutinizes the adequacy of the ongoing speech flow. In this model, only the end-products in the speech production sequences, the preverbal (propositional) message, the phonetic plan, and the auditory results, are verified. The production-based account assumes multiple local, autonomous monitoring devices, which can look inside formulation components. Moreover, these devices might be tuned to various signals from the actual speech motor execution, e.g. efferent, tactile, and proprioceptive feedback. Finally, node structure theory views error detection as a natural outflow of the activation patterns in the node system for speech production. Errors result in prolonged activation of uncommitted nodes, which in turn may incite error awareness. The approaches differ on the points of consciousness, volition and control, the number of monitoring channels, and their speed, flexibility, and capacity, and whether they can account for concurrent language comprehension disorders. From the empirical evidence presently available, it is argued for a central perception-based monitor, potentially augmented with a few automatic, production-based error detection devices.

Humans↗

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas.

Gene associated with retinoid interferon-induced mortality (GRIM)-19, an inhibitor of transcription factor STAT3, was originally identified as a critical regulatory protein in a genetic screen that was designed to identify the gene products necessary for Interferon (IFN)-beta- and retinoic acid-induced cell death. Over expression of GRIM-19 activates cell death. Conversely, inactivation of its expression promotes cell growth. STAT3 is a transcription factor that regulates gene expression in response to multiple extra cellular growth factors. In contrast to its normal feedback inhibition, a constitutive activation of STAT3 has been documented in several tumors. Although many STAT3-inhibitors are described, their relevance to human cancer is unclear. In an attempt to define the molecular alterations associated with human renal cell carcinoma (RCC) using mass spectrometry, we have discovered that expression of GRIM-19 is lost or severely depressed in a number of primary RCC and in some urinogenital tumors. Using an RCC cell line, we show that down regulation of GRIM-19 promotes tumor growth via an augmentation of STAT3-dependent gene expression. These studies for the first time show a tumor-suppressor like activity of GRIM-19.

Apoptosis Regulatory Proteins↗

Modulation of hair cell voltage responses to tones by low-frequency biasing of the basilar membrane in the guinea pig cochlea.

Inner (IHC) and outer (OHC) hair cell receptor potentials were recorded during stimulation with combinations of high-frequency (HF) tones and a 100 Hz tone burst of constant level (80 dB SPL). For frequencies at and below characteristic frequency (CF), OHC AC receptor potentials were suppressed by the 100 Hz tone at levels of the HF tone below about 70 dB SPL (the initial steep part of the AC/level function) and at levels that were frequency specific for frequencies above CF. Suppression was associated with a phase lead for frequencies at and close to the CF. For frequencies above CF, the OHC AC response was either suppressed or augmented at levels of the HF tone both below and above 70 dB SPL, depending on the frequency. The action of the 100 Hz tone on the AC response/level functions was to change nonmonotonic functions into monotonic functions or vice versa. IHC DC receptor potentials were suppressed maximally at the CF and at levels and frequencies where suppression of the OHC AC response and the appearance of the IHC DC response overlapped. For levels of the HF tone above 70 dB SPL, the amplitude of the responses of both IHCs and OHCs to the 100 Hz tone are suppressed and become more symmetrical through selective attenuation of the depolarizing phase of the IHC response and the hyperpolarizing phase of the OHC response. In IHCs from insensitive preparations, the response to the 100 Hz tone is augmented in the presence of the HF tone, which may indicate a shift in the operating point of transduction. At frequencies about one-half an octave below the CF, the phase of the 100 Hz voltage response of OHCs but not IHCs is inverted for levels of the HF tone above about 90 dB SPL. It is proposed that amplitude and phase changes in the response to the HF tone due to the presence of the 100 Hz tone are the result of changes in OHC feedback processes and in the mode of movement of the interface between OHC stereocilia and tectorial membrane. The interaction between the responses to HF and 100 Hz tones indicates that feedback contributes significantly to the voltage responses of OHCs throughout the frequency response range.

Acoustic Stimulation↗

Micropuncture analysis of tubuloglomerular feedback regulation in transgenic mice.

