From Folke Medicine to Medicine Chemistry: Study, Using in Vitro and Cellular Assays, of Receptors Mechanism Involved in the Activities of Natural Compounds

My Doctorate Research has been focused on the evaluation of the pharmacological activity of a natural extract of chestnut wood (ENC) towards the cardiovascular and gastrointestinal system and on the identification of the active compounds. The ENC has been shown to contain more than 10% (w/w) of phenolic compounds, of which tannins as Vescalgin and Castalgin are the more representative. ENC cardiovascular effects have been investigated in guinea pig cardiac preparations; furthermore its activity has been evalueted in guinea pig aorta strips. ENC induced transient negative chronotropic effect in isolated spontaneously beating right atria and simultaneously positive inotropic effect in left atria driven at 1 Hz. Cardiac cholinergic receptors are not involved in the negative chronotropic effect and positive inotropic effects are not related to adrenergic receptors. In vascular smooth muscle, natural extract of chestnut did not significantly change the contraction induced by potassium (80 mM) or that induced by noradrenaline (1μM). In guinea pig ileum, ENC reduced the maximum response to carbachol in a concentrationdependent manner and behaved as a reversible non competitive antagonist. In guinea pig ileum, the antispasmodic activity of ENC showed a significant antispasmodic activity against a variety of different spasmogenic agents including histamine, KCl, BaCl2. In guinea pig proximal colon, stomach and jejunum, ENC reduced the maximum response to carbachol in a concentrationdependent manner and behaved as a reversible non competitive antagonist. ENC contracted gallbladder guinea pig in a reversible and concentration-dependent manner. This effect does not involve cholinergic and cholecystokinin receptors and it is reduced by nifedipine. ENC relaxed Oddi sphincter smooth muscle. The cholecystokinetic and Oddi sphincter relaxing activities occurred also in guinea pigs fed a lithogenic diet. The cholecystokinetic occurred also in human gallbladder. The Fractionation of the extract led to the identification of the active fraction.

Einfluss von Hilfsstoffen auf die Bioverfügbarkeit von Substanzen der BCS Klasse III

In dieser Arbeit wurde der Effekt verschiedener Hilfsstoffe auf die Permeabilität von Substanzen der BCS Klasse III untersucht. Drei pharmazeutische Hilfsstoffe wurden hinsichtlich der Möglichkeit ihres Einsatzes als Permeationsverbesserer in Arzneistoffformulierungen untersucht. Außerdem wurde die Beteiligung von Gallensalzen an der Nahrungsmittel-Interaktion von Trospium untersucht.rnEs wurden Komplexe aus Trospium und λ-Carrageen hergestellt. Eine verbesserte Permeation, die höchstwahrscheinlich durch Mukoadhäsion zustande kam, war im Ussing-Kammer-Modell sehr gut reproduzierbar. In vivo war der Effekt nur bei einigen Tieren zu sehen und es kam zu hohen Standardabweichungen.rnTrospium bildet Ionenpaare mit Gallensalzen, welche zu einer besseren Permeabilität des Wirkstoffes führten. In Gegenwart von Nahrungsfetten blieb dieser Effekt aus. Eine Beteiligung der Interaktion von Trospium und Gallensalzen am Food-Effekt kann auf Basis dieser Ergebnisse als wahrscheinlich gelten.rnIm Caco-2-Modell konnte bereits eine Verbesserung der Permeabilität von Trospium durch Zusatz von Eudragit E gezeigt werden. Nun konnte gezeigt werden, dass durch den Hilfsstoff auch in vivo in Ratten eine verbesserte Permeation erreicht werden kann.rnDie Permeationsverbesserung von Aciclovir durch Zusatz von Chitosan-HCl sollte untersucht werden. Im Caco-2-Modell kam es zu einer signifikanten Permeationsverbesserung. Im Ussing-Kammer-Modell wurde die Permeation nicht verbessert. In Loop-Studien konnte nur bei hohen Hilfsstoff-Konzentrationen eine Tendenz zur Permeationsverbesserung erkannt werden.rn

Counterbalancing effects of competition for resources and facilitation against grazing in alpine snowbed communities

