This data are in correlation with previous studies IRAS (The Insulin Resistance Atherosclerosis Study) has shown that diabetes and glucose intolerance are independent risk factors connected with increase in intima–media thickness (IMT). SANDS trial (The Stop Atherosclerosis in Native Diabetics Study) have shown that reduction in other cerebrovascular risk factors (hypertension, hyperlipoproteinemia) can slower progression of IMT thickening in diabetic patients [16] and [17]. Previous studies as well as our results suggest that mechanical arterial properties (changes in BHI, AS as functional parameters) are affected first while hemodynamic remains

preserved (mean velocities were unchanged due to cerebral autoregulation BMN 673 mouse mechanisms which are preserved in healthy individuals). Our results suggesting that there is a good correlation of BHI as functional parameter which reflect

functional state of the intracerebral blood vessels with arterial stiffness as functional parameter for extracranial blood vessels (CCA in our case) in population with diabetes mellitus [10], [15], [16] and [17]. Different pathophysiological VX-809 ic50 mechanisms during the lifetime cause vessel wall aging and subclinical endothelial dysfunction which is the first stage of the atherosclerosis, subtle change of vessel wall before appearance of either vascular remodeling this website (diameter increase), intima–media thickening or plaque formation. This state is irreversible and it is early marker of atherosclerosis as well as systolic pressure increase and pulse pressure increase. Increased arterial stiffness and decrease in BHI values are normal in advanced age, but in younger individuals this changes are first signs of subclinical atherosclerosis, such individuals should be screened for cerebrovascular risk factors and followed up. In our case we have shown that glucose control is of great importance in diabetic patients in order to prevent vascular aging [3], [7], [11] and [15]. We have shown

that diabetic patients are at increased risk for cerebrovascular disease, but further studies should be performed in order to evaluate impact of changes in AS and BHI on other clinical manifestations (cognitive decline, every day activities, etc.) in diabetic patients [18] and [19]. “
“Some present studies show that OSAS is associated with a high risk of cardiovascular and cerebrovascular diseases, because of the high frequency of the risk factors for their appearance [12], [13] and [16]. Epidemiological data say that patients with OSAS often are overweight and have arterial hypertension, they usually smoke and are involved in alcohol abuse [7]. Apneic episodes can induce cardiovascular, hemodynamic and hemorrhagic changes, which are potential promoters for stroke incidence in patients with RF for CVD [4] and [9].

Uma pesquisa na base de dados Publine/Medline foi realizada utilizando os termos «videofluoroscopic evaluation» e «modified barium swallow», nas línguas «português, EGFR inhibitor inglês, francês e espanhol», em agosto de 2013. A razão para a exclusão

de alguns artigos foi ausência de resumos, ausência de publicação do artigo completo e ausência de relação entre a utilização do procedimento e avaliação da deglutição. Foram também acrescentados 6 artigos selecionados em pesquisa prévia. Foram selecionados no total 67 artigos, e incluídos mais alguns trabalhos importantes publicados há mais de 5 anos. Apesar de ser considerado um método complementar na avaliação da deglutição, a VFS é distinguida dentre os demais métodos17. De forma não invasiva, possibilita a visualização de todas as fases da deglutição, desde a fase preparatória do alimento a ser deglutido, como a abertura dos lábios, BEZ235 os movimentos das regiões anterior, média e posterior da língua, até à movimentação de abertura do esfíncter superior do esôfago durante a passagem do bolo alimentar18 and 19. É possível identificar a

presença de escape anterior e/ou posterior do alimento, regurgitação nasofaríngea20, disparo do reflexo de deglutição, fechamento velofaríngeo17, 21 and 22, elevação do complexo hiolaríngeo, fechamento glótico e supraglótico23, presença de refluxo gastroesofágico e movimentação peristáltica da faringe e esôfago24. Permite, de maneira detalhada, a observação anatômica e fisiológica da deglutição25 and 26. Desta PTK6 maneira, a identificação da aspiração traqueal, penetração laríngea e resíduos oral e faríngeo, o momento de sua ocorrência, suas possíveis causas, e reações a tais alterações, como a presença e a efetividade do reflexo de tosse, são facilmente percebidos27. Considerando-se que a deglutição orofaríngea ocorre em espaço de tempo extremamente pequeno, menor que