Micropuncture methods have been used widely as a means to define the function of single tubules and study the functional connection between tubules and afferent arterioles (so-called tubuloglomerular feedback [TGF]). Transgenic mouse strains have become a new research tool with the potential of shedding new light on the role of specific gene products in renal tubular and vascular function. The micropuncture approach has therefore been adapted to studies in the mouse kidney. Although the data presented here support the feasibility of using this technique in the mouse, technical improvements are desirable in the areas of anesthesia, ureteral urine collections, blood collections, volume replacement, and functional stability for extended time periods. During ketamine/inactin anesthesia, TGF responses could regularly be elicited in wild-type mice. In contrast, changes in loop flow did not alter stop-flow pressure in angiotensin II type 1A receptor and angiotensin-converting enzyme knockout mice. Infusion of angiotensin II in subpressor doses partially restored TGF responsiveness in angiotensin-converting enzyme knockout animals. Normal TGF responses compared to wild type were found in nitric oxide synthase I and thromboxane receptor knockout mice. Using free-flow micropuncture techniques, the proximal-distal single-nephron GFR difference was found to be augmented in aquaporin-1 and Na/H exchanger-3 knockout mice, suggesting TGF activation in these strains of mice. These results support an essential role of angiotensin II in TGF regulation mediated through the angiotensin II type 1A receptor. Chronic nitric oxide synthase I and thromboxane receptor deficiency did not change TGF responsiveness. Aquaporin-1 and Na/H exchanger-3 deficiency enhances TGF suppression of TGF probably by volume depletion-mediated TGF sensitization. The use of micropuncture methodology in transgenic mice combines old and new research tools in a way that promises to yield important new insights into single-nephron function in physiologic and pathophysiologic conditions.

Anesthesia↗

Indomethacin enhances endothelial NO release--evidence for a role of PGI2 in the autocrine control of calcium-dependent autacoid production.

OBJECTIVE: We studied whether NO or prostacyclin (PGI2), which are continuously released by endothelial cells, have autocrine/paracrine effects on the calcium-dependent autacoid production by modulating the intracellular Ca2+ concentration ([Ca2+]i). METHODS: Histamine(His)-induced [Ca2+]i increases (Fura 2-method) and NO-dependent cGMP increase were measured in human umbilical vein endothelial cell (HUVECs) before and after cyclooxygenase inhibition or application of cAMP- and cGMP-elevating drugs. RESULTS: 0.3 microM His increased endothelial [Ca2+]i from 77 +/- 2 nM to 418 +/- 59 nM. The His-induced [Ca2+]i increases were significantly attenuated following treatment with PGI2 (by 23%) and forskolin (by 33%), both increasing the cAMP release from HUVECs (by 49% and 66%). The His-induced [Ca2+]i increases were inhibited by the protein kinase A-activator cBIMPS (by 61%) which also abolished the His-induced PGI2 release. Conversely, inhibition of the PGI2 production with indomethacin significantly augmented the His-induced [Ca2+]i increases (by 32%), resulting in a significantly augmented NO production as indicated by an enhanced LNNA-sensitive cGMP increase in HUVECs. In contrast, neither increases of cGMP (basal 0.4 +/- 0.1 pmol/mg) elicited by 10 microM SNP (21 +/- 2 pmol/mg) or 10 microM C-type natriuretic peptide (CNP, 4.6 +/- 1.6 pmol/mg) nor its reduction by 30 microM LNNA had any effect on the His-induced [Ca2+]i increases. CONCLUSION: PGI2 attenuates agonist-induced [Ca2+]i increases by a cAMP-dependent mechanism, thereby modulating not only its own synthesis via a negative feedback but also that of NO. Consequently, reduced PGI2 levels result in an increased NO production. NO which does not cause a negative feedback control by cGMP might therefore compensate for the lack of PGI2.

Autocrine Communication↗

Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition.

Central melanocortin (MC) receptor agonists inhibit food intake and may be downstream mediators of the effects of central leptin, which (1) reduces food intake by selectively decreasing meal size and (2) augments the feeding-inhibitory effects of gastrointestinal food stimuli. Central administration of the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its effects on meal pattern and potential interactions with gastrointestinal controls of food intake remain unclear. We examined meal patterns and intake in male Sprague-Dawley rats following central intracerebroventricular administration of MTII (0.01-1.0 nmol) in two situations: (1) during daytime 60-min scheduled access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5% glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads and MTII reduced subsequent glucose intake. However, no dose of MTII augmented the reductions in food intake produced by duodenal glucose alone. During overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced food intake, meal size, meal duration, and body weight, and increased the satiety ratio (duration of intermeal interval/preceding meal size) but did not change meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces food intake by a selective reduction in meal size and not meal frequency, and (2) suggest that MTII increases the feeding-inhibitory potency of negative feedback signals critical to the control of meal size during spontaneous chow access, but not scheduled access to palatable liquid nutrient solutions.

