Difference between revisions of "7° Clinical case: Brainstem neoplasm in Orofacial pain"

Latest revision as of 17:15, 19 October 2024

7° Clinical case: Brainstem neoplasm in Orofacial pain

Article by Gianni Frisardi

Abstract:The brainstem, a crucial structure connecting the brain to the spinal cord, plays a vital role in sensory, motor, and autonomic functions. This chapter explores a clinical case from 1995 involving a 60-year-old woman, pseudonymously named 'Capsaicin,' who presented with chronic orofacial pain, burning mouth syndrome (BMS), and a history of maxillofacial prosthetic rehabilitation. Initial gnathological and neurological tests did not reveal significant abnormalities, leading to diagnostic uncertainty. However, persistent symptoms, exacerbated by spicy food, raised suspicion of a deeper neurological pathology. The application of the "Coherence Demarcator" model failed to identify a definitive diagnosis, prompting further investigation.

Subsequent MRI scans revealed a brainstem schwannoma, confirming the presence of severe organic neurological damage. Additionally, the involvement of TRPV1 (Transient Receptor Potential Vanilloid 1) channels was highlighted as a possible link between capsaicin-induced pain and neuroinflammation. This case underscores the importance of considering neuro-immune interactions and the limitations of traditional diagnostic frameworks such as the RDC/TMD when addressing complex orofacial pain.

The case emphasizes the need for a more integrated diagnostic approach, one that accounts for rare neurological conditions like brainstem tumors, and suggests that future research focus on TRPV1’s role in pain modulation and neuroinflammation. Capsaicin's paradoxical effect, both as a pain exacerbator and potential therapeutic agent, serves as a reminder of the intricacies in understanding chronic pain conditions.

Introduction

The brain stem is the caudal portion of the brain that connects the diencephalon to the spinal cord and cerebellum.^[1] The brainstem mediates the sensory and motor pathways between the spinal cord and the brain and contains the nuclei of the cranial nerves, the ascending reticular activating system (ARAS), and the autonomic nuclei. It controls brainstem reflexes and the sleep-wake cycle and is responsible for autonomous control of the cardiovascular, respiratory, digestive and immune systems. Brainstem dysfunction can result from various acute or chronic insults, including stroke, infectious, cancer, inflammatory, and neurodegenerative diseases. In the context of critical illness, the brain stem can be susceptible to various insults that can be classified as structural and non-structural in origin. Brainstem dysfunction can therefore contribute to impaired consciousness, cardiocirculatory and respiratory insufficiency and therefore to increased mortality ^[2]^[3]^[4]^[5] and especially manifest as orofacial pain (OP).Brainstem dysfunction in critically ill patients:

These important premises extracted from an interesting article by Sarah Benghanem^[6] are essential details, expression of a clinical experience which led the author of the chapter to scientific and epistemological reflections on the typology of language to be used in the creation of diagnostic models. and consequently to found Masticationpedia. One cannot, personal and responsible assertion of the author of the chapters, slavishly follow an axiom, a protocol such as the DRC or whatever and risk an error of differential diagnosis which can cost the life of a human being. If there is a gap in the model, which we will demonstrate during the implementation of Masticationpedia, then it should be noted as an anomaly, analyzed and eliminated or at least modified otherwise it is not a question of paradigmatic progress but only of intensive progress.

Presentation of the clinical case

It was the year 1995 when the 60-year-old female patient, who we will call with a fancy name 'Capsaicin' (we will understand the reason below) presented herself to our observation reporting bilateral diffuse orofacial pain in the temporal muscles region and in the occipital region , in addition, to the presence of burning mouth (BMS), for more than 10 years. The pain lasted for hours especially at night and did not occur cyclically. The patient was the bearer of a long-standing upper and lower ceramic fixed prosthetic rehabilitation with various fractures of the ceramic structure and wear veneers on the remaining natural teeth. However, no occlusal discrepancies were found in the prosthetic rehabilitation, but a release plate was performed by other health professionals to be used at night. The patient reported pain even with the plate inserted and was initially considered to be affected by Atypical Orofacial Pain (AOP) with a strong psychosomatic component and subsequently, according to the RDC protocol, affected by 'Temporomandibular Disorders'.

Having come to our observation, as per the Masticationpedia protocol, the main gnathological tests were performed, such as paraocclusal axiography of the condylar tracings and an interferential EMG of the masseter muscles. In this case, an ATM CT was not requested, much less an MR. We present in a schematic and representative way reporting some paragraphs exposed in the previous chapters the Masticationpedia protocol in its schematization as: assertions in the dental, neurological context and finally the diagnostic conclusion through the 'Demarcator $\tau$ ':

Significance of contexts

For the dental context we will have the following sentences and statements to which we give a numerical value to facilitate the treatment and that is $\delta _{n}=[0|1]$ where $\delta _{n}=0$ indicates 'normality' and $\delta _{n}=1$ 'abnormality and therefore positivity of the report:

$\delta _{1}=$ Paraocclusal axiographic tracing of the right condyle, negative in Figure 1, Normality, negative report

$\delta _{2}=$ Paraocclusal axiography tracing of the left condyle, negative in Figure 2, Normality, negative report

$\delta _{3}=$ Symmetric EMG interference pattern in Figure 5. Normality, negative report

Figure 1: Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline , h) consular hinge axis in maximum intercuspidation,
Figure 2: $\delta _{2}$ Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline.
Figura 3: $\delta _{3}$ Interferential EMG of right (top) and left (bottom) masseter muscles. Amplitude 200μV per division, time division 100 msec

The sentence $\Im _{o}$ (dental context) with a number $n\geq 1$ of other logically compatible statements $(\delta _{1},\delta _{2},.....\delta _{n}\ )$ determine the union and coherence between them $\Im _{o}\cup \{\delta _{1},\delta _{2}.....\delta _{n}\}$ and are represented with a mathematical formalism to facilitate the diagnostic dialectic in the following way $\Im _{o}\cup \{\delta _{1},\delta _{2}.....\delta _{n}\}\rightarrow \Im _{o}\cup \{0,0.....0\}=0$ which represents the average of the individual assertions reported. The average has been designed because it can often happen that some tests give answers with negative reporting to which to give the value $\delta _{n}=0$ . The result in this case is $\delta _{n}=0$ and contextually derives the coherent affirmation of the sentence $\Im _{o}$ in which it is argued that the symptomatology of the 'Capsaicin' patient is not determined by the presence of a TMDs.

In the neurological context we will therefore have the following sentences and assertions to which we obviously give, as for the dental context, a numerical value to facilitate the treatment and that is $\gamma _{n}=[0|1]$ where i $\gamma _{n}=0$ indicates 'normality' and $\gamma _{n}=1$ 'abnormality' and therefore positivity of the report:

$\gamma _{1}=$ _bRoot-MEPs symmetrical in amplitude and latency in Figure 4, $\gamma _{1}=0\longrightarrow$ Normality, negative report

$\gamma _{2}=$ Jaw jerk symmetrical in amplitude and in latency in Figure 8, $\gamma _{2}=0\longrightarrow$ Normality, negative report

$\gamma _{3}=$ Symmetry in duration of the masseter silent period in Figure 6, $\gamma _{3}=0\longrightarrow$ Normality, negative report

Consequently even in sentence $\Im _{n}$ with a number $n\geq 1$ of other logically compatible assertions $(\gamma _{1},\gamma _{2},.....\gamma _{n}\ )$ they determine the union and coherence between them $\Im _{n}\cup \{\gamma _{1},\gamma _{2}.....\gamma _{n}\}$ and the formal representation will be similar to that of the dental context. $\Im _{n}\cup \{\gamma _{1},\gamma _{2}.....\gamma _{n}\}\rightarrow \Im _{n}\cup \{0,0.....0\}=0$ with contextual coherent affirmation of the sentence $\Im _{n}$ in which it is argued that the symptomatology of the patient 'Capsiacin' does not electrophysiologically highlight any element that could indicate a correlation between orofacial pain and neuromotor damage.

Figura 4: $\gamma _{1}=$ Motor trigeminal roots evoked potentials bRoot-MEPs.
Figura 5: $\gamma _{1}=$ Mandibular tendon reflex (jaw jerk) recorded on the right (top) left (bottom) masseter muscles
Figura 6: $\gamma _{1}=$ Mechanical silent period recorded on masseter muscles right (top black corresponds to mean) left (bottom black corresponds to mean)

«In this scenario both the statements

\Im _{o}

and

\Im _{n}

are compatible, consistent and therefore true until a 'Consistency Demarcator 'τ' is found which highlights the greater weight in terms of clinical severity.»

Coherence Demarcator $\tau$

The $\tau$ is a representative clinical specific weight, complex to research and develop because it varies from discipline to discipline and for pathologies, essential for not colliding logical assertions $\Im _{o}$ and $\Im _{n}$ in diagnostic procedures and fundamental for initializing the decryption of the machine code. Basically it allows to confirm the coherence of one union $\Im \cup \{\delta _{1},\delta _{2}.....\delta _{n}\}$ with respect to another $\Im \cup \{\gamma _{1},\gamma _{2}.....\gamma _{n}\}$ and vice versa, giving greater weight to the seriousness of the assertions and of the report in the appropriate context. Sometimes the doctor is faced with a series of positive reports to which he must give the right weight, he must consider the positivity of a report which highlights, for example, an osteoarticular renewal of the TMJ cannot have the same weight as a positivity of a report confirming latency delay of a trigeminal reflex. The demarcation $\tau$ weight, therefore, gives more significance to the more serious assertions in the clinical context from which they derive and therefore beyond the positivity of the assertions $\delta _{n}=1$ or which $\gamma _{n}=1$ in any case are always verified and respected, these must be multiplied by a $\tau =[0|1]$ where $\tau =0$ indicates 'Low seriousness ' while $\tau =1$ 'Severe Gravity'.

A consistency marker could be defined as a real number between 0 and 1 in the event that we have more than two reports and therefore a number close to zero would correspond to a report of 'low severity' while a number close to one to a reporting of 'severe severity'. But this is redundant. What is done is to compare the reports two by two and then use the values we have indicated to express the 'Gravity'.

So to recap we have:

$\Im _{o}\cup ({{\bar {\delta }}_{n})}\tau _{o}+\Im _{n}\cup ({{\bar {\gamma }}_{n})}\ \tau _{n}=\Im _{d}$

where

${{\bar {\delta }}_{n}}=$ average of the value of the clinical statements in the dental context which in our case in question is ${{\bar {\delta }}_{n}}=0$

${{\bar {\gamma }}_{n}}=$ average of the value of clinical statements in the neurological context and therefore ${{\bar {\gamma }}_{n}}=0$

$\tau _{o}=0$ reporting of low severity of the dental context

$\tau _{n}=0$ reporting of low severity of the neurological context

where the 'demarcator of coherence $\tau$ marker' will define the diagnostic path as follows $\Im _{o}\cup 0\cdot 0+\Im _{n}\cup 0\cdot 0=\Im _{d}\longrightarrow \Im _{d}=\Im _{n}\cup 0\cdot 0\longrightarrow \Im _{d}=0$

As we will see during the exposition of the clinical cases in Masticationpeida, one will be faced with similar clinical situations in which you are in the presence of orofacial pain but the reporting results in specialist contexts will be of low severity such as to cancel the discriminate value of $\tau$ .

