Partial Loss of Function ABCA12 Mutations Generate Reduced Deposition of Glucosyl-Ceramide, Leading to Patchy Ichthyosis and Erythrodermia Resembling Erythrokeratodermia Variabilis et Progressiva (EKVP).

Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.

Gradient impact of cognitive decline in unilateral vestibular hypofunction after rehabilitation: preliminary findings.

PURPOSE: Considering recent advances in central cognitive- and age-related processing interfering with balance and sensory reweighting in uncompensated vestibular disorders, purpose of this study is to highlight the vestibular rehabilitation (VR) outcomes in a population of older adults and age-matched mild cognitive impairment (MCI) patients, both affected by unilateral vestibular hypofunction (UVH) and undergoing VR. METHODS: Vestibulo-ocular reflex (VOR), postural sway examination (respectively, performed by video head impulse test and static posturography) and dizziness-related and quality-of-life scores were collected in 12 UVH MCI individuals ≥ 55 years and 12 matched UVH older adults with age-appropriate cognitive function-cognitively evaluated by means of Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-before and after a VR protocol. RESULTS: A significant post-treatment reduction in surface, length and power spectra (PS) values within low-frequency domain and an improvement in performance measures were recorded in both groups. Moreover, the VR protocol highlighted-when comparing pre-/post-treatment differences (Δ)-a significant (i) increase in Δ VOR gain; (ii) decrease in Δ surface and length and (iii) increase in Δ PS within low-frequency domain in older adults when compared to MCI patients. Positive correlations were found between MMSE and Δ Dynamic Gait Index, Δ surface and Δ PS within low-frequency domain when treating patients as 'a continuum' along the cognitive decline. CONCLUSIONS: Present pilot findings suggest that the cognitive domain insight in older adults scheduled for VR protocols may positively impact on disability consequences.

Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity.

Multiple chemical sensitivity (MCS) patients usually react to odour compounds and the majority of neuroimaging studies assessed, especially at the cortical level, many olfactory-related correlates. The purpose of the present study was to depict sub-cortical metabolic changes during a neutral (NC) and pure (OC) olfactory stimulation by using a recently validated (18)F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computer tomography procedure in 26 MCS and 11 healthy (HC) resting subjects undergoing a battery of clinical tests. Twelve subcortical volumes of interest were identified by the automated anatomical labeling library and normalized to thalamus FDG uptake. In both groups, when comparing OC to NC, the within-subjects ANOVA demonstrated a relative decreased metabolism in bilateral putamen and hippocampus and a relative increased metabolism in bilateral amygdala, olfactory cortex (OLF), caudate and pallidum. The between-groups ANOVA demonstrated in MCS a significant higher metabolism in bilateral OLF during NC. As in HC subjects negative correlations were found in OC between FDG uptake in bilateral amygdala and hippocampus and odor pleasantness scale, the latter positively correlated with MCS subjects' bilateral putamen FDG uptake in OC. Besides FDG uptake resemblances in both groups were found, for the first time a relative higher metabolism increase in OLF in MCS subjects at rest with respect to HC was found. When merging this aspect to the different subcortical FDG uptake correlations patterns in the two groups, the present study demonstrated to describe a peculiar metabolic index of behavioral and neurological aspects of MCS complaints.

Role of p63 and the Notch pathway in cochlea development and sensorineural deafness.

The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis--Puma, Noxa, or both--are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.

Lack of contralateral suppression in transient-evoked otoacoustic emissions in multiple chemical sensitivity: a clinical correlation study.

Multiple chemical sensitivity (MCS) is a chronic disorder characterized by a variety of symptoms associated with the exposure to chemicals at a concentration below the toxic level. Previous studies have demonstrated peculiar responses in brain activity in these patients with respect to sensory stimuli while the association between chemical sensitivity and other environmental intolerances such as noise sensitivity has been questioned by researchers. In this study, a cohort of 18 MCS patients underwent transient-evoked otoacoustic emission (TEOAE) testing with and without contralateral suppression to evaluate the functionality of the medial olivocochlear (MOC) reflex involved in speech-in-noise sensitivity. Results were compared with an age- and gender-matched control group (n = 20) and correlation analysis with disease onset and quick environmental exposure sensitivity inventory (qEESI) symptom severity scale was performed. Subjects affected by MCS showed statistically significant impairment of MOC reflex, and the onset of the disease and several symptom subscales showed to be correlated to such reduction in some of the frequencies tested. These data suggest that alterations of MOC reflex could be part of the complex features of this disease although more studies are needed to further explore auditory perception disorders in environmental intolerances.