Animals↗

Trinitrobenzenesulphonic acid-induced unresponsiveness at the systemic level.

To investigate the mechanism underlying B-cell tolerance, which is still discussed as being the consequence of (functional) clonal deletion or suppression, limiting dilution (LD) analysis of the frequencies of B cells as well as regulatory cells after tolerance induction with trinitrobenzenesulphonic acid (TNBS) was performed. It was shown that the frequency of functionally active hapten-specific B cells was decreased to less than 10% of the frequency in untreated BALB/c mice. After an immunogenic challenge, trinitrophenyl (TNP)-specific B cells of tolerized mice expanded, but did not reach the level of TNP-specific B cells in untreated mice. The expansion of TNP-specific B cells in TNBS-tolerized mice after challenge with TNP-horse red blood cells (HRBC) as observed in LD cultures was in contrast to the absence of anti-TNP plaque-forming cells (PFC) in freshly harvested spleen cells (SC) and the non-detectability of anti-TNP antibodies (AB). Hence, the functional deletion (= anergy) of B cells in vivo appears to be sustained by regulatory cells. Analysis of the regulatory compartment revealed that tolerance induction resulted in transient augmentation of TNP-specific helper T cells (TH), continuously elevated levels of suppressor T cells (TS), and a low level of contrasuppressor T cells (TCS). But, contrary to non-tolerized mice, TCS of tolerized mice were rather refractory to stimulation with TNP-HRBC. Hence, we would like to hypothesize that clonal anergy of B cells leads to inappropriate activation of TCS, whose nominal antigens are antibodies. This in turn sustains the persistence of high levels of TS, i.e. tolerance would be maintained by interruption of feedback activation of regulatory cells via effector cells/molecules.

Animals↗

Influence of opioids on LH secretion in gilts during the estrous cycle.

The effect of endogenous opioid peptides (EOP) on LH secretion is variable during different physiological states. A series of experiments concerning the role of EOP on LH secretion in cyclic gilts was performed. They were comprised of (1) an administration of an opioid antagonist or agonist in gilts during the estrous cycle and in ovariectomized (OVX) gilts in which the LH surge was induced with estradiol benzoate (EB) and (2) in vitro studies on GnRH release from the stalk median eminence (SME) of cyclic gilts and OVX estrogen and progesterone primed gilts in response to naloxone (NAL). Naloxone and met-enkephalin analogue (FK 33-824) administration as a single independent injections did not affect LH secretion during the early (Day 16) or late (Day 19 or 20) follicular phase. However, continuous infusion of FK 33-824 for 4 h decreased LH secretion during the infusion period on Day 19 of the estrous cycle. Morphine also exerts an inhibitory effect on the EB-induced LH surge during the positive feedback phase (60-64 h after EB administration) in OVX gilts. On the contrary, NAL infusion in OVX gilts during the negative feedback phase (30-34 h after EB administration) did not alter LH secretion. A single injection of FK 33-824 in luteal phase gilts decreased the number of LH pulses for a 3 h period. This allows to hypothesize that EOP participates in the regulation of pulsatile LH secretion in pigs during the luteal phase. In vitro studies indicate that influence of EOP on LH secretion also takes place at the SME level. GnRH efflux from the SME of gilts during the luteal and late follicular phases was augmented in the presence of NAL. Unexpectedly, the priming of OVX gilts with estrogens caused the highest increase in GnRH release from the SME in vitro in response to NAL. These results confirm the variety of functional links between the opioid system and LH secretion in gilts during different stages of the estrous cycle.

Animals↗

Idiopathic inflammatory bowel diseases: immunological hypothesis.