Alpine snowbeds are habitats where the major limiting factors for plant growth are herbivory and a small time window for growth due to late snowmelt. Despite these limitations, snowbed vegetation usually forms a dense carpet of palatable plants due to favourable abiotic conditions for plant growth within the short growing season. These environmental characteristics make snowbeds particularly interesting to study the interplay of facilitation and competition. We hypothesised an interplay between resource competition and facilitation against herbivory. Further, we investigated whether these predicted neighbour effects were species-specific and/or dependent on ontogeny, and whether the balance of positive and negative plant–plant interactions shifted along a snowmelt gradient. We determined the neighbour effects by means of neighbour removal experiments along the snowmelt gradient, and linear mixed model analyses. The results showed that the effects of neighbour removal were weak but generally consistent among species and snowmelt dates, and depended on whether biomass production or survival was considered. Higher total biomass and increased fruiting in removal plots indicated that plants competed for nutrients, water, and light, thereby supporting the hypothesis of prevailing competition for resources in snowbeds. However, the presence of neighbours reduced herbivory and thereby also facilitated survival. For plant growth the facilitative effects against herbivores in snowbeds counterbalanced competition for resources, leading to a weak negative net effect. Overall the neighbour effects were not species-specific and did not change with snowmelt date. Our finding of counterbalancing effects of competition and facilitation within a plant community is of special theoretical value for species distribution models and can explain the success of models that give primary importance to abiotic factors and tend to overlook interrelations between biotic and abiotic effects on plants.

Perceived Influence and Friendship as Antecedents of Cooperation in Top Management Teams: A Network Approach

Using the relational dyad as unit of analysis this study examines the effects of perceived influence and friendship ties on the formation and maintenance of cooperative relationships between corporate top executives. Specifically, it is argued that perceived influence as well as friendship ties between any two managers will enhance the likelihood that these managers collaborate with each other. Additionally, a negative interaction effect between perceived influence and friendship on cooperation is proposed. The empirical analyses draw on network data that have been collected among all members of the top two organizational levels for the strategy-making process in two multinational firms headquartered in Germany. Applying logistic regression based on QAP the empirical results support our hypotheses on the direct effects between perceived influence, friendship ties, and cooperative relationships in both companies. In addition, we find at least partial support for our assumption that perceived influence and friendship interact negatively with respect to their effect on cooperation. Seemingly, perceived influence is partially substituted by managerial friendship ties.

Perceived organizational support and intention to stay in host countries among self-initiated expatriates: the role of career satisfaction and networks

Previous literature in SIE (self-initiated expatriation) has been mostly focused on an individual perspective. Studies on SIEs in organizational context are scarce. The current paper sought to examine the effect of perceived organizational support (POS) on SIE employees’ intention to stay in the host country, mediated by career satisfaction. Furthermore, we examined the moderating roles of career-related social networks with host and home country nationals on the effectiveness of POS. Data from 112 SIE employees in Germany were collected and analyzed. Empirical results partially supported our proposed model: there were significant negative indirect effect between POS and intention to stay, when career network size with home country nationals was high. The direct effect between POS and intention to stay was positive. For HR practice, our paper gave insight to understand SIE employees’ needs for support and mobility preferences, which can help organizations to develop more targeted HR development measures and assignment strategies for them.

The consequences of social intolerance on non-violent protest behavior

This paper scrutinizes the impact of intolerance toward diverse ethnic, religious, and cultural groups on an individuals willingness to actively engage in non-violent protest. Following new insights, we examine the individual as well as the ecological effect of social intolerance on protest behavior. Drawing from insights of social psychology and communication science, we expect that the prevalence of intolerance reinforces the positive effect of individual-level intolerance on protest participation. From a rational choice perspective, however, a negative moderating effect is expected, as the expression of opinions becomes redundant for intolerant individuals in an intolerant society. We base our multilevel analyses on data from the World Values Surveys covering 32 established democracies. Our results reveal that intolerance leads to more non-violent protest participation. This relationship, however, is strongly influenced by the prevalence of intolerance in a country.