Intra-parotid facial nerve schwannoma with intra-temporal extension; a case report. Is there a role for stereotactic radiotherapy?

Facial nerve schwannoma (FNS) is an extremely rare benign tumour that may arise anywhere along the course of the facial nerve; the standard treatment is total removal via microsurgery. Stereotactic radiotherapy has been shown to be effective in the treatment of skull base tumours, in particular for acoustic neuromas; it is interesting to notice that also the few data existing in literature about the use of radiotherapy for non acoustic schwannomas show an excellent local control rate and few adverse effects. Here we report a case of facial nerve neuroma, involving the nerve sheath from the geniculate ganglion to the parotid gland, treated with fractionated stereotactic radiotherapy after debulking surgery.

Persistent benign paroxysmal positional vertigo: our experience and proposal for an alternative treatment.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo. Despite the great efficacy of canalith repositioning procedures (CRPs), BPPV may persist (PBPPV). The aim of the study was to evaluate whether a prolonged and self-assessed temporal bone vibration (TBV) could change the outcome of PBPPV after 12 months of repeated treatments, in order to avoid further invasive and/or drug therapies. This evaluation was also conducted with respect to the entire BPPV population treated with CRPs. Seventy-two patients affected by PBPPV were enrolled in the study: 51 and 21 of them suffering from posterior semicircular canal (PSC) and lateral semicircular canal (LSC), respectively. PBPPV patients underwent a twice-a-day self-assessed TBV, using a common low-intensity massaging cushion. Patients were re-tested 1 week later and they were considered free from disease as the results of the positioning tests continued to be negative after 1 month. 70.6 % of PSC PBPPV and 61.9 % of LSC PBPPV patients had positive and statistically significant (P < 0.01) outcomes not biased by "age" and "gender" variables. The recurrence rate of BPPV (RBPPV) was also studied in the BPPV and PBPPV groups after a 12/24-month follow-up and any statistically significant result was found in multiple regression analysis between nuisance variables and RBPPV patients previously treated by CRPs or TBV. The present study suggests that the self-assessed and prolonged TBV could be an alternative treatment in patients affected by PBPPV otherwise addressed to undergo more invasive procedures and pharmacological treatment that are not completely side effects free.

Nose sinus manometry in evaluating functional outcomes of anterior and posterior endoscopic dacryocystorhinostomy.

OBJECTIVE: The aim of this study is to evaluate the effectiveness of anterior and posterior dacryorhinocystostomy (En-Dcr) by assessing the surgical outcome with a new objective technique, nose sinus manometry. MATERIALS AND METHODS: Thirty adult patients presenting nasolacrimal duct obstruction were enrolled in this study and randomly divided in two groups. In group A patients underwent anterior endonasal dacryorhinocystostomy, group B underwent the posterior approach. All patients were evaluated through Nose Sinus Manometry, endoscopic dye disappearance functional test (EDFT) and subjective assessment three months post-op. Pearson test and T-student Test were used for evaluations. RESULTS: The mean differences in the pressure values were significantly different in the two groups of treatment, therefore, the patients of group B had strong improvement in pressure values compared with patients of group A. CONCLUSION: This study confirms a relevant physical distinction between posterior En-Dcr outcomes compared to anterior En-Dcr and reveals a significant success rate difference between the two groups of patients. The posterior surgical technique shows better results than the anterior one, by providing an almost physiological post- operative endonasal outcome. These results also showed the effectiveness of Nose Sinus Manometry in assessing the post- operative outcomes after En-Dcr.

Benzene-Exposed Army Soldiers: Nasal Cytology as a Screening Tool.

