Gian Gaetano Ferri

A different modulation of vascular endothelial growth factor (VEGF) activation in response to hypoxia could cause different clinical pictures in inner ear disorders

Abstract When envisaging inner ear damage, the general tendency is to classify the damage into separate entities, according to the differences in clinical presentation, regardless of the frequent absence of a completely satisfactory explanation for the damage and, consequently, absence of a specific therapy. Nevertheless, a common ground can be found in haemodynamic changes and subsequent abnormal vasomotor reaction, which can be responsible for various kinds of labyrinthine effects depending on the extent, the duration and the severity of the consequent ischaemia. A key to a better understanding of the different effects of the resulting ischaemia and hypoxia could be found by considering the regulation of vascular endothelial growth factor (VEGF), which is known as a protective factor for inner ear structures under threat. If the haemodynamic change is mild, the possibility of VEGF up-regulation, which despite its finality could be a trigger for an imbalance of labyrinthine hair cells or fluids, could be a reliable indicator of damage. In contrast, if the vasoconstriction leads to a more severe hypoxia, this could directly lead to an acute, more or less transient damage according to a more direct mechanism. This damage could not, or could only partially, permit a useful activation of VEGF, and the total or partial recovery could therefore depend on the entity of the damage itself and on the efficacy of other, less specific protective endogenous or exogenous factors.

Drugs and tinnitus: A review of a controversial matter

Abstract Tinnitus is a major problem for a significant proportion of the population, and at this time no specific pharmacological therapies are available. On the other hand, a number of pharmaceutical drugs are labelled as able to induce tinnitus. The list of the latter is reviewed, as well as the principal pharmacological proposals for relieving this symptom. Unexpectedly, some drugs that can be considered as a potential source of tinnitus, such as the angiotensin II receptor blockers, conversely seem to be the most favourable anti-hypertensive drugs from the audiological point of view, in order to maintain a steady blood perfusion to the inner ear. The problem of matching the necessity of preserving the homeostasis of a sensory organ with a terminal blood supply for which no specific pharmacological treatments are proposed, and to obtain a safe cardiocirculatory balance, is outlined. More generally, the necessity of a multidisciplinary approach in treating inner ear disorders that are not fully understood is considered.

IFI16 Expression Is Related to Selected Transcription Factors during B-Cell Differentiation

The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood lymphocytes; however, little is known regarding its regulation during maturation of B- and T-cells. We explored the role of IFI16 in normal B-cell subsets by analysing its expression and relationship with the major transcription factors involved in germinal center (GC) development and plasma-cell (PC) maturation. IFI16 mRNA was differentially expressed in B-cell subsets with significant decrease in IFI16 mRNA in GC and PCs with respect to naïve and memory subsets. IFI16 mRNA expression is inversely correlated with a few master regulators of B-cell differentiation such as BCL6, XBP1, POU2AF1, and BLIMP1. In contrast, IFI16 expression positively correlated with STAT3, REL, SPIB, RELA, RELB, IRF4, STAT5B, and STAT5A. ARACNE algorithm indicated a direct regulation of IFI16 by BCL6, STAT5B, and RELB, whereas the relationship between IFI16 and the other factors is modulated by intermediate factors. In addition, analysis of the CD40 signaling pathway showed that IFI16 gene expression directly correlated with NF-κB activation, indicating that IFI16 could be considered an upstream modulator of NF-κB in human B-cells.

Idiopathic sudden hearing loss: another kind of circulatory risk should not be neglected

