The Clinical Significance of MicroRNAs in Colorectal Cancer Signaling Pathways: A Review.

Colorectal carcinoma (colon and rectum) is currently considered among the most prevalent malignancies of Western societies. The pathogenesis and etiological mechanisms underlying colorectal cancer (CRC) development remain complex and heterogeneous. The homeostasis and function of normal human intestinal cells is highly regulated by microRNAs. Therefore, it is not surprising that mutations and inactivation of these molecules appear to be linked with progression of colorectal tumors. Recent studies have reported significant alterations of microRNA expression in adenomas and CRCs compared with adjacent normal tissues. This observed deviation has been proposed to correlate with the progression and survival of disease as well as with choice of optimal treatment and drug resistance. MicroRNAs can adopt either oncogenic or tumor-suppressive roles during regulation of pathways that drive carcinogenesis. Typically, oncogenic microRNAs termed oncomirs, target and silence endogenous tumor-suppressor genes. On the other hand, tumor-suppressive microRNAs are critical in downregulating genes associated with cell growth and malignant capabilities. By extensively evaluating robust studies, we have emphasized and distinguished a discrete set of microRNAs that can modulate tumor progression by silencing specific driver genes crucial in signaling pathways including Wnt/b-catenin, epidermal growth factor receptor, P53, mismatch repair DNA repair, and transforming-growth factor beta.

Monocular Torsional Oscillopsia in Dentato-olivary Disconnection.

Monocular torsional eye oscillations are a rare form of disconjugate nystagmus and the underlying pathophysiology is not well understood. Here, we present and discuss a case with disabling torsional oscillopsia in one eye only. The patient exhibited (i) spontaneous pendular torsional nystagmus of the left eye and (ii) rhythmic involuntary movements of the soft palate and uvula, consistent with the syndrome of oculopalatal tremor with monocular nystagmus. Brain MRI revealed an infarct of the left dentate nucleus in the cerebellum and, more caudally, a secondary hypertrophic degeneration of the right inferior olivary nucleus. To account for the presence of torsional nystagmus on the eye contralateral to the side of inferior olivary hypertrophy and ipsilateral to the lesioned dentate nucleus, we discuss the hypothesis of a (inferior olivary nucleus-mediated) malfunctioning adaptation of the anterior canal vestibulo-ocular reflex.

Mutational screening of Greek patients with axonal Charcot-Marie-Tooth disease using targeted next-generation sequencing: Clinical and molecular spectrum delineation.

BACKGROUND AND AIMS: Axonal forms of Charcot-Marie-Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population. METHODS: Sixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and next-generation sequencing custom-made gene panel covering 24 commonly mutated genes in axonal CMT. RESULTS: Overall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/likely pathogenic and six were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1. INTERPRETATION: A wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favourably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.

The Rise Slope of the Compound Sensory Nerve Action Potential in Normal and Pathological Human Nerves.

In spite of the diagnostic importance of the early phase of the sensory nerve action potential (SNAP), reliable electrodiagnostic metrics for this part of the recorded waveform are lacking. The average rise slope of the SNAP appreciates the steepness of the initial negative deflection of the waveform, which might be a useful metric for the first part of the potential. Sural nerve sensory neurography was performed in patients with various axonal neuropathies, and median nerve sensory studies were carried out in patients with carpal tunnel syndrome. Age-matched healthy individuals served as controls. The rise slope was compared to conventional SNAP parameters such as conduction velocity, latency, duration, and rise time. Overall, 537 sensory studies were prospectively analyzed. The rise slope of the sural SNAP demonstrated superior classification performance in terms of sensitivity (92.5%), specificity (97%), and area under the receiver operating characteristic curve (0.986), as compared to conventional SNAP parameters. Its diagnostic power was similarly excellent in median nerve studies, whereas here a slightly better classification performance was obtained by SNAP latency and conduction velocity. The average rise slope appears to do justice to the tight interplay between amplitude and rise time of the initial negative spike deflection, outperforming many conventional measures. This composite metric proved high diagnostic potency in particular with regard to axonal sensory nerve dysfunction.

The role of maternal physical activity on in vitro fertilization outcomes: a systematic review and meta-analysis.