«This formal logical syntax procedure has allowed us to verify how the clinical conclusion in the dental and neurological context is null and

\Im _{o}=0

and

\Im _{n}=0

. This means that the diagnosis is unknown

\Im _{d}=0

»
(The fact remains that the patient continues to experience orofacial pain and particularly with exacerbation after a spicy dinner.)

In the rare but real clinical cases in which the ' $\tau$ Demarcator' is reset, we are motivated to carry out an even more extensive and in-depth check, hypothesizing serious pathologies ^[7]^[8] including head and neck tumors which simulate symptoms that can be superimposed on other pathologies. It is a serious mistake to consider the patient with such clinical manifestations and the simultaneous absence of systemic anomalies as a patient with psychosomatic disorders. Elements of psychophysical damage can certainly coexist but, if the 'Demarcator' fails, it is mandatory to deepen the diagnostics. In fact, head and neck cancer (HNC) affects over 890,000 people each year worldwide and has a 50% mortality rate. Aside from poor survival, HNC pain impairs eating, drinking and speaking, severely reducing quality of life. The different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between tumors^[9]. Glial and immune modulation of the tumor microenvironment, as well explained in the article by Ye et al., influences not only cancer progression but also pain signaling among which transient receptor potentials contained in gustatory somatosensory systems are an example.^[10]^[11]

For the above reasons and for the persistence of the OP, the difficulty in concluding a certain diagnosis, the absence of organic-functional discrepancies and the zeroing of the ' $\tau$ Demarcator', an MR of the brain was requested.

Imaging showed a neoplastic mass most likely a brainstem schwannoma with invagination of the occipital frame. (figure 7 and 8)

Figura 7: Axial section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame
Figura 8: Coronal section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame

«Unfortunately, the patient died a few years later of trochoencephalic neuroma.»
(.......leaving a doubt, that of the correlation between pain and capsaicin as reported by the patient on the occasion of a spicy diet.)

Thoughts and conclusions

The mammalian gustatory system is made up of taste buds, which are clusters of 50-100 taste cells found throughout the oral cavity. On the tongue, which is the central topic of the case report 'Capsaicin', the taste buds are located on circumvallate, foliate and fungiform papillae. Taste cells synapse with afferent fibers from branches of the cranial facial (CN VII), glossopharyngeal (CN IX) and vagus (CN X) nerves which, in turn, transmit information to the central nervous system (CNS) about gustatory attributes , intensity and hedonic nature. ^[12]^[13]^[14] The taste buds are embedded in a stratified squamous epithelium, which contains somatosensory branches of the trigeminal (CN V), glossopharyngeal (CN IX), and vagus (CN X) cranial nerves. Information from these general sensory nerves provides information to the central nervous system about mechanical, thermal, and pain stimuli.^[11]^[15] Painful stimuli can result from strong or sharp mechanical stimuli, abnormally high or low temperatures, or chemical stimuli such as capsaicin, which is found in hot peppers and causes a burning taste sensation through the intervention of Transient Receptor Potentials (TRPs).^[10] These TRPs are divided into six subfamilies including TRPV1, which we are interested in to hypothesize the phenomenon of pain exacerbation of the patient 'Capsaicin' in spicy diet.

Figura 9: TRPV1, VR1, transient receptor potential cation channel subfamily V member 1. Wikipedia

TRPV1 and neuroinflammation

TRPV1s constitute a distinct subset of non-selective cation channels (Transient Receptor Potential) responsible for many cellular responses. They are activated by various stimuli such as acids, extracellular protons, high temperatures, plant toxins and vanilloid agonists. The TRPV1s present in mammals can be considered as sensors of chemical substances (capsaicin), thermal substances (heat) and/or harmful stimuli. The activation of TRPV1 leads to the depolarization necessary for the propagation of action potentials along the axons of the dorsal root ganglia (DRG) of neurons that project to the spinal cord and consequently also to the nociceptive trigeminal nuclei. What makes TRPV1 so critical for pain signaling is undeniably its ability to transduce inflammatory signals into electrical signals with the activation of both voltage-gated sodium and calcium channels located at the nociceptor level.^[16] The implication of TRPV1 in pathological pain prompted a careful study of these proteins. The limiting element in pharmacological research at the application level was the peculiarity of the TRPV1 channel, i.e. its polymodal mechanism of activation (heat, capsaicin, pH), which led to a high level of complexity in the design of a specific modality inhibitor.

The interaction between neurons and immune cells is a well-known phenomenon.^[17] TRPV1 plays its role, too, in neuroinflammation by being expressed in both neurons and immune cells. Significant importance should be given to the confirmed expression of TRPV1 in microglia and astrocytes, cells found in the vicinity of neurons. The neuro-immune axis is the site of production of neuroinflammatory molecules and receptors that interact between the two systems and ensure a complex response to external stimuli (or to the body's own pathologies). TRPV1 is said to contribute to microglia autophagy through its Ca²⁺ signaling, which leads to mitochondria-induced cell death. Basically, TRPV1 is a pro-apoptotic element.

Ligands

Antagonists

Antagonists block the activity of TRPV1, thereby reducing pain. Antagonists identified include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red. These agents could be beneficial if applied systematically.^[18] TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.^[19] This provides evidence that TRPV1 is the sole receptor for capsaicin.^[20] In humans, drugs that target TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.^[21]

Agonists

TRPV1 is activated by several agonists of natural origin.^[22] Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of the TRPV1-mediated release of inflammatory molecules upon exposure to noxious stimuli.

An interesting study by the Tominaga group extends the list of TRPV1 interactions also to Anoctamin 1 (ANO 1) also known as Transmembrane member 16A (TMEM16A) a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.

These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.

TRPV1 is activated by several agonists of natural origin. Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of TRPV1-mediated release of inflammatory molecules following administration. exposure to noxious stimuli.

An interesting study by the Tominaga group extends the list of TRPV1 interactions also to Anoctamin 1 (ANO 1) also known as Transmembrane member 16A (TMEM16A)^[23] a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga^[23] highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.

These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.

«Why, then, did the capsaicin taken in the food reported by the patient generate an exacerbation of pain?»
(....for chronic damage to the brainstem nerve fibers with consequent alteration of the neuro-immune homeostasis and contextual paradoxical effect of the analgesic action of capsaicin.)

In these cases, as stated in other chapters, we are dealing with an epistemological profile in which the basic knowledge, what we have called $KB$ (Knowledge Base) corresponds to a temporal limit of scientific information and consequently serious difficulties of differential diagnosis. We had to wait 12 years to reach an ezipathogenetic conclusion overwritten from 1995, a period in which the patient 'Capsaicin' was being treated, to 2007 in which a research gave the elements to suspect the presence of an organic neurological damage with manifestations of pain and burning mouth.^[24] Burning mouth syndrome (BMS) is often an idiopathic, chronic intractable pain condition, affecting 1.5-5.5% of middle-aged and older women. We investigated heat and capsaicin receptor TRPV1, and its regulatory nerve growth factor (NGF), in BMS. BMS patients (n=10) and controls (n=10) were evaluated for baseline and post-topical capsaicin pain scores, and their tongue biopsies were immunostained for TRPV1, NGF, and neurofilament structural nerve markers and periphery. Nerve fibers penetrating the epithelium were less abundant in the BMS (p<0.0001), indicating small fiber neuropathy. TRPV1-positive fibers were overall significantly increased in BMS (p=0.0011), as were NGF fibers (p<0.0001) and NGF staining of basal epithelial cells (p<0.0147). There was a significant correlation between baseline pain score and TRPV1 (p=0.0143) and NGF (p=0.0252) fibers. A significant correlation was observed between baseline and post-capsaicin pain (p=0.0006).

«We are sure we know everything»

Bibliography & references

↑ Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010;22(1):iv. doi: 10.1176/jnp.2010.22.1.iv.
↑ Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med août. 1999;160(2):458–465. doi: 10.1164/ajrccm.160.2.9810073.
↑ Sharshar T, Porcher R, Siami S, Rohaut B, Bailly-Salin J, Hopkinson NS, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med août. 2011;39(8):1960–1967. doi: 10.1097/CCM.0b013e31821b843b.
↑ Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl. 2003;362(9398):1799–1805. doi: 10.1016/S0140-6736(03)14899-4.
↑ Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T. Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med. 2016;37(2):333–345. doi: 10.1016/j.ccm.2016.01.013.
↑ Benghanem S, Mazeraud A, Azabou E, Chhor V, Shinotsuka CR, Claassen J, Rohaut B, Sharshar T. Brainstem dysfunction in critically ill patients. Crit Care. 2020 Jan 6;24(1):5. doi: 10.1186/s13054-019-2718-9.PMID: 31907011
↑ Chloé Gibeili, Arek Sulukdjian, Audrey Chanlon, Nathan Moreau. Unilateral glossodynia as a harbinger of an occult cerebellopontine angle tumour. BMJ Case Report.. 2022 Apr 12;15(4):e249408.doi: 10.1136/bcr-2022-249408.
↑ Irappa Madabhavi, Malay Sarkar, K S Sandeep, Mitul Modi. Isolated trigeminal neuralgia: An early weird presentation of carcinoma breast. J Cancer Res Ther. . 2022 Oct-Dec;18(6):1820-1822.doi: 10.4103/jcrt.JCRT_712_20.
↑ e Y, Jensen DD, Viet CT, Pan HL, Campana WM, Amit M, Boada MD.Advances in Head and Neck Cancer Pain.YJ Dent Res. 2022 Aug;101(9):1025-1033. doi: 10.1177/00220345221088527. Epub 2022 Apr 13.PMID: 35416080
↑ ^10.0 ^10.1 Ramsey, I.S., M. Delling, and D.E. Clapham. 2006. An introduction to TRP channels. Annu Rev Physiol, 68: 619–647.
↑ ^11.0 ^11.1 Julius, D. 2013. TRP channels and pain. Annu Rev Cell Dev Biol, 29: 355–584.
↑ Gutierrez, R., and S.A. Simon. 2011. Chemosensory processing in the taste-reward pathway. Flavour Fragr J, 26(4): 231–238.
↑ Carleton, A., R. Accolla, and S.A. Simon. 2010. Coding in the mammalian gustatory system. Trends Neurosci, 33(7): 326–334.
↑ Vincis, R. and A. Fontanini. 2016. A gustocentric perspective to understanding primary sensory cortices. Curr Opin Neurobiol, 40: 118–124
↑ Kaneko, Y., and A. Szallasi. 2014. Transient receptor potential (TRP) channels: A clinical perspective. Br J Pharmacol, 171(10): 2474–2507.
↑ Bourinet E, Altier C, Hildebrand M E, Trang T, Salter MW, Zamponi GW. Calcium permeable ion channels in pain signaling. Physiol Rev 2014; 94: 81–140.
↑ Jacobson A, Yang D, Vella M, Chiu IM (May 2021). "The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes". Mucosal Immunology. 14 (3): 555–565. doi:10.1038/s41385-020-00368-1. PMC 8075967. PMID 33542493.
↑ Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". Trends in Molecular Medicine. 15 (1): 14–22. doi:10.1016/j.molmed.2008.11.004. PMID 19097938.
↑ Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (July 2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". The European Journal of Neuroscience. 22 (2): 361–370. doi:10.1111/j.1460-9568.2005.04227.x. PMID 16045489. S2CID 24664751.
↑ Story GM, Crus-Orengo L (2008). "Feel the Burn". American Scientist. 95 (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. Archived from the original on January 19, 2008.
↑ Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". Current Pharmaceutical Design. 14 (1): 32–41. doi:10.2174/138161208783330754. PMID 18220816.
↑ Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [1]doi:10.1007/7355_2015_98.
↑ ^23.0 ^23.1 Yasunori Takayama, Daisuke Uta, Hidemasa Furue, and Makoto Tominaga. Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons. Proc Natl Acad Sci 2015; 21; 112(16): 5213-5218. doi: 10.1073/pnas.1421507112. Epub 2015 Apr 6.
↑ Z Yilmaz, T Renton, Y Yiangou, J Zakrzewska, I P Chessell, C Bountra, P Anand. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep;14(9):864-71. doi: 10.1016/j.jocn.2006.09.002. Epub 2007 Jun 19.