2 segundos28, a visualização quadro a quadro repetida e imediata do evento torna-se fundamental na análise e discussão dos casos estudados8. Estudos demonstraram que a VFS é vantajosa em relação à avaliação clínica quanto aos custos e efetividade diagnóstica9 and 29. Por tratar-se de um método objetivo, não é limitado pelas alterações cognitivas e déficit de linguagem, muito comum em pacientes com lesões neurológicas30. O exame é indicado em casos de suspeita de aspiração silenciosa31 and 32, ou silente, e na confirmação de alterações na deglutição orofaríngea detectadas por testes clínicos22, 33 and 34. Aspiração silenciosa é assim considerada quando não há reação à ocorrência de aspiração, como tosse e sinais de engasgo. VFS é frequentemente utilizada na recomendação da nutrição oral ou parenteral de pacientes disfágicos35 and 36.

The closely related members of the Rho family, Rac and Cdc42, have been extensively studied due to their pivotal roles in actin cytoskeleton find more organization, migration/invasion and metastasis, epithelial to mesenchymal transition, transcription, cell proliferation, cell cycle progression, apoptosis, vesicle trafficking, angiogenesis, and cell adhesions [3], [4] and [5]. Indeed, studies from us and others have implicated hyperactive Rac1 and Rac3 with increased survival, proliferation, and invasion of many cancer types [6], [7], [8], [9] and [10]. In addition

to promoting cancer malignancy, Rac and Cdc42 have also been shown to be essential for Ras and other oncogene-mediated transformation [11] and [12]. Racs [1], [2] and [3] are activated by a myriad of cell surface receptors that include: integrins, G protein coupled receptors, growth factor receptors, and cytokine receptors. These cell surface receptors regulate cancer promoting signal cascades that have been implicated with Rac and its direct downstream effector p21-activated kinase (PAK) activity [13].

These pathways include: phosphoinositide 3-kinase (PI3-K)/Akt/mammalian target of Rapamycin (mTOR); signal transducer and activator of transcription (STATs); and the mitogen activated protein kinases (MAPKs): extracellular regulated kinase (ERK), jun kinase (JNK), and p38 MAPK [14], [15], [16], [17] and [18]. Activated Rac has also been shown to affect cell proliferation via Alectinib order signaling to the oncogenes c-Myc and Cyclin D [19]. Therefore, Rac GTPases play

a pivotal role in regulation of cancer malignancy, and targeting Racs appear to be a viable strategy to impede cancer metastasis [8], [15], [20] and [21]. Unlike Ras, Rho GTPases are not mutated in disease but activated via the deregulation of expression and/or activity of their upstream regulators, guanine nucleotide exchange factors (GEFs) [22]. Accordingly, although ~ 9% of melanomas were recently found to contain an activating Rac mutation [23], and the hyperactive splice variant Rac1b is frequently overexpressed in cancer [24], a majority of the Rac proteins in human cancer are activated due to up-regulated GEFs [21], [25] and [26]. So far, over 70 potential Rac GEFs are known; and many members of the largest family Adenosine triphosphate of Rac GEFs, the Dbl family, have been identified as oncogenes [22], [27], [28] and [29]. Of the Rac GEFs, T-cell invasion and metastasis gene product (Tiam-1), Trio, Vav (1/2/3), and PIP3-dependent Rac exchanger (p-Rex1/2) have been implicated in the progression of metastatic breast and other cancers [30], [31], [32], [33], [34] and [35]. Therefore, the binding of GEFs to Rac and Cdc42 has been targeted as a rational strategy to inhibit their activity; and thus, metastasis. The Rac inhibitor NSC23766 was identified as a small molecule compound that inhibits the interaction of Rac with the GEFs Trio and Tiam1 [36], [37] and [38].