PURPOSE: This systematic review is designed to summarize the evidence concerning the impact of maternal physical activity on the reproductive outcomes following assisted reproduction techniques (ART), namely in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). METHODS: We searched for eligible studies on PubMed, EMBASE databases and the Cochrane Library from their inception until September 2021. Our primary outcomes were live birth rate and miscarriage, while secondary ones included clinical pregnancy and implantation rates. The quality of the evidence was evaluated using a study-specific adaptation of the Robins I tool. RESULTS: Quantitative data from 10 cohort studies (CS) and 2 randomized control trials (RCT), involving 3431 women undergoing ART treatments, were included in the analyses. The pooled results exhibited uncertainty regarding the effect of physical activity on live birth rate per woman (OR 1.15, 95% CI 0.92-1.43, p = 0.23, I2 = 61%, 9 studies) and miscarriage rates (OR 0.79, 95% CI 0.44-1.43, p = 0.43, I2 = 44%, 6 studies). However, physical activity was associated with significantly improved clinical pregnancy rate after ART (OR 1.39, 95% CI 1.08-1.79, p = 0.0009, I2 = 68%, 10 studies), whereas implantation rate after ART almost reached statistical significance (OR = 1.95, 95% CI 0.99-3.82, p = 0.05, I2 = 77%). CONCLUSION: The current evidence is still insufficient to firmly conclude on the effect of maternal physical activity on live birth, miscarriage and implantation rates. Although clinical pregnancy rates favored physical activity in this group of patients, these results must be undertaken with caution due to the low quality and the high heterogeneity of the studies included.

Joint entropy analysis of anterior-posterior and medial-lateral body sway.

We studied the Shannon entropy of center of pressure (COP) trajectories under different sensory feedback conditions and analyzed the interrelations between medial-lateral (ML), anterior-posterior (AP) and joint (ML and AP) sway entropy. Static balance was assessed on a force platform under different visual and proprioceptive feedback conditions: Standing on firm support with eyes open (condition 1) or closed (condition 2) and standing on foam with eyes closed (condition 3). Postural sway was analyzed by means of linear and nonlinear, information theoretic metrics (entropy of ML and AP sway, joint ML and AP entropy). ML entropy, AP entropy and joint ML and AP entropy remained stable from condition 1 through condition 3. The values of ML and AP entropies were practically at their theoretical maximum in all conditions. On the other hand, joint ML and AP entropies were clearly submaximal. Decreasing the reliability of visual and proprioceptive input does not alter the Shannon entropy of body sway, although it does increase the magnitude of conventional linear sway metrics. Importantly, individual ML and AP sway entropies tend towards absolute randomness, whereas the joint, ML and AP, sway entropy exhibits a higher degree of regularity, suggesting its role as the actual controlled variable.

Bilateral palsy of the hypoglossal nerve following general anesthesia for emergency surgery. A case report.

INTRODUCTION AND IMPORTANCE: Hypoglossal nerve palsy is a rare condition usually associated with tumors, trauma, stroke or multiple sclerosis. It can be associated with other cranial nerve palsies while injury to this nerve typically affects a patient's articulation by causing lingual motility disturbance and swallowing difficulty. Bilateral isolated hypoglossal nerve palsy is an even more infrequent condition, which can occasionally be due to airway manipulation. CASE PRESENTATION: We describe a case of bilateral hypoglossal nerve damage following general anesthesia for emergency surgery, presenting with dysarthria, immobility of the tongue and dysphagia after extubation. The patient had a gradual recovery of all lost functions during the next four months. CLINICAL DISCUSSION: Bilateral hypoglossal nerve palsy is a very rare entity and tracheal tube malposition or prolonged but unnoticed tracheal cuff pressure especially in the face of low blood pressure, should be considered as possible causative mechanisms for this condition. This underlines the importance of careful positioning of the patient's head and neck during surgery as well as the meticulous and correct performance of routine maneuvers of airway management. CONCLUSION: Bilateral hypoglossal nerve palsy is a very rare entity. Diagnosis and management of twelfth nerve palsy require a multidisciplinary approach to achieve the best patient outcome.

