Remote olfactory assessment using the NIH Toolbox Odor Identification test and the brain health registry.

BACKGROUND: Early identification of deficits in our ability to perceive odors is important as many normal (i.e., aging) and pathological (i.e., sinusitis, viral, neurodegeneration) processes can result in diminished olfactory function. To realistically enable population-level measurements of olfaction, validated olfaction tests must be capable of being administered outside the research laboratory and clinical setting. AIM: The purpose of this study was to determine the feasibility of remotely testing olfactory performance using a test that was developed with funding from the National Institutes of Health as part of a ready-to-use, non-proprietary set of measurements useful for epidemiologic studies (NIH Toolbox Odor ID Test). MATERIALS AND METHODS: Eligible participants older than 39 years and active (within 6 months) in the Brain Health Registry (BHR), an online cognitive assessment platform which connects participants with researchers, were recruited for this study. Interested participants were mailed the NIH Toolbox Odor ID Test along with instructions on accessing a website to record their responses. Data obtained from subjects who performed the test at home was compared to the normative data collected when the NIH Toolbox Odor ID Test was administered by a tester in a research setting and validated against the Smell Identification Test. The age-range and composition of the population ensured we had the ability to observe both age-related decline and gender-related deficits in olfactory ability, as shown in the experimental setting. RESULTS: We observed that age-associated olfactory decline and gender-associated performance was comparable to performance on the administered test. Self-administration of this test showed the age-related loss in olfactory acuity, F(4, 1156)=14.564, p<.0001 as well as higher accuracy for women compared to men after controlling for participants' age, F(1, 1160) = 22.953, p <.0001. The effect size calculated as Hedge's g, was 0.41. CONCLUSION: These results indicate that the NIH Toolbox Odor ID Test is an appropriate instrument for self-administered assessment of olfactory performance. The ability to self-administer an inexpensive olfactory test increases its utility for inclusion in longitudinal epidemiological studies and when in-person testing is not feasible.

Análisis de la evolución de los operados mediante cirugía de mínimo acceso en nuestro hospital. ¿Presenta mejores resultados que la convencional? / Analysis of the evolution of those operated on with minimal access surgery in our hospital. Does it present better results than the conventional one?

Resumen La estenosis aórtica severa sintomática es la patología quirúrgica más prevalente en cirugía cardiaca y su sustitución aislada se ha realizado históricamente mediante esternotomía media completa. Sin embargo, se ha producido recientemente una gran revolución, especialmente tras la llegada de las prótesis aórticas sin suturas que, unido a un nuevo impulso por la cirugía cardiaca hacia un rumbo menos invasivo, ha provocado que el reemplazo de dicha válvula se lleve a cabo cada vez más frecuentemente por dichas prótesis y por incisiones de mínimo acceso. Por ello, realizamos una revisión de los casos intervenidos en nuestro servicio desde el inicio del programa de cirugía de mínimo acceso comparándolos con los resultados de los casos intervenidos en la misma época mediante cirugía convencional.

Abstract Symptomatic severe aortic stenosis is the most prevalent surgical pathology in cardiac surgery, and its isolated replacement has historically been performed by means of complete middle sternotomy. However, a great revolution has recently taken place, especially after the arrival of sutureless aortic prostheses that, together with a new impulse by cardiac surgery towards a less invasive course, has caused the replacement of said valve to be carried out more and more frequently due to these prostheses and minor access incisions. For this reason, we carried out a review of the cases operated on in our service from the beginning of the minimum access surgery program, comparing them with the results of the cases operated at the same time using conventional surgery.

Analysis of the evolution of those operated on with minimal access surgery in our hospital. Does it present better results than the conventional one? / Análisis de la evolución de los operados mediante cirugía de mínimo acceso en nuestro hospital. ¿Presenta mejores resultados que la convencional?

Symptomatic severe aortic stenosis is the most prevalent surgical pathology in cardiac surgery, and its isolated replacement has historically been performed by means of complete middle sternotomy. However, a great revolution has recently taken place, especially after the arrival of sutureless aortic prostheses that, together with a new impulse by cardiac surgery towards a less invasive course, has caused the replacement of said valve to be carried out more and more frequently due to these prostheses and minor access incisions. For this reason, we carried out a review of the cases operated on in our service from the beginning of the minimum access surgery program, comparing them with the results of the cases operated at the same time using conventional surgery.

