A Logical Modeling of Severe Ignorance.

In the logical context, ignorance is traditionally defined recurring to epistemic logic. In particular, ignorance is essentially interpreted as "lack of knowledge". This received view has - as we point out - some problems, in particular we will highlight how it does not allow to express a type of content-theoretic ignorance, i.e. an ignorance of φ that stems from an unfamiliarity with its meaning. Contrarily to this trend, in this paper, we introduce and investigate a modal logic having a primitive epistemic operator I, modeling ignorance. Our modal logic is essentially constructed on the modal logics based on weak Kleene three-valued logic introduced by Segerberg (Theoria, 33(1):53-71, 1997). Such non-classical propositional basis allows to define a Kripke-style semantics with the following, very intuitive, interpretation: a formula φ is ignored by an agent if φ is neither true nor false in every world accessible to the agent. As a consequence of this choice, we obtain a type of content-theoretic notion of ignorance, which is essentially different from the traditional approach. We dub it severe ignorance. We axiomatize, prove completeness and decidability for the logic of reflexive (three-valued) Kripke frames, which we find the most suitable candidate for our novel proposal and, finally, compare our approach with the most traditional one.

Dysautonomia in RFC1-related disorder: Clinical and neurophysiological evaluation.

OBJECTIVE: To characterize and quantify autonomic involvement in patients with RFC1-related disorder of adult-onset cerebellar ataxia and idiopathic sensory neuropathy. METHODS: We enrolled 16 subjects with biallelic RFC1 (AAGGG)n expansions and 16 age and sex-matched healthy controls that underwent comprehensive clinical and neurophysiological evaluation. Scales for Outcomes in Parkinson's Disease Autonomic Dysfunction (SCOPA-AUT) score was used to assess autonomic symptoms. Electrophysiological testing included assessment of heart rate variability and quantitative sudomotor axon reflex test (QSART). Between-group comparisons were assessed using non-parametric tests. RESULTS: In the patient group, there were 9 men/7 women and the median age was 60.5 years. SCOPA-AUT scores were significantly higher in the RFC1 group compared to controls (22 vs 10, p < 0.001). Half of patients had cardiac autonomic neuropathy. In neurophysiology, there was resting tachycardia combined with abnormal responses during Valsalva maneuver and deep breathing among patients. QSART responses were also significantly reduced in the RFC1 group, especially in the lower limbs. CONCLUSIONS: Autonomic dysfunction is frequent, clinically relevant and involves multiple domains in RFC1-related disorder. Patients have both sympathetic and parasympathetic involvement. From a topographical perspective, this condition is characterized by a small fiber autonomic axonopathy. SIGNIFICANCE: Dysautonomia is frequent, severe and related to peripheral damage in RFC1-related disorder.

Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes.

BACKGROUND: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. OBJECTIVE: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. METHODS: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. RESULTS: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. CONCLUSIONS: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease. © 2021 International Parkinson and Movement Disorder Society.

A Proposal for Classification of Retinal Degeneration in Spinocerebellar Ataxia Type 7.

The aim of this study is to propose a classification system for the spinocerebellar ataxia type 7 retinal degeneration (SCA7-RD). Twenty patients with molecularly confirmed SCA7 underwent slit lamp examination, fundus photography, and optical coherence tomography (Spectralis®). Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS) were applied, and age, sex, age at symptom onset, and number of CAG expansions were recorded. After analyzing the ophthalmological findings in each participant, a panel of retinal disease experts created a qualitative classification system for SCA7-RD comprising four stages. We assessed the correlations of retinal degeneration severity with SARA and ICARS scores, number of CAG repeats in ATXN7 allele, and age at symptom onset. We graded retinal degeneration as stage 1 in nine participants, as stage 2 in five, and as stage 3 in six. No differences in age and visual symptoms duration were found between groups. SARA and ICARS scores correlated with the severity of SCA7-RD on the classification system (p = 0.024 and p = 0.014, respectively). After adjusting for disease duration, retinal disease stage association with SARA and ICARS scores remained significant (ANCOVA, p < 0.05). The classification system for SCA7-RD was able to characterize different disease stages representing the landmarks in the cone-rod dystrophy natural history. Neurodegeneration appears to occur in parallel in the cerebellum and in the visual pathway. We conclude that retinal degeneration in SCA7 is a potential biomarker of the neurological phenotype severity.