Two-step treatment of a giant skull vault hemangioma: A rare case report and literature review / Tratamiento en dos pasos de un hemangioma de la bóveda craneal gigante: informe de un caso poco frecuente y revisión de la literatura

kull vault hemangiomas are benign vascular tumours of the calvaria that are usually asymptomatic or present as firm, painless lumps. We present a case of a 59-year-old female with a giant intraosseous calvarial hemangioma that was admitted in our department with a palpable mass over the left frontoparietal region, personality changes and impaired emotional and cognitive functions. The patient was treated with a two-step approach involving endovascular and surgical treatment, and suffered two rare, but recognized complications, a contrecoup intracerebral haemorrhage and valproate-induced stupor and parkinsonism. At the 6-month follow-up, the patient had complete recovery with a good neurological outcome (AU)

Los hemangiomas de la bóveda craneal son tumores vasculares benignos de la calota que suelen ser asintomáticos o aparecen como bultos firmes e indoloros. Presentamos el caso de una mujer de 59 años con un hemangioma de calota intraóseo gigante que ingresó en nuestra unidad con una masa palpable en la región frontoparietal izquierda, con cambios de personalidad y con la alteración de las funciones emocional y cognitiva. La paciente recibió tratamiento con un método de dos pasos que incluía terapia endovascular y quirúrgica, y experimentó dos complicaciones poco frecuentes, pero reconocidas: hemorragia cerebral por contragolpe, así como estupor y parkinsonismo inducidos por valproato. A los seis meses de seguimiento, la mujer se recuperó por completo con un buen desenlace neurológico (AU)

Two-step treatment of a giant skull vault hemangioma: A rare case report and literature review.

Skull vault hemangiomas are benign vascular tumours of the calvaria that are usually asymptomatic or present as firm, painless lumps. We present a case of a 59-year-old female with a giant intraosseous calvarial hemangioma that was admitted in our department with a palpable mass over the left frontoparietal region, personality changes and impaired emotional and cognitive functions. The patient was treated with a two-step approach involving endovascular and surgical treatment, and suffered two rare, but recognized complications, a contrecoup intracerebral haemorrhage and valproate-induced stupor and parkinsonism. At the 6-month follow-up, the patient had complete recovery with a good neurological outcome.

Novel Cell-Based Assay for Alpha-3 Nicotinic Receptor Antibodies Detects Antibodies Exclusively in Autoimmune Autonomic Ganglionopathy.

BACKGROUND AND OBJECTIVES: Autoantibodies against α3-subunit-containing nicotinic acetylcholine receptors (α3-nAChRs), usually measured by radioimmunoprecipitation assay (RIPA), are detected in patients with autoimmune autonomic ganglionopathy (AAG). However, low α3-nAChR antibody levels are frequently detected in other neurologic diseases with questionable significance. Our objective was to develop a method for the selective detection of the potentially pathogenic α3-nAChR antibodies, seemingly present only in patients with AAG. METHODS: The study involved sera from 55 patients from Greece, suspected for autonomic failure, and 13 patients from Italy diagnosed with autonomic failure, positive for α3-nAChR antibodies by RIPA. In addition, sera from 52 patients with Ca2+ channel or Hu antibodies and from 2,628 controls with various neuroimmune diseases were included. A sensitive live cell-based assay (CBA) with α3-nAChR-transfected cells was developed to detect antibodies against the cell-exposed α3-nAChR domain. RESULTS: Twenty-five patients were found α3-nAChR antibody positive by RIPA. Fifteen of 25 patients were also CBA positive. Of interest, all 15 CBA-positive patients had AAG, whereas all 10 CBA-negative patients had other neurologic diseases. RIPA antibody levels of the CBA-negative sera were low, although our CBA could detect dilutions of AAG sera corresponding to equally low RIPA antibody levels. No serum bound to control-transfected cells, and none of the 2,628 controls was α3-CBA positive. DISCUSSION: This study showed that in contrast to the established RIPA for α3-nAChR antibodies, which at low levels is of moderate disease specificity, our CBA seems AAG specific, while at least equally sensitive with the RIPA. This study provides Class II evidence that α3-nAChR CBA is a specific assay for AAG. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an α3-nAChR cell-based assay is a more specific assay for AAG than the standard RIPA.

