Variables description.
\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control.
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Many questions have plagued the study of the etiology and subsequent treatment of mental illness. In part, it is simply because, as far as we know, some mental illnesses are somewhat unique to the human condition. Moreover, clinical studies have produced many different results concerning potential biomarkers for conditions such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). In this chapter, we review how we approached modeling a specific behavioral condition, suppression of the startle reflex, by examining whether one of two commonly associated peripheral biomarkers of anxiety and depression could potentially cause this rather specific symptom. The two peripheral systems under investigation were the hypothalamic-pituitary-adrenal (HPA) axis and the peripheral pro-inflammatory immune response, both of which have been implicated as a vulnerability factor, causal factor, or resultant (perpetuating) effect of PTSD and MDD.
Our general theory is that peripheral endocrine and immune signals, measured to be abnormal in patients with either PTSD or MDD (as well as other mental disorders), are actually perpetuating the behavioral features of these disorders. At the same time, if an individual has an immunosensitivity or has an overactive adrenal gland, s/he would be more likely to experience some of the symptoms associated with one of the particular mental illnesses. This may then lead the brain to compensate for those peripheral abnormalities, but, at the same time, cause other imbalances, which lead to the experience of a decline into mental illness. Thus, treating these peripheral markers as part of the “mental” disorder may be quite beneficial in normalizing certain aspects of the diagnosed abnormal behavior.
One of the major impediments to the mechanistic study of mental illness is establishing analogs of the abnormal behaviors expressed in humans in animal models, especially in sub-primate species. This has led some to adopt reflex-based measures such that the face and construct validity of the behavior change can be readily translated between the model and patient populations. Consequently, a popular measures for the study of anxiety disorders has been the potentiation of the startle reflex; however, there is growing evidence that a dampening of the startle response may be indicative of changes in physiology that underlie different mental disorders.
The startle reflex comprises a 3-synaptic sensory-motor neuronal pathway that serves as a defensive behavioral response to abrupt, usually intense, stimuli. The acoustic startle response (ASR) is the most commonly used form for studying this reflex. As shown in Figure 1, the primary ASR circuit begins with neurons in the cochlear nerve, transmitting the representation of the acoustic stimulus from the cochlea of the inner ear to the cochlear nucleus (in the brainstem). Efferent pathways from the cochlear nucleus project to the nucleus reticularis pontis caudalis (PnC), in the pons, forming the second synapse in this reflex arc. The third synapse forms from the efferent projections from the PnC to various motor nuclei, through the recticulospinal spinal tracts to the muscles of the torso [1] and the muscles enervated by the facial nerve. These muscle enervations create a rapid cascade of near-immediate behavioral responses to abrupt acoustic stimuli, ranging from less than 10 ms to approximately 50 ms.
The ASR is modulated by several afferent connections originating from higher brain areas (midbrain, limbic, and cortical nuclei). At the level of the PnC, there are several inputs that can either enhance or inhibit the magnitude of an elicited ASR. In the area of fear and anxiety, the central amygdala and bed nucleus of the stria terminalis (BNST) are considered the 2 major excitatory modulation structures on this reflex [2]. Some have proposed that the BNST is the origin of anxiety-like behaviors whereas the nuclei of the amygdala are the origin of acute fear responses and explicit fear-learning [3, 4]. The amygdala is predominately associated with causing classically conditioned fear-potentiated ASRs [5], and, in fact, has been specifically shown not to have a role in startle inhibition, at least via a learned conditioned inhibitor [6]. On the other hand, the process known as pre-pulse inhibition of the startle reflex (PPI) has elucidated neural pathways that can inhibit the expression of the ASR. For instance, the substantial nigra pars retriculata (SNR), pedunculopontine tegmentum (PPT) and laterodorsal tegmental nuclei (LDT) have inhibitory influence upon the PnC, thus reducing the measured ASR [7-10]. These three mid-brain nuclei (inhibitory) receive projections from various forebrain areas, including the amygdala, BNST, and medial prefrontal cortex (mPFC). Thus, limbic system modulation of the ASR can occur through direct enervation of the PnC (excitatory) or indirect enervation through mid-brain nuclei.
There are several nuclei within the midbrain/brainstem area that can directly modulate the intrinsic ASR circuit at the level of the nucleus reticularis pontis caudalis (PnC). Dashed red lines represent cholinergic inhibitory influences from the laterodorsal tegmental nuclei (LDT) and pedunculopontine tegmentum (PPT). Dashed black lines represent inhibitory GABAergic projections from the substantial nigra pars reticulata (SNR). A solid line from the parabrachial nucleus (PBN) is an example of a direct excitatory input to the PnC.
Over all other mental disorders, PTSD is associated with changes in the startle reflex. Commonly associated with exaggerated startle responses [11-14], higher or exaggerated startle reflex responses are a criteria symptom for the diagnosis of PTSD [15]. However, recent evidence suggests that this may not always be the case. In fact, others have reviewed the literature and found there are a significant number of reports where the startle responses in PTSD patients are not exaggerated [16]. More extreme, there are reports, albeit limited, where patients diagnosed with PTSD appeared to have blunted motor reflex responses to an acoustic stimulus [17, 18]. These populations had distinctive qualities that were different than those studies that had found enhanced startle reactivity in their PTSD patients. First, the one study was exclusively female [18] and the other had a majority of female subjects [17], suggesting there may be a sex difference in the presentation of ASR in females as a result of experiencing trauma. However, others have reported enhanced startle responses in a different population of women diagnosed with PTSD following automobile accidents [19]. Thus, a second distinction between the two studies that observed suppressed startle reactions, which should be considered, is that the trauma was specifically associated with being the target of violence [17, 18]. Although women with a PTSD diagnosis stemming from a prior rape have not always exhibited blunted startle responses [20], this discrepancy may be due to individual differences and/or methodological differences in being sensitive to such changes, as some have reported laterality effects in PTSD patients, notably of those having been raped in the past [21]. A third quality of at least one of these two reports is that the subjects also exhibited symptoms associated with major depressive disorder [18]. This suggests stressful experiences may not cause a uniform change in sensory reactivity, and the expression of the coping response to the trauma may have psychophysiological ramifications that are quite different, both in terms of effects upon sensory-motor responding to acoustic stimuli as well as the full expression of symptoms.
There is evidence that symptoms associated with depression may also include a blunted reaction to acoustic stimuli. Patients designated as “depressed”, having either a diagnosis of MDD or a significantly higher score on the Beck Depression Inventory (with or without additional neurological conditions), have been reported to exhibit blunted reactivity to acoustic stimuli, either with or without manipulations of affect [22-26]. Similarly, there is also evidence that bipolar disorder (BPD), the occurrence of at least one manic or mixed manic episode over the course of a patient’s lifetime, is characterized by blunted startle reactions as well, even during periods of remission [27]. A study by Carroll and colleagues found patients suffering from BPD exhibit attenuated baseline startle, most notably in those having experienced mixed episodes, not pure mania [28]. These data suggest there is a neurobiology of startle suppression that may provide critical insight to the underlying biological conditions that cause areas of the brain to improperly process information, in this case sensory-motor responses.
Across the studies that have documented reductions in the expression of the startle reflex in rodents, the common-most feature is that the magnitude of the response is dampened following exposure to a stressor manipulation. Reduced startle amplitudes have been documented in rats following: repeated 20 min restraint [29]; inescapable tailshock [30-32]; predator exposure coupled with an intraperitoneal injection [33]; immune-challenge [34, 35], and a single session of footshocks [36]. Interestingly, despite some differences in methodology, inescapable tailshock [30], inescapable footshock [36], and predator exposure with injection [33], all showed reduction in ASR measurements that could
There are significant differences in the temporal characteristics of these different startle-suppression models in rodents. Inescapable tailshock causes a reduction in startle magnitude in female rats that is evident hours within exposure [31, 32], possibly lasting up to a day later, when the bouts of shock are expanded to a few consecutive days [30]. The footshock-induced suppression of startle reactivity is evident 4 h following stressor exposure [36]. The immune-challenge models parallel these stressor manipulations by causing reductions in startle reactivity within a couple hours of administration of the challenge [34, 35]. Thus, one interpretation of these data is that painful stressors are causing changes in the peripheral immune system, which, in turn, dampen startle reactivity during the time of their activity [34], on the range of hours. Following this logic, when females were tracked 4 and 8 days following tailshock, reductions in startle reactivity in the stressor-exposed rats did not reach statistical significance [30]. In contrast, the predator-exposure + injection model shows immediate suppression following the stressor exposure, which continues to be present 1 week later [33]. In addition, it is evident both under dark and light conditions [33], suggesting the change in the startle response is not occurring due to a change in reactivity to other stimuli that are known to modulate startle reactivity, such as light-enhanced startle [37]. Thus, this observance suggests that changes in ASR magnitude may be extended beyond the acute effects of stressor exposure that could be attributed to the short-term effects of immune signaling that would be in response to the injection (or possibly even shock).