[1] Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010;22(1):iv. doi: 10.1176/jnp.2010.22.1.iv.

[2] Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med août. 1999;160(2):458–465. doi: 10.1164/ajrccm.160.2.9810073.

[3] Sharshar T, Porcher R, Siami S, Rohaut B, Bailly-Salin J, Hopkinson NS, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med août. 2011;39(8):1960–1967. doi: 10.1097/CCM.0b013e31821b843b.

[4] Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl. 2003;362(9398):1799–1805. doi: 10.1016/S0140-6736(03)14899-4.

[5] Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T. Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med. 2016;37(2):333–345. doi: 10.1016/j.ccm.2016.01.013.

[6] Benghanem S, Mazeraud A, Azabou E, Chhor V, Shinotsuka CR, Claassen J, Rohaut B, Sharshar T. Brainstem dysfunction in critically ill patients. Crit Care. 2020 Jan 6;24(1):5. doi: 10.1186/s13054-019-2718-9.PMID: 31907011

[7] Chloé Gibeili, Arek Sulukdjian, Audrey Chanlon, Nathan Moreau. Unilateral glossodynia as a harbinger of an occult cerebellopontine angle tumour. BMJ Case Report.. 2022 Apr 12;15(4):e249408.doi: 10.1136/bcr-2022-249408.

[8] Irappa Madabhavi, Malay Sarkar, K S Sandeep, Mitul Modi. Isolated trigeminal neuralgia: An early weird presentation of carcinoma breast. J Cancer Res Ther. . 2022 Oct-Dec;18(6):1820-1822.doi: 10.4103/jcrt.JCRT_712_20.

[9] Y, Jensen DD, Viet CT, Pan HL, Campana WM, Amit M, Boada MD.Advances in Head and Neck Cancer Pain.YJ Dent Res. 2022 Aug;101(9):1025-1033. doi: 10.1177/00220345221088527. Epub 2022 Apr 13.PMID: 35416080

[:0-10] 10.0 ^10.1 Ramsey, I.S., M. Delling, and D.E. Clapham. 2006. An introduction to TRP channels. Annu Rev Physiol, 68: 619–647.

[:1-11] 11.0 ^11.1 Julius, D. 2013. TRP channels and pain. Annu Rev Cell Dev Biol, 29: 355–584.

[12] Gutierrez, R., and S.A. Simon. 2011. Chemosensory processing in the taste-reward pathway. Flavour Fragr J, 26(4): 231–238.

[13] Carleton, A., R. Accolla, and S.A. Simon. 2010. Coding in the mammalian gustatory system. Trends Neurosci, 33(7): 326–334.

[14] Vincis, R. and A. Fontanini. 2016. A gustocentric perspective to understanding primary sensory cortices. Curr Opin Neurobiol, 40: 118–124

[15] Kaneko, Y., and A. Szallasi. 2014. Transient receptor potential (TRP) channels: A clinical perspective. Br J Pharmacol, 171(10): 2474–2507.

[16] Bourinet E, Altier C, Hildebrand M E, Trang T, Salter MW, Zamponi GW. Calcium permeable ion channels in pain signaling. Physiol Rev 2014; 94: 81–140.

[17] Jacobson A, Yang D, Vella M, Chiu IM (May 2021). "The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes". Mucosal Immunology. 14 (3): 555–565. doi:10.1038/s41385-020-00368-1. PMC 8075967. PMID 33542493.

[18] Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". Trends in Molecular Medicine. 15 (1): 14–22. doi:10.1016/j.molmed.2008.11.004. PMID 19097938.

[19] Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (July 2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". The European Journal of Neuroscience. 22 (2): 361–370. doi:10.1111/j.1460-9568.2005.04227.x. PMID 16045489. S2CID 24664751.

[20] Story GM, Crus-Orengo L (2008). "Feel the Burn". American Scientist. 95 (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. Archived from the original on January 19, 2008.

[21] Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". Current Pharmaceutical Design. 14 (1): 32–41. doi:10.2174/138161208783330754. PMID 18220816.

[22] Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [1]doi:10.1007/7355_2015_98.

[:2-23] 23.0 ^23.1 Yasunori Takayama, Daisuke Uta, Hidemasa Furue, and Makoto Tominaga. Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons. Proc Natl Acad Sci 2015; 21; 112(16): 5213-5218. doi: 10.1073/pnas.1421507112. Epub 2015 Apr 6.

[24] Z Yilmaz, T Renton, Y Yiangou, J Zakrzewska, I P Chessell, C Bountra, P Anand. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep;14(9):864-71. doi: 10.1016/j.jocn.2006.09.002. Epub 2007 Jun 19.