STUDIES OF DISULFOTON TOLERANCE IN RATS

Disulfoton (O,O, diethyl S-2-(ethylthio)ethyl phosphorodithioate) and other organophosphorus ester compounds are insecticides which inhibit acetylcholinesterase. Chemicals of this class cause signs of toxicity in mammals which are referable to acculmulation of acetylcholine at neuroeffector sites. A tolerance to this toxic action can be induced in experimental animals by giving multiple, sublethal doses of the compounds. There is strong evidence that disulfoton tolerance occurs because of a reduction in the sensitivity of tissues in the affected animals to acetylcholine.^ Experiments were designed to test the possibility that a decrease in the number of muscarinic cholinergic receptors could be downmodulating the sensitivity of tissues to acetylcholine. It was found that, concomitant with the onset of disulfoton tolerance, there was a decrease relative to control values in the specific binding of {('3)H} quinuclidinyl benzilate ({('3)H}QNB, a compound which selectively labels muscarinic cholinergic receptors) to homogenates of rat brain and ileal muscle. The decrease in {('3)H}QNB binding was due to a reduction in the density of muscarinic receptors. There was, however, no alteration in the binding of {('3)H} QNB, or the muscarinic agonists {('3)H} oxotremorine-M and oxotremorine to atria from disulfoton-tolerant rats. The possibility that cardiac tissue was not subsensitive to cholinergic agonists was ruled out in experiments testing the effect of the muscarinic agonist carbachol on heart rate in vivo, and the negative chronotropic effect of oxotremorine on atria from disulfoton-tolerant rats: a clear reduction in the sensitivity to cholinergic agonists was seen in each case. It was, therefore concluded that the specificity and temporal correlation of {('3)H}QNB binding decreases suggested that the loss of muscarinic receptors might play a role in modulating the sensitivity of several tissues to acetylcholine, but that other mechanisms also contribute to the tolerance phenomenon.^ Other experiments revealed that disulfoton tolerance, as measured by resistance to the lethal effects of carbachol, could be induced by feeding rats low levels of the organophosphorus ester in the diet. The concentration of disulfoton used inhibited acetylcholinesterase, but not to the extent that overt signs of toxicity were observed. These results suggested that tolerance to organophosphorus ester insecticides could be induced in rodents with a dosing scheme which more closely modeled the sort of low level exposures which would be expected in humans environmentally or occupationally in contact with these compounds. ^

Export Promotion through Exchange Rate Policy: Exchange Rate Depreciation or Stabilization?

Exchange rate movements affect exports in two ways -- its depreciation and its variability (risk). A depreciation raises exports, but the associated exchange rate risk could offset that positive effect. The present paper investigates the net effect for eight Asian countries using a dynamic conditional correlation bivariate GARCH-M model that simultaneously estimates time varying correlation and exchange rate risk. Depreciation encourages exports, as expected, for most countries, but its contribution to export growth is weak. Exchange rate risk contributes to export growth in Malaysia and the Philippines, leading to positive net effects. Exchange rate risk generates a negative effect for six of the countries, resulting in a negative net effect in Indonesia, Japan, Singapore, Taiwan and a zero net effect in Korea and Thailand. Since the negative effect of exchange rate risk may offset, or even dominate, positive contributions from depreciation, policy makers need to reduce exchange rate fluctuation along with and possibly before efforts to depreciate the currency.

Financial impact of the Medicare prospective payment system on long term acute care hospitals

Objective. Long Term Acute Care Hospitals (LTACs) are subject to Medicare rules because they accept Medicare and Medicaid patients. In October 2002, Medicare changed the LTAC reimbursement formulas, from a cost basis system to a Prospective Payment System (PPS). This study examines whether the PPS has negatively affected the financial performance of the LTAC hospitals in the period following the reimbursement change (2003-2006), as compared to the period prior to the change (1999-2003), and if so, to what extent. This study will also examine whether the PPS has resulted in a decreased average patient length of stay (LOS) in the LTAC hospitals for the period of 2003-2006 as compared to the prior period of 1999-2003, and if so, to what extent. ^ Methods. The study group consists of two large LTAC hospital systems, Kindred Healthcare Inc. and Select Specialty Hospitals of Select Medical Corporation. Financial data and operational indicators were reviewed, tabulated and dichotomized into two groups, covering the two periods: 1999-2002 and 2003-2006. The financial data included net annual revenues, net income, revenue per patient per day and profit margins. It was hypothesized that the profit margins for the LTAC hospitals were reduced because of the new PPS. Operational indicators, such as annual admissions, annual patient days, and average LOS were analyzed. It was hypothesized that LOS for the LTAC hospitals would have decreased. Case mix index, defined as the weighted average of patients’ DRGs for each hospital system, was not available to cast more light on the direction of LOS. ^ Results. This assessment found that the negative financial impacts did not materialize; instead, financial performance improved during the PPS period (2003-2006). The income margin percentage under the PPS increased for Kindred by 24%, and for Select by 77%. Thus, the study’s working hypothesis of reduced income margins for the LTACs under the PPS was contradicted. As to the average patient length of stay, LOS decreased from 34.7 days to 29.4 days for Kindred, and from 30.5 days to 25.3 days for Select. Thus, on the issue of LTAC shorter length of stay, the study’s working hypothesis was confirmed. ^ Conclusion. Overall, there was no negative financial effect on the LTAC hospitals during the period of 2003-2006 following Medicare implementation of the PPS in October 2002. On the contrary, the income margins improved significantly. ^ During the same period, LOS decreased following the implementation of the PPS. This was consistent with the LTAC hospitals’ pursuit of financial incentives.^