Two interrelated mechanisms have been proposed as potential causes of startle suppression, the first being glucocorticoid hormone reception. Adamec and colleagues showed the reduction of startle magnitudes following combined cat exposure and saline injection could be blocked by substituting the saline injection with the glucocorticoid receptor antagonists RU-486 [33]. We subsequently tried to induce the effect in our female rats by administering the synthetic glucocorticoid agonist, dexamethasone. Startle responses were assessed 2 and 4 h following dexamethasone administration. As shown in Figure 2, the dexamethasone did not appreciably change the magnitude of the elicited ASRs, nor did it affect the number of ASRs elicited (data not shown). These findings suggest that the reception of corticosterone at the glucorticoid receptor is not sufficient to reduce ASR magnitudes. One possibility is that RU-486 blocked the suppressed startle, in that model system, via a non-glucocorticoid mechanism, for example via progesterone receptor antagonism. A connection to progesterone will be discussed further below as it pertains to a pro-inflammatory response mechanism, in contrast to an anti-inflammatory glucocorticoid response, but this finding is supported by previous work that shows elevations in circulating corticosterone are not necessary for corticotrophin releasing hormone to increase ASR magnitudes, despite stimulating increased activity in the HPA-axis [38]. Likewise, the suppression of ASR magnitudes in Occidental low saccharine consuming rats is not recapitulated by substituting corticosterone administration for the shock exposure [36]. Therefore, a role of glucocorticoids in the suppression of ASR magnitudes may be limited.
In order to increase binding at the glucocorticoid receptors, the synthetic glucocorticoid analog, dexamethasone, was administered s.c. (0.1 mg/kg) to female Sprague Dawley rats (n= 8-9). The magnitudes of the elicited ASRs only differed across the Stimulus Intensity, F (1, 15) = 135.3, p <.001, not drug administration. Data are collapsed over the 2 startle test sessions. A cross (†) represents within-group difference from the highest stimulus intensity (p <.05, Fishers LSD).
The second mechanism, which is intertwined with the HPA-axis, is the peripheral pro-inflammatory immune response. We first showed that a ovarian hormone-dependent suppression of startle magnitudes could be induced by a single injection of the pro-inflammatory cytokine interleukin (IL)-1β [34], an effect that appears to parallel that observed following tailshock [31]. This effect was later replicated in male rats using lipopolysaccharide (LPS) [35]. Still, peripherally released IL-1β elicits the release of glucocorticoids from the adrenal through stimulation of the vagus nerve, paraventricular nucleus of the hypothalamus, and pituitary gland, which provides an anti-inflammatory response to the pro-inflammatory signal [39-44]. In order to further delineate that pro-inflammatory cytokines, and not anti-inflammatory glucocorticoids, are necessary for stress-induced startle suppression, we compared the effect of inescapable tailshock upon the induction of ASRs in two strains of rats, specifically chosen because of their pro-inflammatory and glucocorticoid responsiveness to stressors. Low-glucocorticoid/high-pro-inflammatory releasing Lewis (LEW) rats [45-49] and high-glucocorticoid releasing Wistar-Kyoto (WKY) rats [50-52] were compared. Females of each of these strains were exposed to inescapable tailshock and subsequently tested for startle reactivity 1 and 3 h later. If pro-inflammatory signaling, not anti-inflammatory glucocorticoid release is critical for eliciting startle suppression, then LEW rats would exhibit suppression of the ASR, and the WKY rats would not. As shown in Figure 3, this is the case. This suggest the suppression of startle responsivity in female rats is more likely due to an overactive pro-inflammatory cytokine signaling response, instead of an overactive anti-inflammatory glucocorticoid response via the HPA-axis.
LEW rats exposed to the stressor differed from both their same-strain controls and the WKY groups on the measure of startle magnitude (responsivity). These impressions were confirmed by both main effects of Stimulus Intensity, F (1, 36) = 285.0, p <.0001, Strain, F (1, 36) = 6.4, p <.02, and Stressor exposure, F (1, 36) = 5.3, p <.03, as well as a marginal Strain x Stressor interaction, F (1, 36) = 3.3, p <.07. In addition to the expected differences in ASR magnitude due to Stimulus Intensity, F (2, 72) = 186.5, p <.0001, there were differences in the number of elicited startles across the two strains at the lowest stimulus intensity, with WKY rats having responded with more startles (4.5) than did the LEW rats (3.8) to 92 dBA stimulus. This impression was confirmed by a significant Strain x Stimulus Intensity interaction, F (2, 72) = 3.0, p <.05 (data not shown).
The hypothesis that pro-inflammatory cytokines are a necessary component in the suppression of startle responses following stress was further evaluated in the immune-sensitive Lewis rat strain by determining if elevations of peripheral IL-1β is sufficient to suppress startle reactivity in female rats. Startle responsivity has been found to be suppressed in female SD rats [34], but, we questioned whether immune-sensitive Lewis rats would show either greater effect sizes in the suppression of the startle magnitudes and/or reduced startle sensitivity as well. As shown in Figure 4, both startle responsivity and sensitivity were reduced in female Lewis rats administered IL-1β. This confirms that pro-inflammatory signaling can influence both aspects of startle behavior, with sensitivity effects requiring a greater sensitivity to the pro-inflammatory signals or, possibly, greater elevations of the signal.
One consequence of the peripheral immune system having an effect on behavior, in this case sensory reactivity to acoustic stimuli, is that prior immune challenges may influence how future pro-inflammatory signaling or anti-inflammatory glucocorticoid responses influences behavior following stressor exposure. LPS is a commonly used endotoxin that elicits sickness behaviors due to a release of peripheral and central pro-inflammatory cytokines, followed by an increase in circulating glucocorticoids [53, 54]. Others have shown that immune challenges days prior to shock exposure causes a greater increase in glucocorticoid release in response to shocks [55, 56]; therefore, we used this known method of causing a sensitized glucocorticoid response to determine if a greater glucocorticoid release enhances or reduces the degree by which tailshock suppresses startle responsivity.
Female LEW rats (n = 16) exhibited significant differences in both startle sensitivity and startle responsivity measures following a single systemic injection of IL-1β (3 μg/kg, i.p.). Startle sensitivity was equally effected 1 and 3 h following administration and is shown collapsed over Session Time. Startle responsivity was only effected 1 h following administration; therefore, the 3 h time-point is not shown. An asterisk (*) represents a significant difference from saline-treated controls at the same stimulus intensity. A cross (†) represents a significant difference from saline-treated controls during the same test session (all p <.05, Fishers LSD).
We hypothesized that pro-inflammatory signaling causes stress-induced startle suppression; therefore, experiencing an immune challenge 3 days prior to shock would cause a sensitized anti-inflammatory release of glucocorticoids in response to inescapable shock, blocking the reduction of startle responsivity caused by the acute release of pro-inflammatory cytokines. As expected, the number of startle responses elicited did not differ based on prior treatment but did differ across stimulus intensity (data not shown); however, prior exposure to LPS reduced the effectiveness of inescapable shock to attenuate startle magnitudes (see Figure 5). Although LPS has a short-term suppressing effect upon the startle response [35], it both causes an acute increase in pro-inflammatory cytokines (and sickness behaviors) followed by an increase in anti-inflammatory glucocorticoid signaling. This “priming” effect upon the anti-inflammatory glucocorticoid response to shock is a likely mechanism for “buffering” the behavior from being affected. Again, this suggests the glucocorticoid response may actually counteract the suppressive effects originating from peripheral pro-inflammatory cytokine signaling.