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-{{Versions
+{{main menu}}{{ArtBy|autore=Gianni Frisardi}}
- | en = 7° Clinical case: Brainstem neoplasm in Orofacial pain
+'''Abstract:'''The brainstem, a crucial structure connecting the brain to the spinal cord, plays a vital role in sensory, motor, and autonomic functions. This chapter explores a clinical case from 1995 involving a 60-year-old woman, pseudonymously named 'Capsaicin,' who presented with chronic orofacial pain, burning mouth syndrome (BMS), and a history of maxillofacial prosthetic rehabilitation. Initial gnathological and neurological tests did not reveal significant abnormalities, leading to diagnostic uncertainty. However, persistent symptoms, exacerbated by spicy food, raised suspicion of a deeper neurological pathology. The application of the "Coherence Demarcator" model failed to identify a definitive diagnosis, prompting further investigation.
- | it = 7° Caso clinico: Neoplasia del tronco encefalico nel dolore orofacciale
- | fr = '7° Cas clinique : Tumeur du tronc cérébral dans Douleur orofaciale'
- | de = '7° Klinischer Fall: Hirnstammneoplasie bei orofazialen Schmerzen'
- | es = '7° Caso clínico: Neoplasia de tronco encefálico en dolor orofacial'
- | pt = <!-- portoghese -->
- | ru = <!-- russo -->
- | pl = <!-- polacco -->
- | fi = <!-- finlandese/suomi -->
- | ca = <!-- catalano -->
- | ja = <!-- giapponese -->
- }}
+Subsequent MRI scans revealed a brainstem schwannoma, confirming the presence of severe organic neurological damage. Additionally, the involvement of TRPV1 (Transient Receptor Potential Vanilloid 1) channels was highlighted as a possible link between capsaicin-induced pain and neuroinflammation. This case underscores the importance of considering neuro-immune interactions and the limitations of traditional diagnostic frameworks such as the RDC/TMD when addressing complex orofacial pain.
-[[File:Capsaicina.jpg|left|300x300px]]
+The case emphasizes the need for a more integrated diagnostic approach, one that accounts for rare neurological conditions like brainstem tumors, and suggests that future research focus on TRPV1’s role in pain modulation and neuroinflammation. Capsaicin's paradoxical effect, both as a pain exacerbator and potential therapeutic agent, serves as a reminder of the intricacies in understanding chronic pain conditions.
-In questo capitolo si presenta un caso di assoluta importanza epistemologica nel senso che evidenzia una lacuna nel processo diagnostico basato sull'evidenza based in medicine (EBM). Quest'ultimo termine, infatti, è legato in modo indissolubile alla conoscenza di base scientifica già conosciuto come <math>KB </math> ( Conoscenza di base).
-Lo <math>KB </math>, ovviamente, dipende dal progresso scientifico e dall'evoluzione tecnologica, metodologica ma anche filosofica in quanto l'interpretazione dei dati clinici in un modello probabilistico classico non può rappresentare appieno la realtà sottostante in quanto le variabili sono dipendetti e compatibili mentre in un modello quantistico le variabili sono indipendenti ed incompatibili. Questo cambiamento paradigmatico ci avrebbe permesso di fare diagnosi differenziale dettagliata e precoce senza aspettare la conoscenza di base sull'argomento specifico della capsaicina sul dolore.
-Questo capitolo è stata una pietra miliare che ha indotto l'autore alla realizzazione di Masticationpedia perchè questi casi si possano prendere in tempo giusto per garantire almeno una fine di vita relativamente serena e non in 10 anni di Dolore Orofacciale (OP) facendo la collezione di diagnosi errate.
+=== Introduction ===
+The brain stem is the caudal portion of the brain that connects the diencephalon to the spinal cord and cerebellum.<ref>Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010;22(1):iv. doi: 10.1176/jnp.2010.22.1.iv. </ref> The brainstem mediates the sensory and motor pathways between the spinal cord and the brain and contains the nuclei of the cranial nerves, the ascending reticular activating system (ARAS), and the autonomic nuclei. It controls brainstem reflexes and the sleep-wake cycle and is responsible for autonomous control of the cardiovascular, respiratory, digestive and immune systems. Brainstem dysfunction can result from various acute or chronic insults, including stroke, infectious, cancer, inflammatory, and neurodegenerative diseases. In the context of critical illness, the brain stem can be susceptible to various insults that can be classified as structural and non-structural in origin. Brainstem dysfunction can therefore contribute to impaired consciousness, cardiocirculatory and respiratory insufficiency and therefore to increased mortality <ref>Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. [https://www.atsjournals.org/doi/10.1164/ajrccm.160.2.9810073?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach.] Am J Respir Crit Care Med août. 1999;160(2):458–465. doi: 10.1164/ajrccm.160.2.9810073.</ref><ref>Sharshar T, Porcher R, Siami S, Rohaut B, Bailly-Salin J, Hopkinson NS, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med août. 2011;39(8):1960–1967. doi: 10.1097/CCM.0b013e31821b843b.</ref><ref>Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl. 2003;362(9398):1799–1805. doi: 10.1016/S0140-6736(03)14899-4. </ref><ref>Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T. Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med. 2016;37(2):333–345. doi: 10.1016/j.ccm.2016.01.013.</ref> and especially manifest as orofacial pain (OP).[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945639/ Brainstem dysfunction in critically ill patients]:
-{{ArtBy|autore=Gianni Frisardi}}
+<blockquote>These important premises extracted from an interesting article by Sarah Benghanem<ref>Benghanem S, Mazeraud A, Azabou E, Chhor V, Shinotsuka CR, Claassen J, Rohaut B, Sharshar T. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31907011/ Brainstem dysfunction in critically ill patients.] Crit Care. 2020 Jan 6;24(1):5. doi: 10.1186/s13054-019-2718-9.PMID: 31907011</ref> are essential details, expression of a clinical experience which led the author of the chapter to scientific and epistemological reflections on the typology of language to be used in the creation of diagnostic models. and consequently to found Masticationpedia. One cannot, personal and responsible assertion of the author of the chapters, slavishly follow an axiom, a protocol such as the DRC or whatever and risk an error of differential diagnosis which can cost the life of a human being. If there is a gap in the model, which we will demonstrate during the implementation of Masticationpedia, then it should be noted as an anomaly, analyzed and eliminated or at least modified otherwise it is not a question of paradigmatic progress but only of intensive progress. </blockquote>
-=== Introduzione ===
+====Presentation of the clinical case====
-Il tronco encefalico è la porzione caudale del cervello che collega il diencefalo al midollo spinale e al cervelletto.<ref>Hurley RA, Flashman LA, Chow TW, Taber KH. The brainstem: anatomy, assessment, and clinical syndromes. J Neuropsychiatry Clin Neurosci. 2010;22(1):iv. doi: 10.1176/jnp.2010.22.1.iv. </ref> Il tronco cerebrale media le vie sensoriali e motorie tra il midollo spinale e il cervello e contiene i nuclei dei nervi cranici, il sistema di attivazione reticolare ascendente (ARAS) e i nuclei autonomi. Controlla i riflessi del tronco encefalico e il ciclo sonno-veglia ed è responsabile del controllo autonomo del sistema cardiocircolatorio, respiratorio, digestivo e immunitario. La disfunzione del tronco cerebrale può derivare da vari insulti acuti o cronici, tra cui ictus, malattie infettive, tumori, infiammatorie e neurodegenerative. Nel contesto della malattia critica, il tronco cerebrale può essere suscettibile a vari insulti che possono essere classificati come origine strutturale e non strutturale. La disfunzione del tronco cerebrale può quindi contribuire alla compromissione della coscienza, all'insufficienza cardiocircolatoria e respiratoria e quindi all'aumento della mortalità <ref>Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med août. 1999;160(2):458–465. doi: 10.1164/ajrccm.160.2.9810073.</ref><ref>Sharshar T, Porcher R, Siami S, Rohaut B, Bailly-Salin J, Hopkinson NS, et al. Brainstem responses can predict death and delirium in sedated patients in intensive care unit. Crit Care Med août. 2011;39(8):1960–1967. doi: 10.1097/CCM.0b013e31821b843b.</ref><ref>Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet Lond Engl. 2003;362(9398):1799–1805. doi: 10.1016/S0140-6736(03)14899-4. </ref><ref>Mazeraud A, Pascal Q, Verdonk F, Heming N, Chrétien F, Sharshar T. Neuroanatomy and physiology of brain dysfunction in sepsis. Clin Chest Med. 2016;37(2):333–345. doi: 10.1016/j.ccm.2016.01.013.</ref>e soprattutto manifestarsi come dolore orofacciale (OP).[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945639/ Brainstem dysfunction in critically ill patients]:<blockquote>Queste importanti premesse estratte da un interessante articolo di Sarah Benghanem <ref>Benghanem S, Mazeraud A, Azabou E, Chhor V, Shinotsuka CR, Claassen J, Rohaut B, Sharshar T. Brainstem dysfunction in critically ill patients. Crit Care. 2020 Jan 6;24(1):5. doi: 10.1186/s13054-019-2718-9.PMID: 31907011</ref> sono dettagli essenziali espressione di una esperienza clinica che ha indotto  l'autore del capitolo a riflessioni scientifiche ed epistemologiche sulla tipologia di linguaggio da impiegare nella realizzazione di modelli diagnostici. e di conseguenza a fondare Masticationpedia. Non si può, personale e responsabile asserzione dell'autore del capitoli, seguire pedissequamente un assioma, un protocollo quale lo RDC o quant'altro e rischiare un errore di diagnosi differenziale che può costare la vita di un essere umano. Se c'è una lacuna nel modello, che dimostreremo nel corso dell'implementazione di Masticationpedia, allora va notata come anomalia, analizzata ed eliminata od almeno modificata altrimenti non si tratta di progresso paradigmatico ma soltanto di progresso intensivo. </blockquote>
+It was the year 1995 when the 60-year-old female patient, who we will call with a fancy name 'Capsaicin' (we will understand the reason below) presented herself to our observation reporting bilateral diffuse orofacial pain in the temporal muscles region and in the occipital region , in addition, to the presence of burning mouth (BMS), for more than 10 years. The pain lasted for hours especially at night and did not occur cyclically. The patient was the bearer of a long-standing upper and lower ceramic fixed prosthetic rehabilitation with various fractures of the ceramic structure and wear veneers on the remaining natural teeth. However, no occlusal discrepancies were found in the prosthetic rehabilitation, but a release plate was performed by other health professionals to be used at night. The patient reported pain even with the plate inserted and was initially considered to be affected by Atypical Orofacial Pain (AOP) with a strong psychosomatic component and subsequently, according to the RDC protocol, affected by 'Temporomandibular Disorders'.
-==== Presentazione del caso clinico ====
+Having come to our observation, as per the Masticationpedia protocol, the main gnathological tests were performed, such as paraocclusal axiography of the condylar tracings and an interferential EMG of the masseter muscles. In this case, an ATM CT was not requested, much less an MR. We present in a schematic and representative way reporting some paragraphs exposed in the previous chapters the Masticationpedia protocol in its schematization as: assertions in the dental, neurological context and finally the diagnostic conclusion through the 'Demarcator <math>\tau</math>':