Circumstantial evidence indicates that immunological mechanisms are important in the pathogenesis of inflammatory bowel diseases. In Crohn's disease lesions the naive T cells are reduced and memory T cells are increased in number. Colonocytes of normal mucosa do not express MHC class II molecules but aberrant HLA-DR expression is induced in inflammatory conditions. Also in ileal epithelial cells there is increased MHC class II molecules expression suggesting augmented antigen presentation. Once the initiating event (environmental, dietary, infectious or enterobacterial products) has activated inflammatory cells, an auto-amplifying inflammatory immune cascade is induced by numerous agents such as cytokines, transforming growth factors, leukotrienes, prostaglandins and other mediators. Tissue injury may be caused by oxygen free radicals generated by neutrophils and macrophages. The inflammatory process can be perpetuated by a persistent antigenic stimulus or alternatively, by abnormal regulation of immune and inflammatory responses. This can mean exaggerated activation of inflammatory responses to "normal" stimuli or defective feedback mechanisms of down-regulation. The early lesions of inflammatory bowel disease are patchy necrosis of the surface epithelium, focal accumulations of leukocytes adjacent to crypts and an increased number of intraepithelial lymphocytes. In Crohn's disease the earliest lesions are aphthoid ulcers overlying lymphoid follicles in the terminal ileum. In patients with spondylarthropathy and asymptomatic intestinal inflammation we demonstrated lesions in the top of the follicle associated epithelium. The changes consist of increase in number of membranous (M) epithelial cells, ruptures, fissures and perforations of M cells. Aphthoid ulcers that may occur in the entire gastrointestinal tract are typically found at the M cell level.(ABSTRACT TRUNCATED AT 250 WORDS)

Colitis, Ulcerative↗

Superior laryngeal and hypoglossal afferents tonically influence upper airway motor excitability in anesthetized rats.

Upper airway (UA) muscle activity is stimulated by changes in UA transmural pressure and by asphyxia. These responses are reduced by muscle relaxation. We hypothesized that this is due to a change in afferent feedback in the ansa hypoglossi and/or superior laryngeal nerve (SLN). We examined 1) the glossopharyngeal motor responses to UA transmural pressure and asphyxia and 2) how these responses were changed by muscle relaxation in animals where one or both of these afferent pathways had been sectioned bilaterally. Experiments were performed in 24 anesthetized, thoracotomized, artificially ventilated rats. Baseline glossopharyngeal activity and its response to UA transmural pressure and asphyxia were moderately reduced after bilateral section of the ansa hypoglossi (P < 0.05). Conversely, bilateral SLN section increased baseline glossopharyngeal activity, augmented the response to asphyxia, and abolished the response to UA transmural pressure. Muscle relaxation reduced resting glossopharyngeal activity and the response to asphyxia (P < 0.001). This occurred whether or not the ansa hypoglossi, the SLN, or both afferent pathways had been interrupted. We conclude that ansa hypoglossi afferents tonically excite and SLN afferents tonically inhibit UA motor activity. Muscle relaxation depressed UA motor activity after section of the ansa hypoglossi and SLN. This suggests that some or all of the response to muscle relaxation is mediated by alterations in the activity of afferent fibers other than those in the ansa hypoglossi or SLN.

Afferent Pathways↗

Changes in tetrahydrobiopterin levels in endothelial cells and adult cardiomyocytes induced by LPS and hydrogen peroxide--a role for GFRP?

Alterations in tetrahydrobiopterin (BH4) levels have significant consequences in vascular pathophysiology. However, the mechanisms regulating BH4 remain poorly understood. The activity of GTP cyclohydrolase I (GTPCH-I), the first enzyme in BH4 biosynthesis, is controlled by protein levels, posttranslational modifications and interaction with GTPCH-I feedback regulatory protein (GFRP). This work examined the correlation between GTPCH-I protein levels and activity and changes in BH4 in human endothelial cells (HAECs) and adult rat cardiomyocytes (ARCM). Changes in BH4 were stimulated with LPS in HAECs and ARCM, and with hydrogen peroxide in HAECs only. Biopterin production by HAECs and ARCM were attained with concentrations of LPS >>1 microg/ml and responses were nonlinear with respect to LPS concentrations. Western blot analysis demonstrated that induction of biopterin synthesis in HAECs and ARCM by LPS does not entail augmentation of constitutive GTPCH-I protein levels. However, LPS diminished GFRP mRNA, suggesting that disruption of GTPCH-I:GFRP complex enhances de novo biopterin synthesis. Conversely, treatment with hydrogen peroxide increased GTPCH-I and GFRP mRNA levels in HAECs while depleting BH4 and GSH, which was counteracted by catalase. This indicates that GFRP may override increases in GTPCH-I protein inhibiting enzyme activity. This conclusion is further supported by depletion of biopterin in cells transiently transfected with GFRP. Thus, allosteric regulation of GTPCH-I activity in the cardiovascular system maybe an important mechanism regulating BH4 levels through GFRP signaling.