As mentioned above, studies of pre-pulse inhibition of the ASR have elucidated neural circuitry that underlie the suppression of ASRs when they are immediately preceded by a salient auditory stimulus, for a review see [57]. Both the BNST and AMG have indirect projections to the PnC through the PPT [58]. Inputs from the PPT, LDT, and SNR to the PnC cause inhibition of the startle response [7, 9, 59, 60]. More specifically, it appears the magnocellular portion of the PnC has muscarinic receptors to receive the inhibitory cholinergic signal from PPT and LDT [61] and GABAB receptors receive the inhibitory signal from the SNR [62]. The question is whether these areas could provide more tonic inhibition of the ASR, outside of the attentional processes associated with PPI. For instance, it is known that lesions to the medial septum and the fimbra-fornix increase startle reactivity because these areas provide tonic inhibition upon the amygdala [63]; thus, removal of inhibition upon the amygdala increases tonic excitatory activity to the PnC (from the amygdala). In contrast, lesions to the noradrenergic cell bodies of the LC reduce startle response magnitudes, as these neurons probably serve a tonic excitation function upon the PnC [64]. Thus, there are circuits within the brain that are situated such that they could provide more tonic changes in the ASR.
The expression of stress-induced startle suppression became evident 3 h following stressor exposure; however, this effect was blocked in those rats previously exposed to 30 µg/kg LPS (i.p.) 3 days earlier. These impressions were confirmed by a significant LPS x Stress x Session interaction, F (1, 28) = 10.2, p <.005. Hence, the pretreatment with LPS, which should have increased the glucocorticoid response to the inescapable tailshocks, blocked the suppression of startle responsivity following shock exposure. This suggests that prior experiences likely cause a more robust anti-inflammatory glucocorticoid response that actually
Specific to the female startle-suppression model, a central mechanism that caused this change in reactivity should be influenced by the presence/absence of ovarian hormones [31, 32]. Ovarian hormones can have a significant impact on many of the neural structures associated with startle regulation. The cochlear nuclei [65], the nucleus accumbens [66], the hippocampus, [67] and the SNR [57] all exhibit changes in morphology, neurotransmission, and/or receptor expression with the presence of ovarian hormones. Yet, despite all these areas of influence, rodent studies usually do not find any differences in baseline startle reactivity across the estrus cycle or with hormone replacement [68, 69]; however, see [70] for an example of oral-contraceptive usage effecting baseline startle in women. When significant arousal or stress occurs in the rodents, however, the modulatory actions of ovarian hormones on startle become evident. For example, Toufexis and colleagues have shown the magnitude of CRH-enhanced startle is attenuated when progesterone levels are increased [71]. CRH is thought to enhance startle reactivity in the BNST via CRF1-type receptors [72-75]. The result is an increase in excitatory afferents signaling to the PnC [76]. One possibility is that progesterone, or its metabolite allopregnanolone, may decrease the excitatory signaling from the BNST to the PnC by increasing GABA inhibition in this structure [77]. However, in vitro, BNST CRF-1 receptors increase local GABA activity [78]. Thus, it appears that progesterone or allopregnanolone should facilitate the actions of CRH on startle, unless they act through different mechanisms within the BNST or outside of the BNST. On the other hand, progesterone also affects how IL-1β influences sexual receptivity [79], and both glucocorticoid receptor activation [77] and progesterone-induced changes in central neuroadrenergic activity [80] have been suggested to attenuate startle reactivity selectively in female rats. As shown in Figure 6, the administration of progesterone to ovariectomized rats appears to be necessary for IL-1β to suppress startle magnitudes. Thus, ovarian hormones are not sufficient to cause changes in startle reactivity in female rats. In fact, IL-1β appears to increase startle responsivity following estradiol pretreatment (17β-estradiol), whereas progesterone pretreatment sets the stage for IL-1β to suppress startle responsivity. Therefore, stress-induced startle suppression in female rats appears to necessitate a combination of the two factors, a peripheral pro-inflammatory immune response and the presence of progesterone.
Startle sensitivity and responsiveness were assessed 2 h following IL-1β administration. Hormone treatment occurred 2 h prior to IL-1β injection. Differences in startles elicited (sensitivity) and the magnitudes of those elicited startle responses (responsivity) each were assessed via a 5 (Condition) x 3 (Stimulus Intensity) repeated measures ANOVA. No significant differences in startle sensitivity were detected (data not shown). However, a significant main effect of Stimulus Intensity, F (2, 70) = 392.2, p <.001 and a significant Condition x Stimulus Intensity interaction, F [
Peripheral IL-1β is known to have a significant impact on brain activity. Systemic IL-1 administration activates key afferent pathways in brainstem (lateral parabrachial nucleus and dorsomedial and ventrolateral medulla) and limbic system nuclei (BNST and central nucleus of the amygdala) [81]. In fact, peripheral IL-1β activates the amygdala and BNST more than i.c.v. administered IL-1β [82], probably because the vagal-mediated signals to these nuclei are more direct, to those nuclei via the NTS, than the diffusion of the IL-1β from the ventricles. Still, increasing peripheral IL-1β signaling increases NE and serotonin levels in these brain areas [83] and noradrenergic metabolism in the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus (LC), and amygdala [83]. In fact, as the IL-1β dose is increased, the amount of NE metabolism increases linearly in the amygdala, lasting as much as an hour [83]. It should be noted, this was not tested in the BNST. Yet, stimulation of α-adrenergic receptors also attenuate startle responses and facilitate non-associative habituation of the startle response [84-88]. IL-1β affects activity in the LC in a dose dependent manner as well, with low doses inhibiting activity and higher doses causing excitation; a process mediated by CRH at the time of IL-1β release [89]. Further, when the exposure to painful stimuli is prolonged or LPS is used to cause a significant pro-inflammatory response, additional release of central IL-1β occurs, especially in the hypothalamus [90, 91]. These data suggest that activity in the limbic system, monoamine activity in particular, is significantly affected by peripheral immune signaling.
Based on the above logic, we hypothesized that the reduction in ASR magnitude occurring as a result of IL-1β administration to progesterone-pretreated female rats could be associated with changes in the central noradrenergic activity in one of the known modulatory nuclei of the acoustic startle response. Therefore, we measured norepinephrine levels in brain tissue-punches from 4 brain areas: BNST, amygdala, medial prefrontal cortex (mPFC), and dorsal hippocampus. As stated above, both the BNST and cAMG have direct excitatory projections to the PnC and indirect inhibitory connections via the PPT. The medial prefrontal cortex projects to the primary startle circuit via the LDT, whereas the dorsal hippocampus was included as an area that is both reactive to stress and ovarian hormone manipulation, but it is actually several synapses removed from the PPT. As shown in Figure 7, differences due to hormone pretreatment and subsequent IL-1β administration were found in the BNST, not in any of the other 3 areas.
Significant effects of IL-1 treatment on NE levels in the BNST were observed in rats pretreated with progesterone (100 μg/kg, s.c.). This was confirmed by a significant Hormone x IL-1 interaction F (2, 42) = 4.5, p <.02. IL-1β treatment to oil-treated controls was associated with significantly lower NE levels than oil-treated saline-controls (*). IL-1β-administered rats, which were pretreated with either estradiol [20 μg/kg, s.c.) or progesterone, exhibited higher levels of NE compared to oil-pretreated rats that subsequently received IL-1β (†). In addition, the 2 hormone treated saline control conditions also differed from each other, with the estradiol-treated saline-controls exhibiting higher levels of NE than those pretreated with progesterone prior to saline administration (‡). All post-hoc tests utilized Fisher’s LSD (p <.05).
The role of the BNST in this cytokine-induced change in behavior is logical given recent work associating activity in this structure with changes in behavior associated with behavioral depression or sickness behavior. For example, an endotoxin-induced suppression of social interactions is both associated with increased activity in the BNST as well as reduced activity in the BNST when the suppressed behavior is blocked by IL-1ra [92]. Similarly, the behavioral depression exhibited in the forced-swim test can be reduced by stimulating the vagus nerve, leading to changes in brainstem nuclei activation (including the NTS) and also activation of the BNST [93]. Others have shown NE release is elevated with stressor exposure in the BNST, which is necessary for some stress-induced behaviors [94, 95]. With particular attention to the startle reflex, the BNST is commonly associated with enhancing startle reactivity [2, 96]. However, as shown in Figure 8), there is an inhibitory pathway from the BNST to the PnC via the PPT that has been examined as a cholinergic mechanism for eliciting PPI [97, 98]. Further, PPI has been shown to fluctuate over the estrus cycle, while not being sensitive to apomorphine disruption, implicating a non-dopaminergic mechanism for these hormone-induced changes in female pre-pulse inhibition, which could rule-out a role of the substantia nigra in this process [68]. In addition, the changes in measured NE levels in the BNST are consistent with previous studies citing peripheral IL-1β administration as a trigger for central noradrenergic activity [82, 99].