Financial impact of the Medicare prospective payment system on long term acute care hospitals

Objective. Long Term Acute Care Hospitals (LTACs) are subject to Medicare rules because they accept Medicare and Medicaid patients. In October 2002, Medicare changed the LTAC reimbursement formulas, from a cost basis system to a Prospective Payment System (PPS). This study examines whether the PPS has negatively affected the financial performance of the LTAC hospitals in the period following the reimbursement change (2003–2006), as compared to the period prior to the change (1999–2003), and if so, to what extent. This study will also examine whether the PPS has resulted in a decreased average patient length of stay (LOS) in the LTAC hospitals for the period of 2003–2006 as compared to the prior period of 1999-2003, and if so, to what extent. ^ Methods. The study group consists of two large LTAC hospital systems, Kindred Healthcare Inc. and Select Specialty Hospitals of Select Medical Corporation. Financial data and operational indicators were reviewed, tabulated and dichotomized into two groups, covering the two periods: 1999–2002 and 2003–2006. The financial data included net annual revenues, net income, revenue per patient per day and profit margins. It was hypothesized that the profit margins for the LTAC hospitals were reduced because of the new PPS. Operational indicators, such as annual admissions, annual patient days, and average LOS were analyzed. It was hypothesized that LOS for the LTAC hospitals would have decreased. Case mix index, defined as the weighted average of patients’ DRGs for each hospital system, was not available to cast more light on the direction of LOS. ^ Results. This assessment found that the negative financial impacts did not materialize; instead, financial performance improved during the PPS period (2003–2006). The income margin percentage under the PPS increased for Kindred by 24%, and for Select by 77%. Thus, the study’s working hypothesis of reduced income margins for the LTACs under the PPS was contradicted. As to the average patient length of stay, LOS decreased from 34.7 days to 29.4 days for Kindred, and from 30.5 days to 25.3 days for Select. Thus, on the issue of LTAC shorter length of stay, the study’s working hypothesis was confirmed. ^ Conclusion. Overall, there was no negative financial effect on the LTAC hospitals during the period of 2003–2006 following Medicare implementation of the PPS in October 2002. On the contrary, the income margins improved significantly. ^ During the same period, LOS decreased following the implementation of the PPS. This was consistent with the LTAC hospitals’ pursuit of financial incentives. ^

Cenomanian/Turonian sea surface temperatures of the equatorial Atlantic reconstructed from geochemical data

Oceanic anoxic event 2 (OAE-2) occurring during the Cenomanian/Turonian (C/T) transition is evident from a globally recognized positive stable carbon isotopic excursion and is thought to represent one of the most extreme carbon cycle perturbations of the last 100 Myr. However, the impact of this major perturbation on and interaction with global climate remains unclear. Here we report new high-resolution records of sea surface temperature (SST) based on TEX86 and d 18O of excellently preserved planktic foraminifera and stable organic carbon isotopes across the C/T transition from black shales located offshore Suriname/French Guiana (Demerara Rise, Ocean Drilling Program Leg 207 Site 1260) and offshore Senegal (Cape Verde Basin, Deep Sea Drilling Project Leg 41 Site 367). At Site 1260, where both SST proxy records can be determined, a good match between conservative SST estimates from TEX86 and d 18O is observed. We find that late Cenomanian SSTs in the equatorial Atlantic Ocean (33°C) were substantially warmer than today (27°-29°C) and that the onset of OAE-2 coincided with a rapid shift to an even warmer (35°-36°C) regime. Within the early stages of the OAE a marked (4°C) cooling to temperatures lower than pre-OAE conditions is observed. However, well before the termination of OAE-2 the warm regime was reestablished and persisted into the Turonian. Our findings corroborate the view that the C/T transition represents the onset of the interval of peak Cretaceous warmth. More importantly, they are consistent with the hypotheses that mid-Cretaceous warmth can be attributed to high levels of atmospheric carbon dioxide (CO2) and that major OAEs were capable of triggering global cooling through the negative feedback effect of organic carbon-burial-led CO2 sequestration. Evidently, however, the factors that gave rise to the observed shift to a warmer climate regime at the onset of OAE-2 were sufficiently powerful that they were only briefly counterbalanced by the high rates of carbon burial attained during even the most extreme interval of organic carbon burial in the last 100 Myr.

