Episodic Vestibulocerebellar Ataxia Associated with a CACNA1G Missense Variant

Episodic vestibulocerebellar ataxias are rare diseases, frequently linked to mutations in different ion channels. Our objective in this work was to describe a kindred with episodic vestibular dysfunction and ataxia, associated with a novel CACNA1G variant. Two individuals from successive generations developed episodes of transient dizziness, gait unsteadiness, a sensation of fall triggered by head movements, headache, and cheek numbness. These were suppressed by carbamazepine (CBZ) administration in the proband, although acetazolamide and topiramate worsened instability, and amitriptyline and flunarizine did not prevent headache spells. On examination, the horizontal head impulse test (HIT) yielded saccadic responses bilaterally and was accompanied by cerebellar signs. Two additional family members were asymptomatic, with normal neurological examinations. Reduced vestibulo-ocular reflex gain values, overt and covert saccades were shown by video-assisted HIT in affected subjects. Hearing acuity was normal. Whole-exome sequencing demonstrated the heterozygous CACNA1G missense variant c.6958G>T (p.Gly2320Cys) in symptomatic individuals. It was absent in 1 unaffected member (not tested in the other asymptomatic individual) and should be considered likely pathogenic. CACNA1G encodes for the pore-forming, a1G subunit of the T-type voltage-gated calcium channel (VGCC), in which currents are transient owing to fast inactivation, and tiny, due to small conductance. Mutations in CACNA1G cause generalized absence epilepsy and adult-onset, dominantly inherited, spinocerebellar ataxia type 42. In this kindred, the aforementioned CACNA1G variant segregated with disease, which was consistent with episodic vestibulocerebellar ataxia. CBZ proved successful in bout prevention and provided symptomatic benefit in the proband, probably as a result of interaction of this drug with VGCC. Further studies are needed to fully determine the vestibular and neurological manifestations of this form of episodic vestibulocerebellar ataxia. This novel disease variant could be designated episodic vestibulocerebellar ataxia type 10. © 2021 The Author(s). Published by S. Karger AG, Basel

Wind-induced Cross-Strait Sea Level Variability in the Strait of Gibraltar using Coastal Altimetry and In-Situ Measurements

In this work, we retracked altimeter waveforms of ESA satellites. ERS2 RA and Envisat RA2 from descending track 0360 over the eastern side of the Strait of Gibraltar using the Adaptive Leading Edge Subwaveform ALES retracker

Partitioning of trace elements in a entrained flow IGCC plant: Influence of selected operational conditions

The partitioning of trace elements and the influence of the feed conditions (50:50 coal/pet-coke feed blend and limestone addition) was investigated in this study. To this end feed fuel, fly ash and slag samples were collected under different operational conditions at the 335 MW Puertollano IGCC power plant (Spain) and subsequently analysed. The partitioning of elements in this IGCC plant may be summarised as follows: (a) high volatile elements (70–>99% in gas phase): Hg, Br, I, Cl and S; (b) moderately volatile elements (up to 40% in gas phase and 60% in fly ash): As, Sb, Se, B, F, Cd, Tl, Zn and Sn; (c) elements with high condensation potential: (>90% in fly ash): Pb, Ge, Ga and Bi; (d) elements enriched similarly in fly ash and slag 30–60% in fly ash: Cu, W, (P), Mo, Ni and Na; and (e) low volatile elements (>70% in slag): Cs, Rb, Co, K, Cr, V, Nb, Be, Hf, Ta, Fe, U, Ti, Al, Si, Y, Sr, Th, Zr, Mg, Ba, Mn, REEs, Ca and Li. The volatility of As, Sb, and Tl and the slagging of S, B, Cl, Cd and low volatile elements are highly influenced by the fuel geochemistry and limestone dosages, respectively

Clinical implication of FMR1 intermediate alleles in a Spanish population

FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X-associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P =.427). When comparing the allelic frequencies of IA = 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA = 50CGGs remains to be further elucidated