La estenosis aórtica severa sintomática es la patología quirúrgica más prevalente en cirugía cardiaca y su sustitución aislada se ha realizado históricamente mediante esternotomía media completa. Sin embargo, se ha producido recientemente una gran revolución, especialmente tras la llegada de las prótesis aórticas sin suturas que, unido a un nuevo impulso por la cirugía cardiaca hacia un rumbo menos invasivo, ha provocado que el reemplazo de dicha válvula se lleve a cabo cada vez más frecuentemente por dichas prótesis y por incisiones de mínimo acceso. Por ello, realizamos una revisión de los casos intervenidos en nuestro servicio desde el inicio del programa de cirugía de mínimo acceso comparándolos con los resultados de los casos intervenidos en la misma época mediante cirugía convencional.

The human olfactory cleft mucus proteome and its age-related changes.

Age-related decreases in olfactory sensitivity are often accompanied by a decrease in the quality of life. However, the molecular mechanisms underlying these changes are not well described. Inhaled substances including odorants are detected by sensory neurons in the olfactory cleft covered with a layer of mucus. This olfactory mucus is the first molecular machinery responsible for tissue protection and for detection of environmental odorants. Yet, little is known about the molecular identities of the actors because of the lack of information on the mucus proteome and its age-related changes. Here, we sampled human mucus from different nasal locations and from young and elderly subjects. The composition of the mucus was extensively analyzed by shotgun proteomic analysis for a vast array of proteins. We also explored correlations between the levels of each mucus proteins with the olfactory sensitivity of subjects. This analysis revealed previously unrecognized proteins with potentially important functions in olfaction. Taken together, this report describes the most comprehensive catalogue of the nasal mucus proteins to date, their positional and age-related differences, and candidate proteins associated with olfaction. This catalogue will provide fundamental information useful for future studies, such as identification of olfactory auxiliary proteins, causes of age-related declines in olfaction, and biomarkers for neurodegenerative disorders.

Asthma and odors: the role of risk perception in asthma exacerbation.

OBJECTIVE: Fragrances and strong odors have been characterized as putative triggers that may exacerbate asthma symptoms and many asthmatics readily avoid odors and fragranced products. However, the mechanism by which exposure to pure, non-irritating odorants can elicit an adverse reaction in asthmatic patients is still unclear and may involve both physiological and psychological processes. The aim of this study was to investigate how beliefs about an odor's relationship to asthmatic symptoms could affect the physiological and psychological responses of asthmatics. METHODS: Asthmatics classified as 'moderate-persistent', according to NIH criteria, were exposed for 15 min to a fragrance which was described either as eliciting or alleviating asthma symptoms. During exposure, participants were asked to rate odor intensity, perceived irritation and subjective annoyance while physiological parameters such as electrocardiogram, respiratory rate, and end tidal carbon dioxide (etCO2) were recorded. Before, immediately after, and at 2 and 24h post-exposure, participants were required to subjectively assess their asthma symptom status using a standardized questionnaire. We also measured asthma status at each of those time points using objective parameters of broncho-constriction (spirometry) and measures of airway inflammation (exhaled nitric oxide, FeNO). RESULTS: Predictably, manipulations of perceived risk altered both the quality ratings of the fragrance as well as the reported levels of asthma symptoms. Perceived risk also modulated the inflammatory airway response. CONCLUSIONS: Expectations elicited by smelling a perceived harmful odor may affect airway physiology and impact asthma exacerbations.

Chemosignals of stress influence social judgments.

Human body odors have important communicative functions regarding genetic identity, immune fitness and general health, but an expanding body of research suggests they can also communicate information about an individual's emotional state. In the current study, we tested whether axillary odors obtained from women experiencing psychosocial stress could negatively influence personality judgments of warmth and competence made about other women depicted in video scenarios. 44 female donors provided three types of sweat samples: untreated exercise sweat, untreated stress sweat and treated stress sweat. After a 'washout' period, a commercial unscented anti-perspirant product was applied to the left axilla only to evaluate whether 'blocking' the stress signal would improve the social evaluations. A separate group of male and female evaluators (n = 120) rated the women in the videos while smelling one of the three types of sweat samples. Women in the video scenes were rated as being more stressed by both men and women when smelling the untreated vs. treated stress sweat. For men only, the women in the videos were rated as less confident, trustworthy and competent when smelling both the untreated stress and exercise sweat in contrast to the treated stress sweat. Women's social judgments were unaffected by sniffing the pads. The results have implications for influencing multiple types of professional and personal social interactions and impression management and extend our understanding of the social communicative function of body odors.

Mechanisms of chloride uptake in frog olfactory receptor neurons.