Barriers were mainly organisational, including limited opening hours, poor or delayed availability learn more of named practitioners, gate-keeping practices by reception staff, and restrictive appointment systems. Sometimes I don’t have the money to go up to see my doctors, and to see my doctor you have

to be there at, like, 8 o’clock, half past eight because there’s a queue (…) It doesn’t open on 9 o’clock but there could be (…) 15 people stood outside waiting to go in to see [the doctor] (P40, male, 57 yrs, COPD) Some patients, like P40, found travelling to primary care practices difficult, due to a combination of ill-health, inability to afford taxis, and poor public transport. When patients talked about walk-in centres and out-of-hours primary care providers, they were described as more

accessible than routine primary care, as the barriers around appointment systems and travel tended to be reduced: Very, very rare have I phoned up the doctor and been able to get in, you know what I mean, like, you know, to see my GP within two or three days. It’s nearly always PLX 4720 next week, or the week after or whatever, so you need the err, you need the out of hours doctors really to help you out for them situations (P24, male, 59 yrs, asthma) Out-of-hours doctors who could perform home visits, and walk-in centres based in central locations with good transport links (in city centres or at hospitals) reduced the resources required for access. [The out of hours service have] come out and seen me [at home] (P23, female, 53 yrs, asthma) However, whilst some patients described these services as accessible, we saw

above that they were thought unable to meet patients’ needs. The hospital ED, by contrast, was seen as both readily accessible and providing technological expertise: [At the hospital ED] I always get seen to straightaway, no matter Cediranib (AZD2171) what (…) Once when I’m there, I know I’m alright, because I know they can pinpoint what it is and what’s doing it (P02, male, 57 yrs, CHD & asthma) The accessibility of a service therefore influenced patients’ use of healthcare both in the event of non-urgent need, and in the event of urgent need. Routine primary care was typically least accessible, requiring the most effort to use, whereas the hospital ED was the most accessible, with the additional benefit of readily available technological expertise. Patients draw on previous experiences of services and practitioners when choosing how to respond to illness exacerbations. The choice of EC vs routine primary care was shaped by patients’ perceptions of urgency, which were in turn influenced by previous responses from healthcare practitioners, and by involvement of friends or family. Choosing between different EC providers was also shaped by perceptions of those services, formed by previous experiences of their accessibility, and technological expertise.

Als hauptsächliche Biotransformationsprodukte wurden ein Pt-DACH-Biscysteinkomplex, ein Pt-DACH-Monomethioninkomplex und freies DACH identifiziert. Weniger häufige Produkte waren u. a. ein Pt-DACH-Dichlorokomplex, ein Pt-DACH-Diglutathionkomplex und ein Pt-DACH-Monoglutathionkomplex. Die Interaktionen von Cisplatin, Carboplatin und ihren Analoga mit Nukleosid-Monophosphaten, Di- und Trinukleotiden wurden von Keppler und Mitarbeitern mittels CE in Kombination mit einem Diodenarray-Detektor systematisch untersucht [37], [38], [39] and [40]. Die XL184 Adduktbildung führte bei den modifizierten Nukleotiden im Vergleich zu den freien

Nukleotiden zu einer deutlichen Verschiebung von λmax in einen niedrigeren Energiebereich. Daher konnte die Identifizierung der einzelnen Platin-Nukleotid-Addukte auf der Grundlage sowohl der charakteristischen UV-Spektren als auch der Unterschiede im elektrophoretischen Verhalten erfolgen. Die Kinetik der Bindungseigenschaften von

5’-GMP an Cisplatin unter simulierten physiologischen Bedingungen wurde von derselben Gruppe untersucht, wobei der Chloridkonzentration im Inter- und Intrazellulärraum besondere Aufmerksamkeit gewidmet wurde [38]. Es konnte nachgewiesen werden, dass die Bildung von Addukten deutlich durch die this website Anwesenheit von Chloridionen beeinflusst wird. Darüber hinaus wurde der Einfluss der schwefelhaltigen α-Aminosäuren L-Methionin und L-Cystein untersucht, die eine starke Interaktion mit Pt-haltigen Chemotherapeutika zeigten. Unglücklicherweise liefert die Analyse mittels