Optimización del Abonado Nitrogenado en el Melón (Cucumis Melo L.) Tipo Piel de Sapo

Spain is the fifth-largest producer of melon (Cucumis melo L.) and the second exporter in the world. To a national level, Castilla-La Mancha emphasize and, specifically, Ciudad Real, where is cultivated 27% of national area dedicated to this crop and 30% of melon national production. Melon crop is cultivating majority in Ciudad Real and it is mainly located in the Alto Guadiana, where the major aquifers of the region are located, the aquifer 23 or Mancha Occidental and the aquifer 24 or Campo de Montiel, both declared overexploited and vulnerable zones to nitrate pollution from agricultural sources. The problem is exacerbated because in this area, groundwater is the basic resource of supply to populations, and even often the only one. Given the importance of melon in the area, recent research has focused on the irrigation of melon crop. Unfortunately, scant information has been forthcoming on the effect of N fertilizer on melon piel de sapo crop, so it is very important to tackle in a serious study that lead to know the N requirements on the melon crop melon by reducing the risks of contamination by nitrate leaching without affecting productivity and crop quality. In fact, the recommended dose is often subjective and practice is a N overdose. In this situation, the taking of urgent measures to optimize the use of N fertilization is required. To do it, the effect of N in a melon crop, fertirrigated and on plastic mulch, was studied. The treatments consisted in different rates of N supply, considering N fertilizer and N content in irrigation water, so the treatment applied were: 30 (N30), 85 (N85), 112 (N112) and 139 (N139) Kg N ha-1 in 2005; 93 (N93), 243 (N243) and 393 (N393) kg ha-1 in 2006; and 11 (N11), 61 (N61), 95 (N95) and 148 (N148) kg ha-1 in 2007. A randomized complete-block design was used and each treatment was replicated four times. The results showed a significant effect of N on dry biomass and two patterns of growth were observed. On the one hand, a gradual increase in vegetative biomass of the plant, leaves and stem, with increasing N, and on the other hand, an increase of fruit biomass also with increasing N up to a maximum of biomass corresponding to the optimal dose determined in 90 kg ha-1 of N applied, corresponding to 160 kg ha-1 of N available for melon crop, since this optimum dose, the fruit biomass suffers a decline. A significant effect was observed in concentration and N uptake in leaf, steam, fruit and whole plant, increasing in all of them with increasing of N doses. Fast N uptake occurred from 30-35 to 70-80 days after transplanting, coinciding with the fruit development. The N had a clear influence on the melon yield, its components, skin thickness and flesh ratio. The melon yield increased, as the mean fruit weight and number of fruits per m2 with increasing N until achieve an above 95% of the maximum yield when the N applied is 90 kg ha-1 or 160 kg ha-1 of N available. When N exceeds the optimal amount, there is a decline in yield, reducing the mean fruit weight and number of fruits per square meter, and was also observed a decrease in fruit quality by increasing the skin thickness and decrease the flesh ratio, which means an increase in fruit hollowed with excessive N doses. There was a trend for all indexes of N use efficiency (NUE) to decline with increasing N rate. We observed two different behaviours in the calculation result of the NUE; on the one hand, all the efficiency indexes calculated with N applied and N available had an exponential trend, and on the other hand, all the efficiency indexes calculated with N uptake has a linear trend. The linear regression cuts the exponential curve, delimiting a range within which lies the optimum quantity of N. The N leaching as nitrates increased exponentially with the amount of N. The increase of N doses was affected on the N mineralization. There was a negative exponential effect of N available on the mineralization of this element that occurs in the soil during the growing season, calculated from the balances of this element. The study of N leaching for each N rate used, allowed to us to establish several environmental indices related to environmental risk that causes the use of such doses, a simple way for them to be included in the code of Best Management Practices.

Disruption of cellular translational control by a viral truncated eukaryotic translation initiation factor 2α kinase homolog

Phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a common cellular mechanism to limit protein synthesis in stress conditions. Baculovirus PK2, which resembles the C-terminal half of a protein kinase domain, was found to inhibit both human and yeast eIF2α kinases. Insect cells infected with wild-type, but not pk2-deleted, baculovirus exhibited reduced eIF2α phosphorylation and increased translational activity. The negative regulatory effect of human protein kinase RNA-regulated (PKR), an eIF2α kinase, on virus production was counteracted by PK2, indicating that baculoviruses have evolved a unique strategy for disrupting a host stress response. PK2 was found in complex with PKR and blocked kinase autophosphorylation in vivo, suggesting a mechanism of kinase inhibition mediated by interaction between truncated and intact kinase domains.