OBJECTIVE: Assessment of the nasal cytology in revealing early nasal mucosa alteration of workers exposed to benzene. METHODS: Nasal cytology was compared among non-exposed and exposed workers to benzene. A comparison of the two groups was performed considering rhino-cytological features. RESULTS: In the exposed group neutrophils count range was 14 to 70, compared to 2 to 5 in control group. Ciliated cells ratio range was respectively 0.28 to 2.8 and 0.25 to 0.31. In subjects exposed to benzene >10 years, nasal mucosa showed an inflammatory status and an ongoing mucipar metaplasia, defined by an alteration of mucipar/ciliated cells ratio. CONCLUSIONS: Nasal cytology may be a useful research tool for the health surveillance of workers exposed to benzene and may be applied to study the effects of other upper airways chemicals irritants.

Cochlear Dysfunction Is a Frequent Feature of Facioscapulohumeral Muscular Dystrophy Type 1 (FSHD1).

INTRODUCTION: Facioscapulohumeral muscular dystrophy type 1 (FSHD) represents one of the most common forms of muscular hereditary diseases and it is characterized by a great clinical variability with the typical muscular symptoms and other clinical features, including hearing impairment. However, etiopathogenetic mechanisms of auditory dysfunction are still not completely understood and it has been suggested that it could be assigned to a cochlear alteration that is present even in those subjects with a normal pure tonal audiometry (PTA) examination. METHODS: We found out the cochlear function in 26 patients with molecular diagnosis of FSHD1 and in healthy controls. All patients underwent complete neurological and audiological examinations, including FSHD clinical score, pure-tone audiometry (PTA), and otoacoustic emissions (OAEs), in particular transient evoked otoacoustic emissions (TEOAEs) and distortion product evoked otoacoustic emissions (DPOAEs). RESULTS: All FSHD1 patients showed significantly reduced DPOAEs and TEOAEs, bilaterally and at all frequencies, even when considering only subjects with a normal PTA or a mild muscular involvement (FSHD score ≤ 2). No correlation between OAEs and FSHD clinical score was found. DISCUSSION: Cochlear echoes represent a sensitive tool in detecting subclinical cochlear dysfunction in FSHD1 even in subjects with normal hearing and/or subtle muscle involvement. Our study is focused on the importance of evaluating the cochlear alteration through OAEs and, in particular, by performing TEOAEs and DPOAEs sequentially, to evaluate more frequent specificities of cochlear dysfunction with a wider spectrum of analysis.

Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation.

The autosomic dominant KID Syndrome (MIM 148210), due to mutations in GJB2 (connexin 26, Cx26), is an ectodermal dysplasia with erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. The Cx26 protein is a component of gap junction channels in epithelia, including the cochlea, which coordinates the exchange of molecules and ions. Here, we demonstrate that different Cx26 mutants (Cx26D50N and Cx26G11E) cause cell death in vitro by the alteration of intra-cellular calcium concentrations. These results help to explain the pathogenesis of both the hearing and skin phenotypes, since calcium is also a potent regulator of the epidermal differentiation process.

Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss.

KID syndrome (MIM 148210) is an ectodermal dysplasia characterized by the occurrence of localized erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. KID syndrome is inherited as an autosomic dominant disease, due to mutations in the gene encoding gap junction protein GJB2 (connexin 26, Cx26). Cx26 is a component of gap junction channels in the epidermis and in the stria vascularis of the cochlea. These channels play a role in the coordinated exchange of molecules and ions occurring in a wide spectrum of cellular activities. In this paper we describe two patients with Cx26 mutations cause cell death by the alteration of protein trafficking, membrane localization and probably interfering with intracellular ion concentrations. We discuss the pathogenesis of both the hearing and skin phenotypes.

Cerebral plasticity in acute vestibular deficit.

The aim of this study was to analyze the effect of acute vestibular deficit on the cerebral cortex and its correlation with clinical signs and symptoms. Eight right-handed patients affected by vestibular neuritis, a purely peripheral vestibular lesion, underwent two brain single photon emission computed tomography (SPECT) in 1 month. The first SPECT analysis revealed reduced blood flow in the temporal frontal area of the right hemisphere in seven of eight patients, independent of the right/left location of the lesion. The alteration was present always in the right, non-dominant hemisphere and was reversible in some patients 1 month after the onset, together with attenuation of signs and symptoms. It may be hypothesized that the transient reduction of cortical blood flow and subsequently of cortical activity in the non-dominant hemisphere, also the expression of cerebral plasticity, may serve as a defense mechanism aimed to attenuate the vertigo symptom.

Dual-energy X-ray absorptiometry analysis of body composition in patients affected by OSAS.