-Era l'anno 1995 quando la paziente femmina di anni 60, che chiameremo con nome di fantasia 'Capsaicina' ( si capirà di seguito il motivo) si presentò alla nostra osservazione riferendo dolore oro facciale diffuso bilaterale in regione dei muscoli temporali ed in regione occipitale, oltre, alla presenza di bruciore della bocca (BMS), da più di 10 anni. Il dolore aveva una durata di ore specialmente notturna e non si presentava ciclicamente. La paziente era portatrice di una riabilitazione protesica fissa in ceramica superiore ed inferiore di vecchia data con varie fratture della struttura ceramica e faccette di usura sui restanti denti naturali. Non furono rilevate, comunque, discrepanze  occlusali nella riabilitazione protesica ma fu eseguito, da altri operatori sanitari, una placca di svincolo da impiegare di notte. La paziente riferiva dolore anche con la placca inserita ed è stata considerata, dapprima, affetta da Dolore Orofacciale Atipico (AOP) con forte componente psicosomatica e successivamente, secondo il protocollo RDC, affetta da 'Disordini Temporomandibulari'.
-Giunta alla nostra osservazione, come da protocollo Masticationpedia, sono stati eseguiti i principali test gnatologici quali assiografia paraocclusale dei tracciati condilari ed una EMG interferenziale dei muscoli masseteri. Non è stata, in questo caso, richiesta una TC della ATM tanto meno una MR. Presentiamo in modo schematico e rappresentativo riportando alcuni paragrafi esposti nei capitoli precedenti il protocollo Masticationpedia nella sua schematizzazione quale: asserzioni nel contesto odontoiatrico, neurologico ed in fine la conclusione diagnostica attraverso il 'Demarcatore <math>\tau</math>':
+=====Significance of contexts=====
+For the ''dental context'' we will have the following sentences and statements to which we give a numerical value to facilitate the treatment and that is <math>\delta_n=[0|1]</math> where <math>\delta_n=0</math> indicates 'normality' and <math>\delta_n=1</math> 'abnormality and therefore positivity of the report:
-===== Significatività dei contesti =====
+{{:F:Delta1}} Paraocclusal axiographic tracing of the right condyle, negative in Figure 1, Normality, negative report
-Per il '''contesto odontoiatrico''' avremo le seguenti frasi ed asserzioni a cui diamo un valore numerico per facilitare la trattazione e cioè <math>\delta_n=[0|1]</math> dove lo <math>\delta_n=0</math> indica 'normalità' e <math>\delta_n=1</math> 'anormalità e dunque positività del referto:
-{{:F:Delta1}} Tracciato assiografico paraocclusale del condilo di destra negativo in Figura 1, <math>\delta_1 =0\longrightarrow</math> Normalità, positività del referto
+{{:F:Delta2}} Paraocclusal axiography tracing of the left condyle, negative in Figure 2, Normality, negative report
-{{:F:Delta2}} Tracciato assiografico paraocclusale del condilo di sinistra negativo in Figura 2, <math>\delta_2 =0\longrightarrow</math> Normalità, positività del referto
+<math>\delta_3=</math> Symmetric EMG interference pattern in Figure 5. Normality, negative report<center>
+<gallery widths="230" heights="200" perrow="3" slideshow""="">
-<math>\delta_3=</math> Schema di interferenza EMG asimmetrico nella Figura 5, .<math>\delta_3 =0\longrightarrow</math> Normalità, positività del referto<center>
+File:Assiografia dx modificata.jpeg|'''Figure 1:''' Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline , h) consular hinge axis in maximum intercuspidation,
-<gallery widths="250" heights="200" perrow="3" slideshow""="">
+File:Assiografia sn.jpg|'''Figure 2:''' <math>\delta_2</math> Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline.
-File:Assiografia dx modificata.jpeg|'''Figura 2:''' <math>\delta_1</math> Tracciato assiografico paraocclusale consolare destro: a) Centro asse cerniera, b) piano asse orbitale, c) tracciato protruso, d) tracciato mediotrusivo, e) area dei cicli masticatori mediotrusivi, f) area cicli masticatori laterotrusivi, g) backline laterotrusiva, h) asse cerniera consolare in massima intercuspidazione,
+File:Frisardi Gianni 0001.bmp.png|'''Figura 3:''' <math>\delta_3</math> Interferential EMG of right (top) and left (bottom) masseter muscles. Amplitude 200μV per division, time division 100 msec
-File:Assiografia sn.jpg|'''Figura 2:''' <math>\delta_2</math> Tracciato assiografico paraocclusale consolare destro: a) Centro asse cerniera, b) piano asse orbitale, c) tracciato protruso, d) tracciato mediotrusivo, e) area dei cicli masticatori mediotrusivi, f) area cicli masticatori laterotrusivi, g) backline laterotrusiva.
-File:Frisardi Gianni 0001.bmp.png|'''Figura 3:''' <math>\delta_3</math> EMG interferenziale dei muscoli masseteri destro ( in alto) sinistro ( in basso). Ampiezza 200μV a divisione, time division 100 msec
 </gallery>
 </center>
-La frase {{:F:Imo}} ( contesto odontoiatrico) con un numero <math>n\geq1</math> di altre asserzioni <math>(\delta_1,\delta_2,.....\delta_n \ )</math> logicamente compatibili determinano l'unione e la coerenza tra di loro <math>\Im_o\cup\{\delta_1,\delta_2.....\delta_n\}</math> e vengono rappresentate con un formalismo matematico per facilitare la dialettica diagnostica nel seguente modo.<math>\Im_o\cup\{\delta_1,\delta_2.....\delta_n\}\rightarrow
+The sentence {{:F:Imo}} (dental context) with a number <math>n\geq1</math> of other logically compatible statements <math>(\delta_1,\delta_2,.....\delta_n \ )</math> determine the union and coherence between them <math>\Im_o\cup\{\delta_1,\delta_2.....\delta_n\}</math> and are represented with a mathematical formalism to facilitate the diagnostic dialectic in the following way <math>\Im_o\cup\{\delta_1,\delta_2.....\delta_n\}\rightarrow
-\Im_o\cup\{0,0.....0\}=0</math> che rappresenta la media delle singole asserzioni refertate. La media è stata pensata perchè spesso può capitare che alcuni test diano risposte con refertazione negative a cui dare il valore <math>\delta_n=0</math>. Il risultato in questo caso è <math>\delta_n=0</math> e contestualmente ne deriva l'affermazione coerente della frase <math>\Im_o</math> in cui si sostiene che la sintomatologia della paziente 'Capsaicina' non è determinata dalla presenza di una DTMs.
+\Im_o\cup\{0,0.....0\}=0</math> which represents the average of the individual assertions reported. The average has been designed because it can often happen that some tests give answers with negative reporting to which to give the value <math>\delta_n=0</math>. The result in this case is <math>\delta_n=0</math> and contextually derives the coherent affirmation of the sentence <math>\Im_o</math> in which it is argued that the symptomatology of the 'Capsaicin' patient is not determined by the presence of a TMDs.
+In the ''neurological context'' we will therefore have the following sentences and assertions to which we obviously give, as for the dental context, a numerical value to facilitate the treatment and that is <math>\gamma_n=[0|1]</math> where i<math>\gamma_n=0</math> indicates 'normality' and <math>\gamma_n=1</math>'abnormality' and therefore positivity of the report:
+<math>\gamma_1=</math> <sub>b</sub>Root-MEPs symmetrical in amplitude and latency in Figure 4, <math>\gamma_1=0\longrightarrow</math> Normality, negative report
-Nel '''contesto neurologico''' avremo, perciò, le seguenti frasi ed asserzioni a cui diamo, ovviamente, come per il contesto odontoiatrico, un valore numerico per facilitare la trattazione e cioè <math>\gamma_n=[0|1]</math> dove lo <math>\gamma_n=0</math> indica 'normalità' e <math>\gamma_n=1</math> 'anormalità e dunque positività del referto:
+<math>\gamma_2=</math> Jaw jerk symmetrical in amplitude and in latency in Figure 8, <math>\gamma_2=0\longrightarrow</math> Normality, negative report
-<math>\gamma_1=</math> <sub>b</sub>Root-MEPs simmetrica in ampiezza e latenza in Figure 4,  <math>\gamma_1=0\longrightarrow</math> Normalità, positività del referto
+<math>\gamma_3=</math> Symmetry in duration of the masseter silent period in Figure 6, <math>\gamma_3=0\longrightarrow</math> Normality, negative report
-<math>\gamma_2=</math> Jaw jerk simmetrico in ampiezza ed in latenza in Figure 8,  <math>\gamma_2=0\longrightarrow</math> Normalità, positività del referto
+Consequently even in sentence <math>\Im_n</math> with a number <math>n\geq1</math> of other logically compatible assertions <math>(\gamma_1,\gamma_2,.....\gamma_n \ )</math> they determine the union and coherence between them <math>\Im_n\cup\{\gamma_1,\gamma_2.....\gamma_n\}</math> and the formal representation will be similar to that of the dental context. <math>\Im_n\cup\{\gamma_1,\gamma_2.....\gamma_n\}\rightarrow
+\Im_n\cup\{0,0.....0\}=0</math>with contextual coherent affirmation of the sentence <math>\Im_n</math> in which it is argued that the symptomatology of the patient 'Capsiacin' does not electrophysiologically highlight any element that could indicate a correlation between orofacial pain and neuromotor damage.
-<math>\gamma_3=</math> Simmetria in durata  del periodo silente masseterino in Figure 6,  <math>\gamma_3=0\longrightarrow</math> Normalità, positività del referto
-Di conseguenza anche a frase <math>\Im_n</math> con un numero <math>n\geq1</math> di altre asserzioni <math>(\gamma_1,\gamma_2,.....\gamma_n \ )</math> logicamente compatibili determinano l'unione e coerenza tra di loro <math>\Im_n\cup\{\gamma_1,\gamma_2.....\gamma_n\}</math> e la rappresentazione formale ssarà simile a quella del contesto odontoiatrico.
-<math>\Im_n\cup\{\gamma_1,\gamma_2.....\gamma_n\}\rightarrow
-\Im_n\cup\{0,0.....0\}=0</math> con contestuale affermazione coerente della frase <math>\Im_n</math> in cui si sostiene che la sintomatologia della paziente 'Capsiacina' non evidenzia elettrofisiologicamente nessun elemento che possa indicare una correlazione tra dolore orofacciale e danno neuromotorio.
 <center>
 <gallery widths="200" mode="slideshow">
-File:Capsaicinica.jpeg|'''Figura 4:''' <math>\gamma_1=</math> Potenziali evocati dalle radici trigeminali motorie <sub>b</sub>Root-MEPs.
+File:Capsaicinica.jpeg|'''Figura 4:''' <math>\gamma_1=</math> Motor trigeminal roots evoked potentials bRoot-MEPs.
-File:Jaw jerk in capsaicinica.bmp.png|'''Figura 1:''' <math>\gamma_1=</math> Riflesso tendineo mandibolare (jaw jerk) registrato sui muscoli masseteri destro ( in alto) sinistro ( in basso)
+File:Jaw jerk in capsaicinica.bmp.png|'''Figura 5:''' <math>\gamma_1=</math> Mandibular tendon reflex (jaw jerk) recorded on the right (top) left (bottom) masseter muscles
-File:Immagine5.bmp.png|'''Figura 1:''' <math>\gamma_1=</math> Periodo silente meccanico registrato sui muscoli masseteri destro ( in alto nero corrisponde alla media) sinistro ( in basso nero corrisponde alla media)
+File:Immagine5.bmp.png|'''Figura 6:''' <math>\gamma_1=</math> Mechanical silent period recorded on masseter muscles right (top black corresponds to mean) left (bottom black corresponds to mean)
-File:Immagine5.bmp|'''Figura 1:''' <math>\gamma_1=</math> Tracciato EMG interferenziale dei muscoli massetere destro ( in alto) e massetere sinistro ( in basso)
 </gallery>
-</Center>
+</center>
-{{Q2|In questo scenario ambedue le asserzioni <math>\Im_o </math> e <math>\Im_n </math> sono compatibili, coerenti e dunque vere fino a che non si trova un 'Demarcatore di coerenza 'τ' che evidenzi il maggior peso in termini di gravità  clinica.