An interesting paper very recently published in the European Archives of Otorhinolaryngology [1] about the possibility that an increased level of mean platelet volume may be linked with sudden hearing loss (SHL) permits to focus on the opportunity for ENT specialists and cardiovascular specialist to join in studying inner ear diseases: it is an updated point of view that we totally share [2], as the strict link between circulation and inner ear homeostasis, due to the terminal vasculature and the highly energy-requiring metabolism of this sensory organ, cannot be neglected in dealing with inner ear disorders. Among them, SHL is one of the most challenging affections especially because its causal factors often remain substantially unknown. The proposed etiopathogenesis is intriguing and could give a satisfying interpretation to a number of ‘‘idiopathic’’ cases, thus contributing to explain how this affection not exceptionally concerns subjects free from more classical vascular risk factors. It should be kept in mind, not only in attempting to better understand some apparently unexplainable labyrinthine sufferances but even in terms of prevention. Moreover, the simple and common character of the reported investigation makes it automatic to apply in the routine practice to obtain an important additional information. As a matter of fact, a circulatory origin is often at the basis of SHL: however, circulatory causative factors may have different nature and do not necessarily depend on organic alterations. Indeed the vascular risk-free population has been extensively studied over the last years and the possibility of a cochlear damage as SHL in young and healthy subjects with low blood pressure values was demonstrated: in such cases, an abrupt lowering of blood pressure followed by an abnormal vasoconstriction could be responsible for the damage [3–5]; the same model subsequently permitted to draw a hemodynamic profile of subjects possibly more prone to some kind of inner ear ‘‘idiopathic’’ imbalance [6], and to outline a link between a transiently insufficient peripheral perfusion of systemic origin and an acute inner ear sufferance both in subjects submitted to an aggressive anti-hypertensive therapy [7] and in subjects with severe heart failure [8]. Briefly, the possibility of an inner ear abrupt damage deriving from dysfunctional causes rather than an underlying organic disorder has been widely elucidated in the last 15 years and has found a series of confirmations over the time: accordingly, among the numerous causative factors that must be considered as responsible for SHL it is widely reminded in the literature [9–16]. When considering that even systemic hemodynamic changes can play a crucial role in the labyrinthine homeostasis, it is possible to yield an exhaustive scenario of the complex considered problem and, in some cases at least, to widen the horizon and more easily plan an effective therapeutic strategy. In our opinion, such an interpretation is not in contrast with the exposed possibility but should be considered among the others. In particular, this assumption is reliable when treating young patients that are supposed to be less prone to vascular damages; for instance, if a clinical orientation addresses to a deeper study of blood pressure values, an ambulatory measurement can A. Pirodda G. G. Ferri (&) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, S. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138 Bologna, Italy e-mail: giangaetano.ferri@unibo.it

Proton pump inhibitors: A possible effect on Ménière's disease?

Background: The model of explanation for the pathogenesis of Ménières disease (MD) proposed by our group postulates a crucial role for the maintained activity of the labyrinthine gastric-type proton pump under ischaemic conditions. Thus, the administration of the common proton pump inhibitors (PPI) could exert a favourable influence on MD symptoms. Method: In order to help assess the validity of this hypothesis a questionnaire was administered to a selected population of sufferers from MD; the aim was to verify the percentage of PPI users and the incidence of MD symptoms among users and non-users. Results: These showed a higher prevalence of PPI users in the selected sample compared to an unselected large series in the literature; the difference was statistically significant in all cases. In contrast, no statistically significant differences between users and non-users were found regarding the incidence of symptoms in the previous six months, even though the group of PPI users had a slightly better performance. Conclusion: Despite these inconclusive findings and the consequent need for further studies to eventually propose PPI as a therapy for MD, some physiological and pharmacological aspects seem to support a possible positive influence of this category of drugs on the inner ear.

About plasma arginin vasopressin levels and Meniere ' s disease

International Journal of Audiology suggested elevated levels of plasma arginin vasopressin (AVP) during acute phases of Meniere ’ s disease are associated with the disease prognosis. Evidence of a possible causal relationship between enhanced AVP levels and Meniere ’ s disease has also been reported by Takeda et al (2000) and Naganuma et al (2006). Additional studies using a systematic approach are needed to examine factors inducing hemodynamic changes due to the involvement of a very complex, peripheral sensory organ that requires large amounts of energy from a small volume of blood perfusion. On the other hand, an ischemic and hypoxic, more or less transient, condition may be the origin of hydrops as well as other non-Menieric inner ear disorders. This idea has been advanced (Pirodda et al, 2010), possibly in relation with an abrupt lowering of blood pressure values followed by an abnormal sympathetic reaction (Pirodda et al, 1997, 2001, 2004). Actually, this orientation is in agreement with the experimental models proposed by Hultcrantz et al (1977) and Maass (1981), suggesting an effect of decreased blood pressure and changes in sympathetic tone on the cochlear circulation; however, the effect of the sympathetic system, the renin-angiotensin-aldosterone system, and vasopressin is generally considered as critical in maintaining blood pressure through a substantially synergic action. Considering an analogy between the kidney and the inner ear pathophysiology, the possibility that the inner ear proton pumps maintain their function under ischemia causing hydrops (Pirodda et al, 2010) suggests elevated plasma levels of vasopressin may be an effect rather than a cause of Meniere ’ s disease: An abrupt decrease in blood pressure followed by a sharp vasoconstriction and subsequent insuffi ciency of peripheral blood perfusion could transmit ‘ misleading ’ information to the local receptors, thus inducing an abnormal release of vasopressin. As thoroughly analysed by Aoki et al (2010), a sum of complex interactions between local and general effects of vasopressin on the labyrinth must be considered and further investigation is needed. However, the terminal type of the blood supply to this organ, the complexity of the mechanisms regulating systemic hemodynamic homeostasis, and the presence of labyrinthine volume receptors that can affect the entire body (Bartoli et al, 1989) could, in our opinion, make it more probable that Menieric attacks infl uence vasopressin release than result from elevated levels of vasopressin.