UV-spektroskopischer Detektion allein nur begrenzte Strukturinformationen für die Platin-DNA-Addukte. Daten zur Struktur wurden jedoch mittels ESI-MS-Detektion bei der Charakterisierung platinierter DNA-Nukleotide erhalten [41]. In zwei weiteren Arbeiten schlug Abiraterone Reedijk vor, dass in Proteine eingebaute Pt-Methionin-Addukte als Platin-Reservoir für die spätere DNA-Platinierung dienen könnten [42]. Alle oben dargestellten Untersuchungen haben gezeigt, dass sich bei Patienten, die mit Pt-haltigen Medikamenten behandelt werden, eine große Anzahl von Pt-Addukten bildet, und dass die Bildung von DNA-Addukten mit Cisplatin ein entscheidender pharmakokinetischer Parameter ist, der bei einer Krebstherapie, die sich auf Pt-haltige Medikamente stützt, in jedem Fall optimiert werden muss. Daher ist nicht nur die Identifizierung von Pt-DNA-Adduktspezies sondern auch die Quantifizierung der DNA-Addukte mit Cisplatin außerordentlich wichtig. Folglich haben Sar et al. [43] eine Studie durchgeführt, bei der DNA-Nukleotide nach in-vitro-Inkubation mit Cisplatin mittels ESI-Q-TOF-MS untersucht wurden. Es gelang die strukturelle Charakterisierung der zwischen reinem Guanosinmonophosphat (dGMP) und Cisplatin gebildeten Komplexe. Anschließend wurden die DNA-Addukte mittels HPLC–ICP-MS quantifiziert, wobei das DNA-Rückgrat anhand des 31P in P-Peptiden detektiert wurde.

These

results suggest that protein feeding alone may improve muscle strength and function more readily than muscle mass.138 In young and old people alike, protein ingestion together with exercise training increased synthesis of skeletal muscle24, 30, 52, 53 and 139; effects were evident for both aerobic exercise51 and 52 and resistance exercise.24, 30 and 139 Exercise consistently reduced the difference between muscle protein breakdown and synthesis; net positive protein balance (ie, synthesis greater than breakdown) was achieved only when protein or amino check details acid intake was supplemented.140 and 141 In a clinical study, frail older people who engaged in resistance training and consumed supplemental dietary protein for 24

weeks showed significant muscle hypertrophy, together with increases in muscle strength and performance; study researchers concluded that protein intake was necessary for training-associated gains in muscle mass.142 In addition, the quality of the protein consumed may exert an influence on the protein synthetic response. High-leucine–containing and rapidly digested whey proteins showed an advantage over isolated casein and soy proteins,24, 30, 61 and 139 Epacadostat research buy which was particularly evident in short-term experiments.62 and 143 As for the combination of protein and exercise, a recent RCT in 175 community-dwelling women with sarcopenia showed that the combination of exercise twice weekly and 3 g of leucine twice daily for 3 months was superior compared with either intervention alone.144 In another study, blends HSP90 of whey and soy protein stimulated muscle protein synthesis after exercise to a similar extent as did whey protein alone.145 Yet another trial compared resistance training in mobility-limited older adults in subgroups who received either whey protein supplementation or an isocaloric diet over 6 months; no statistically different changes were seen in lean body mass, muscle cross-sectional area, muscle strength, or stair-climbing.146

More long-term studies are needed to confirm potential benefits of whey protein. With combination exercise-protein therapy, the timing of protein or amino acid intake relative to exercise is central to muscle anabolism. Exercise enhances muscle protein synthesis by sensitizing muscle to insulin- or amino acid-mediated anabolic actions, an effect that appears to peak in the first 3 hours after exercise147 and may persist 18 to 24 hours after an exercise bout.52 and 148 Such findings suggest that protein should be consumed close after exercise (or physical therapy) to take advantage of its sensitizing effect. The short-term complementary effects of exercise and protein supplementation were underscored in long-term studies as well.

This would be consistent with recent fMRI (e.g. Ress et al., 2000 and Munneke et al., 2010) and animal research (e.g. Chen et al., 2008). Second, the relationship between N2pc and intertrial priming we identify is probably limited to feature priming. Dimension priming can be observed in experiments where there are multiple manners in which the Selleck LDK378 target can be defined (for example, when red items of any shape are targets and so are diamonds of any color). Under these circumstances there is a performance benefit when the target is defined in the same dimension in sequential trials (e.g.

Found and Müller, 1996 and Müller et al., 2004). Dimension priming is apparent even when a target is presented by itself ( Goolsby and Suzuki, 2001 and Mortier et al., 2005), a situation where the N2pc is not elicited ( Luck and Hillyard, 1994b). This dissociates dimension priming from the attentional mechanisms that underlie the N2pc, and the implication is that feature priming might reflect different underlying processes than those involved in dimension priming. However, the idea that dimension priming may fundamentally differ from feature priming is not far-fetched. The two types of priming are known to have very different characteristics: dimension priming has a substantially find more larger and more reliable impact on search ( Found and Müller, 1996, Müller et al., 1995 and Becker, 2008), and