+{{Q2|In this scenario both the statements <math>\Im_o </math> and <math>\Im_n </math> are compatible, consistent and therefore true until a 'Consistency Demarcator 'τ' is found which highlights the greater weight in terms of clinical severity.
 }}
-==== Demarcatore di Coerenza <math>\tau</math>====
+====Coherence Demarcator <math>\tau</math>====
-Il <math>\tau</math> è un rappresentativo peso specifico clinico, complesso da ricercare e mettere a punto perchè varia da disciplina a disciplina e per patologie, essenziale per non far collidere le asserzioni logiche  <math>\Im_o</math> e <math>\Im_n</math> nelle procedure diagnostiche e fondamentale per inizializzare la decriptazione del codice macchina. Sostanzialmente permette di confermare la coerenza di una unione <math>\Im\cup\{\delta_1,\delta_2.....\delta_n\}</math> rispetto ad una altra <math>\Im\cup\{\gamma_1,\gamma_2.....\gamma_n\}</math> e viceversa, dando un peso maggiore alla gravità delle asserzioni e del referto nel contesto appropriato. A volte il medico si trova di fronte ad una serie di refertazioni positive a cui dare il giusto peso, deve considerare la positività di un referto che evidenzia, per esempio,  un rimodernamento osteoarticolare della ATM non può avere lo stesso peso di una positività di un referto che conferma un ritardo di latenza di un riflesso trigeminale. Il peso di demarcazione <math>\tau</math>, perciò, dà più significatività alle asserzioni più gravi nel contesto clinico da cui derivano e dunque al di là della positività delle asserzioni <math>\delta_n=1</math> oppure <math>\gamma_n=1</math> che comunque sono sempre verificate e rispettate, queste dovranno essere moltiplicate per un <math>\tau=[0|1]</math> dove lo <math>\tau=0</math> indica 'Gravità bassa'  mentre <math>\tau=1</math> 'Gravità severa'.
+The <math>\tau</math>is a representative clinical specific weight, complex to research and develop because it varies from discipline to discipline and for pathologies, essential for not colliding logical assertions <math>\Im_o</math> and <math>\Im_n</math> in diagnostic procedures and fundamental for initializing the decryption of the machine code. Basically it allows to confirm the coherence of one union <math>\Im\cup\{\delta_1,\delta_2.....\delta_n\}</math> with respect to another <math>\Im\cup\{\gamma_1,\gamma_2.....\gamma_n\}</math> and vice versa, giving greater weight to the seriousness of the assertions and of the report in the appropriate context. Sometimes the doctor is faced with a series of positive reports to which he must give the right weight, he must consider the positivity of a report which highlights, for example, an osteoarticular renewal of the TMJ cannot have the same weight as a positivity of a report confirming latency delay of a trigeminal reflex. The demarcation <math>\tau</math> weight, therefore, gives more significance to the more serious assertions in the clinical context from which they derive and therefore beyond the positivity of the assertions <math>\delta_n=1</math> or which <math>\gamma_n=1</math> in any case are always verified and respected, these must be multiplied by a <math>\tau=[0|1]</math> where <math>\tau=0</math> indicates 'Low seriousness ' while <math>\tau=1</math> 'Severe Gravity'.
-Si potrebbe definire un demarcatore di coerenza come un numero reale compreso fra 0 e 1 nel caso in cui abbiamo più di due refertazioni e quindi un numero vicino allo zero corrisponderebbe ad una refertazione di 'Gravità bassa' mentre con un numero vicino allo uno ad una refertazione di 'Gravità severa'. Questo però è ridondante. Quello che si fa è confrontare a due a due le refertazioni e quindi usare i valori che abbiamo indicato per esprimere la 'Gravità'.
+A consistency marker could be defined as a real number between 0 and 1 in the event that we have more than two reports and therefore a number close to zero would correspond to a report of 'low severity' while a number close to one to a reporting of 'severe severity'. But this is redundant. What is done is to compare the reports two by two and then use the values we have indicated to express the 'Gravity'.
-Per ricapitolare abbiamo dunque:
+So to recap we have:
 <math>\Im_o\cup ( {\bar\delta_n)} \tau_o + \Im_n\cup({\bar\gamma_n)}\
@@ Line 88: / Line 72: @@
 </math>
-dove
+where
-<math>{\bar\delta_n}=</math> media del valore delle asserzioni cliniche nel contesto odontoiatrico che nel nostro caso in questione è <math>{\bar\delta_n}=0</math>
-<math>{\bar\gamma_n}=</math> media del valore delle asserzioni cliniche nel contesto neurologico e dunque <math>{\bar\gamma_n}=0</math>
-<math>\tau_o=0</math> refertazione di bassa gravità del contesto odontoiatrico
+<math>{\bar\delta_n}=</math> average of the value of the clinical statements in the dental context which in our case in question is <math>{\bar\delta_n}=0</math>
-<math>\tau_n=0</math> refertazione di bassa gravità del contesto neurologico
+<math>{\bar\gamma_n}=</math> average of the value of clinical statements in the neurological context and therefore <math>{\bar\gamma_n}=0</math>
-in cui il 'demarcatore di coerenza <math>\tau</math>' definirà il percorso diagnostico nel seguente modo
+<math>\tau_o=0</math> reporting of low severity of the dental context
+<math>\tau_n=0</math> reporting of low severity of the neurological context
+where the 'demarcator of coherence <math>\tau</math> marker' will define the diagnostic path as follows
 <math>\Im_o\cup 0\cdot 0 + \Im_n\cup0 \cdot 0 =
 \Im_d \longrightarrow
@@ Line 107: / Line 89: @@
 </math>
-Come vedremo nel corso dell'esposizione dei casi clinici in Masticationpeida ci si troverà di fronte a situazioni cliniche simili in cui sei è in presenza di dolore orofacciale ma i risultati di refertazione nei contesti specialistici risulteranno di bassa gravità tale da annullare il valore discriminate del <math>\tau</math>.
+As we will see during the exposition of the clinical cases in Masticationpeida, one will be faced with similar clinical situations in which you are in the presence of orofacial pain but the reporting results in specialist contexts will be of low severity such as to cancel the discriminate value of <math>\tau</math> .
-{{Q2|Questa procedura di sintassi logica formale ci ha permesso di verificare come la conclusione clinica nel contesto odontoiatrico e neurologico siano nulle sia <math>\Im_o= 0
+{{Q2|This formal logical syntax procedure has allowed us to verify how the clinical conclusion in the dental and neurological context is null and <math>\Im_o= 0
-</math> e  <math>\Im_n= 0
+</math> and <math>\Im_n= 0
-</math> . Ciò significa che la diagnosi è sconosciuta <math>\Im_d= 0 </math> |Rimane il fatto che la paziente continua ad accusare dolore orofacciale ed in particolare con esacerbazione dopo una cena piccante.}}
+</math> . This means that the diagnosis is unknown <math>\Im_d= 0 </math>|The fact remains that the patient continues to experience orofacial pain and particularly with exacerbation after a spicy dinner.}}
-Nei rari ma reali casi clinici in cui si assiste ad un azzeramento del 'Demarcatore <math>\tau</math>' siamo motivati ad un controllo ancor più vasto ed approfondito ipotizzando patologie gravi <ref>Chloé Gibeili, Arek Sulukdjian, Audrey Chanlon, Nathan Moreau. Unilateral glossodynia as a harbinger of an occult cerebellopontine angle tumour. BMJ Case Report.. 2022 Apr 12;15(4):e249408.doi: 10.1136/bcr-2022-249408.
+In the rare but real clinical cases in which the ' <math>\tau</math> Demarcator' is reset, we are motivated to carry out an even more extensive and in-depth check, hypothesizing serious pathologies <ref>Chloé Gibeili, Arek Sulukdjian, Audrey Chanlon, Nathan Moreau. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/35414584/ Unilateral glossodynia as a harbinger of an occult cerebellopontine angle tumour.] BMJ Case Report.. 2022 Apr 12;15(4):e249408.doi: 10.1136/bcr-2022-249408.
 </ref><ref>Irappa Madabhavi, Malay Sarkar, K S Sandeep, Mitul Modi. Isolated trigeminal neuralgia: An early weird presentation of carcinoma breast. J Cancer Res Ther. . 2022 Oct-Dec;18(6):1820-1822.doi: 10.4103/jcrt.JCRT_712_20.
+</ref> including head and neck tumors which simulate symptoms that can be superimposed on other pathologies. It is a serious mistake to consider the patient with such clinical manifestations and the simultaneous absence of systemic anomalies as a patient with psychosomatic disorders. Elements of psychophysical damage can certainly coexist but, if the 'Demarcator' fails, it is mandatory to deepen the diagnostics. In fact, head and neck cancer (HNC) affects over 890,000 people each year worldwide and has a 50% mortality rate. Aside from poor survival, HNC pain impairs eating, drinking and speaking, severely reducing quality of life. The different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between tumors<ref>e Y, Jensen DD, Viet CT, Pan HL, Campana WM, Amit M, Boada MD.[https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/35416080/ '''Advances''' in '''Head''' and '''Neck''' '''Cancer''' '''Pain'''.]YJ Dent Res. 2022 Aug;101(9):1025-1033. doi: 10.1177/00220345221088527. Epub 2022 Apr 13.PMID: 35416080 </ref>. Glial and immune modulation of the tumor microenvironment, as well explained in the article by [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305840/ '''Ye et al.'''], influences not only cancer progression but also pain signaling among which transient receptor potentials contained in gustatory somatosensory systems are an example.<ref name=":0">Ramsey, I.S., M. Delling, and D.E. Clapham. 2006. An introduction to TRP channels. Annu Rev Physiol, 68: 619–647.</ref><ref name=":1">Julius, D. 2013. TRP channels and pain. Annu Rev Cell Dev Biol, 29: 355–584.</ref>
-</ref>compreso tumori della testa e del collo che simulano sintomatologie sovrapponibili ad altre patologie. Un grave errore considerare il paziente con tali manifestazioni cliniche e contestuale assenza di anomalie di sistema, come paziente con turbe psicosomatica. Certamente posso coesistere elementi di danno psicofisico ma, se fallisce il 'Demarcatore <math>\tau</math>', è obbligatorio approfondire la diagnostica. Il cancro della testa e del collo (HNC), infatti, colpisce oltre 890.000 persone ogni anno in tutto il mondo e ha un tasso di mortalità del 50%. A parte la scarsa sopravvivenza, il dolore HNC compromette il mangiare, bere e parlare, riducendo gravemente la qualità della vita. Il diverso fenotipo del dolore nei pazienti (allodinia, iperalgesia e dolore spontaneo) deriva da una combinazione di differenze anatomiche, istopatologiche e molecolari tra i tumori. .<ref>'''Advances''' in '''Head''' and '''Neck''' '''Cancer''' '''Pain'''.
+For the above reasons and for the persistence of the OP, the difficulty in concluding a certain diagnosis, the absence of organic-functional discrepancies and the zeroing of the '<math>\tau</math> Demarcator', an MR of the brain was requested.
-Ye Y, Jensen DD, Viet CT, Pan HL, Campana WM, Amit M, Boada MD.J Dent Res. 2022 Aug;101(9):1025-1033. doi: 10.1177/00220345221088527. Epub 2022 Apr 13.PMID: 35416080 </ref> La modulazione gliale e immunitaria del microambiente tumorale, come ben spiegato nell'articolo di [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9305840/ '''Ye et al.'''], influenza non solo la progressione del cancro ma anche la segnalazione del dolore tra cui i Potenziali di recettore transitori contenuto nei sistemi somatosensoriali  gustativi ne sono un esempio.<ref name=":0" /><ref name=":1" />