Waldenström's macroglobulinemia presenting with bilateral vestibular loss: a case report

Waldenstrom’s macroglobulinemia (WM) is a low-grade lymphoma originally described in 1944. It is a malignant lymphoproliferative disease characterized by the clonal expansion of B cells with lymphoplasmacytic differentiation that secrete monoclonal immunoglobulin M (IgM). Diagnostic criteria are based on specific clinical, morphological, and immunophenotypic parameters, besides the evidence of pathologic plasmacytoid cells in the bone marrow. Symptoms can be related either to tumor infiltration or to the amount and properties of the circulating monoclonal protein: cardiac and renal failure, mucosal bleeding, headache, visual disturbances, ataxia, and eventually coma have been described as part of the clinical spectrum of WM. Peripheral neuropathy occurs in nearly half of the patients and is mostly related to the reactivity of the IgM protein with different neural antigens. Frequently, it represents the initial presentation of the disease; sometimes it could precede the diagnosis of macroglobulinemia by several years.

The role of high-resolution computed tomography in the diagnostic protocol of cochleo-vestibular disorders

Abstract The utility of high-resolution computed tomography (HRCT) has been to a certain extent neglected in order to investigate on acquired cochleo-vestibular disorders of uncertain origin until the wide range of labyrinthine dehiscences has been discovered. In the last decade both the technical progress, that has permitted a diagnostic refinement in general terms, and the better definition of the width of the dehiscence syndromes, that proved larger than previously expected, has restored CT to its crucial role in detecting inner ear affections. Despite its evidence, this statement has not uniformly entered the habit of clinical practice. For this reason, a review of the literature of the last years, aimed at underlying the real significance of this tool for the otologist, appears of some utility in order to contribute to eliminate deep-rooted diagnostic incongruities.

Superior canal dehiscence with tegmen defect revealed by otoscopy: Video clip demonstration of pulsatile tympanic membrane

Superior canal dehiscence is a pathologic condition of the otic capsule acting as aberrant window of the inner ear. It results in reduction of inner ear impedance and in abnormal exposure of the labyrinthine neuroepithelium to the action of the surrounding structures. The sum of these phenomena leads to the onset of typical cochleo-vestibular symptoms and signs. Among them, pulsatile tinnitus has been attributed to a direct transmission of intracranial vascular activities to labyrinthine fluids. We present the first video-otoscopic documentation of spontaneous pulse-synchronous movements of the tympanic membrane in two patients with superior canal dehiscence. Pulsating eardrum may represent an additional sign of third-mobile window lesion.

A possible mechanism to explain how ischaemia and the maintained function of gastric type proton pumps could lead to hydrops of the inner ear in Ménière's disease

Abstract A possible explanation of the genesis of Ménières disease (MD) and other labyrinthine disorders on the basis of a direct involvement of the inner ear gastric type proton pump under ischaemia was recently outlined: maintained activity of the proton pump under acidic conditions could favour the onset of an endolymphatic hydrops through enhanced ion concentration in the endolymph and subsequent osmotic movement. The details of such a mechanism could be explained by considering the capability of sensory cells to extrude H+ into the endolymph in exchange for K+ through organellar isoforms that can transiently appear on plasma membranes and permit an electroneutral ion exchange. This capability appears to be rapidly activated under acidic conditions, which can be a consequence of a local ischaemia. This could mean that in an acidic milieu with an enhanced intracellular amount of H+, provided that the proton pumps maintain their activity as in other organs, a greater amount of K+ can finally be involved in the physiological cycling process and enter into the endolymph; this hypothesis seems reliable and could explain how an osmotic mechanism causing the onset of the hydrops could paradoxically be related to defensive responses to a vasospasm.