whereas dimension priming appears to be cognitively penetrable ( Müller et al., 2003) feature priming seems rather automatic ( Maljkovic and Nakayama, 1994). Moreover, the

two types of priming appear additive: the magnitude of feature priming does not vary as a function of whether dimensional context changes ( Olivers and Meeter, 2007). The current paper focuses on the impact of perceptual ambiguity on feature priming, with the N2pc acting as an indirect index of ambiguity. This is subtly distinct from the investigation of priming on the mechanisms indexed in the N2pc, which has been the focus of other recent studies. Eimer et al. (2010) have demonstrated that the N2pc occurs more quickly when target and distractor colors repeat between trials, suggesting a speeding of target 4-Aminobutyrate aminotransferase selection, and that this occurs even under conditions of relatively low perceptual ambiguity. We did not find the same pattern in the distractor-absent condition of the current study (i.e. the N2pc did not vary much as a function of intertrial contingency; see Fig. 3), but this likely reflects a fundamental difference in experimental designs: in Eimer et al. (2010) the target was defined by color, whereas in the current study the target was defined by shape and color was effectively irrelevant, likely rendering color priming less effective. Similar to Eimer et al. (2010), but in the context of dimension priming, Töllner et al.

Gene deletion is a frequent mechanism of LKB1 loss, which can be assessed by CN [30]. The fact that the LKB1 mutant group also had lower CN is consistent with the common two-hit model for tumorigenesis which Obeticholic Acid chemical structure requires an individual to be heterozygous for a mutant tumor suppressor gene to lose the normal allele in order for tumor development to occur, which is frequently achieved through deletion of the normal allele. Based on clear evidence in animal models that LKB1 haploinsufficiency accelerates KRAS driven lung cancer in mice [6], even a single copy inactivation of LKB1

might be oncogenic. A striking result from murine melanocyte models showed that somatically LKB1 inactivation and KRAS activation can induce highly metastatic melanoma with 100% penetrance, suggesting that LKB1 inactivation can greatly facilitate recurrence, especially in the context of RAS activation [31]. Studies on effects of KRAS alteration on metastasis in NSCLC are less conclusive than of LKB1. A recent report [32] on a specific stage IV NSCLC patient population indicated that KRAS was not associated with increased brain metastases; however, the result cannot be extrapolated directly

to the surgically treated NSCLC patient population Buparlisib clinical trial such as in the current study where the goal is prediction of future brain metastasis. The current study assessed the effect of LKB1 and KRAS in the same

model, and may clarify that brain metastasis is part of the adverse outcomes of the combined LKB1/KRAS abnormality. CN might be a good proxy for LKB1 mutation, supported by our result that the mutated group is associated with reduced CN. It is also possible that a combination of these events is at work in inducing cancers and tumor invasion. Finding the best measurement that can adequately predict brain metastasis and is relatively straightforward to estimate in the clinical setting is very helpful in patient management. The current study has limitations inherent to retrospective genomic analyses of clinical outcomes. The overall number of brain metastases was limited and the sample size was modest. It is therefore important to put the current study in the context of prior case reports of brain relapses in lung cancer. It is well established that the rate Tyrosine-protein kinase BLK of brain metastasis in lung cancer is associated with both increasing tumor stage and adenocarcinoma histology. While autopsy series have reported incidence as high as 54% [33] in lung adenocarcinoma, surgical case series of mixed histologic types have generally documented lower rates of brain recurrence in a stage specific manner. A large study by Figlin reported rates as low as 7% in a population of surgically treated patients of all histologic subtypes which is comparable to the rate of 9.7% seen in the current analysis [34].

Two periods can be distinguished: one was from 1900 to 1950, when the annual rate of increase in total zinc in the sediments was 2.5 μg g−1 y−1, and the other from 1950 to 1990, when the annual rate of increase of zinc in the sediments fell to 1.5 μg g−1 y−1. Several authors

relate the elevated zinc concentration in sediments to anthropogenic discharges to the aquatic environment ( Zhu et al. 2001, Taylor & Kesterton 2002, Bi 2003, Dassenakis et al. 2003, Wu et al. 2004, Dong et al. 2004, Yuan et al. 2004, Abd El-Azim & El-Moselhy 2005, Saad & Ahdy 2006, Huang et al. 2007, Luo et al. 2008). As long as Nozha Hydrodrome received untreated sewage from the surrounding urban areas, the rise in zinc concentrations in the sediments reflected the progressive expansion in Buparlisib mouse urbanization with time during the period from 1900 to 1990. In 1990, the municipality of Alexandria city completed the construction