Beyond the direct connections of the brainstem/midbrain nuclei, there are many other nuclei that indirectly influence the modulation of the ASR. Graphically represented here are the noradrenergic projections (in blue) from the nucleus of the solitary tract (NTS) and locus coeruleus (LC) to the various nuclei of the limbic system that then modulate the ASR via the inhibitory brainstem/midbrain nuclei. Input to the NTS via either the from the vagus nerve (X n.) or diffusion of IL-1β across the blood-brain barrier in the nearby area postrema is necessary for the noradrenergic changes in the brain in response to peripheral pro-inflammatory cytokine signaling. As above, red lines denote cholinergic pathways, and dashed lines represent inhibitory circuits. The orange represents CRH-mediated neural circuits. See text for further details.
There is evidence that could suggest a connection between the known effects of peripheral cytokine activity upon brain noradrenergic activity (most reported males) and an ovarian hormone influence upon these processes. For one, there is growing information pertaining to ovarian hormone influences on noradrenergic activity initiated from the NTS. Many of the brainstem noradrenergic nuclei, including the NTS, exhibit cyclic changes in estrogen and progesterone receptors [100]. Removal of ovarian hormones with or without hormone replacement particularly has a significant impact on NTS physiology. Specifically, the mRNA for prolactin-releasing peptide (PrRP) in noradrenergic neurons is decreased by ovariectomy and increased with subsequent replacement of either estradiol or progesterone [101]. Although the PrRP mRNA levels are reported to not change significantly across the estrus cycle in the NTS, an inspection of the data suggests the levels are a bit higher during proestrus [102]. PrRP labeling in the NTS is also preferentially sensitive to painful stressors, such as tailshock [103]. Estradiol has also been reported to increase neural inhibition in the NTS [104]. These data suggest ovarian hormone influences on NE NTS physiology could occur through changes in the regulation of a co-expressing neuropeptide. This could serve a filtering function for the vagal activity representing immune activity changes in the periphery, as the NTS projects its NE efferent connections to key areas involved in arousal and sensory reactivity, such as the BNST, AMG, hypothalamus, and parabrachial nucleus [105]. For example, core body temperature increases from peripheral IL-1β occur for a longer period of time during proestrus (compared to diestrus) apparently do to the actions of progesterone [106]. Although it is clear hypothalamic cyclooxygenase is the necessary mechanism for this effect [107] the noradrenergic input to the hypothalamus is required and may be changed as well [108]. Therefore, there are anatomical and pharmacological reasons to link NTS noradrenergic projections to the BNST as the primary pathway by which changes in vagal activity could influence startle responsivity through known inhibitory circuitry.
Other possible mechanism for startle suppression could occur as a cascade of effects that begin with the hormone-specific effects upon NE in the brain, but end with non-specific hormonal influences upon 5-HT. NE was shown above to be changed in the BNST following systemic increases in IL-1β, confirming the results of others showing noradrenergic activity increases within 30 minutes of a peripheral injection of IL-1β and may last 2 hours [109, 110]. Importantly, as proposed above, the effect of systemic IL-1β injections on brain NE in rodents is dependent upon transmission in the vagus nerve [111]. The effects of peripheral IL-1β on 5-HT are quite different in terms of timing, route, and influence of ovarian hormones. First the increases observed in brain serotonin metabolism are evident 2-4 h following IL-1β administration and, at least in male rats, are reported to be less region specific (compared to NE activity changes) [110]. In addition, the effects of peripheral IL-1β on brain 5-HT are not dependent upon the vagus nerve in male mice but neither are the effects upon brain NE activity [112]. Thus, it is not known if 5-HT requires the same pathway as IL-1β to effect central 5-HT activity, but the difference in the temporal cascade would suggest such a difference is logical. Further, as shown in Figure 9, the same peripheral IL-1β injections that elicited a hormone-dependent change in BNST NE levels caused an increase in 5-HT activity in both estradiol and progesterone-treated female rats. This somewhat conforms to the data previously describing less specificity in the upregulation of 5-HT activity, although we did not observe this pattern beyond the BNST.
Serotonin activity (5HIAA/5HT ratio) appears to be increased in the BNST of hormone-pretreated OVX female rats 2 h after a systemic injection of IL-1β, as suggested by a marginal effect of IL-1β, F (1, 42) = 3.6, p <.06.
The peripheral immune system also has counter-inflammation mechanisms that could also be potential mechanisms for what appears to be a pro-inflammatory cytokine-mediated effect. Thus, another response to pro-inflammatory cytokine release, is the increase in the endogenous IL-1 receptor antagonist (IL-1ra), which has been shown to attenuate the reductions in food-intake elicited by systemic administration of LPS or IL-1β [113]. Our hypothesis was that elevations in IL-1ra, from systemic administration, would counteract the effects of IL-1β. Thus, IL-1ra was administered systemically, followed by an assessment of startle reactivity 1 and 3 h later. As shown in Figure 10, the peripheral immune mechanism for stifling the pro-inflammatory response of IL-1β is sufficient to increase startle sensitivity. This suggests the nervous system is responsive to elevated acute pro-inflammatory signaling, suppressing startle, and elevations in the counter-active IL-1ra, increasing sensitivity to acoustic stimuli. These interactions illustrate the constant inter-relationship between the peripheral immune system and the nervous system regulation of sensory-motor activity.
Startle magnitudes in female SD rats (n = 7) were not affected by the administration of IL-1ra (10μg/kg); however, ASRs were elicited more often following the administration of IL-1ra. These impressions were confirmed by a significant main effect of Drug F (1, 12) = 9.7, p <.01. The higher sensitivity to the stimuli was superimposed upon the general difference in elicited startles across the three intensities, as reflected by a main effect of Stimulus Intensity, F (2, 24) = 67.4, p <.0001. An asterisk (*) represents a significant between-group difference from the vehicle-treated controls at the same intensity. A cross (†) represents a significant within-subject difference from the lowest intensity, and a double cross (‡) represents a significant within-subject difference from the highest intensity (all p <.05, Fishers LSD).
Serotonin (5-HT) is an essential modulator of the startle reflex and disruption of serotonin synthesis and metabolism has been shown to result in startle suppression. As shown in Figure 11, during the synthesis of serotonin, L-tryptophan is converted to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase. In a subsequent reaction, 5-HTP is converted to 5-HT by the enzyme L-aromatic amino acid decarboxylase. Disruption to any part of the 5-HT synthesis pathway is capable of reducing whole brain levels of serotonin resulting in unique abnormalities to the startle reflex. For example, when normal fasted women were tested after having ingested a tryptophan-free amino-acid mixture, the result was lower ASR magnitudes compared to those that received a mixture with L-tryptophan in its contents [114]. When a similar study was conducted in men, a non-significant trend for the same effect appears evident, although it was represented in the analysis as a failure to obtain significant PPI [115]. Alternatively, increasing tryptophan catabolism has also shown to affect PPI. Increasing levels of kynurenine, the first product of tryptophan degradation via indoleamine2, 3-dioxygenase, disrupts PPI in male Sprague-Dawley Rats [116]. Thus, the balance of serotonin and kynurenine is a likely secondary mechanism the body uses to modulate startle sensitivity and responsivity to stimuli.
The normal synthesis of serotonin (5-HT) involves the metabolism of tryptophan to 5-hydroxytryophan by tryptophan hydroxylase; however, in the presence of interferon-γ, another, competing enzyme, indolamine1,3-dioxygenase is upregulated. The result of this shift in the metabolism of tryptophan towards the formation of kynurenine is a reduction in the amount available for metabolism towards the formation of serotonin (i.e. serotonin depletion).
In addition to exhibiting reduced startle responses [18] women exhibiting PTSD, linked to previous intimate partner violence, also exhibit greater circulating levels of interferon (INF)-γ [117]. INF-γ is a downstream Th-1 mediated signal from the pro-inflammatory IL-1β signal and is a potent inhibitor of 5-HT synthesis, decreasing the amount of tryptophan available for 5-HT production. In the presence of IFN-γ, tryptophan is shunted to kynurenic acid synthesis by increasing activity of indoleamine2, 3-dioxygenase [118]. An intermediary signal between IL-1β and INF-γ is IL-2. Female rats treated with IL-1ra (to combat the induction of EAE) exhibit an attenuated IL-2 response [119], which would, presumably, decrease INF-γ signaling (see Figure 12). There is limited experimental evidence that has focused upon delineating INF-γ or IL-2 effects on startle reactivity in rats, and those that have been conducted use an early development administration paradigm to assess later changes on behavior (e.g. [120]). However, one study conducted in mice did access acute IL-2 effects upon startle reactivity and reported no change in behavior [121]. Unfortunately, that study did not test more than one time-point and only utilized male mice.