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin

Signatura genètica; Biomarcadors predictius; TrabectedinaFirma genética; Biomarcadores predictivos; TrabectedinaGene signature; Predictive biomarkers; TrabectedinPredictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.This study was funded by the Spanish Group for Research on Sarcoma (GEIS) and partially by PharmaMar. The authors would like to thank the GEIS data center for data management. The authors also thank the donors and the Hospital Universitario Virgen del Rocío—Instituto de Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for part of the human specimens used in this study. David S. Moura is recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155)

Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein–Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach

Iron-refractory iron deficiency anemia (Irida): a propósito de un caso

Poster [PC-130] Introducción: IRIDA es una entidad que cursa con anemia ferropénica, de herencia autosómica recesiva, aunque se han reportado algunos casos que son sólo heterocigotos (herencia autosómica dominante), debidos a mutaciones en el gen TMPRSS6 que codifica la proteína matriptasa-2. Se cree que la prevalencia de IRIDA es inferior a 1: 1.000.000, pero probablemente está infradiagnosticada. Caso clínico: Mujer de 17 años con antecedentes personales de retraso psicomotor y trastorno de espectro autista. Cariotipo 46 XX, descartándose síndrome X-frágil FRAXA, síndrome de Angelman y síndrome de Rett. Ha presentado varios episodios de trastornos de conducta con desorganización motora y dificultad de convivencia. Controlada en Hematología desde 2015 por anemia microcítica hipocrómica ferropénica sin respuesta al hierro oral y con respuesta parcial al hierro intravenoso. A lo largo del seguimiento en esta consulta se han descartado enfermedad celiaca (anticuerpos anti-gliadina (IgG e IgA), anti-transglutaminasa (IgA) negativos), helicobacter pylori (test del aliento negativo), pérdidas digestivas de hierro (sangre oculta en heces negativa), pérdidas urinarias y pulmonares. Ha presentado niveles bajos de hemoglobina (máximo 69 g/L) con microcitosis importante (máximo VCM 68, 50 fl) e índices de saturación de hasta 2, 5%. Desarrollo ponderoestatural y puberal normal. Tras recibir diferentes compuestos de hierro oral, sin respuesta a ninguno de ellos, se inicia tratamiento con hierro endovenoso, precisando medidas de contención para la administración del mismo, motivo por el que ha recibido tratamiento con hierro-carboximaltosa (Ferinject®) 500 mg, permitiendo administrar mayor cantidad de hierro en una sola dosis (Figura 1 y 2). Ante la sospecha de IRIDA se solicita un análisis de mutaciones puntuales en el gen TMPRSS6 que codifica la proteína matriptasa-2. La paciente no presenta mutaciones puntuales en las regiones analizadas, sin embargo, en el análisis de las secuencias se observan los siguientes polimorfismos (SNPs) en el gen TMPRSS6: p.Lys253Glu (exón 7), IVS7+23A>G (intrón 7), p.Val736Ala (exón17) interpretados como variantes benignas (no patogénicas). Conclusiones: Existen aproximadamente 69 defectos diferentes del gen TMPRSS6 en 65 familias diferentes. Sin embargo, están apareciendo nuevas mutaciones, no descritas por el momento y que podrían ser causa IRIDA, respaldando la hipótesis de que este síndrome clínico puede ser más común de lo que se pensaba anteriormente y su genética ser más heterogénea de lo que se describió inicialmente. Además se han descrito nuevos polimorfimos como p.Val736Ala que asocian mayor susceptibilidad al desarrollo de anemia ferropénica. Dado que su cuadro neurológico sigue sin diagnóstico preciso, ante la presencia concomitante de estos polimorfismos, se decide el estudio de secuenciación del exoma completo

Patients receiving a high burden of antibiotics in the community in Spain: a cross-sectional study