Inhibition of selective signaling events in natural killer cells recognizing major histocompatibility complex class I.

Many studies have characterized the transmembrane signaling events initiated after T-cell antigen receptor recognition of major histocompatibility complex (MHC)-bound peptides. Yet, little is known about signal transduction from a set of MHC class I recognizing receptors on natural killer (NK) cells whose ligation dramatically inhibits NK cell-mediated killing. In this study we evaluated the influence of MHC recognition on the proximal signaling events in NK cells binding tumor targets. We utilized two experimental models where NK cell-mediated cytotoxicity was fully inhibited by the recognition of specific MHC class I molecules. NK cell binding to either class I-deficient or class I-transfected target cells initiated rapid protein tyrosine kinase activation. In contrast, whereas NK cell binding to class I-deficient targets led to inositol phosphate release and increased intracellular free calcium ([Ca2+]i), NK recognition of class I-bearing targets did not induce the activation of these phospholipase C-dependent signaling events. The recognition of class I by NK cells clearly had a negative regulatory effect since blocking this interaction using anti-class I F(ab')2 fragments increased inositol 1,4,5-trisphosphate release and [Ca2+]i and increased the lysis of the targets. These results suggest that one of the mechanisms by which NK cell recognition of specific MHC class I molecules can block the development of cell-mediated cytotoxicity is by inhibiting specific critical signaling events.

Pleasant sweeping grooming touch in rhesus monkey: effects on autonomic nervous system and its codification in posterior insular and secondary somatosensory cortex