Aging↗

Catching a ball: contributions of intrinsic muscle stiffness, reflexes, and higher order responses.

In three sets of experiments in nine normal subjects and a patient with a percutaneous wrist-stabilizing splint, we quantified the open-loop gain (OLG) of the stretch reflex acting about the elbow. The subjects exerted a steady mean flexing force and were instructed not to intervene (i.e., not to resist actively) when force or displacement perturbations were imposed on the forearm. The method was either to reconstruct transmission around the entire loop in a two-part experiment, or to use the attenuation of external perturbations in normal and electrically stimulated muscle to compute gain. Across all experiments, the mean magnitude of stretch reflex OLG was close to unity in the frequency range 1-2 Hz, and declined at higher frequencies, as required to ensure stability, given that the phase lag approached 180 degrees at 5 Hz. Inherent muscle stiffness was approximately equal to reflex stiffness. In functional terms, an OLG of 1 means that the yield caused by a force perturbation is approximately halved by reflex action (prevailing inherent muscle stiffness is doubled). Automatic scaling of reflex transmission at Ia/alpha-motoneuronal synapses ensures that the OLG remains close to unity as inherent stiffness increases. Trials in the patient with the wrist fixator gave similar results, indicating that the reflexes were proprioceptive ly mediated. In a fourth experiment in which the task was to catch a heavy ball, we compared the efficacy of inherent muscle stiffness and reflexes alone, with the subject's intentional reactions, which included predictive and voluntary components of response. The latter were far more effective in maintaining the position of the hand after the ball was caught than inherent and reflex stiffnesses alone. We conclude that stability requirements limit the extent to which stretch reflexes can augment inherent muscle stiffness. When inherent muscle stiffness is low, such as in our ball-catching task, the reflex stiffness is also low, and predictive and pre-programmed reactions predominate in load compensation, thus shifting the emphasis from automatic servo or equilibrium-point behaviour to higher order control.

Elbow Joint↗

Function-dependent development in a colonial animal.

How does the way an organism functions affect its subsequent development? Bryozoans are colonial animals that capture suspended food particles from water currents they generate using crowns of ciliated tentacles (lophophores). In many encrusting bryozoans the water passes through and then under the lophophores until it exits the colony at "chimneys" where the lophophores spread apart to form an opening. To determine whether these water currents can induce the formation of new chimneys, I augmented the excurrent flow by injecting seawater into the colony. New chimneys began to develop near the site of seawater injection within as little as one to two days. New chimneys rarely began to develop within this time interval at control sites where I did not inject seawater. This shows that fluid flow controls development in an external fluid transport system lacking pipe-like conduits, as has been found in the vertebrate circulatory system, an internal fluid transport system with pipe-like conduits. These fluid transport systems show feedback between the way they function and their own development. This kind of "function-dependent development" should be differentiated from phenotypic plasticity, since the developing system, not the environment, produces the signals that induce morphological change.

Animals↗

Effects of estrogen on the release of gonadotropins and prolactin in male pseudohermaphrodites.

Three adult patients with male pseudohermaphroditism were given 15 microgram/kg body weight of 17 beta-estradiol im daily (at 08:00 hours) for 12-15 days and circulating levels of gonadotropins, prolactin and estradiol were determined by radioimmunoassay before and during the steriod course. All patients had elevated gonadotropin levels prior to starting on estradiol. During estrogen treatment all patients demonstrated suppression of FSH and LH with a subsequent rise in LH (positive feedback) while estrogen levels remained elevated. A similar positive feedback effect on the secretion of FSH could not be demonstrated. In two patients, who had never received estrogen treatment prior to this study, estradiol induced a significant elevation of serum prolactin levels within 24 h and levels remained higher than basal values for the rest of the estrogen treatment period. In the third patient, who had been previously treated with estrogen, serum prolactin levels did not change significantly during estrogen treatment. This study was afforded evidence for the presence in humans of an estrogen mediated LH release concomitant with an augmented prolactin secretion.

Adolescent↗

A model for a G-protein-mediated mechanism for synaptic channel modulation.