The initiation of an inflammatory response begins with the non-specific macrophage pro-inflammatory response (Th0), which then diverges into either a Th1 (cell-based) or Th2 (humoral-mediated) response. There is evidence that suggests ovarian hormones may influence the path of the subsequent immune cascade from the Th0 response. To date, the Th1 response has been more intently studied for its possible role in effecting behavior (i.e. causing changes in behavior).
Given the lack of data pertaining to IFN-γ effects upon startle sensitivity and responsivity, we conducted a study focusing on determining whether IFN-γ could change ASR sensitivity or responsivity. As stated above, LEW rats exhibit greater pro-inflammatory responses to infection than do other strains; therefore, we tested whether acute administration of IFN-γ is sufficient to reduce startle reactivity, presumably from reducing serotonin availability. Although still preliminary, our results suggest IFN-γ may have a bi-potential effect on startle sensitivity. The higher dose of IFN-γ caused an apparent decrease in the percentage of startles elicited 1.5 h following injection, whereas the lower dose caused significantly more startles to be elicited than the high dose (see Figure 13). This is an important distinction, for it suggests that reduced startle responding due to IFN-γ (and possibly low serotonin tone) is due to a decrease in the ability to sense a startling stimulus, rather than the ability to mount the physical response (although there are trends suggesting that responsivity may be decreased as well with higher doses). Hence, there may be more than a hypothetical link between stress, IL-1 release, and an identified difference in basal immune functioning in a population of women with PTSD that have also been described to have blunted startle responses. There may be instances where the downstream Th1-response is elevated, thus causing a seemingly similar “blunting” of the ASR but the suppression is different in form and occurs through different neural pathways.
The suppression of startle reactions has only gained significant attention in the past decade, and, as researchers have looked for
When one considers stress-related mental disorders, typically, anxiety disorders, MDD, BPD, and maybe even schizophrenia are cited as examples, but how distinct are anxiety disorders from MDD or MDD from BPD? In all cases, there is an overlap of various symptoms that could be experienced with any of these diagnoses. The DSM clinical criteria do provide some flexibility in categorizing subjects into the different classes of disorders. What that allows for are physiological conditions that are not specific to just one of these classes, and chronic or phasic abnormalities in the activities of the peripheral immune system could be common in some patients that meet the criteria for PTSD, the non-mania phase of BPD, or even MDD.
For example, there is a growing body of literature that suggests abnormal immune system signaling may be at the core of BPD. Several studies have shown abnormalities in the cytokine profiles of BPD patients, with differences present in both depressed and manic subpopulations [122-124]. Multiple studies have shown a characteristic increase in TNF-α among both bipolar depressed and manic patients [122, 123], whereas patients suffering from bipolar mania commonly exhibit decrease in IL-1β, IL-2, and IFN-γ. When stimulated with LPS, a common procedure used to model behavioral depression in animals, the monocytes from non-lithium treated patients exhibit a decrease in the production of IL-1β and an increase in IL-6, compared to healthy controls. This abnormality was shown to be reversed in lithium treatment patients [125]. This suggests a by-product of lithium administration may be an influence on the pro-inflammatory response signals in the periphery. Additionally, Boufidou and colleges found that lithium is capable of down regulating the production of IL-2, IL-6, IL-10 and IFN-γ from peripheral blood lymphocytes in BPD patients, and a similar down regulation of pro-inflammatory cytokines was observed in previously non-medicated BDP after three months of lithium treatment [126]. These data further implicate a peripheral immune mechanism for BPD that is normalized by lithium treatment.
Startle sensitivity and responsivity were assessed 30 and 90 min following an acute systemic injection of IFN-γ (n = 16). Startle sensitivity was significantly altered by the specific dose administered. The low dose showed an increase in elicited startles over time, whereas the high dose showed a reduction in elicited startles over time, IFNγ x Session F (2, 29)= 3.3, p <.05. An asterisk represents a significant difference in the low-dose group at the 90 min test as compared to the same time high-dose and the 30-min low-dose test.
Based on the literature and the collected data from our laboratory, concerning the modulation of the ASR, we propose the following cascade of events may occur as a result of stressor exposure in our female rat model. First, the acute-phase (pro-inflammatory) response causes a transient reduction in startle responsivity (magnitude) that appears to last as long as IL-1 continues to be elevated above the levels of circulating IL-1ra. IL-1ra serves to normalize the response; thus, when the levels of IL-1ra are elevated to a sufficient degree, it causes an increase in ASR sensitivity (a rebound effect). However, in the cases where the stressor exposure is prolonged and/or severe enough to engage a downstream Th-1 response (i.e. increase IFN-γ signaling), then a reduction in ASR sensitivity occurs, whereby the sensory threshold for eliciting the response is increased. This could cause a chronic condition where ASRs are “blunted” in people with conditions ranging from PTSD to MDD to BPD.
The ASR could have a potential use as a functional index of abnormal peripheral immune functioning; thus, if the ASR is suppressed, it may represent an elevated level of pro-inflammatory or Th1 signaling in the patient. This could be of great importance from a therapeutic standpoint when one considers the suppressive effects of IL-1 upon sexual motivation in female rats are attenuated by indomethacin and ibuprofen [127]. Although blocking prostaglandin synthesis [128] or knocking-out the prostaglandin EP2 receptor does not change startle reactivity [129], prostaglandin EP1 knock-out mice do exhibit higher startle magnitudes compared to their wild-type control strain [130]. This suggests that EP1 receptors are in a position to serve as neuroimmune mechanisms to inhibit startle responsivity as well. Still, beyond the possible pharmacological implications, blunted reactivity to stimuli can have profound effects on other neural processes as well, and may explain some of the other symptoms associated with anxiety, MDD, or BPD. For instance, when the same dose of IL-1β, sufficient to blunt startle responsivity in female SD and Lewis rats, is administered to female SD rats prior to a simple associative learning procedure the rate of learning is slowed. This effect is attributed to a reduction in the neural representation of the unconditional reflexive response (i.e. the response is weaker), causing less optimal neural representation of the behavioral response to the predictive, conditional stimulus [131]. The implication is that associative learning may be impaired by either acute or chronic elevations in pro-inflammatory or Th1 cytokines. Interestingly, this pattern of effect is not observed in male rats, at these low to moderate dosages of IL-1β; in fact, these learning processes are facilitated [132, 133]. Thus, the ASR can serve as a tool to better understand the blunting of sensory reactivity, but may also have implications for more complex associative learning processes as well. In Figure 14, we present our theory as to how the ASR may be changed over time as a function of neuroimmune interactions between peripheral cytokine signaling (specifically the acute pro-inflammatory response and the downstream Th-1 response) and brain monoamines.
The evidence accumulated from these experiments favors a pro-inflammatory mechanism, over a HPA-axis glucocorticoid mechanism, as the necessary pathway that ultimately leads to the suppression of startle reactivity following stressor exposure. This finding adds to the ever-growing evidence that peripheral immune signaling has a significant role in influencing how the nervous systems functions. In this particular case, we have illustrated how a simple behavioral reflex can be dampened by pro-inflammatory signals, in the absence of any physical injury. This shows abnormal levels of peripheral immune signaling could lead to perceived symptoms reported by patients with PTSD, MDD, or BPD.
Biological differences in how different animals respond to stressor may reflect vulnerability factors for experiencing different symptoms associated with stress-related disorders, such as PTSD, MDD, and BPD. Thus, differences observed in the literature concerning startle reactivity in female PTSD patients (e.g. [18, 19]) could be due to the types of stressor exposure or individual differences in biological responses. In addition, one cannot rule-out the role of coping mechanisms. In fact, one could hypothesize that the suppression of startle is an evolutionary selected response that keeps individuals within a species from continuing to fight a “losing battle”. If this were the case, then it would be logical for the immune system to play a role in that trigger-mechanism and not the HPA-axis. The HPA-axis is designed to maintain the fight-or-flight response [134], which would be in opposition to a behavioral suppression coping response. Others have proposed females are particularly selected to engage in alternative coping strategies that are in opposition to the fight-or-flight response [135], and one possibility is that signal reception of the peripheral immune response by the central nervous system is an early point of diversion in stress coping strategies between males and females. This could provide inherent propensities to respond differently, but, at the same time, could be modified by experience. Such propensities could translate into vulnerability factors for abnormal behaviors where that response becomes, potentially, maladaptive.