Il tatto assume un'importanza fondamentale nella vita quotidiana, in quanto ci permette di discriminare le caratteristiche fisiche di un oggetto specifico, di identificarlo e di eventualmente integrare le suddette informazioni tattili con informazioni provenienti da altri canali sensoriali. Questa è la componente sensoriale-discriminativa del tatto. Tuttavia quotidianamente il tatto assume un ruolo fondamentale durante le diverse interazioni sociali, positive, come quando abbracciamo o accarezziamo una persona con cui abbiamo un rapporto affettivo e negative, per esempio quando allontaniamo una persona estranea dal nostro spazio peri-personale. Questa componente è la cosiddetta dimensione affettiva-motivazionale, la quale determina la codifica della valenza emotiva che l'interazione assume. Questa componente ci permette di creare, mantenere o distruggere i legami sociali in relazione al significato che il tocco assume durante l'interazione. Se per esempio riceviamo una carezza da un familiare, questa verrà percepita come piacevole e assumerà un significato affiliativo. Questo tipo di tocco è comunente definito come Tocco Sociale (Social Touch). Gli aspetti discriminativi del tatto sono stati ben caratterizzati, in quanto storicamente, il ruolo del tatto è stato considerato quello di discriminare le caratteristiche di ciò che viene toccato, mentre gli aspetti affettivi sono stati solo recentemente indagati considerando la loro importanza nelle interazioni sociali. Il tocco statico responsabile dell'aspetto discriminante attiva a livello della pelle le grandi fibre mieliniche (Aβ), modulando a livello del sistema nervoso centrale le cortecce sensoriali, sia primarie che secondarie. Questo permette la codifica a livello del sistema nervoso centrale delle caratteristiche fisiche oggettive degli oggetti toccati. Studi riguardanti le caratteristiche del tocco affiliativo sociale hanno messo in evidenza che suddetta stimolazione tattile 1) è un particolare tocco dinamico che avviene sul lato peloso delle pelle con una velocità di 1-10 cm/sec; 2) attiva le fibre amieliniche (fibre CT o C-LTMRs); 3) induce positivi effetti autonomici, ad esempio la diminuzione della frequenza cardiaca e l'aumento della variabilità della frequenza cardiaca; e 4) determina la modulazione di regioni cerebrali coinvolte nella codifica del significato affiliativo dello stimolo sensoriale periferico, in particolare la corteccia insulare. Il senso del tatto, con le sue due dimensioni discriminativa e affiliativa, è quotidianamente usato non solo negli esseri umani, ma anche tra i primati non umani. Infatti, tutti i primati non umani utilizzano la componente discriminativa del tatto per identificare gli oggetti e il cibo e l'aspetto emotivo durante le interazioni sociali, sia negative come durante un combattimento, che positive, come durante i comportamenti affiliativi tra cui il grooming. I meccanismi di codifica della componente discriminativa dei primati non umani sono simili a quelli umani. Tuttavia, si conosce ben poco dei meccanismi alla base della codifica del tocco piacevole affiliativo. Pur essendo ben noto che i meccanorecettori amilienici C-LTMRs sono presenti anche sul lato peloso della pelle dei primati non umani, attualmente non ci sono studi riguardanti la correlazione tra il tocco piacevole e la loro modulazione, come invece è stato ampiamente dimostrato nell'uomo. Recentemente è stato ipotizzato (Dunbar, 2010) il ruolo delle fibre C-LTMRs durante il grooming, in particolare durante il cosiddetto swepping. Il grooming è costituito da due azioni motorie, lo sweeping e il picking che vengono eseguite in modo ritmico. Durante lo sweeping la scimmia agente muove il pelo della scimmia ricevente con un movimento a mano aperta, per poter vedere il preciso punto della pelle dove eseguire il picking, ovvero dove prendere la pelle a livello della radice del pelo con le unghie dell'indice e del pollice e tirare per rimuovere parassiti o uova di parassiti e ciò che è rimasto incastrato nel pelo. Oltre il noto ruolo igenico, il grooming sembra avere anche una importante funzione sociale affiliativa. Come la carezza nella società umana, cosi il grooming tra i primati non umani è considerato un comportamento. Secondo l'ipotesi di Dunbar l'attivazione delle C-LTMRs avverrebbe durante lo sweeping e questo porta a supporre che lo sweeping, come la carezza umana, costituisca una componente affiliativa del grooming, determinando quindi a contribuire alla sua codifica come comportamento sociale. Fino ad ora non vi è però alcuna prova diretta a sostegno di questa ipotesi. In particolare, 1) la velocità cui viene eseguito lo sweeping è compatibile con la velocità di attivazione delle fibre CT nell'uomo e quindi con la velocità tipica della carezza piacevole di carattere sociale affiliativo (1-10 cm/sec)?; 2) lo sweeping induce la stessa modulazione del sistema nervoso autonomo in direzione della modulazione del sistema vagale, come il tocco piacevole nell'uomo, attraverso l'attivazione delle fibre CT?; 3) lo sweeping modula la corteccia insulare, cosi come il tocco piacevole viene codificato come affiliativo nell'uomo mediante le proiezioni delle fibre CT a livello dell'insula posteriore? Lo scopo del presente lavoro è quella di testare l'ipotesi di Dunbar sopra citata, cercando quindi di rispondere alle suddette domande. Le risposte potrebbero consentire di ipotizzare la somiglianza tra lo sweeping, caratteristico del comportamento affiliativo di grooming tra i primati non umani e la carezza. In particolare, abbiamo eseguito 4 studi pilota. Nello Studio 1 abbiamo valutato la velocità con cui viene eseguito lo sweeping tra scimmie Rhesus, mediante una analisi cinematica di video registrati tra un