Obstructive sleep apnoea syndrome (OSAS) is a disorder characterized by recurrent episodes of apnoea. This study evaluates the body composition in OSAS patients compared to normal weight, pre-obese and obese subjects. Body composition has been measured by dual-energy X-ray absorptiometry in the whole body and in three different body regions. Abdominal region revealed no significant differences in fat mass percentage between patients and controls and no correlation between fat mass percentage and severity of OSAS. At the level of oral region, OSAS patients showed a significant decrease of fat free mass compared to control groups. At the level of neck region, OSAS patients showed a significant increase of fat mass compared to control groups and a significant correlation between the neck fat mass percentage and severity of OSAS. Regional fat distribution constitutes a risk factor for OSAS and a prognostic factor for severity of OSAS.

Evaluation of Task-Related Brain Activity: Is There a Role for 18F FDG-PET Imaging?

Positron emission tomography (PET) with 2-[18F]-fluorodeoxyglucose (FDG) has been widely used for the evaluation of cortical glucose metabolism in several neurodegenerative disorders while its potential role in the evaluation of cortical and subcortical activity during a task in the healthy and pathological brain still remains to be a matter of debate. Few studies have been carried out in order to investigate the potential role of this radiotracer for the evaluation of brain glucose consumption during dynamic brain activation. The aim of this review is to provide a general overview of the applications of FDG-PET in the evaluation of cortical activation at rest and during tasks, describing first the physiological basis of FDG distribution in brain and its kinetic in vivo. An overview of the imaging protocols and image interpretation will be provided as well. As a last aspect, the results of the main studies in this field will be summarized and the results of PET findings performed in healthy subjects and patients suffering from various diseases will be reported.

Nose sinus manometry in evaluating functional outcomes of anterior and posterior endoscopic dacryocystorhinostomy

Objective: The aim of this study is to evaluate the effectiveness of anterior and posterior dacryorhinocystostomy (En-Dcr) by assessing the surgical outcome with a new objective technique, nose sinus manometry.Materials and methodsThirty adult patients presenting nasolacrimal duct obstruction were enrolled in this study and randomly divided in two groups. In group A patients underwent anterior endonasal dacryorhinocystostomy, group B underwent the posterior approach. All patients were evaluated through Nose Sinus Manometry, endoscopic dye disappearance functional test (EDFT) and subjective assessment three months post-op. Pearson test and T-student Test were used for evaluations.ResultsThe mean differences in the pressure values were significantly different in the two groups of treatment, therefore, the patients of group B had strong improvement in pressure values compared with patients of group A.ConclusionThis study confirms a relevant physical distinction between posterior En-Dcr outcomes compared to anterior En-Dcr and reveals a significant success rate difference between the two groups of patients. The posterior surgical technique shows better results than the anterior one, by providing an almost physiological post- operative endonasal outcome. These results also showed the effectiveness of Nose Sinus Manometry in assessing the post- operative outcomes after En-Dcr. (AU)

Antecedentes y objetivo: El objetivo de este estudio es evaluar la efectividad de la dacriocistorrinostomía anterior y posterior (En-Dcr) mediante la evaluación del resultado quirúrgico con una nueva técnica objetiva, la manometría del seno nasal.Materiales y métodosTreinta pacientes adultos que presentaban obstrucción del conducto nasolagrimal se inscribieron en este estudio y se dividieron al azar en dos grupos. En el grupo A, los pacientes se sometieron a dacriocistorrinostomía endonasal anterior, en el grupo B se sometió al abordaje posterior. Todos los pacientes fueron evaluados mediante manometría de seno nasal, prueba EDFT y evaluación subjetiva tres meses después de la operación. Análisis estadístico utilizado: la prueba de Pearson y la prueba t Student se utilizaron para las evaluaciones.ResultadosLas diferencias medias en los valores de presión fueron significativamente diferentes en los dos grupos de tratamiento, por lo tanto, los pacientes del grupo B tienen una fuerte mejora en los valores de presión en comparación con los pacientes del grupo A.ConclusionesEste estudio confirma una distinción física relevante entre los resultados posteriores de En-Dcr, en comparación con los anteriores En-Dcr, y revela una diferencia significativa en la tasa de éxito entre los dos grupos de pacientes. La técnica quirúrgica posterior muestra mejores resultados que la anterior, al proporcionar un resultado endonasal postoperatorio casi fisiológico. Estos resultados también mostraron la efectividad de la manometría de seno nasal para evaluar los resultados postoperatorios después de En-Dcr. (AU)

Vestibular impairment in Multiple Chemical Sensitivity: Component analysis findings.