Odorant stimulation of olfactory receptor neurons (ORNs) leads to the activation of a Ca(2+) permeable cyclic nucleotide-gated (CNG) channel followed by opening of an excitatory Ca(2+)-activated Cl(-) channel, which carries about 70% of the odorant-induced receptor current. This requires ORNs to have a [Cl(-)](i) above the electrochemical equilibrium to render this anionic current excitatory. In mammalian ORNs, the Na(+)-K(+)-2Cl(-) co-transporter 1 (NKCC1) has been characterized as the principal mechanism by which these neurons actively accumulate Cl(-). To determine if NKCC activity is needed in amphibian olfactory transduction, and to characterize its cellular location, we used the suction pipette technique to record from Rana pipiens ORNs. Application of bumetanide, an NKCC blocker, produced a 50% decrease of the odorant-induced current. Similar effects were observed when [Cl(-)](i) was decreased by bathing ORNs in low Cl(-) solution. Both manipulations reduced only the Cl(-) component of the current. Application of bumetanide only to the ORN cell body and not to the cilia decreased the current by again about 50%. The results show that NKCC is required for amphibian olfactory transduction, and suggest that the co-transporter is located basolaterally at the cell body although its presence at the cilia could not be discarded.

Responses to odors in occupational environments.

PURPOSE OF REVIEW: There is mounting evidence that the presence of airborne chemicals that produce odor and irritation can be a significant impediment to a productive and healthy workforce, even among individuals without chemical sensitivity. RECENT FINDINGS: Studies investigating odor and irritant-induced symptoms in occupational environments suggest that poor indoor air quality, coupled with psychosocial factors such as the work environment, personality and stress, can lead to the development of building-related complaints and exacerbate chemical intolerance and symptoms. The practice of introducing pleasant odors in the workplace to improve productivity and mood is not well supported by current research. SUMMARY: Managing the response to odors and irritants in the workplace is critical to maintaining the health and well being of workers. There is a critical need for regulatory organizations in the United States and elsewhere to harmonize guidelines for occupational exposure limits. In addition, management must engage in risk communication and education of workers in order to ensure that misperception of risk from odors does not lead to illness and loss of well being.

TBCD links centriologenesis, spindle microtubule dynamics, and midbody abscission in human cells.

Microtubule-organizing centers recruit alpha- and beta-tubulin polypeptides for microtubule nucleation. Tubulin synthesis is complex, requiring five specific cofactors, designated tubulin cofactors (TBCs) A-E, which contribute to various aspects of microtubule dynamics in vivo. Here, we show that tubulin cofactor D (TBCD) is concentrated at the centrosome and midbody, where it participates in centriologenesis, spindle organization, and cell abscission. TBCD exhibits a cell-cycle-specific pattern, localizing on the daughter centriole at G1 and on procentrioles by S, and disappearing from older centrioles at telophase as the protein is recruited to the midbody. Our data show that TBCD overexpression results in microtubule release from the centrosome and G1 arrest, whereas its depletion produces mitotic aberrations and incomplete microtubule retraction at the midbody during cytokinesis. TBCD is recruited to the centriole replication site at the onset of the centrosome duplication cycle. A role in centriologenesis is further supported in differentiating ciliated cells, where TBCD is organized into "centriolar rosettes". These data suggest that TBCD participates in both canonical and de novo centriolar assembly pathways.

RGS3 and RGS4 differentially associate with G protein-coupled receptor-Kir3 channel signaling complexes revealing two modes of RGS modulation. Precoupling and collision coupling.

RGS3 and RGS4 are GTPase-activating proteins expressed in the brain and heart that accelerate the termination of G(i/o)- and G(q)-mediated signaling. We report here the determinants mediating selective association of RGS4 with several G protein-coupled receptors (GPCRs) that form macromolecular complexes with neuronal G protein-gated inwardly rectifying potassium (Kir3 or GIRK) channels. Kir3 channels are instrumental in regulating neuronal firing in the central and peripheral nervous system and pacemaker activity in the heart. By using an epitope-tagged degradation-resistant RGS4 mutant, RGS4(C2V), immunoprecipitation of several hemagglutinin-tagged G(i/o)-coupled and G(q)-coupled receptors expressed in Chinese hamster ovary (CHO-K1) cells readily co-precipitated both Kir3.1/Kir3.2a channels and RGS4(C2V). In contrast to RGS4(C2V), the closely related and functionally active RGS3 "short" isoform (RGS3s) did not interact with any of the GPCR-Kir3 channel complexes examined. Deletion and chimeric RGS constructs indicate both the N-terminal domain and the RGS domain of RGS4(C2V) are necessary for association with m2 receptor-Kir3.1/Kir3.2a channel complexes, where the GPCR was found to be the major target for RGS4(C2V) interaction. The functional impact of RGS4(C2V) "precoupling" to the GPCR-Kir3 channel complex versus RGS3s "collision coupling" was a 100-fold greater potency in the acceleration of G protein-dependent Kir3 channel-gating kinetics with no attenuation in current amplitude. These findings demonstrate that RGS4, a highly regulated modulator and susceptibility gene for schizophrenia, can directly associate with multiple GPCR-Kir3 channel complexes and may affect a wide range of neurotransmitter-mediated inhibitory and excitatory events in the nervous and cardiovascular systems.