gruppo di scimmie Rhesus. Negli Studi 2 e 3 abbiamo valutato gli effetti sul sistema nervoso autonomo dello sweeping eseguito dallo sperimentatore su una scimmia Rhesus di sesso maschile in una tipica situazione sperimentale. La stimolazione tattile è stata eseguita a diverse velocità, in accordo con i risultati dello Studio 1 e degli studi umani che hanno dimostrato la velocità ottimale e non ottimale per l'attivazione delle C-LTMRs. In particolare, nello Studio 2 abbiamo misurato la frequenza cardiaca e la variabilità di questa, come indice della modulatione vagale, mentre nello Studio 3 abbiamo valutato gli effetti dello sweeping sul sistema nervoso autonomo in termini di variazioni di temperatura del corpo, nello specifico a livello del muso della scimmia. Infine, nello Studio 4 abbiamo studiato il ruolo della corteccia somatosensoriale secondaria e insulare nella codifica dello sweeping. A questo scopo abbiamo eseguito registrazioni di singoli neuroni mentre la medesima scimmia soggetto sperimentale dello Studio 2 e 3, riceveva lo sweeping a due velocità, una ottimale per l'attivazione delle C-LTMRs secondo gli studi umani e i risultati dei tre studi sopra citati, ed una non ottimale. I dati preliminari ottenuti, dimostrano che 1) (Studio 1) lo sweeping tra scimmie Rhesus viene eseguito con una velocità media di 9.31 cm/sec, all'interno dell'intervallo di attivazione delle fibre CT nell'uomo; 2) (Studio 2) lo sweeping eseguito dallo sperimentatore sulla schiena di una scimmia Rhesus di sesso maschile in una situazione sperimentale determina una diminuzione della frequenza cardiaca e l'aumento della variabilità della frequenza cardiaca se eseguito alla velocità di 5 e 10 cm/sec. Al contrario, lo sweeping eseguito ad una velocità minore di 1 cm/sec o maggiore di 10 cm/sec, determina l'aumento della frequenza cardiaca e la diminuzione della variabilità di questa, quindi il decremento dell'attivazione del sistema nervoso parasimpatico; 3) (Studio 3) lo sweeping eseguito dallo sperimentatore sulla schiena di una scimmia Rhesus di sesso maschile in una situazione sperimentale determina l'aumento della temperatura corporea a livello del muso della scimmia se eseguito alla velocità di 5-10 cm/sec. Al contrario, lo sweeping eseguito ad una velocità minore di 5 cm/sec o maggiore di 10 cm/sec, determina la diminuzione della temperatura del muso; 4) (Studio 4) la corteccia somatosensoriale secondaria e la corteccia insulare posteriore presentano neuroni selettivamente modulati durante lo sweeping eseguito ad una velocità di 5-13 cm/sec ma non neuroni selettivi per la codifica della velocità dello sweeping minore di 5 cm/sec. Questi risultati supportano l'ipotesi di Dunbar relativa al coinvolgimento delle fibre CT durante lo sweeping. Infatti i dati mettono in luce che lo sweeping viene eseguito con una velocità (9.31 cm/sec), simile a quella di attivazione delle fibre CT nell'uomo (1-10 cm/sec), determina gli stessi effetti fisiologici positivi in termini di frequenza cardiaca (diminuzione) e variabilità della frequenza cardiaca (incremento) e la modulazione delle medesime aree a livello del sistema nervoso centrale (in particolare la corteccia insulare). Inoltre, abbiamo dimostrato per la prima volta che suddetta stimolazione tattile determina l'aumento della temperatura del muso della scimmia. Il presente studio rappresenta la prima prova indiretta dell'ipotesi relativa alla modulazione del sistema delle fibre C-LTMRs durante lo sweeping e quindi della codifica della stimolazione tattile piacevole affiliativa a livello del sistema nervoso centrale ed autonomo, nei primati non umani. I dati preliminari qui presentati evidenziano la somiglianza tra il sistema delle fibre CT dell'uomo e del sistema C-LTMRs nei primati non umano, riguardanti il Social Touch. Nonostante ciò abbiamo riscontrato alcune discrepanze tra i risultati da noi ottenuti e quelli invece ottenuti dagli studi umani. La velocità media dello sweeping è di 9.31 cm / sec, rasente il limite superiore dell’intervallo di velocità che attiva le fibre CT nell'uomo. Inoltre, gli effetti autonomici positivi, in termini di battito cardiaco, variabilità della frequenza cardiaca e temperatura a livello del muso, sono stati evidenziati durante lo sweeping eseguito con una velocità di 5 e 10 cm/sec, quindi al limite superiore dell’intervallo ottimale che attiva le fibre CT nell’uomo. Al contrario, lo sweeping eseguito con una velocità inferiore a 5 cm/sec e superiore a 10 cm/sec determina effetti fisiologici negativo. Infine, la corteccia insula sembra essere selettivamente modulata dallo stimolazione eseguita alla velocità di 5-13 cm/sec, ma non 1-5 cm/sec. Quindi, gli studi sul sistema delle fibre CT nell’uomo hanno dimostrato che la velocità ottimale è 1-10 cm/sec, mentre dai nostri risultati la velocità ottimale sembra essere 5-13 cm / sec. Quindi, nonostante l'omologia tra il sistema delle fibre CT nell'umano deputato alla codifica del tocco piacevole affiliativo ed il sistema delle fibre C-LTMRs nei primati non umani, ulteriori studi saranno necessari per definire con maggiore precisione la velocità ottimale di attivazione delle fibre C-LTMR e per dimostrare direttamente la loro attivazione durante lo sweeping, mediante la misurazione diretta della loro modulazione. Studi in questa direzione potranno confermare l'omologia tra lo sweeping in qualità di tocco affiliativo piacevole tra i primati non umani e la carezza tra gli uomini. Infine, il presente studio potrebbe essere un importante punto di partenza per esplorare il meccanismo evolutivo dietro la trasformazione dello sweeping tra primati non umani, azione utilitaria eseguita durante il grooming, a carezza, gesto puramente affiliativo tra gli uomini.