+Imaging showed a neoplastic mass most likely a brainstem schwannoma with invagination of the occipital frame. (figure 7 and 8)
-Per i motivi sovraesposti e per il persistere del OP, della difficoltà nel concludere una diagnosi certa, l'assenza di discrepanze organico-funzionali  e l'azzeramento del 'Demarcatore <math>\tau</math>' si è chiesta una MR dell'encefalo.
-L'imaging ha evidenziato una massa di tipo neoplasica con molta probabilità un neurinoma troncoencefalico con invaginazione del frame occipitale. (figura 7 e 8)
 <center>
 <gallery widths="500" heights="200" perrow="2" slideshow""="">
-File:Capsaicina.jpg|'''Figura 7:''' Sezione assiale dell'encefalo a livello del midollo allungato in cui si evidenzia una massa ( freccia) che invade parzialmente il frame ovale
+File:Capsaicina.jpg|'''Figura 7:''' Axial section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame
-File:Capsaicina 1.jpeg
+File:Capsaicina 1.jpeg|'''Figura 8:''' Coronal section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame
 </gallery>
 </center>
-{{Q2|La paziente, purtroppo, mori qualche anno dopo per neurinoma trocoencefalico. |.......lasciando un dubbio, quello della correlazione tra il dolore e la capsaicina come riferito dalla paziente nelle occasioni di una alimentazione piccante.}}
+{{Q2|Unfortunately, the patient died a few years later of trochoencephalic neuroma.|.......leaving a doubt, that of the correlation between pain and capsaicin as reported by the patient on the occasion of a spicy diet.}}
+===Thoughts and conclusions===
+The mammalian gustatory system is made up of taste buds, which are clusters of 50-100 taste cells found throughout the oral cavity. On the tongue, which is the central topic of the case report 'Capsaicin', the taste buds are located on circumvallate, foliate and fungiform papillae. Taste cells synapse with afferent fibers from branches of the cranial facial (CN VII), glossopharyngeal (CN IX) and vagus (CN X) nerves which, in turn, transmit information to the central nervous system (CNS) about gustatory attributes , intensity and hedonic nature. <ref>Gutierrez, R., and S.A. Simon. 2011. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21731190/ Chemosensory processing in the taste-reward pathway.] Flavour Fragr J, 26(4): 231–238.</ref><ref>Carleton, A., R. Accolla, and S.A. Simon. 2010. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20493563/ Coding in the mammalian gustatory system.] Trends Neurosci, 33(7): 326–334.</ref><ref>Vincis, R. and A. Fontanini. 2016. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27455038/ A gustocentric perspective to understanding primary sensory cortices.] Curr Opin Neurobiol, 40: 118–124</ref> The taste buds are embedded in a stratified squamous epithelium, which contains somatosensory branches of the trigeminal (CN V), glossopharyngeal (CN IX), and vagus (CN X) cranial nerves. Information from these general sensory nerves provides information to the central nervous system about mechanical, thermal, and pain stimuli.<ref name=":1" /><ref>Kaneko, Y., and A. Szallasi. 2014. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24102319/ Transient receptor potential (TRP) channels: A clinical perspective.] Br J Pharmacol, 171(10): 2474–2507. </ref> Painful stimuli can result from strong or sharp mechanical stimuli, abnormally high or low temperatures, or chemical stimuli such as capsaicin, which is found in hot peppers and causes a burning taste sensation through the intervention of Transient Receptor Potentials (TRPs).<ref name=":0" /> These TRPs are divided into six subfamilies including TRPV1, which we are interested in to hypothesize the phenomenon of pain exacerbation of the patient 'Capsaicin' in spicy diet. [[File:Trpv1 pip2 bilayer.png|thumb|'''Figura 9:''' TRPV1, VR1, transient receptor potential cation channel subfamily V member 1. [[wikipedia:TRPV1|Wikipedia]]]]
+==== TRPV1 and neuroinflammation====
+TRPV1s constitute a distinct subset of non-selective cation channels (Transient Receptor Potential) responsible for many cellular responses. They are activated by various stimuli such as acids, extracellular protons, high temperatures, plant toxins and vanilloid agonists. The TRPV1s present in mammals can be considered as sensors of chemical substances (capsaicin), thermal substances (heat) and/or harmful stimuli. The activation of TRPV1 leads to the depolarization necessary for the propagation of action potentials along the axons of the dorsal root ganglia (DRG) of neurons that project to the spinal cord and consequently also to the nociceptive trigeminal nuclei. What makes TRPV1 so critical for pain signaling is undeniably its ability to transduce inflammatory signals into electrical signals with the activation of both voltage-gated sodium and calcium channels located at the nociceptor level.<ref>Bourinet E, Altier C, Hildebrand M E, Trang T, Salter MW, Zamponi GW. [https://journals.physiology.org/doi/full/10.1152/physrev.00023.2013?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org Calcium permeable ion channels in pain signaling.] Physiol Rev 2014; 94: 81–140.</ref> The implication of TRPV1 in pathological pain prompted a careful study of these proteins. The limiting element in pharmacological research at the application level was the peculiarity of the TRPV1 channel, i.e. its polymodal mechanism of activation (heat, capsaicin, pH), which led to a high level of complexity in the design of a specific modality inhibitor.
+The interaction between neurons and immune cells is a well-known phenomenon.<ref>Jacobson A, Yang D, Vella M, Chiu IM (May 2021). "[https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/33542493/ The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes]". ''Mucosal Immunology''. '''14''' (3): 555–565. doi:10.1038/s41385-020-00368-1. PMC 8075967. <nowiki>PMID 33542493</nowiki>.</ref> TRPV1 plays its role, too, in neuroinflammation by being expressed in both neurons and immune cells. Significant importance should be given to the confirmed expression of TRPV1 in microglia and astrocytes, cells found in the vicinity of neurons. The neuro-immune axis is the site of production of neuroinflammatory molecules and receptors that interact between the two systems and ensure a complex response to external stimuli (or to the body's own pathologies). TRPV1 is said to contribute to microglia autophagy through its Ca<sup>2+</sup> signaling, which leads to mitochondria-induced cell death. Basically, TRPV1 is a pro-apoptotic element.
+=====Ligands=====
-=== Riflessioni  e conclusioni  ===
+=====Antagonists=====
+Antagonists block the ''activity of TRPV1'', thereby reducing pain. Antagonists identified include the [[wikipedia:Receptor_antagonist#Competitive|competitive antagonist capsazepine and the non-competitive antagonist]] [[wikipedia:Ruthenium_red|ruthenium red]]. These agents could be beneficial if applied systematically.<ref>Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". ''Trends in Molecular Medicine''. '''15''' (1): 14–22. doi:10.1016/j.molmed.2008.11.004. <nowiki>PMID 19097938</nowiki>.</ref> TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.<ref>Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (July 2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". ''The European Journal of Neuroscience''. '''22''' (2): 361–370. doi:10.1111/j.1460-9568.2005.04227.x. <nowiki>PMID 16045489</nowiki>. S2CID 24664751.</ref> This provides evidence that TRPV1 is the sole receptor for [[wikipedia:Capsaicin|capsaicin]].<ref>Story GM, Crus-Orengo L (2008). "Feel the Burn". ''American Scientist''. '''95''' (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. Archived from the original on January 19, 2008.</ref> In humans, drugs that target TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.<ref>Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". ''Current Pharmaceutical Design''. '''14''' (1): 32–41. doi:10.2174/138161208783330754. <nowiki>PMID 18220816</nowiki>.</ref>
-Il sistema gustativo dei mammiferi è costituito da papille gustative, che sono gruppi di 50-100 cellule gustative che si trovano in tutta la cavità orale. Sulla lingua, che è l'argomento centrale del caso clinico 'Capsaicina', le papille gustative si trovano su papille circumvallate, foliate e fungiformi. Le cellule gustative fanno sinapsi con le fibre afferenti dai rami dei nervi cranici facciale (CN VII), glossofaringeo (CN IX) e vago (CN X) che, a loro volta, trasmettono informazioni al sistema nervoso centrale (SNC) attributi di qualità gustativa, intensità e natura edonica. <ref>Gutierrez, R., and S.A. Simon. 2011. Chemosensory processing in the taste-reward pathway. Flavour Fragr J, 26(4): 231–238.</ref><ref>Carleton, A., R. Accolla, and S.A. Simon. 2010. Coding in the mammalian gustatory system. Trends Neurosci, 33(7): 326–334.</ref><ref>Vincis, R. and A. Fontanini. 2016. A gustocentric perspective to understanding primary sensory cortices. Curr Opin Neurobiol, 40: 118–124</ref> Le papille gustative sono incorporate in un epitelio squamoso stratificato, che contiene rami somatosensoriali dei nervi cranici trigemino (CN V), glossofaringeo (CN IX) e vago (CN X). Le informazioni provenienti da questi nervi sensoriali generali forniscono informazioni al sistema nervoso centrale sugli stimoli meccanici, termici e dolorosi.<ref name=":1">Julius, D. 2013. TRP channels and pain. Annu Rev Cell Dev Biol, 29: 355–584.</ref><ref>Kaneko, Y., and A. Szallasi. 2014. Transient receptor potential (TRP) channels: A clinical perspective. Br J Pharmacol, 171(10): 2474–2507. </ref> Gli stimoli dolorosi possono derivare da stimoli meccanici forti o acuti, temperature anormalmente alte o basse o stimoli chimici come la capsaicina, che si trova nei peperoncini e provoca una sensazione di gusto bruciante attraverso l'intervento dei Potenziale di recettore transitorio (TRPs).<ref name=":0">Ramsey, I.S., M. Delling, and D.E. Clapham. 2006. An introduction to TRP channels. Annu Rev Physiol, 68: 619–647.</ref> Questi TRPs sono divisi in sei sottofamiglie tra cui il TRPV1, che a noi interessa per ipotizzare il fenomeno di riacutizzazione algica della paziente' Capsaicina' nell'alimentazione piccante. [[File:Trpv1 pip2 bilayer.png|thumb|'''Figura 9:''' TRPV1, VR1, transient receptor potential cation channel subfamily V member 1. [[wikipedia:TRPV1|Wikipedia]]]]
+=====Agonists=====
-==== TRPV1 e neuroinfiammazione ====
+TRPV1 is activated by several agonists of natural origin.<ref>Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [1]doi:10.1007/7355_2015_98.</ref> Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of the TRPV1-mediated release of inflammatory molecules upon exposure to noxious stimuli.
-I TRPV1 costituiscono un sottogruppo distinto di canali cationici non selettivi (Transient Receptor Potential) responsabili di molte risposte cellulari. Sono attivati da diversi stimoli come acidi, protoni extracellulari, alte temperature, tossine di piante e agonisti vanilloidi. I TRPV1 presenti nei  mammiferi possono essere considerati  dei  sensori di sostanze chimiche (capsaicina), termiche (calore) e/o di stimoli nocivi. L'attivazione del TRPV1 porta alla depolarizzazione necessaria alla   propagazione dei potenziali d'azione lungo gli assoni dei gangli delle radici dorsali (DRG) dei neuroni che proiettano al midollo spinale e di conseguenza anche nei nuclei trigeminali nocicettivi. Ciò che rende il TRPV1 così critico per la segnalazione del dolore è innegabilmente la sua capacità di trasdurre segnali infiammatori in segnali elettrici con l'attivazione dei canali del sodio e del calcio entrambi voltaggio-dipendenti localizzati a livello dei nocicettori.<ref>Bourinet E, Altier C, Hildebrand M E, Trang T, Salter MW, Zamponi GW. Calcium permeable ion channels in pain signaling. Physiol Rev 2014; 94: 81–140.</ref> L'implicazione dei TRPV1 nel dolore patologico ha spinto un accurato studio delle suddette proteine. L’elemento limitativo nella ricerca farmacologica a livello applicativo  è stata la peculiarità del canale TRPV1 cioè il suo ''meccanismo polimodale'' di attivazione (calore, capsaicina, pH) che ha portato a un alto livello di complessità nella progettazione di un inibitore a modalità specifica.