It is well documented that more women experience anxiety disorders and affective disorders, and there is a significant degree of comorbidity across these disorders – especially as cases become more severe [136]. There are many potential reasons for the higher rates reported in women. For instance, some have recently suggested there is a link between ovarian hormones and the occurrence of specific peptide isoforms that modulate stress responsiveness and fear conditioning [137]. The data presented here provide another example of how ovarian hormones can influence physiological processes associated with stress responsiveness. The role of progesterone in this immune model of startle suppression is particularly intriguing since progesterone can amplify the pro-inflammatory response through macrophage migration inhibitory factor [138]. This endocrine influence could, potentially, cause more Th1 signaling to occur, which, we hypothesize leads to an increase in IL-1β, causing more Th1 signaling to occur, eventually leading to an increase in IFN-γ release and subsequent reductions in sensitivity to auditory stimuli. If that same individual has central nervous system vulnerabilities, such as a particular peptide isoform, then, in addition to an apparent blunted startle response, the patient may also be exhibiting flashbacks due to enhanced neural processing of fear-associated memory. Thus, female vulnerability for anxiety and depression symptoms can be seen as a product of multiple mechanisms that modulate the female physiology and behavior in a manner that, at times, may even be counter to fight-or-flight, but, nonetheless lead to changes in nervous system functioning, causing the expression of a particular set of behavioral symptoms.
There is a growing literature pointing towards a complex interaction between the central nervous system and the peripheral immune system that underlies anxiety or affective disorder vulnerability and/or the presence of acute symptoms [139-143]. The utility of being able to use species-common measures, such as the startle response, has been advantageous to researchers in aiding them to understand how the brain functions under normal and abnormal conditions. Here we illustrate how such measures can be applied to the understanding of psychoneuroimmune interaction as they pertain to the influence of the peripheral immune system upon the brain and behavior. As we gain a greater understanding of the signaling cascades in the peripheral immune system, delineating how those signals affect the brain will continue to be important for our future understanding of the etiology of mental illnesses.
This research was supported by a U.S. Department of Veterans Affairs Merit Review research program to KDB and program support through the UMDNJ – Stress & Motivated Behavior Institute. The described experimentation was conducted with approval by the VANJHCS Institutional Animal Care and Use and Research and Development Committees, in accordance with the NIH Guide for the Care and Use of Animals. The authors want to thank Toni Marie Dispenziere, Tracey Longo, Ian Smith, and Paul William Ong for their technical assistance in conducting the experiments. Some of the described work was included in the undergraduate honors thesis of Mr. Ong. The authors also thank Dr. Victoria Luine for the use of the laboratory in the processing and measurement of the brain monoamine data.
The link between Corporate Social Responsibility (CSR) and Firm Financial Performance (FFP) remains one of the most controversial issues during the past fifty years. Despite the extensive research, both theoretical and empirical carried out in different contexts; it seems that no consensus has been reached on causality, sign and even less on its shape. On a theoretical level, the arguments in favor of a positive relationship are mainly found in the social impact hypothesis defended by the stakeholder approach according to which good stakeholder management would generate better performance. In contrast, the trade-off hypothesis stemming from a liberal view postulates that CSR would divert the company from its main mission of profit maximization Friedman [1]. Regarding the causality of the relationship, two hypotheses are also theoretically defensible: on the one hand, it is the Available Fund Hypothesis [2, 3] that would play an initiating element in CSR practices. This hypothesis is based on Slack Resource Theory [4, 5], maintaining that availability of financial resources would encourage companies to get involved in CSR activities, [6, 7]. On the other hand, according to the Managerial Opportunism Hypothesis [8], good financial performance would push managers to reduce their commitment to CSR actions to increase short-term profitability as well as their personal remuneration. Conversely, poor financial performance would lead to an increase in social spending in order to divert attention and justify their poor performance [8, 9]. On an empirical level, the researches carried out to date do not seem to have been sufficient either to draw a definitive conclusion as to the relationship between CSR and financial performance. Indeed, these investigations do not allow us to rule on a general and stable relationship between CSR and performance given many contingent factors that affect this relationship. In recent Meta-analysis, [10, 11] conclude that even if empirical research on the CSR-FFP relationship favors a positive link, the latter would be affected by several contingent variables (moderators and mediators). Thus, several variables are likely to influence this relationship such us firm size [12], firm’ origin country [13], Competition intensity within the industry [14], Industry [15, 16], earning management [17], ownership concentration [18], R and D expenditures [19], leadership styles [20], cultural differences and the crucial role that owner-managers could play when dealing with CSR agenda [21].
Furthermore, others arguments have been put forward to justify the lack of consensus on the nature of this relationship, such as the difficulties and biases related to the operationalization of CSR, the performance measurement indicators retained as well as the delay effects necessary to be able to judge the interaction between the two variables [22]. At last, some other recent empirical research questions the linearity of the relationship - when it exists - evoking cubic, or quadratic forms [23, 24]. Thus, specifying the nature of the relationship between CSP and FFP is a very “challenging task”. According to legitimacy theory [25], a firm needs to appropriate certain legitimacy granted by the stakeholders. Indeed, Stakeholders tend to pay more attention, surveillance and exert more intense pressure on the most visible companies by their size, their industry, their presence in the media …. The response to these different pressures depends on the firm’s Corporate Social Responsiveness as firms may tend to manage their legitimacy according to the intensity of the pressures to which they are subject. Thus, CSR commitment would be a way of responding to various pressures whose intensity depends on the degree of visibility of the company. The main arguments put forward to justify the impact of organizational visibility on social performance relate to the fact that large companies are supposed to be more visible would be subject to greater pressure from stakeholders to encourage them to consolidate their legitimacy. Much more, firm visibility has been identified as a factor impacting the social performance by recent empirical work [26, 27]. On the other hand, by reducing information asymmetry, firm visibility is supposed to attract more investor’s attention. Investors could better assess the company’s financial performance and make predictions on firm prospects. Firm visibility could also be affected by its sustainable innovation commitment. Cillo et
However, if firm visibility is liable to affect CSR on one hand and financial performance on the other hand, it will probably be a moderating variable in the CSR-FFP relationship. Hence, our research aims to test the impact of CSR on FFP and to highlight the moderating effect of firm visibility on this relationship on a sample of large French companies. This study makes three contributions to the literature. First, it provides proof of the significant impact of visibility on CSR. Then, it contributes to the literature on CSR by presenting visibility as a predictor of CSR initiatives. Third, this study demonstrates that visibility has a moderating effect on the link between CSR and FFP.
The remainder of this study will be organized as follows: Section 2 represents the research hypothesis, Section 3 describes the methodology, Section 4 provides the results and discussion of results and Section 5 presents the conclusion and recommendations.
CSR can be defined as the commitment to an improvement process in which companies integrate social, environmental, and economic considerations into management in a voluntary, systematic, and consistent manner with their stakeholders. Two theories are likely to shed light on the behavior of the company in society. Firstly, stakeholder theory [30] suggests that the success of the company depends on its ability to develop and maintain exchanges and transactions involving several resources with the various stakeholders [31]. It also recognizes that the expectations and interests of stakeholders are varied and sometimes contradictory [32]; it would therefore be called upon to take care of a real dialog to reply to its conflicting expectations and continually seek their support. From this angle, CSR is considered as a form of a dialog between the company and the various stakeholders. Secondly, legitimacy theory postulates that organizations continually seek to confirm that they operate within the bounds and in step with the standards of their respective Societies. According to Chiu and Sharfman [33], any institution – firms in particular - operates in society through an explicit or implicit contract. This continuous look for legitimacy could depend upon the degree of exposure of the firm to the assorted stakeholders and so, on the degree of its visibility. Indeed, visibility increases the company’s exposure to implicit claims, media, and the general public and can therefore lead to higher CSR; visibility is more consistent and a more powerful predictor of CSR initiatives than other factors previously studied [34].
Stakeholder theory [30], has marked the literature on the relationship between CSR and company performance [11, 35]. It states that if a company satisfies its stakeholders, by carrying out social projects, for instance, it will improve its image and reputation, and thereby it’s financial performance [4]. However, if the company fails to achieve a positive social impact, this will create fears among its stakeholders about its image which will increase costs and decrease profits [36]. A company that seeks to reduce its implicit costs (environmental costs, product quality costs, etc.) through irresponsible social actions should face higher explicit cost (reputation, payment of penalties, etc.). This will have a negative effect on its profitability and competitiveness. Therefore, authors who support this view predicting a positive correlation between CSR and FFP. This assumption is called “positive social impact” or “good management”. According to Cristache et al. [37], integration of social responsibility dimensions into companies’ strategies, would help to increase their long-term performance.