of the Nozha district sewer system and the new East Wastewater Treatment Plant (EWTP) that serves the southern and western districts of the city. After the implementation of the sewer system and sewage treatment plant, much of the discharge of untreated domestic effluents BIBF 1120 mw to Nozha Hydrodrome stopped (WWCG 1992). Since then, and despite the ongoing urbanization around the Hydrodrome, the zinc concentration in the sediments has been decreasing at a rate of 1.5 μg g−1 y−1. The point of determining the concentrations

of zinc and cadmium in the mobile and residual phases was to assess the stability of the studied metals in the solid phase. The similar vertical distribution patterns (temporal behaviour) for the concentrations of the metals in the different phases indicate that there is a slow or probably no mobilization with time and that the metals tend to be trapped in the GNA12 solid phase. By contrast, an insignificant relationship indicates mobilization of the metal from the solid to the dissolved phase. To test the potential mobilization from sediment to water the average cosine θ coefficients (Rphases) for zinc and cadmium were calculated. This measure represents the relationship between the mobile phases and the residual phase of a metal with time. The average Rphases for zinc concentrations in sediment is 0.9 (Figure 2). This highly significant relationship, together with the environmental conditions prevailing in Nozha Hydrodrome – pH=8.9 (Youssef & Masoud 2004) and DO=6.02 mg l−1 (Saad & Safty 2004) – suggests that zinc tends to be trapped in the sedimentary compartment. This interpretation could also be inferred from the similarity of the patterns of the vertical distribution curves for zinc in the different phases (Figure 2). Moreover, the average concentration of dissolved zinc in Nozha Hydrodrome water is 8.1 μg 1−1 ( Saad 1987).

However, previous studies have found evidence for parallel processing of nociceptive stimuli in S1 and S2 (Liang et al., 2011; Ploner Small molecule library et al., 2009), so differences in latency of S1 and S2 coding seem unlikely. Finally, Porro et al.’s location judgements differed from ours in two respects. They used a restricted portion of the hand dorsum between the thumb and index that was not stimulated in our study. Their participants named which of four locations was stimulated, while our participants judged only the proximal/distal dimension of any of 16 stimuli. These differences in stimulation may account for the different results. Additional studies are required to investigate whether S1 and S2 are differentially

involved in different types of location judgement and to compare the effects of single-pulse TMS to S1 and S2 applied at various latencies after nociceptive stimulation. Nevertheless, our study also has limitations. First, the effect observed is relatively small, amounting to a 6.25% decrease in accuracy of intensity judgements following S2 stimulation, relative to vertex control. Pain intensity is notoriously variable, even when nociceptive input remains constant (e.g., Iannetti et al., 2005). Thus, while our results suggest that S2 is involved in the precision or discriminative coding of pain

intensity, the clinical importance of this effect remains to be determined. Moreover, clinical interventions generally aim at reducing pain levels, rather than reducing sensitivity to pain. In particular, the absence of any TMS-induced bias in perceived pain level AZD9291 in our data suggests caution about any possible S2 interventions to reduce chronic pain. However, our result does help to answer a classic question in the basic science underlying pain. The question regarding whether parts of the ‘pain matrix’ produce nociceptive sensations and, if so, which ones, has long been controversial. Intracranial microstimulation studies previously suggested that only the insula and opercular regions were involved in the feeling of pain, because these Tolmetin are the only areas which sometimes can evoke pain sensations when stimulated (Ostrowsky et al.,

2002). Our results provide direct and causal evidence that S2 is also involved in coding pain intensity. Second, invasive recording and fMRI studies in humans show nociceptive-related activity both on the S2 surface (e.g., Mazzola et al., 2012), and more deeply in the parietal operculum and insula (e.g., Frot et al., 2007). Given the depth and spatial specificity of TMS effects (Jalinous, 1991) presumably our S2 stimulation mainly affected the superficial area of S2. Our results cannot therefore clarify whether deeper parts of S2, and surrounding operculo-inusular regions also contribute to pain perception. This comment of course applies to other TMS studies of S2, which used similar localisation methods to ours (Bolognini et al., 2011; Kanda et al., 2003).