Multiple chemical sensitivity (MCS) is a common clinical diagnosis in western populations and its symptoms are thought to be mainly related to chemical compounds exposure. Although MCS subjects refer to complain from many central nervous system symptoms, including dizziness, no study to now deepened vestibular detriment nor to what extent such an impairment could worsen MCS. Thus, the purpose of present study was to objectively highlight those clinical/subclinical aspects of vestibular impairment that could be related to MCS symptoms cohorts. A principal component analysis within a wide battery of otoneurological test scores was employed in 18 right-handed MCS patients and 20 sex- and age-matched healthy individuals. A deranged dimensionality in near-optimal re-weighting within otoneurological variables was found in MCS as compared with healthy subjects. These data seem to support the idea that MCS physiopathological underpinnings could lead to a peripheral and higher vestibular decay that could be addressed as a further aspect to better follow MCS patients up along natural history of disease in clinical practice.

Indium111 pentetreotide single photon emission computed tomography (In111 pentetreotide SPECT): a new technique to evaluate somatostatin receptors in chordomas.

Chordomas are rare neoplasms originating along the neuraxis. Although they do not usually show cytological atypia, metastases have been reported in 30 per cent of cases. Survival rates in cases of skull base locations are low, and local recurrence is common after local excision. Radiation therapy is used in post-operative treatment and proton radiation therapy as the primary treatment. In the present paper we present the case of a 50-year-old Caucasian man affected by chordoma of the clivus, with liver and chest metastases, relapsed after several surgical local excisions, to discuss improvements in therapeutic and imaging techniques. Indium111 (In111) pentetreotide single photon emission computed tomography (SPECT) was employed to assess the presence of somatostatin receptors and to treat the tumour with radiolabelled Y90-DOTA-lanreotide. Imaging, performed 2 months afterwards, showed stable disease in the lungs but a local progression in the metastases, in comparison with pre-treatment uptake. These data suggest the usefulness of radiolabelled somatostatin analogues in the diagnosis and therapy of chordomas.

OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development.

OTX proteins, homologs of the Drosophila orthodenticle (Otd), are important for the morphogenesis of the neuroectoderm, and for the central nervous system formation. OTX1 and OTX2 are important for the cochlea and macula development, indeed when OTX1 is knocked down, these organs undergo developmental failure. Moreover OTX2 transfection revert this effect in OTX1(-/-) mice. The TA isoform of TP63, involved in Notch regulation pathway, has a critical function in the cochlear neuroepithelium differentiation. TAp63 positively regulates Hes5 and Atoh1 transcription. This pathway has been also demonstrated in p63(-/-) mice, and in patients p63 mutated, affected by Ectodermal Dysplasia (ED, OMIM 129810). These patients are affected by mild sensorineural deafness, most likely related to the mutation in p63 gene impairing the Notch pathway. We demonstrated the role of OTX2 on TAp63 regulation necessary for the correct formation of macular neuroepithelium and we confirmed the impairment of vestibular function caused by p63 mutations. Although the abnormalities found in our patient were still at a subclinical extent, aging could exacerbate this impairment and cause a decrease in quality of life.

Vestibular compensation: analysis of postural re-arrangement as a control index for unilateral vestibular deficit.

Patients with an acute unilateral vestibular lesion show an impaired balance control. The initial presentation is vertigo followed by postural instability; but with time, the global balance functions can be completely restored by a process called vestibular compensation. The aim of our study was to evaluate short and long-term variations of postural parameters in 20 patients affected by vestibular neuritis (VN), and to compare these patients to 20 normal individuals using computerized static posturography (CSP) along with patient feedback throughout the spectral frequency analysis. This analysis showed in patients with no residual dizziness a frequency shift of body sway from low to middle frequencies as a probable expression of the compensatory strategies used by the central nervous system. On the other hand, patients with persistence of postural instability did not show any frequency shift. Our results seem to provide an early index of a proper occurring compensation so that we can adjust therapeutic protocols according to each patient's functional modifications.