Some patients in the community receive a high burden of antibiotics. We aimed at describing the characteristics of these patients, antibiotics used, and conditions for which they received antibiotics. We carried out a cross-sectional study. Setting: Thirty Health Primary Care Areas from 12 regions in Spain, covering 5, 960, 191 inhabitants. Patients having at least 30 packages of antibacterials for systemic use dispensed in 2017 were considered. Main outcome measures: Prevalence of antibiotic use, conditions for which antibiotics were prescribed, clinical characteristics of patients, comorbidities, concomitant treatments, and microbiological isolates. Patient''s average age was 70 years; 52% were men; 60% smokers/ex-smokers; 54% obese. Overall, 93% of patients had, at least, one chronic condition, and four comorbidities on average. Most common comorbidities were cardiovascular and/or hypertension (67%), respiratory diseases (62%), neurological/mental conditions (32%), diabetes (23%), and urological diseases (21%); 29% were immunosuppressed, 10% were dead at the time of data collection. Patients received three antibiotic treatments per year, mainly fluoroquinolones (28%), macrolides (21%), penicillins (19%), or cephalosporins (12%). Most frequently treated conditions were lower respiratory tract (infections or prophylaxis) (48%), urinary (27%), and skin/soft tissue infections (11%). Thirty-five percent have been guided by a microbiological diagnosis, being Pseudomonas aeruginosa (30%) and Escherichia coli (16%) the most frequent isolates. In conclusion, high antibiotic consumers in the community were basically elder, with multimorbidity and polymedication. They frequently received broad-spectrum antibiotics for long periods of time. The approach to infections in high consumers should be differentiated from healthy patients receiving antibiotics occasionally

An observational efficacy and safety analysis of the treatment of acute invasive aspergillosis using voriconazole

The purpose of this study was to evaluate efficacy and safety of voriconazole in patients with acute invasive aspergillosis (IA) in a real-life, clinical setting. This was a multicenter observational study in adult patients treated with voriconazole for invasive mycosis. The study evaluated clinical response, mortality, use of other licensed antifungal therapy (OLAT), and treatment duration. This sub-analysis evaluated treatment and outcome data specifically from adult patients with proven/probable IA, while safety data were assessed in patients with proven/probable/possible IA. Of the 141 patients enrolled, 113 were adults with proven/probable IA and six had possible IA. Voriconazole treatment duration ranged from 1 to 183 days (median, 49.5 days). Voriconazole was used exclusively in 64% (72/113) of patients and in combination/sequentially with OLAT in 36%. Overall successful treatment response was 50% (57/113 patients). Twelve percent (14/113) of patients were switched to OLAT, either because of insufficient response (four patients) or for safety reasons (10 patients). Overall and attributable (entirely or partially due to fungal infection) mortality rates were 52% (59/113) and 17%, respectively. Treatment-related adverse events were reported for 18% (22/119) of patients. This observational study confirms the results of previous clinical trials demonstrating voriconazole as an effective and safe agent for treatment of confirmed acute IA

Superior Neuroprotective Efficacy of LAU-0901, a Novel Platelet-Activating Factor Antagonist, in Experimental Stroke

Platelet-activating factor (PAF) accumulates during cerebral ischemia, and inhibition of this process plays a critical role in neuronal survival. Recently, we demonstrated that LAU-0901, a novel PAF receptor antagonist, is neuroprotective in experimental stroke. We used magnetic resonance imaging in conjunction with behavior and immunohistopathology to expand our understanding of this novel therapeutic approach. Sprague–Dawley rats received 2 h middle cerebral artery occlusion (MCAo) and were treated with LAU-0901 (60 mg/kg) or vehicle 2 h from MCAo onset. Behavioral function, T2-weighted imaging (T2WI), and apparent diffusion coefficients were performed on days 1, 3, and 7 after MCAo. Infarct volume and number of GFAP, ED-1, and NeuN-positive cells were conducted on day 7. Behavioral deficit was significantly improved by LAU-0901 treatment compared to vehicle on days 1, 3, and 7. Total lesion volumes computed from T2WI were significantly reduced by LAU-0901 on days 1, 3, and 7 (by 83%, 90%, and 96%, respectively), which was consistent with decreased edema formation. Histopathology revealed that LAU-0901 treatment resulted in significant reduction of cortical and subcortical infarct volumes, attenuated microglial infiltration, and promoted astrocytic and neuronal survival. These findings suggest LAU-0901 is a promising neuroprotectant and provide the basis for future therapeutics in patients suffering ischemic stroke