Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model.

CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model's strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease.

"Lombard Effect" and Voice Changes in Adductor Laryngeal Dystonia: A Pilot Study.

OBJECTIVES: The aim was to describe the acoustic, auditory-perceptive, and subjective voice changes under the Lombard effect (LE) in adductor laryngeal dystonia (AdLD) patients. METHODS: Subjective perception of vocal effort (OMNI Vocal Effort Scale OMNI-VES), Maximum Phonation Time (MPT), and the perceptual severity of dysphonia (GRBAS scale) were assessed in condition of stillness and under LE in 10 AdLD patients and in 10 patients with typical voice. Speakers were asked to produce the sustained vowel /a/ and to read a phonetically balanced text aloud. Using the PRAAT software, the following acoustic parameters were analyzed: Mean Pitch (Hz), Minimum and Maximum Intensity (dB), the Fraction of Locally Unvoiced Frames, the Number of Voice Breaks, the Degree of Voice Breaks (%), the Cepstral Peak Prominence-Smoothed (CPPS) (dB). RESULTS: Under LE, the AdLD group showed a decrease of both G and S parameters of GRBAS and subjective effort, mean MPT increased significantly; in the controls there were no significant changes. In both groups under LE, pitch and intensity of the sustained vowel /a/ significantly increased consistently with LE. In the AdLD group the mean gain of OMNI-VES score and the mean gain of each parameter of the speech analysis were significantly greater than the controls' ones. CONCLUSION: Auditory feedback deprivation obtained under LE improves subjective, perceptual-auditory, and acoustics parameters of AdLD patients. These findings encourage further research to provide new knowledge into the role of the auditory system in the pathogenesis of AdLD and to develop new therapeutic strategies. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3754-3760, 2024.

Zebrafish Feed Intake: A Systematic Review for Standardizing Feeding Management in Laboratory Conditions.

Zebrafish are one of the most used animal models in biological research and a cost-effective alternative to rodents. Despite this, nutritional requirements and standardized feeding protocols have not yet been established for this species. This is important to avoid nutritional effects on experimental outcomes, and especially when zebrafish models are used in preclinical studies, as many diseases have nutritional confounding factors. A key aspect of zebrafish nutrition is related to feed intake, the amount of feed ingested by each fish daily. With the goal of standardizing feeding protocols among the zebrafish community, this paper systematically reviews the available data from 73 studies on zebrafish feed intake, feeding regimes (levels), and diet composition. Great variability was observed regarding diet composition, especially regarding crude protein (mean 44.98 ± 9.87%) and lipid content (9.91 ± 5.40%). Interestingly, the gross energy levels of the zebrafish diets were similar across the reviewed studies (20.39 ± 2.10 kilojoules/g of feed). In most of the reviewed papers, fish received a predetermined quantity of feed (feed supplied). The authors fed the fish according to the voluntary intake and then calculated feed intake (FI) in only 17 papers. From a quantitative point of view, FI was higher than when a fixed quantity (pre-defined) of feed was supplied. Also, the literature showed that many biotic and abiotic factors may affect zebrafish FI. Finally, based on the FI data gathered from the literature, a new feeding protocol is proposed. In summary, a daily feeding rate of 9-10% of body weight is proposed for larvae, whereas these values are equal to 6-8% for juveniles and 5% for adults when a dry feed with a proper protein and energy content is used.

Automatic speaking valve in tracheo-esophageal speech: treatment proposal for a widespread usage.

PURPOSE: Aim of this study was to calculate the percentage of the Automatic Speaking Valve (ASV) use in a large cohort of laryngectomized patients with voice prosthesis (VP) and to analyze the main reasons for non-use. Subsequently, a specific rehabilitation training was proposed. METHODS: One hundred-ten laryngectomized patients with VP were enrolled in the first phase of the study (census). Among them, 57 patients were included in the second phase (intervention), in which a training based on moving phonatory exercises was proposed. Structured questionnaires were used before and after training in order to investigate ASV use rate (days/week and hours/day; reasons for impeding the ASV use), average adhesive life-time during ASV use; hands-free speech duration; skin irritation. Patients also expressed their degree of on a VAS scale from 0 to 100. RESULTS: In the census phase the percentage of use of ASV (everyday, without problems) was equal to 17.27% (19/110 patients). The main causes of disuse concerned excessive fatigue and poor durability of the adhesives. The analysis of the results pre vs. post-training showed a statistically significant increase (p < 0.05) in all the investigated parameters. Patients reported a good level of treatment compliance (average frequency of performing exercises equal to 4.2 ± 2.5 days/week for 1.4 ± 1.01 h/day) and high degrees of satisfaction. After treatment, the percentage of use of AVS increased by 43% reaching a rate of 60% (66/110 patients). CONCLUSION: A specific and targeted approach that simulate the phonatory and breathing difficulties of everyday life can increase the ASV usage rate.