The surgical treatment of unilateral vocal cord paralysis (UVCP): qualitative review analysis and meta-analysis study.

PURPOSE: The objectives of this meta-analysis were to summarize the key surgical procedures for UVCP and to evaluate which of these is associated with better results in terms of vocal improvement. METHODS: A systematic review of the literature was conducted in search of articles focused on the comparison of voice outcome between different techniques for the UVCP treatment. Then, a quantitative analysis was carried out for papers published from 2013 onwards, reporting only adult patients with unilateral paralysis for each study, and each surgical technique was evaluated for its capability of achieving good functional outcomes in terms of GRBAS-I scale and maximum phonation time in seconds (MPT). RESULTS: The search identified 1853 publications. A total of 159 articles were stratified and included according to our selection criteria. 21 out of 159 articles were selected for quantitative synthesis. For trans-oral techniques: the mean GRBAS-I scale were 2.33 before injection and 0.41 after injection. The mean MPT before injection were 4.78 and 12.50 after injection. For open techniques the mean GRBAS-I scale were 2.43 before surgery and 0.68 after surgery. For open technique, the mean MPT were 3.50 before surgery and 12.40 after surgery. CONCLUSIONS: The two types of techniques lead to an improvement in terms of vocal outcomes emphasizing that from the examined literature an indication emerges to perform an early injection because this could reduce the possible need for a more invasive intervention of permanent medialization in the future.

Neuroimaging in Hereditary Spastic Paraplegias: Current Use and Future Perspectives.

Hereditary spastic paraplegias (HSP) are a large group of genetic diseases characterized by progressive degeneration of the long tracts of the spinal cord, namely the corticospinal tracts and dorsal columns. Genotypic and phenotypic heterogeneity is a hallmark of this group of diseases, which makes proper diagnosis and management often challenging. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool to assist in the exclusion of mimicking disorders and in the detailed phenotypic characterization. Some neuroradiological signs have been reported in specific subtypes of HSP and are therefore helpful to guide genetic testing/interpretation. In addition, advanced MRI techniques enable detection of subtle structural abnormalities not visible on routine scans in the spinal cord and brain of subjects with HSP. In particular, quantitative spinal cord morphometry and diffusion tensor imaging look promising tools to uncover the pathophysiology and to track progression of these diseases. In the current review article, we discuss the current use and future perspectives of MRI in the context of HSP.

Excessive fragmentary myoclonus in Machado-Joseph disease.

OBJECTIVE: Machado-Joseph disease (MJD) is a neurodegenerative disease which usually presents several clinical findings including cerebellar ataxia and other extracerebellar features, such as Parkinsonism, dystonia, peripheral neuropathy, and lower motor neuron disease. Some data have demonstrated a high frequency of sleep disorders in these patients, including excessive daytime sleepiness (EDS), insomnia, obstructive sleep apnea (OSA), rapid eye movement (REM) sleep behavior disorder (RBD), and restless legs syndrome (RLS). Herein, we aimed to describe the high frequency of excessive fragmentary myoclonus (EFM) in MJD. MATERIALS AND METHODS: We recruited 44 patients with MJD and 44 healthy controls. All participants underwent an all-night polysomnography (PSG). EFM was evaluated and defined in accordance to the criteria of the American Academy of Sleep Medicine. RESULTS: Half of the MJD patients (n = 22) had EFM diagnosed through PSG, though no healthy control participant presented this finding (P < .0001). In the MJD group, older participants and men had a higher frequency of EFM. There was no correlation between EFM and the following data: body mass index (BMI), apnea-hypopnea index (AHI), EDS, loss of atonia during REM sleep, periodic limb movements during sleep (PLMS), RLS, RBD, ataxia severity, the number of cytosine-adenine-guanine trinucleotide (CAG) repeats, disease duration, sleep efficiency, sleep fragmentation, and sleep stage percentages between patients with or without EFM. CONCLUSION: EFM is highly prevalent in patients with MJD. Our study demonstrates that EFM must be included in the clinical spectrum of sleep disorders in MJD patients.