High risk factors for craniosynostosis during pregnancy: A case-control study.

Background: Craniosynostosis is a birth defect involving premature cranial sutures' fusion with an increasing prevalence and unknown underlying causes in nearly 80% of cases. The current study investigates a series of high-risk factors associated with a non-syndromic craniosynostosis. Methods: Ninety-seven (97) children were included in the retrospective case-control study, 62 controls and 35 with craniosynostosis. A questionnaire with 143 questions was used in face-to-face interviews. After univariate analyses, stepwise multivariate logistic regression analysis was implemented. Results: In craniosynostosis group, 3 out of 4 were male subjects and 2 out of 3 born with caesarian section. History for central nervous system abnormalities in their younger siblings, low birth weight, extended use of mobile phone from the parents and medications' use differed significantly between craniosynostosis and control group. After adjustment for all factors, only maternal medication use (aOR 6,1 [2.1 - 19], CI 95%) and oral progesterone intake (aOR 4 [1.2 - 14], CI 95%) were significantly associated with an increased risk in craniosynostosis group. Conclusion: The maternal medications' use and particular oral progesterone intake is associated with an increased risk for non-syndromic craniosynostosis. However, due to the study's limitations, further research is warranted.

Retrocollis as the cardinal feature in a de novo ITRP1 variant.

BACKGROUND: ITPR1 gene encodes inositol 1,4,5-trisphosphate-receptor-type 1, a Ca2+ channel highly expressed in cerebellar Purkinje cells. ITPR1 gene variants, through a loss-of-function mechanism, have been found to be related with the manifestation of spinocerebellar ataxia (SCA) 15, an adult-onset slow progressive cerebellar ataxia, SCA 29, a rare non-progressive congenital cerebellar ataxia and Gillepsie syndrome (SCA 29 phenotype plus aniridia). They share an heterogeneity of additional phenotypic features while no genotype-phenotype correlation has ever been found. CASE REPORT: Here we report the case of a boy with cerebellar ataxia who came to our clinic due to his cervical dystonia in the form of retrocollis. He presented an early-onset, non-progressive cerebellar ataxia, with cognitive impairment and delayed motor milestones. Whole exome sequencing (WES) revealed an heterozygous nucleotide variation, c.829A > C (p.Ser277Arg) in ITPR1 gene (NM_001168272.1), a de novo ITPR1 variant, as his parents came up with negative genetic testing. Due to his clinical presentation and genetic result, we came up with the diagnosis of SCA 29. CONCLUSION: We described cervical dystonia as a phenotypic feature of ITPR1 related SCA 29, found in a new de novo ITPR1-variant.

Treatment of carotid cavernous sinus fistulas with flow diverters. A case report and systematic review.

INTRODUCTION: Carotid cavernous fistulas (CCFs) are rare, usually follow head trauma or aneurysmal rupture. Recent treatment options include endovascular techniques such as flow diversion devices (FDDs). OBJECTIVE: To present our case treated with FDD application with transarterial cavernous-sinus coiling and present a systematic review on the use and effectiveness of FDDs in CCF treatment. MATERIALS AND METHODS: We present our case of CCF treatment with FDD. A search was also conducted in PubMed, EMBASE and Cochrane until November 2020. Reference lists were also cross-checked. RESULTS: Including our case, thirty-eight patients were identified with a CCF that was treated with FDDs in sixteen studies. Twenty-two patients were females, nine were males and the rest unidentified. The mean age was 52,6 years (range 17-86, SD± 19.28). Thirty-six patients suffered from direct and two from indirect CCFs. Single FDD was used in four cases, single FDD with embolic materials in eleven cases, multiple overlapping FDDs were used in six cases and multiple overlapping FDDs with embolic materials were used in seventeen cases. Thirty-five patients (92,1%) had clinical improvement, immediate angiographic occlusion was seen in 44,7% of the cases, while long-term occlusion rate was 100% but with variable follow-up periods. One patient (2,6%) presented with a neurological deficit related to FDD deployment. CONCLUSION: Targeted treatment of CCFs with single or overlapping FDDs with or without adjunct embolic agents offers a high success rate, both clinically and long-term angiographically compared to other endovascular methods alone. However, further research with multi-center prospective trials is warranted.