Late Prevalence of Typical and Atypical Symptoms of Frey's Syndrome after Parotidectomy for Benign Tumor.

BACKGROUND: The treatment of choice for tumors located in the parotid gland is surgery. Nevertheless, postoperative complications are not infrequent. Regardless of the type of surgical procedure, the most common complication is Frey's syndrome (FS). Traditionally, FS includes unilateral gustatory sweating and flushing of the facial skin lining the parotid compartment. Recent research describes atypical discomfort associated with FS. The aim of this study was to assess the late prevalence and severity of both usual and atypical symptoms after parotidectomy for benign tumors. METHODS: We conducted a cross-sectional study involving 86 subjects who underwent superficial parotidectomy at least one year before the study. The questionnaire included the sweating-flushing-itch-paresthesia-pain (SFIPP) Frey scale supplemented by specific questions about symptoms. RESULTS: Sixty-seven out of eighty-six (77.9%) cases reported almost one symptom. The most frequent symptom was itch (36/67-53.7%), followed by pain (35/67-52.2%), while 28/67 (41.8%) subjects complained of atypical symptoms without flushing or sweating. A desire to treat the discomfort was reported by 50/67 (74.6%) subjects. CONCLUSIONS: Late postparotidectomy local discomfort is not infrequent and includes both usual and "unusual" symptoms almost equally. Our results suggest the importance of informing patients about the occurrence of the syndrome and the available treatment options during pre- and postoperative counseling.

Penfigoide gestacional y erupción ampollar en el recién nacido / Bullous pemphygoid and blisters in the newborn

El penfigoide gestacional es una dermatosis rara, que se presenta durante el embarazo. Se caracteriza por una respuesta autoinmune contra las proteínas de los hemidesmosomas, que genera un clivaje entre la epidermis y la dermis tanto de la piel como de las mucosas. Clínicamente, presenta prurito intenso, placas y pápulas eritematosas, que evolucionan a apollas con distribución en el abdomen y los miembros. Como complicaciones, en el feto puede generar parto prematuro y bajo peso para la edad gestacional, con alto riesgo de mortalidad. (AU)

Gestational pemphygoid is a rare, autoimmune dermatosis that occurs during pregnancy. It is characterized by an autoimmune response against hemidesmosome proteins, generating a cleavage between the epidermis and the dermis in the skin and mucous membranes. Clinically it presents with intense pruritus, plaques and erythematous papules that evolve to blisters that are distributed mainly in the abdomen and limbs. The complications are preterm birth and low weight for gestational age, with high risk of mortality. (AU)

Linfoma B primario cutáneo difuso de células grandes / Primary diffuse large B-cell lymphoma of the skin

Los linfomas B primarios cutáneos difusos de células grandes corresponden al 6% de los linfomas cutáneos, presentan un comportamiento agresivo y un pronóstico intermedio. La variante de las piernas es la más frecuente. Se presenta generalmente en los miembros inferiores, aunque puede presentarse en otros sitios. Existe un subgrupo de linfomas B difusos de células grandes que por sus características morfológicas no pueden ser incluido en el tipo de las piernas y se los llama la variante otros. Presentamos dos casos clínicos de pacientes con diagnóstico de linfoma B cutáneo difuso de células grandes, uno variante de las piernas con localización en la cara y otro variante no especificada localizado en el antebrazo. La clínica, la histopatología y la inmunohistoquímica son fundamentales para arribar al diagnóstico correcto e iniciar de manera temprana el tratamiento correspondiente...

Fenómeno de regresión como factor pronóstico en melanoma / Regression as a prognostic factor in melanoma

Antecedentes. La regresión histológica se encuentra en un 10 a un 35% de los melanomas cutáneos. Su valor como factor pronóstico de la enfermedad es aún controvertido. Objetivo. Evaluar si la presencia de regresión en el melanoma muestra algún impacto en el compromiso ganglionar. Diseño. Estudio observacional, descriptivo y retrospectivo. Método. Se revisaron las historias clínicas de nuestro hospital de pacientes con diagnósticode melanoma que fueron sometidos a biopsia del ganglio centinela (BGC) entre mayo de 2000 y marzo de 2014. Éstos fueron divididos en dos grupos de acuerdo con la presencia o ausencia de regresión y se analizó el estado del ganglio centinela en cada grupo. El método estadístico utilizado fue el test de chi cuadrado. Resultados. De 108 pacientes con BGC, 19 (18%) informaron regresión presente y 89(82%) regresión ausente. Del grupo que presentó regresión, en 5 pacientes la BGC resultó positiva (26%). En el grupo sin regresión, 21 pacientes presentaron BGC positiva (24%). En el análisis estadístico no se encontró asociación entre la presencia de regresión y la positividad del ganglio centinela (p = 0,80). Conclusiones.En nuestra muestra la presencia de regresión no influyó en el resultado del estudio de ganglio centinela. Se requieren estudios de mayor tamaño muestral para sacarconclusiones acerca de esta relación...