Lingual frenectomy: a comparison between the conventional surgical and laser procedure.

AIM: Ankyloglossia, commonly known as tongue-tie, is a congenital oral anomaly characterized by a short lingual frenulum that may contribute to feeding, speech and mechanical problems. The purpose of this study is to compare the advantages of laser vis-à-vis conventional frenectomy in both intra- and post-surgical phases. METHODS: This study took into consideration two patients, who were respectively 9 and 10-year-old. The first one underwent a common surgical procedure. A Nd:Yap laser device with a micropulsed wavelength of 1340 nm and power of 8 watts was used for the second. The postsurgical discomfort and healing characteristics were evaluated. RESULTS: The results indicated that the Nd:Yap laser has the following advantages when compared to the conventional frenectomy: 1) soft tissue cutting was efficient, with no bleeding, giving a clear operative field; 2) there was no need to use sutures; 3) the surgery was less time-consuming; 4) there was no postsurgical infection and no need for analgesics or antibiotics; 5) wound contraction and scarring were decreased or eliminated; 6) despite the initial slowness of the healing process, the complete and final recovery was faster. CONCLUSIONS: Considering the above elements, it is possible to assert that the laser frenectomy has a series of unquestionable advantages if compared to the conventional surgical technique.

Nonmotor and extracerebellar features in Machado-Joseph disease: a review.

Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia worldwide, and the high frequency of nonmotor manifestations in Machado-Joseph disease demonstrates how variable is the clinical expression of this single genetic entity. Anatomical, physiological, clinical, and functional neuroimaging data reinforce the idea of a degenerative process involving extracerebellar regions of the nervous system in Machado-Joseph disease. Brain imaging and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, medulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occipital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado-Joseph disease. The main nonmotor manifestations of Machado-Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropathy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief discussion of noncerebellar motor manifestations, highlighting movement disorders. © 2013 Movement Disorder Society.

[Is there an interpretational bias for childhood events in anxious adult patients?]. / Existe-t-il un biais d'interprétation des événements d'enfance chez les patients adultes anxieux?

During anamnesis, we attempted often to include the events reported by the patients in our own functional explanation of the disorder. We forget on one hand that the patient reports events intrinsically linked to his pathology, and on the other hand, that an event could not be understood without its context. Concerning the links between the pathology and what is narrated, it is known for a long time that the anxious disorders modify the perception of world by some processes, like the fast detection of the threat in the environment. Questions are: are the anxious encoding bias active to the restitution phase of information processing? Do these bias influence the recall of childhood events? In this article, we present theoretical data and set of experiments who leads us to say that anxious bias exist in the interpretation of childhood events made by anxious patients.

[Treatment of adjustment disorder with anxiety: efficacy and tolerance of etifoxine in a double-blind controlled study]. / Traitement du trouble de l'adaptation avec anxiété: évaluation de l'efficacité et de la tolérance de l'étifoxine par un essai en double aveugle contre produit de référence.

Adjustment disorder with anxiety is defined as a clinically significant anxiety that occurs within 3 months after the onset of an identifiable psychological stressor. Recent studies indicate that this disorder is not uncommon and must be quickly identified and treated. However, few therapeutic trials have been done in relation with this disorder. According to the criteria set by DSM IV, 170 patients with a primary diagnosis of adjustment disorder with anxiety have been enrolled in a double blind multicenter controlled trial. Patients were treated for 4 weeks with etifoxine (150-200 mg/d), or buspirone (15-20 mg/d). Also both etifoxine and buspirone show clinical efficacy and safety, the two treatments are not equivalent. The global improvement score and the efficacy index are significantly improved in the etifoxine group. These results show the interest of using etifoxine in the treatment of adjustment disorder with anxiety and should be confirmed by further studies.