According to the legitimacy theory, CSR legitimizes firm’s businesses and guaranteed their existence [38]. Thus, the disclosure of the assorted CSR activities expected and desired by Society, make it possible to legitimize their commercial activities and failure to go with this instruction compromises overall profitability.
Resource Based View approach [39] suggests that by satisfying the expectations of stakeholders, the company develops inimitable and non-substitutable resources and skills. These resources can be intangible assets [40] such as innovation, human capital, leadership, etc. If the company manages to create and exploit these new resources, it will be able to develop sustainable competitive advantages [41].
Signaling theory [42] also provided an argument for the positive impact of CSR on financial performance. Thus, through their social achievements and especially through their disclosure, companies will try to send a positive signal in order to obtain a positive response from the market.
On an empirical level, several researchers have concluded a positive link between CSR and financial performance. Laskar [43] detected a positive relationship between CSR scores (based on content analysis) and Market-to-Book Value (MBV) on a sample of 119 large Southeast Asian companies over the period 2009–2014. By adopting the same approach, Nguyen [44] established a positive link between CSR scores and ROA on a sample of 31 Vietnamese commercial banks. Choi et al. [45] were also able to conclude that there is a positive link between philanthropic commitment (as an indicator for measuring CSR) and ROA; their research focused on 11,000 observations over the period 2002–2014 in Korea.
In Europe, Rodríguez-Fernández [46] constructed a social behavior index to show the existence of a positive relationship between this index and financial performance apprehended by both ROA, ROE and Tobin’s Q; their study focused on a sample of 107 companies listed on the Madrid stock exchange. Adeneye and Ahmed [47] also found a positive link between CSR scores and market to book value (MBV) on a sample of 500 British companies. More recently, in a recent second-order Meta analysis, covering 25 primary Meta analyzes, 1274 empirical researches, or nearly one million observations, Busch and Fried [10] concluded that a positive and highly significant relationship between CSR and financial performance.
Based on theoretical justifications, empirical literature and our research questions, we make the following central hypothesis (H1):
Firm visibility describes the extent to which companies are observed by their stakeholders. It can be viewed as a unique attribute that reflects the exposure and attractiveness of a firm [48]. Visibility is a concept close to reputation. However, it is necessary to make a distinction: if the reputation reflects the image stakeholders have of the firm (good or bad), visibility mainly reflects the presence and ‘observability’ within the community and it is related to the level of ‘stakeholder recognition’ [49].
Such presence can be affected by size, brand, impact on the natural environment, employability, presence in the media but also by various scandals within which firm may well be involved. Firm visibility could be the source of an “excess” of pressure and oversight on the part of stakeholders, since they have more information on corporate social responsibility. Thus, companies with high visibility are more likely to obtain more positive responses from their external stakeholders prompting them to improve their social performance, with more effort in terms of innovation. On the other hand, companies with high visibility can attract more attention from investors. Additionally, visibility may be a recognizable attribute that can help customers differentiate them from other businesses [50]. In keeping with Pfeffer and Salancik [51], external stakeholders are more curious about visible firms which affect the intensity of the pressures they are subjected to. Visible firms would be under more public scrutiny. Hörisch et al. [52, 53] noted that the more exposed position lead to higher public pressure and more CSR activities.
Firm visibility also can reduce information asymmetry degree between companies and their stakeholders and amplify the information disclosed by companies [54]. Thus, companies with higher visibility are more likely to elicit adverse reactions from their stakeholders. For example, within the case of high firm visibility of companies, violations of environmental regulations are going to be particularly pronounced [55], to which investors react strongly negatively. Additionally, a high firm visibility can even allow customers to understand their environmental irresponsibility [56]. Wu et
Finally, the active CSR behaviors of companies are much easier to know by governments allowing them to access preferential policies, like access to bank loans, tax deductions and market access that stimulate social innovation [33]. Therefore, we make the subsequent assumption:
Our sample consists of French SBF120 listed firms from the year 2008 to 2017. The final sample includes 88 French companies. We are base on a balanced panel dataset of 880 firm-year observations. We used secondary data drawn from the Thomson Reuters Inc. database on the French companies in our sample.
The choice of the period analysis coincides with the adoption of the Grenelle1 law which makes the production of annual CSR report mandatory for all large companies. This period also coincides with the dissemination of the main codes of governance in France. Furthermore, the analysis period of 10 years makes it possible to constitute a fairly large panel which enriches the results and improves the estimates and econometric tests. The SBF120 index includes the 120 largest companies in terms of market capitalization and trading volumes on the Euronext Paris market. These large companies, mostly groups, remain very “visible” when it comes to their societal achievements and are subject to permanent “monitoring” by societal rating organizations, media, and investors. It should be noted that companies with a lot of missing data were also removed from the sample.
There are many ways to measure Firm Financial Performance. However, in this study, we use the return on assets (
Given the multidimensional nature of CSR and taking into consideration that the weights of its various dimensions must consider cross-sectoral specificities and socio-cultural differences, we retain in this research a measure including three fundamental dimensions of CSR (Environmental, Societal, and Governance: ESG). ESG score is based on a company’s performance in the environmental (E), social (S) and governance (G). In this study we use the Thomson Reuters/S-Network which attributes a specific weight to very indicator on the basis of selected considerations and their relative importance. ESG ratings provided by the Thomson Reuters Asset4 are widely employed in the literature as a CSR measure [59].
Visibility is a concept that remains difficult to measure. Previous research has tried to develop own measures. For example, firm citations in the specialized press [60]; firm size [61], the distinction between B2B and B2C companies [49] or even the media coverage [62] were used as proxies of the visibility of the firm. Firm visibility (
Following prior-related studies, we control for a variety of variables that may affect CSR-FFP link.
According to Waluyo [65], firm age affects CSR since mature firms are more experienced and pay more attention to social issues and reputation. Moreover, mature firms are likely to invest significantly more in CSR. Indeed, the predictability of income allows mature companies to invest more in CSR; on the opposite hand, younger companies with less predictable income may pursue survival and growth-oriented strategies and subsequently run out of funds to invest in CSR activities. This hypothesis is criticized by other authors. For instance, Withisuphakorn and Jiraporn [66] who argue that mature companies, enjoy a reputation regardless of their CSR engagement. Otherwise, Age can affect the general public firm’s visibility [67, 68]: On one hand, older firms are speculated to be “known” by the public through patronage and sponsorship, on the other hand, young firms would even be tempted to ascertain a brand image with the public by an increased media presence. In this study, we measure firm age (AGE) by Natural logarithm of the number of years since the inception of the firm.
On the other side, considering that large companies are alleged to have more resources to commit to CSR initiatives [27] and that larger firms have more exposed position lead to higher public pressure and more CSR activities [52, 53], SIZE, measured by Natural logarithm of total assets is introduced into the model as a control variable. Following pervious researches [69, 70], we also control by leverage (LEV). Indeed, we would expect companies with high levels of leverage to have less cash available to engage in CSR actions. On the other hand, excessive leverage could negatively impact financial performance. In this study, we used the total debt ratio by dividing the sum of financial debts (regardless of their horizons) by total assets as a measure of leverage.
Finally, we integrate innovation (RDI) measured by R&D expenditures divided by total annual sales, as a control variable to the extent that it is theoretically accepted that innovation often allows dissipating a competitive advantage and improving profitability [41, 71, 72]. On the other hand, there is empirical evidence that the degree of innovation has an impact on firm social performance [73, 74]. McWilliams and Siegel [75] highlighted that innovation is important for the understanding of the CSR influence on financial performance. According Luo and Du [76], CSR can be a catalyst for innovation.
In this study, we aim at examining the effect of CSR on REM and the moderating role of firm visibility on this relationship. For this purpose, we proceed by two steps. We start first by estimating the following equation:
In order to examine the moderating effect of firm visibility on the CSR-FFP relationship described in our basic model, we regress FFP on the CSR variable, visibility variable and the interaction between both of these variables.
In Eq. (1),
The research design is presented in
Firm financial performance | FFP | Return On Assets ratio |
Corporate Social Responsibility | CSR | ESG global score |
Firm Visibility | VBL | Advertising expenses to sales ratio |
Firm Age | AGE | Natural logarithm of the number of years since the inception of the firm |
Firm Size | SIZE | Natural logarithm of total assets (in millions of Euros) |
Leverage | LEV | Total debt to total assets ratio |
R&D expenditure Intensity | RDI | R&D expenditures divided by total annual sales |
Variables description.
