Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life.

BACKGROUND: Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases. METHODS: We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0-1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR. RESULTS: Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males. CONCLUSIONS: Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming. IMPACT: Heart remodeling involves the alteration of several groups of genes and lactation period plays a key role in establishing gene expression modification caused by fetal programming. We could identify expression changes of relevant genes in cardiac tissue induced by undernutrition during fetal life. We expose the contribution of the lactation period in modulating the expression of Agt and Pparg, relevant genes associated with cardiac hypertrophy. This evidence reveal lactation as a crucial intervention window for preventing or countering fetal programming.

Effect of Supplementation with Coffee and Cocoa By-Products to Ameliorate Metabolic Syndrome Alterations Induced by High-Fat Diet in Female Mice.

Coffee and cocoa manufacturing produces large amounts of waste. Generated by-products contain bioactive compounds with antioxidant and anti-inflammatory properties, suitable for treating metabolic syndrome (MetS). We aimed to compare the efficacy of aqueous extracts and flours from coffee pulp (CfPulp-E, CfPulp-F) and cocoa shell (CcShell-E, CcShell-F) to ameliorate MetS alterations induced by a high-fat diet (HFD). Bioactive component content was assessed by HPLC/MS. C57BL/6 female mice were fed for 6 weeks with HFD followed by 6 weeks with HFD plus supplementation with one of the ingredients (500 mg/kg/day, 5 days/week), and compared to non-supplemented HFD and Control group fed with regular chow. Body weight, adipocyte size and browning (Mitotracker, confocal microscopy), plasma glycemia (basal, glucose tolerance test-area under the curve, GTT-AUC), lipid profile, and leptin were compared between groups. Cocoa shell ingredients had mainly caffeine, theobromine, protocatechuic acid, and flavan-3-ols. Coffee pulp showed a high content in caffeine, protocatechuic, and chlorogenic acids. Compared to Control mice, HFD group showed alterations in all parameters. Compared to HFD, CcShell-F significantly reduced adipocyte size, increased browning and high-density lipoprotein cholesterol (HDL), and normalized basal glycemia, while CcShell-E only increased HDL. Both coffee pulp ingredients normalized adipocyte size, basal glycemia, and GTT-AUC. Additionally, CfPulp-E improved hyperleptinemia, reduced triglycerides, and slowed weight gain, and CfPulp-F increased HDL. In conclusion, coffee pulp ingredients showed a better efficacy against MetS, likely due to the synergic effect of caffeine, protocatechuic, and chlorogenic acids. Since coffee pulp is already approved as a food ingredient, this by-product could be used in humans to treat obesity-related MetS alterations.

Specification of the Drosophila Orcokinin A neurons by combinatorial coding.

The central nervous system contains a daunting number of different cell types. Understanding how each cell acquires its fate remains a major challenge for neurobiology. The developing embryonic ventral nerve cord (VNC) of Drosophila melanogaster has been a powerful model system for unraveling the basic principles of cell fate specification. This pertains specifically to neuropeptide neurons, which typically are stereotypically generated in discrete subsets, allowing for unambiguous single-cell resolution in different genetic contexts. Here, we study the specification of the OrcoA-LA neurons, characterized by the expression of the neuropeptide Orcokinin A and located laterally in the A1-A5 abdominal segments of the VNC. We identified the progenitor neuroblast (NB; NB5-3) and the temporal window (castor/grainyhead) that generate the OrcoA-LA neurons. We also describe the role of the Ubx, abd-A, and Abd-B Hox genes in the segment-specific generation of these neurons. Additionally, our results indicate that the OrcoA-LA neurons are "Notch Off" cells, and neither programmed cell death nor the BMP pathway appears to be involved in their specification. Finally, we performed a targeted genetic screen of 485 genes known to be expressed in the CNS and identified nab, vg, and tsh as crucial determinists for OrcoA-LA neurons. This work provides a new neuropeptidergic model that will allow for addressing new questions related to neuronal specification mechanisms in the future.

Slower Growth during Lactation Rescues Early Cardiovascular and Adipose Tissue Hypertrophy Induced by Fetal Undernutrition in Rats.