Detection of Epstein-Barr virus genome in sinonasal undifferentiated carcinoma by use of in situ hybridization.

Associations between Epstein-Barr virus and undifferentiated carcinomas of nasopharynx, parotid gland, and thymus have recently been reported. Epstein-Barr virus has also been associated with malignant lymphoma of the nose and paranasal sinuses. These findings raise the possibility that Epstein-Barr virus may additionally be linked to undifferentiated carcinoma of the nose and paranasal sinuses (SNUC), an uncommon but distinctive and highly aggressive neoplasm. Histologically, SNUC consists of small and medium cells, the precise characterization of which often requires immunocytochemical analysis. This study investigates the presence of DNA sequences of Epstein-Barr virus in biopsy specimens of 13 cases of SNUC that were defined immunocytochemically by use of previously reported criteria. In situ hybridization was used to detect Epstein-Barr virus genome in different cell types in routinely processed, paraffin-embedded tissues. Epstein-Barr virus-specific DNA sequences were detected in tumor cells of SNUC specimens from 5 of the 13 cases examined. No correlation was found between positive hybridization and primary tumor site, morphologic subtype, or disease course. Epstein-Barr virus DNA was detected in 38% (5 of 13) of the SNUC samples analyzed. This finding suggests that this virus may play a role in the pathogenesis of this rare neoplasm.

Evaluation of two buflomedil tablet formulations in patients with atherosclerotic disease.

The bioequivalence of a 600-mg methocel tablet containing buflomedil hydrochloride in sustained-release form was determined relative to a 300-mg CAP/carbovax-coated tablet of buflomedil hydrochloride in immediate-release form. The tablets were given to 20 patients in a double-blind placebo-controlled clinical study with cross-over between the administration plans. The 300-mg tablets were given b.i.d., at 8 a.m. and 8 p.m. while the 600-mg tablets were taken once a day at 8 a.m. (+placebo at 8 p.m.). Plasma samples were collected at appropriate times up to 24 h after administration and were analyzed for buflomedil with a validated high-performance liquid chromatographic procedure. Results showed an overall significant mean difference in absorption rate between the two formulations. The mean tmax (5.5 +/- 3.5 h) for the 600-mg tablet was longer (P < 0.001) than the tmax value (1.8 +/- 0.8 h) seen after administration of the first 300-mg tablet. Analysis of AUC(O-infinity) values indicated that the sustained-release preparation (32.1 +/- 20.7 micrograms/ml h) was not significantly different from the 300-mg tablet b.i.d. (28.7 +/- 16.0 micrograms/ml h). Furthermore, it was seen that single administration of a 600-mg sustained-release tablet of buflomedil hydrochloride delivered the same amount of total drug as a 300-mg tablet given twice a day.

Undifferentiated carcinoma of the nose and paranasal sinuses. An immunohistochemical and clinical study.

Among twenty-six "undifferentiated" tumors of the nasal cavity and paranasal sinuses treated from 1970 to 1990 at the Institute of Otolaryngology of Florence University, 13 were ultimately diagnosed as true undifferentiated sinusonasal carcinoma (SNUC) by conventional light microscopy and use of monoclonal antibodies to epithelial membrane antigen and cytokeratins. SNUC patients, who ranged in age from 20 to 82 years, often had multiple sinonasal symptoms due to very large tumors (nine of 13 tumors were staged as T3-T4) with short average delay of 4 months between onset of symptoms and diagnosis. Both data suggest the high growth capacity and aggressiveness of such a tumor. In our series, follow-up evidenced an overall crude 5-year survival rate of 15.5%. Worse prognostic factors are neck metastases and orbital invasion, according to the behavior of more common carcinomas of the nose and paranasal sinuses. We also found a better prognosis for SNUC primarily arisen in the nasal cavity than in paranasal sinuses (crude 5-year survival rate of 66% vs. 10%, respectively). The histopathological and clinical analysis of our series shows that SNUC is a highly aggressive, uncommon tumor of the nose paranasal sinuses, which should be recognized in advance for a more aggressive treatment by combined multiple therapy.