Vestibular paroxysmia: Clinical features and imaging findings; a literature review.

According to the definition of neurovascular compression syndromes (NVCS), a vascular structure in direct contact with a cranial nerve is causing mechanical irritation of the neural tissue producing correlating symptoms. Vestibular paroxysmia is an example of a neurovascular compression which is caused by neurovascular contact between the eighth cranial nerve and a vessel. It is crucial to understand the unique anatomy of the vestibulocochlear nerve in order to study the syndrome which is the result of its compression. More specifically, the long transitional zone between central and peripheral myelin plays a central role in clinical significance, as the transitional zone is the structure most prone to mechanical injury. Imaging techniques of the eighth cranial nerve and the surrounding structures are substantial for the demonstration of clinically significant cases and potential surgical decompression. The goal of the current review is to present and study the existing literature on vestibular paroxysmia and to search for the most appropriate imaging technique for the syndrome. An extensive literature search of PubMed database was performed, and the studies were ranked based on evidence-based criteria, followed by descriptive statistics of the data. The present analysis indicates that 3D CISS MRI sequence is superior to any other sequence, in the most studies reviewed, regarding the imaging of neurovascular compression of the eighth cranial nerve.

Spectral Composition of Body Sway in Persistent Postural-Perceptual Dizziness.

OBJECTIVE: Previous studies in phobic postural vertigo patients showed characteristic frequency changes in body sway fluctuations, raising the question whether similar spectral changes can be also observed in the recently defined syndrome of persistent postural-perceptual dizziness (PPPD). STUDY DESIGN: Cross-sectional prospective study. SETTING: Tertiary referral center. SUBJECTS: Sixty-one PPPD patients and 41 healthy controls. INTERVENTIONS: Static balance was assessed while standing on firm surface with eyes open or closed (conditions 1 and 2) and while standing on foam with eyes open or closed (conditions 3 and 4). Postural sway was analyzed by means of time (sway area and standard deviation) and frequency domain metrics. The latter was based on comparisons of the percentage of energy in each of three frequency bands: low (0-0.5 Hz), middle (0.05-2 Hz), and high frequency (2-20 Hz). MAIN OUTCOME MEASURE: Stabilometric time and frequency domain parameters. RESULTS: Time domain metrics deteriorated significantly from conditions 1 through condition 4 in patients and controls. Spectral changes, however, were more abundant in PPPD subjects than in controls. Patients showed increased low frequency, but decreased high frequency spectral power in condition 3 as compared to condition 2. Dizziness Handicap Inventory score was positively correlated with middle frequency and negatively correlated with low frequency fluctuations. CONCLUSIONS: We conclude that PPPD patients exhibit a time domain sway pattern in different conditions which is grossly similar to that of controls. However, sensory feedback conditions with equal sway area show unique differences in their spectral content in PPPD patients. Moreover, perceived severity of dizziness is associated with greater body oscillations in the middle frequency band.

Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late-onset ataxia.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) has been recently linked to biallelic expansions of a pentanucleotide repeat in the replication factor C subunit 1 (RFC1) gene. Herein, we sought to investigate the presence of pathological RFC1 expansions in selected Greek patients with late-onset ataxia and delineate the phenotypic spectrum of genetically confirmed CANVAS in the Greek population. We screened genetically a total of 77 selected index patients, 67 originating from a cerebellar ataxia cohort and 10 from a hereditary neuropathy cohort. We identified five index cases (6.5%) with biallelic pathological RFC1 expansions, two in the cerebellar ataxia cohort (3%) and three in the neuropathy cohort (30%). Overall, four out of five of cases with full-blown CANVAS and one case with sensory ataxic neuropathy had biallelic pathological expansions. The phenotypic spectrum of positive cases (including two affected siblings) was consistent with previous reports and implied that the sensory neuropathy may be the earliest feature in genetically confirmed CANVAS. Screening for biallelic RFC1 expansions is recommended in all cases with late-onset ataxia of unknown cause, particularly when a sensory neuropathy is present.