Neuronal Kir3.1/Kir3.2a channels coupled to serotonin 1A and muscarinic m2 receptors are differentially modulated by the "short" RGS3 isoform.

"Regulators of G protein signaling" (RGS proteins) have profound effects on ion channels regulated by G protein-coupled receptor (GPCR) signaling, including the G protein-gated inwardly rectifying K+ (GIRK) channels that inhibit excitability of neuronal, endocrine, and cardiac cells. Here we describe the effects of an alternatively spliced "short" RGS3 isoform (RGS3s) in comparison to RGS4, on the temporal and steady-state gating properties of neuronal GIRK channels (Kir3.1/Kir3.2a) activated by either serotonin 1A (5-HT(1A)) receptors or muscarinic m2 receptors expressed in Chinese hamster ovary (CHO-K1) cells. RGS3s is abundantly expressed in brain and contains a unique short N-terminus via alternative splicing that distinguishes it from other RGS3 isoforms as well as other members of the B/R4 RGS gene subfamily. Our results indicate that RGS3s and RGS4 similarly affect the temporal and steady-state gating properties of 5-HT(1A) receptor-coupled Kir3.1/Kir3.2a channels, but differentially modulate muscarinic m2 receptor-coupled channels. RGS3s caused a significant approximately 45% reduction in the maximal acetylcholine (ACh)-evoked GIRK current amplitude and a marked shift in the steady-state ACh dose-response relation indicative of a reduction in functionally coupled m2 receptor-GIRK channel complexes. Yet RGS3s still accelerated the m2 receptor-dependent GIRK activation, deactivation, and acute desensitization time course consistent with the RGS-enhanced GAP activity that was also observed with RGS4. Several mechanisms that may contribute to the receptor-dependent effects of RGS3s are discussed with particular attention to the role of the distinct N-terminal domain. Our findings highlight the potential impact of selective RGS-GPCR interactions on neuronal GIRK channel function that may affect the properties of inhibitory postsynaptic potentials activated by different GPCR-GIRK channel complexes.

Measuring the modulatory effects of RGS proteins on GIRK channels.

Discovery of "regulators of G-protein signaling" (RGS) as GTPase-activating proteins for heterotrimeric G proteins has provided a highly sought "missing link," reconciling past discrepancies between the in vitro GTPase activity of purified G proteins and the kinetics of physiological responses mediated by G-protein signaling in vivo. With the number of RGS genes in the mammalian genome at more than 30, associating specific RGS proteins to specific G-protein-coupled receptor (GPCR) signaling events has become a focus of RGS investigators. The ubiquitous expression of multiple RGS proteins has complicated this effort, yet the outlook has been encouraged with the identification of RGS9 as the determinant mediating rapid recovery of the transducin-dependent photoresponse. G-protein-gated inwardly rectifying potassium (GIRK) channels that mediate inhibitory synaptic transmission via GPCR activation of pertussis toxin-sensitive G proteins are similarly accelerated by RGS proteins when reconstituted in heterologous cell expression systems and fully reproduce the gating properties of native GIRK channels in neurons and cardiomyocytes. The endogenous neuronal and cardiac RGS protein(s) that accelerate GPCR-->GIRK channel-gating kinetics are currently not known. This article describes methods used to measure the receptor-dependent GIRK channel-gating parameters reconstituted in Chinese hamster ovary (CHO-K1) cells and Xenopus oocytes, as well as rat atrial myocytes and rat cerebellar granule neurons as model cells with native GPCR-->GIRK channel signaling. Applications of these methods for structure-function-based studies of RGS proteins, G proteins, and GPCRs are discussed. We also describe single cell reverse transcriptase polymerase chain reaction methods developed to profile atrial myocyte and neuronal RGS expression to identify specific RGS proteins for targeted knockdown or knockout.