Low birth weight (LBW) and accelerated growth during lactation are associated with cardiometabolic disease development. LBW offspring from rats exposed to undernutrition during gestation (MUN) develops hypertension. In this rat model, we tested if slower postnatal growth improves early cardiometabolic alterations. MUN dams were fed ad libitum during gestation days 1-10, with 50% of the daily intake during days 11-21 and ad libitum during lactation. Control dams were always fed ad libitum. Pups were maintained with their own mother or cross-fostered. Body weight and length were recorded weekly, and breastmilk was obtained. At weaning, the heart was evaluated by echocardiography, and aorta structure and adipocytes in white perivascular fat were studied by confocal microscopy (size, % beige-adipocytes by Mitotracker staining). Breastmilk protein and fat content were not significantly different between groups. Compared to controls, MUN males significantly accelerated body weight gain during the exclusive lactation period (days 1-14) while females accelerated during the last week; length growth was slower in MUN rats from both sexes. By weaning, MUN males, but not females, showed reduced diastolic function and hypertrophy in the heart, aorta, and adipocytes; the percentage of beige-type adipocytes was smaller in MUN males and females. Fostering MUN offspring on control dams significantly reduced weight gain rate, cardiovascular, and fat hypertrophy, increasing beige-adipocyte proportion. Control offspring nursed by MUN mothers reduced body growth gain, without cardiovascular modifications. In conclusion, slower growth during lactation can rescue early cardiovascular alterations induced by fetal undernutrition. Exclusive lactation was a key period, despite no modifications in breastmilk macronutrients, suggesting the role of bioactive components. Our data support that lactation is a key period to counteract cardiometabolic disease programming in LBW and a potential intervention window for the mother.

Dachshund acts with Abdominal-B to trigger programmed cell death in the Drosophila central nervous system at the frontiers of Abd-B expression.

A striking feature of the nervous system pertains to the appearance of different neural cell subtypes at different axial levels. Studies in the Drosophila central nervous system reveal that one mechanism underlying such segmental differences pertains to the segment-specific removal of cells by programmed cell death (PCD). One group of genes involved in segment-specific PCD is the Hox homeotic genes. However, while segment-specific PCD is highly precise, Hox gene expression is evident in gradients, raising the issue of how the Hox gene function is precisely gated to trigger PCD in specific segments at the outer limits of Hox expression. The Drosophila Va neurons are initially generated in all nerve cord segments but removed by PCD in posterior segments. Va PCD is triggered by the posteriorly expressed Hox gene Abdominal-B (Abd-B). However, Va PCD is highly reproducible despite exceedingly weak Abd-B expression in the anterior frontiers of its expression. Here, we found that the transcriptional cofactor Dachshund supports Abd-B-mediated PCD in its anterior domain. In vivo bimolecular fluorescence complementation analysis lends support to the idea that the Dachshund/Abd-B interplay may involve physical interactions. These findings provide an example of how combinatorial codes of transcription factors ensure precision in Hox-mediated PCD in specific segments at the outer limits of Hox expression.

Selective role of the DNA helicase Mcm5 in BMP retrograde signaling during Drosophila neuronal differentiation.

The MCM2-7 complex is a highly conserved hetero-hexameric protein complex, critical for DNA unwinding at the replicative fork during DNA replication. Overexpression or mutation in MCM2-7 genes is linked to and may drive several cancer types in humans. In mice, mutations in MCM2-7 genes result in growth retardation and mortality. All six MCM2-7 genes are also expressed in the developing mouse CNS, but their role in the CNS is not clear. Here, we use the central nervous system (CNS) of Drosophila melanogaster to begin addressing the role of the MCM complex during development, focusing on the specification of a well-studied neuropeptide expressing neuron: the Tv4/FMRFa neuron. In a search for genes involved in the specification of the Tv4/FMRFa neuron we identified Mcm5 and find that it plays a highly specific role in the specification of the Tv4/FMRFa neuron. We find that other components of the MCM2-7 complex phenocopies Mcm5, indicating that the role of Mcm5 in neuronal subtype specification involves the MCM2-7 complex. Surprisingly, we find no evidence of reduced progenitor proliferation, and instead find that Mcm5 is required for the expression of the type I BMP receptor Tkv, which is critical for the FMRFa expression. These results suggest that the MCM2-7 complex may play roles during CNS development outside of its well-established role during DNA replication.