Neurons communicate with other neurons via specialized structures called synapses, at which the digital voltage signal encoded in an action potential is converted into an analog chemical signal. An action potential that arrives at the presynaptic face triggers release of neurotransmitter from vesicles in a calcium-dependent manner, and the neurotransmitter diffuses across the synaptic cleft and binds to receptors on the post-synaptic face, where it may trigger a postsynaptic action potential. Calcium is a critical component of the release process, and its spatio-temporal dynamics can control the release and can lead to facilitation or augmentation. However, how cells regulate cytoplasmic calcium so that exocytosis can be triggered successfully is still not completely understood. We propose a mechanism, based upon the experimental findings of Barrett and Rittenhouse [C.F. Barrett, A.R. Rittenhouse, Modulation of N-type calcium channel activity by G-proteins and protein kinase C, J. Gen. Physiol. 115 (3) (2000) 277], for the regulation of calcium influx through N-type channels in the presynaptic terminal by PKC and downstream effectors of G-protein activation. This proposed modulatory mechanism consists of a feedback loop involving cytoplasmic calcium, neurotransmitters and G-protein-coupled receptors. We study the dynamics of each component separately and then we address how kinetic properties of the components and the frequency of the stimuli affect the regulatory mechanisms presented here.

Animals↗

An e-learning caregiving program for prostate cancer patients and family members.

e-health interventions have the potential to augment caregiving training for management of chronic disease. Instruction on caregiving functions often key to patients and families' well being is time consuming but not reimbursable in our current health care system. A theoretically defined interactive multimedia program is described which would assess patient and family member's level of preparedness for specific caregiving functions for prostate cancer and provide tailored skill building vignettes on caregiving techniques. Maximizing today's technology, this program is best designed for a hybrid delivery utilizing both web-based resources and a CD-ROM. Feedback from 45 prostate patients and family members from a Midwest cancer center on perceived needs for caregiving training underscores the potential value of a computer supported intervention for some patients and families. Implementation of the software, marketing, and distribution will be guided in part by recent e-health experiences that leave many health professionals appropriately skeptical about the utility of such products.

Caregivers↗

Dendritic cell-derived nitric oxide is involved in IL-4-induced suppression of experimental allergic encephalomyelitis (EAE) in Lewis rats.

Cytokines play a crucial role in initiating and perpetuating EAE, an animal model of multiple sclerosis (MS). A low dose of IL-4, administered by the nasal route over 5 days (100 ng/rat per day) prior to immunization, improved clinical scores of EAE induced in Lewis rats with myelin basic protein (MBP) peptide 68-86 (MBP 68-86). We examined whether dendritic cells (DC) may have contributed to the amelioration of the disease process. These professional antigen-presenting cells (APC) not only activate T cells, but also tolerize T cells to antigens, thereby minimizing autoimmune reactions. We found that IL-4 administration enhanced proliferation of DC. In comparison with DC of PBS-treated rats, DC from IL-4-treated rats secreted high levels of interferon-gamma (IFN-gamma) and IL-10. Nitric oxide (NO) production by DC was also strongly augmented in IL-4-treated rats. In vitro studies showed that IL-4 stimulated DC expansion and that IFN-gamma enhanced NO production by DC. DC-derived NO promoted apoptosis of autoreactive T cells. These results indicate that nasal administration of IL-4 promotes activation of DC and induces production of IFN-gamma and IL-10 by DC. IL-10 suppresses antigen presentation by DC, while IFN-gamma induces NO production by DC which leads to apoptosis in autoreactive T cells. Such a DC-derived negative feedback loop might contribute to the clinical improvement observed in EAE.

Animals↗

Formative development of an intervention to stop family tobacco use: the Parents and Children Talking (PACT) intervention.

Intervening with families is a promising strategy for addressing the continuing problem of adult and youth tobacco use. A four-step formative process was used to develop an innovative self-directed family-based intervention: (1) planning and strategy development through structured telephone interviews, a focus group, and a literature review; (2) development and pretesting of concepts, messages, and materials by using feedback from children and adults on prototypic materials; (3) implementing the program by mailing 6 modules to 50 families (composed of at least one adult smoker and a 9-12-year-old) with overall high levels of engagement; and (4) assessing effectiveness and making refinements by measuring the intervention effect on smoking-related communication, skills, and attitudes. Inconsistent intervention effects related to the difficulty of cessation and the influence of parental smoking suggested needed refinements. Engaging smokers willing to make a quit attempt during the intervention time frame may augment children's appreciation for the difficulty of cessation. Content related to stress management may need greater emphasis. Enhancing the personal context in which the influence of parental behavior is conveyed may be needed. Although the family context offers the opportunity to address the parent-child reciprocal nature of tobacco use, it requires sensitivity to the challenges of addressing this topic.

Child↗