-L'interazione tra neuroni e cellule immunitarie è un fenomeno ben noto.<ref>Jacobson A, Yang D, Vella M, Chiu IM (May 2021). "The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes". ''Mucosal Immunology''. '''14''' (3): 555–565. doi:10.1038/s41385-020-00368-1. PMC 8075967. <nowiki>PMID 33542493</nowiki>.</ref> TRPV1 svolge il suo ruolo, anche, nella neuroinfiammazione essendo espresso sia nei neuroni che nelle cellule immunitarie. Un'importanza significativa dovrebbe essere data all'espressione confermata di TRPV1 nella microglia e negli astrociti, cellule che si trovano in prossimità dei neuroni. L'asse neuro-immunitario è il luogo di produzione delle molecole e dei recettori neuroinfiammatori che interagiscono tra i due sistemi e assicurano una risposta complessa agli stimoli esterni (o alle patologie proprie dell'organismo). Si dice che TRPV1 contribuisca all'autofagia della microglia attraverso la sua segnalazione di Ca<sup>2+</sup>, che porta alla morte cellulare indotta dai mitocondri. Sostanzialmente la TRPV1 è un elemento pro-apoptotico.
+An interesting study by the Tominaga group extends the list of TRPV1 interactions also to Anoctamin 1 (ANO 1) also known as Transmembrane member 16A (TMEM16A) a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.
-===== Ligandi =====
+These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.
-===== Antagonisti =====
+TRPV1 is activated by several agonists of natural origin. Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of TRPV1-mediated release of inflammatory molecules following administration. exposure to noxious stimuli.
-Gli antagonisti bloccano l'''<nowiki/>'<nowiki/>'''''attività del TRPV1, riducendo così il dolore''. Gli antagonisti identificati includono l'[[wikipedia:Receptor_antagonist#Competitive|'''antagonista competitivo capsazepina e l'antagonista non competitivo''']] [[wpit:Rosso_di_rutenio|rosso rutenio]]. Questi agenti potrebbero essere utili se applicati sistematicamente.<ref>Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". ''Trends in Molecular Medicine''. '''15''' (1): 14–22. doi:10.1016/j.molmed.2008.11.004. <nowiki>PMID 19097938</nowiki>.</ref> Gli antagonisti del TRPV1 hanno mostrato efficacia nel ridurre la nocicezione da modelli di dolore infiammatorio e neuropatico nei ratti.<ref>Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (July 2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". ''The European Journal of Neuroscience''. '''22''' (2): 361–370. doi:10.1111/j.1460-9568.2005.04227.x. <nowiki>PMID 16045489</nowiki>. S2CID 24664751.</ref> Ciò fornisce la prova che TRPV1 è l'unico recettore della [[wpit:Capsaicina|capsaicina]]. <ref>Story GM, Crus-Orengo L (2008). "Feel the Burn". ''American Scientist''. '''95''' (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. Archived from the original on January 19, 2008.</ref>Negli esseri umani, i farmaci che agiscono sui recettori TRPV1 potrebbero essere usati per trattare il dolore neuropatico associato a sclerosi multipla, chemioterapia o amputazione, nonché il dolore associato alla risposta infiammatoria del tessuto danneggiato, come nell'osteoartrosi.<ref>Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". ''Current Pharmaceutical Design''. '''14''' (1): 32–41. doi:10.2174/138161208783330754. <nowiki>PMID 18220816</nowiki>.</ref>
-===== Agonisti =====
+An interesting study by the Tominaga group extends the list of TRPV1 interactions also to [[wikipedia:ANO1|'''Anoctamin 1 (ANO 1)''']]  also known as Transmembrane member 16A (TMEM16A)<ref name=":2">Yasunori Takayama, Daisuke Uta, Hidemasa Furue, and Makoto Tominaga. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25848051/ Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons]. Proc Natl Acad Sci 2015; 21; 112(16): 5213-5218. doi: 10.1073/pnas.1421507112. Epub 2015 Apr 6.</ref> a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga<ref name=":2" /> highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.
-TRPV1 è attivato da numerosi agonisti di origine naturale.<ref>Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [1]doi:10.1007/7355_2015_98.</ref>Agonisti come la capsaicina e la resiniferatossina attivano TRPV1 e, dopo un'applicazione prolungata, ''provocano la diminuzione dell'attività di TRPV1 (desensibilizzazione), portando all'attenuazione del dolore'' attraverso la successiva diminuzione del rilascio mediato da TRPV1 di molecole infiammatorie in seguito all'esposizione a stimoli nocivi.
-Un interessante studio del gruppo Tominaga estende l'elenco delle interazioni del  TRPV1 anche all’[[wikipedia:ANO1|'''Anoctamina 1 (ANO 1)''']] conosciuta anche come '''Transmembrane member 16A''' (TMEM16A)<ref name=":2">Yasunori Takayama, Daisuke Uta, Hidemasa Furue, and Makoto Tominaga. Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons. Proc Natl Acad Sci 2015; 21; 112(16): 5213-5218. doi: 10.1073/pnas.1421507112. Epub 2015 Apr 6.</ref> un canale del cloro che di solito è attivato dal Ca<sup>2+</sup>. Gli autori dimostrano, infatti, che quando il TRPV1 interagisce con il canale ANO1 esso media l’efflusso del Cloro evocando la depolarizzazione (dopo stimolazione della capsaicina) con accresciuta eccitabilità del nocicettore. Tominaga<ref name=":2" /> ha evidenziato un chiaro crosstalk sia strutturale sia funzionale tra i TRPV1 a l’ANO1, che interviene nell’'''azione algogenica della capsaicina'''.
+These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.
-Questi risultati dimostrano l’importanza dell’''omeostasi del cloro'' nella regolazione dell’eccitabilità dei DRG neuronali cioè dei gangli delle radici dorsali ed ovviamente dei nuclei somatosensoriali trigeminali e nel fenomeno dolore in toto; uno dei  nuovi approcci, dunque, dove intervenire nel mitigare  l’ipersensibilità dolorosa e l’infiammazione neurogenica.{{Q2|Perchè, allora, la capsaicina assunta negli alimenti riferiti dalla paziente generava una esacerbazione del dolore? |....per un danno cronico a livello delle fibre nervose troncoencefaliche con conseguente alterazione dell'omeostasi neuro-immunitaria e contestuale effetto paradosso dell'azione analgesica della capsaicina. }}In questi casi, come premesso in altri capitoli, siamo di fronte ad un profilo epistemologico in cui la conoscenza di base, ciò che abbiamo chiamato <math>KB</math> (Knowledge Base) corrisponde ad un limite temporale dell'informazione scientifica e di conseguenza grave  difficoltà della diagnosi differenziale.Abbiamo dovuto aspettare ben 12 anni per giungere ad una conclusione ezipatogenetica soprascritta dal 1995 periodo in cui la paziente 'Capsaicina' era in cura al 2007 in cui una ricerca ha dato gli elementi per sospettare della presenza di un danno organico neurologico con manifestazioni di dolore e bruciore della bocca<ref>Z Yilmaz, T Renton, Y Yiangou, J Zakrzewska, I P Chessell, C Bountra, P Anand. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep;14(9):864-71. doi: 10.1016/j.jocn.2006.09.002. Epub 2007 Jun 19.
+{{Q2|Why, then, did the capsaicin taken in the food reported by the patient generate an exacerbation of pain?|....for chronic damage to the brainstem nerve fibers with consequent alteration of the neuro-immune homeostasis and contextual paradoxical effect of the analgesic action of capsaicin.}}In these cases, as stated in other chapters, we are dealing with an epistemological profile in which the basic knowledge, what we have called <math>KB</math> (Knowledge Base) corresponds to a temporal limit of scientific information and consequently serious  difficulties of differential diagnosis. We had to wait 12 years to reach an ezipathogenetic conclusion overwritten from 1995, a period in which the patient 'Capsaicin' was being treated, to 2007 in which a research gave the elements to suspect the presence of an organic neurological damage with manifestations of pain and burning mouth.<ref>Z Yilmaz, T Renton, Y Yiangou, J Zakrzewska, I P Chessell, C Bountra, P Anand. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci. 2007 Sep;14(9):864-71. doi: 10.1016/j.jocn.2006.09.002. Epub 2007 Jun 19.
+</ref> Burning mouth syndrome (BMS) is often an idiopathic, chronic intractable pain condition, affecting 1.5-5.5% of middle-aged and older women. We investigated heat and capsaicin receptor TRPV1, and its regulatory nerve growth factor (NGF), in BMS. BMS patients (n=10) and controls (n=10) were evaluated for baseline and post-topical capsaicin pain scores, and their tongue biopsies were immunostained for TRPV1, NGF, and neurofilament structural nerve markers and periphery. Nerve fibers penetrating the epithelium were less abundant in the BMS (p<0.0001), indicating ''small fiber neuropathy''. TRPV1-positive fibers were overall significantly increased in BMS (p=0.0011), as were NGF fibers (p<0.0001) and NGF staining of basal epithelial cells (p<0.0147). There was a significant correlation between baseline pain score and TRPV1 (p=0.0143) and NGF (p=0.0252) fibers. A significant correlation was observed between baseline and post-capsaicin pain (p=0.0006).
-</ref>
-La sindrome della bocca urente (BMS) è spesso una condizione di dolore cronico e intrattabile idiopatico, che colpisce l'1,5-5,5% delle donne di mezza età e anziane. Abbiamo studiato il calore e il recettore della capsaicina TRPV1, e il suo fattore di crescita del nervo regolatore (NGF), in BMS. I pazienti con BMS (n=10) e i controlli (n=10) sono stati valutati per i punteggi del dolore alla capsaicina al basale e post-topico e le loro biopsie della lingua sono state immunocolorate per TRPV1, NGF e marcatori nervosi strutturali neurofilamento e periferia. Le fibre nervose che penetrano nell'epitelio erano meno abbondanti nel BMS (p<0,0001), indicando una '''neuropatia delle piccole fibre'''. Le fibre TRPV1-positive erano complessivamente significativamente aumentate nel BMS (p=0,0011), così come le fibre NGF (p<0,0001) e la colorazione NGF delle cellule epiteliali basali (p<0,0147). C'era una correlazione significativa tra il punteggio del dolore basale e le fibre TRPV1 (p=0,0143) e NGF (p=0,0252). È stata osservata una correlazione significativa tra il dolore basale e post-capsaicina (p=0,0006).{{Q2|Siamo proprio sicuri di sapere tutto|Con questo caso clinico abbiamo dimostrato la anomalia  che dovrebbe rappresentare una crisi del paradigma attuale e proporne uno nuovo.}}{{bib}}
+{{Q2|We are sure we know everything|}}{{bib}}

Difference between revisions of "7° Clinical case: Brainstem neoplasm in Orofacial pain"

Latest revision as of 17:15, 19 October 2024

Introduction

Presentation of the clinical case

Significance of contexts

Coherence Demarcator τ {\displaystyle \tau }

Thoughts and conclusions

TRPV1 and neuroinflammation

Ligands

Antagonists

Agonists

Coherence Demarcator $\tau$