We consider the GMM equations for panel data to estimate models. The GMM estimator has the advantage of controlling for endogeneity between variables and unobservable heterogeneity. For this purpose, the following two models have been specified by using random-effects panel regression.
Table 2 presents the descriptive statistics. It shows the minimum value, maximum value, average and standard deviation. The dependent variable, ROA, has an average value of 0.398 with a standard deviation of 0.0689. Thus, on average result before taxes and interest represent 3.98% of total assets of companies of our study. The average firm visibility variable equals 5.69% with a standard deviation of 0.1466 suggesting high dispersion between the companies of our sample. The averages of the control variables are 3.670 for firm age, 9.996 for firm size, 0.7328 for leverage and 0.0486 for R&D intensity.
Obs | Mean | SD | Min | Max | |
---|---|---|---|---|---|
FFP | 880 | 0,0398 | 0.0689 | −0.3374 | 0.5571 |
CSR | 880 | 0.5785 | 0.1855 | 0.3220 | 0.9300 |
VBL | 880 | 0.0569 | 0.1466 | 0.01251 | 0.2501 |
AGE | 880 | 3.670 | 1.080 | 0.101 | 5.815 |
SIZE | 880 | 9.996 | 1.902 | 8.887 | 16.570 |
LEV | 880 | 0. 7328 | 0.2281 | 0.2531 | 0.9768 |
RDI | 880 | 0.0486 | 0.1113 | 0.004 | 0.1994 |
The mean value of overall ESG score for all the companies in our sample over the period studied is 0.5787 with a standard deviation of 0.1852. This score did not change significantly over the analysis period with a maximum recorded in 2015 (65.91%) and a minimum of 49.43% in 2011. For international comparison, the average ESG score observed on a sample of 94 Korean companies listed on the KOSPI (Korea Stock Exchange) over the period 2008–2014 is close to 46%. According to the rating agency Novethic, the average ESG score of European companies is 45.4% in 2017.
Table 3 shows the Pearson correlation matrix. All correlation coefficient are less than the acceptable limit (0.5). Therefore, there are no multicoliniarity problems in our study.
Variable | FFP | CSR | VBL | AGE | SIZE | LEV | RDI |
---|---|---|---|---|---|---|---|
FFP | 1 | ||||||
CSR | 0.0458 | 1 | |||||
VBL | 0.1147 | 0.4331 | 1 | ||||
AGE | 0.0341 | 0.0137 | 0.1372 | 1 | |||
SIZE | −0.0746 | 0.0568 | 0.0557* | 0.0965** | 1 | ||
LEV | −0.2844 | −0.0124 | −0.0788 | 0.0299** | −0.1550*** | 1 | |
RDI | 0.1864 | −0.0174 | 0.0936 | 0.1748 | 0. 1562 | 0. 0514 | 1 |
Pearson correlation matrix.
Note: For description of variables see Table 1
The superscripts
The correlation coefficient shows that visibility has a high positive correlation with CSR variable at a significance level of 5%. This is can be in accordance with the hypothesis that more visibility should create incentives for a firm to engage in social initiatives and to divulgate their social performance and is additionally in line with the results of previous researches [62, 77, 78]. There is also a significant positive correlation between visibility and firm age. This is expected as old firms should have more visibility and access to media. Visibility also has strong correlations with R&D intensity [72, 79]. In fine, significant correlation was reported between CSR and firm leverage in our sample. This is consistent with the literature up to this point which has supported a strong positive correlation between leverage and CSR [80]. Indeed, firms that participate in more CSR initiatives are more likely to be less leveraged. This is often expected as firms that are highly leveraged should find it tougher to participate in “non-essential” spending [34].
The main objective of this research was to study the link between CSR and FFP and the moderating effect of firm visibility on CSR and firm performance relationship. Table 4 presents the results. The findings of the first model demonstrate that CSR have a positive and significant relationship with firm performance. Our first hypothesis H1 is accepted. These findings are in line with previous studies [81, 82, 83] which have determined that greater CSR activities enhance firm performance.
Dependant variable: Financial Firm Performance measured by ROA | ||||
---|---|---|---|---|
Model 1 | Model 2 | |||
Coef. | p-value | Coef. | p-value | |
CSR | 0.0141 | 0.021 | 0.0056 | 0.041 |
VBL | 0.1109 | 0.501 | 0.1158 | 0.480 |
CSR x VBL | — | — | 0.0150 | 0.022 |
AGE | −0.0771 | 0.377 | −0.0903 | 0.511 |
SIZE | −0.2240 | 0.050 | −0.3221 | 0.047 |
LEV | −0.0389 | 0.001 | −0.0851 | 0.000 |
RDI | −0.7909 | 0.390 | −0.939 | 0.324 |
Wald χ2 | 73.01 | 79.33 |
Multivariate regression analysis.
The superscripts *, ** and *** indicate significance at the 5%, 1% and 0.01% levels, respectively.
With the second model, we employed Aguinis’s [84] Moderate Multiple Regression (MMR) model by creating a new variable (product between the two predictors). The effect of interaction variable (CSR × VBL) is positive on firm performance (coef. 0.0137, p-value = 0.022) and significant at 5 percent level. Our second hypothesis H2 is accepted which suggests that firm visibility moderates the link between CSR and FFP. This indicates that as a firm is more visible, the positive effect of CSR on ROA becomes stronger. Thus, increased visibility would encourage more commitment and disclosure of societal achievements that can be valued by stakeholders and leading to better financial performance. Our results are also supported by Park [85] who demonstrated that visibility moderates the correlation between CSR and reputation, which mediates the CSR-FFP relationship in the long run. These results are also in accordance with those of Madsen and Rodgers [86] who underlined the role of firm visibility and “stakeholder attention” when studying CSR-FFP link.
Regarding the control variables, firm leverage was found to be negatively and significantly related to firm performance in both models. This finding is congruent with that observed in researchers carried out in the same context (see, for example, [87]).
Firm size has negative and statistically significant effect on firm performance within the two models at a 5 percent level. The results are in line with those of prior studies [88, 89]. Finally, the coefficients of firm age and R&D intensity are negative but not significant.
Over the past decades there has been growing interest, both in academic literature and within the business world, in CSR and its impact on the actions and results of companies. The empirical research carried out to date does not seem to be sufficient to draw a stable and definitive conclusion about the existence, direction and stability of CSR-FFP link, to give for investigations about contingent variables which could affect this relationship. In this research, we essentially mobilized legitimacy theory to advance that the firm’s response to several pressures exerted thereon by the various stakeholders could vary consistently with its degree of visibility and therefore the attention given by the community. The empirical validation on a sample of large French firms allowed us to conclude that visibility plays the role of a positive moderator on the link between CSR and financial performance. Indeed, we have demonstrated the existence of a positive and significant relationship between ESG scores (CSR measure) and the return on assets (firm financial performance measure) to validate our first hypothesis. Likewise, we have demonstrated the existence of a positive relationship between visibility level and CSR to argue that visibility increases the company’s exposure to implicit complaints can therefore lead to higher CSR. This study showed significant positive relationships between visibility and CSR demonstrated by correlation and multivariate analyzes.
This research also made for an interesting finding that might be the topic of further investigations: the chosen visibility indicator has a significant positive relationship with the ESG scores. This observation is in step with that revealed by other studies carried out in other contexts [85, 90, 91]. French companies with high visibility seem to support CSR issues to manage social expectations and reinforce their legitimacy. These results match in particular with what was revealed by Aouadi and Marsat [92] who found that ESG scores are positively related to company value for highly visible companies after using a large sample of over 4,000 companies from 58 countries between 2002 and 2011.
The results of this study have practical implications; they can be interesting and useful for managers in their decision making since they indicate that decision makers should be aware of the importance of visibility to gain legitimacy. Indeed, this research shows that the visibility positively moderates the correlation between CSR and financial performance. This moderating effect would most likely be exerted through the firm’s reputation, suggesting that companies should pay more attention to visibility when implementing and disclosing their CSR programs.
The main limitation of this study is related to the visibility metric, future research may well be inquisitive about further developing indicators for firm visibility measures based, for instance, on media coverage or on the interest given to the company by social networks or Internet search engines. Comparative studies with other countries would be possible. Finally, in this research, we used an overall ESG score; it would be interesting to perform the effect of specific ESG components on financial performance.
The authors declare no conflict of interest.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
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\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
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\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"18",type:"subseries",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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