Effects of zileuton, a new 5-lipoxygenase inhibitor, in experimentally induced colitis in rats.

The efficacy of zileuton, a new 5-lipoxygenase inhibitor, was investigated in comparison with sulphasalazine in an experimental model of rat colitis. Under light anaesthesia with ether, male rats were subjected to intracolonic administration of trinitrobenzene sulfonic acid (TNB) in 50% ethanol and were then sacrificed 2, 4 and 7 days after colitis induction. Untreated rats exhibited elevated colonic levels of leukotriene B4 (LTB4) and 6-keto-PGF1 alpha, and an increase in colonic myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation). Moreover, ulceration and inflammation of the distal colon with formation of granuloma and pathologic connections were observed. Treated rats received zileuton or sulphasalazine (50 mg/kg per os twice a day) 24 h before the induction of colitis until they were sacrificed. Treatment with the specific 5-lipoxygenase inhibitor, zileuton, resulted in significant reductions of colonic leukotriene B4 and 6-keto-PGF1 alpha synthesis, macroscopic and histological colonic damage and colonic inflammation as assessed by the measurement of MPO activity. In contrast, sulphasalazine had a lower effect than zileuton on LTB4 and MPO levels (p < 0.05), while it was able to reduce colonic damage and 6-keto-PGF1 alpha levels as well as zileuton. This study shows, therefore, that zileuton is effective in attenuating the lesions in an experimental model of colitis. Furthermore, the results are consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal bowel diseases (IBD).

[Changes in dietary intake of obese patients treated by diet associated with d-fenfluramine]. / Modificazioni dei consumi alimentari di pazienti obese indotte dal trattamento dietetico associato a d-fenfluramina.

The object of the present research was to study the effect of dexfenfluramine (d-F) and placebo (P) on compliance with dietary treatment, especially as far as changes in kcal and macronutrient intake are concerned. A double-blind study d-F vs P was performed in 36 obese females, age range 20-59 years (mean 37.22 +/- 12.41), with a mean BMI of 33.95 +/- 5.36, suffering from obesity due to overeating without complications: Outpatient control every 30 days. The study protocol provided for a 14-month double-blind treatment with daily administration of either P (2 capsules) or d-F (two 15 mg capsules). Dietary prescription of 1200 kcal (5016 kJ) was given 15 days before enrollment (T/0) and during this period enrollment criteria were checked prior to randomization. Dietary intake was checked by a three-day recall (one working day, one half-holiday and one full holiday) in basal conditions and after 6-12 and 14 months. Administration of d-F and P brought about changes in alimentary behaviour in obese patients according to the dietary regime prescribed. In our patients, no highly significant differences between d-F and P were observed; however, the effect of P on macronutrient intake (carbohydrates, lipids and proteins) tended to peter out around the 12th month. Treatment with d-F reduced the consumption of simple carbohydrates, animal fats but not of animal proteins.

[Preliminary results of an open study on the effects of DEAE-dextran on various lipid metabolism parameters in dyslipidemic subjects]. / Prime osservazioni di uno studio aperto sugli effetti del DEAE-destrano su alcuni parametri lipometabolici di soggetti dislipidemici.

The authors report the results of a study of 1963 patients treated with daily doses of 2 g DEAE-dextran. This was an open trial intended to evaluate the evolution of several biohumoral parameters under treatment for dyslipidemias. Statistically significant results were obtained for cholesterol blood level, triglycerides and body weight, as well as a favorable trend for HDL-cholesterol. Side effects or untoward reactions to DEAE-dextran were not observed.