Integración de marcadores humorales, ecocardiograma Doppler convencional y strain bidimensional sistólico en la detección de toxicidad miocárdica secundaria a la quimioterapia / Serum Markers, Conventional Doppler Echocardiography and Two-dimensional Systolic Strain in the Diagnosis of Chemotherapy-Induced Myocardial Toxicity

Introducción La disfunción ventricular izquierda es una complicación grave del tratamiento antineoplásico, con impacto desfavorable en la evolución clínica futura. El diagnóstico precoz de cardiotoxici-dad en pacientes que reciben quimioterapia podría ser de utilidad para definir una estrategia de prevención del deterioro de la función ventricular. Objetivo Analizar la utilidad de marcadores humorales [troponina T (TnT), BNP y NT-proBNP] y del strain bidimensional sistólico longitudinal (SBL) y radial (SBR) para la detección de disfunción ventricular sistólica en pacientes tratados con quimioterapia cardiotóxica. Material y métodos Se incluyeron forma prospectiva 36 pacientes, edad promedio (± DE) de 47 ± 16 años (42% hombres), con enfermedad neoplásica con masa miocárdica normal y fracción de eyección = 55% tratados con agentes antineoplásicos. Se efectuaron dosajes de marcadores humorales y ecocardiograma basales y al 2°, 3°, 4° y 6° mes posterior al inicio del tratamiento oncológico. Se consideró punto final (PF) a los 6 meses a la caída de la fracción de eyección según consenso internacional. Resultados Alcanzaron el PF 7 pacientes (19,4%). Se observaron los siguientes predictores relacionados con el PF: NT-proBNP 4° mes [PF positivo (G1) 152 ± 42 pg/ml vs. PF negativo (G2) 61 ± 38 pg/ml; p < 0,001], BNP 4° mes (G1 41 ± 12 pg/ml vs. G2 26 ± 11 pg/ml; p < 0,01), SBL 3er mes (G1 -16,3 ± 2,4% vs. G2 -19,6 ± 2,02%; p < 0,01) y 4° mes (G1 -15,9 ± 1,77% vs. G2 -19,9 ± 2,2%; p < 0,001) y SBR 4° mes (G1 46,4 ± 2,4% vs. G2 52 ± 3,4%; p < 0,001). Conclusiones El dosaje de péptidos natriuréticos y la medición del strain bidimensional sistólico longitudinal y radial fueron de utilidad para predecir disfunción sistólica ventricular de grado leve en pacientes tratados con quimioterapia.

Background Left ventricular dysfunction is a serious complication of antineoplastic treatment with unfavorable impact in future clinical outcome. Early diagnosis of cardiotoxicity in patients receiving chemotherapy might be useful to define a strategy for the prevention of ventricular function impairment. Objective The aim of this study was to analyze the usefulness of serum markers [troponin T (TnT), BNP and NT-proBNP] and two-dimensional longitudinal (LS) and radial (RS) strain to detect ventricular systolic dysfunction in patients treated with cardiotoxic chemotherapy. Methods Thirty six patients [average age (±SD) 47±16 years, 42% men], with neoplastic disease with normal myocardial mass and left ventricular ejection fraction (LVEF) =55% receiving chemotherapy treatment, were prospectively included. Assessment of serum markers and echocardiography were performed before chemotherapy and at 2, 3, 4 and 6 months after onset of cancer treatment. The 6-month cardiotoxicity endpoint (EP) was defined as reduced LVEF according to international consensus. Results Seven patients reached the EP (19.4%). Endpoint predictors were: NT-proBNP at 4 months (positive EP (G1): 152 ±42 pg/ml vs. negative EP (G2) 61±38 pg/ml; p <0.001), BNP at 4 months (G1 41±12 pg/ml vs. G2 26±11 pg/ml; p <0.01), two-dimensional LS at 3 months (G1 -16.3±2.4% vs. G2 19.6±2.02%; p <0.01) and 4 months (G1 -15.9±1.77% vs. G2 19.9±2.2%; p <0.001), and two-dimensional RS at 4 months (G1 46.4±2.4% vs. G2 52±3.4%; p <0.001). Conclusions Natriuretic peptides and two-dimensional LS and RS were useful to predict mild ventricular systolic dysfunction in chemotherapy-treated patients.

Integración de marcadores humorales, ecocardiograma Doppler convencional y strain bidimensional sistólico en la detección de toxicidad miocárdica secundaria a la quimioterapia / Serum Markers, Conventional Doppler Echocardiography and Two-dimensional Systolic Strain in the Diagnosis of Chemotherapy-Induced Myocardial Toxicity

Introducción La disfunción ventricular izquierda es una complicación grave del tratamiento antineoplásico, con impacto desfavorable en la evolución clínica futura. El diagnóstico precoz de cardiotoxici-dad en pacientes que reciben quimioterapia podría ser de utilidad para definir una estrategia de prevención del deterioro de la función ventricular. Objetivo Analizar la utilidad de marcadores humorales [troponina T (TnT), BNP y NT-proBNP] y del strain bidimensional sistólico longitudinal (SBL) y radial (SBR) para la detección de disfunción ventricular sistólica en pacientes tratados con quimioterapia cardiotóxica. Material y métodos Se incluyeron forma prospectiva 36 pacientes, edad promedio (± DE) de 47 ± 16 años (42% hombres), con enfermedad neoplásica con masa miocárdica normal y fracción de eyección = 55% tratados con agentes antineoplásicos. Se efectuaron dosajes de marcadores humorales y ecocardiograma basales y al 2°, 3°, 4° y 6° mes posterior al inicio del tratamiento oncológico. Se consideró punto final (PF) a los 6 meses a la caída de la fracción de eyección según consenso internacional. Resultados Alcanzaron el PF 7 pacientes (19,4%). Se observaron los siguientes predictores relacionados con el PF: NT-proBNP 4° mes [PF positivo (G1) 152 ± 42 pg/ml vs. PF negativo (G2) 61 ± 38 pg/ml; p < 0,001], BNP 4° mes (G1 41 ± 12 pg/ml vs. G2 26 ± 11 pg/ml; p < 0,01), SBL 3er mes (G1 -16,3 ± 2,4% vs. G2 -19,6 ± 2,02%; p < 0,01) y 4° mes (G1 -15,9 ± 1,77% vs. G2 -19,9 ± 2,2%; p < 0,001) y SBR 4° mes (G1 46,4 ± 2,4% vs. G2 52 ± 3,4%; p < 0,001). Conclusiones El dosaje de péptidos natriuréticos y la medición del strain bidimensional sistólico longitudinal y radial fueron de utilidad para predecir disfunción sistólica ventricular de grado leve en pacientes tratados con quimioterapia.(AU)

Background Left ventricular dysfunction is a serious complication of antineoplastic treatment with unfavorable impact in future clinical outcome. Early diagnosis of cardiotoxicity in patients receiving chemotherapy might be useful to define a strategy for the prevention of ventricular function impairment. Objective The aim of this study was to analyze the usefulness of serum markers [troponin T (TnT), BNP and NT-proBNP] and two-dimensional longitudinal (LS) and radial (RS) strain to detect ventricular systolic dysfunction in patients treated with cardiotoxic chemotherapy. Methods Thirty six patients [average age (±SD) 47±16 years, 42% men], with neoplastic disease with normal myocardial mass and left ventricular ejection fraction (LVEF) =55% receiving chemotherapy treatment, were prospectively included. Assessment of serum markers and echocardiography were performed before chemotherapy and at 2, 3, 4 and 6 months after onset of cancer treatment. The 6-month cardiotoxicity endpoint (EP) was defined as reduced LVEF according to international consensus. Results Seven patients reached the EP (19.4%). Endpoint predictors were: NT-proBNP at 4 months (positive EP (G1): 152 ±42 pg/ml vs. negative EP (G2) 61±38 pg/ml; p <0.001), BNP at 4 months (G1 41±12 pg/ml vs. G2 26±11 pg/ml; p <0.01), two-dimensional LS at 3 months (G1 -16.3±2.4% vs. G2 19.6±2.02%; p <0.01) and 4 months (G1 -15.9±1.77% vs. G2 19.9±2.2%; p <0.001), and two-dimensional RS at 4 months (G1 46.4±2.4% vs. G2 52±3.4%; p <0.001). Conclusions Natriuretic peptides and two-dimensional LS and RS were useful to predict mild ventricular systolic dysfunction in chemotherapy-treated patients.(AU)