Hypothyroidism confers tolerance to cerebral malaria.

The modulation of the host's metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.

Variational autoencoding of gene landscapes during mouse CNS development uncovers layered roles of Polycomb Repressor Complex 2.

A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that Polycomb Repressor Complex 2 (PRC2), a protein complex responsible for applying key repressive histone modifications, acts by several mechanisms to promote anterior CNS expansion. However, it is unclear what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 intersects with the epigenetic landscape. We removed PRC2 function from the developing mouse CNS, by mutating the key gene Eed, and generated spatio-temporal transcriptomic data. To decode the role of PRC2, we developed a method that incorporates standard statistical analyses with probabilistic deep learning to integrate the transcriptomic response to PRC2 inactivation with epigenetic data. This multi-variate analysis corroborates the central involvement of PRC2 in anterior CNS expansion, and also identifies several unanticipated cohorts of genes, such as proliferation and immune response genes. Furthermore, the analysis reveals specific profiles of regulation via PRC2 upon these gene cohorts. These findings uncover a differential logic for the role of PRC2 upon functionally distinct gene cohorts that drive CNS anterior expansion. To support the analysis of emerging multi-modal datasets, we provide a novel bioinformatics package that integrates transcriptomic and epigenetic datasets to identify regulatory underpinnings of heterogeneous biological processes.

Implication of RAS in Postnatal Cardiac Remodeling, Fibrosis and Dysfunction Induced by Fetal Undernutrition.

Fetal undernutrition is a risk factor for cardiovascular diseases. Male offspring from rats exposed to undernutrition during gestation (MUN) exhibit oxidative stress during perinatal life and develop cardiac dysfunction in ageing. Angiotensin-II is implicated in oxidative stress-mediated cardiovascular fibrosis and remodeling, and lactation is a key developmental window. We aimed to assess if alterations in RAS during lactation participate in cardiac dysfunction associated with fetal undernutrition. Control dams received food ad libitum, and MUN had 50% nutrient restriction during the second half of gestation. Both dams were fed ad libitum during lactation, and male offspring were studied at weaning. We assessed: ventricular structure and function (echocardiography); blood pressure (intra-arterially, anesthetized rats); collagen content and intramyocardial artery structure (Sirius red, Masson Trichromic); myocardial and intramyocardial artery RAS receptors (immunohistochemistry); plasma angiotensin-II (ELISA) and TGF-ß1 protein expression (Western Blot). Compared to Control, MUN offspring exhibited significantly higher plasma Angiotensin-II and a larger left ventricular mass, as well as larger intramyocardial artery media/lumen, interstitial collagen and perivascular collagen. In MUN hearts, TGF-ß1 tended to be higher, and the end-diastolic diameter and E/A ratio were significantly lower with no differences in ejection fraction or blood pressure. In the myocardium, no differences between groups were detected in AT1, AT2 or Mas receptors, with MrgD being significantly lower in the MUN group. In intramyocardial arteries from MUN rats, AT1 and Mas receptors were significantly elevated, while AT2 and MrgD were lower compared to Control. Conclusions. In rats exposed to fetal undernutrition, RAS disbalance and associated cardiac remodeling during lactation may set the basis for later heart dysfunction.

Diagnostic Accuracy of Intracochlear Test Electrode for Acoustic Nerve Monitoring in Vestibular Schwannoma Surgery.

OBJECTIVES: Cochlear implants (CIs) are a well-known hearing restoration option for patients with vestibular schwannoma (VS) in cases of neurofibromatosis type-2 and, more recently, for patients with sporadic VS. One of the main limitations when performing CI during VS surgery is the capability to preserve the acoustic nerve (AN) anatomically and functionally. Significant efforts have been directed toward developing an intraoperative testing method for monitoring the AN function to determine if, after tumor removal, it is suitable for conducting stimuli delivered by a CI. However, all these methods have significant limitations, and none of them have documented diagnostic efficacy. To overcome these limitations and to obtain reliable information before CI insertion, a minimally invasive intracochlear test electrode (TE) has been recently developed. This TE has demonstrated to be suitable to test the integrity of the AN before CI in patients without any residual hearing by recording electrically evoked auditory brainstem responses (EABR). The present study constitutes the next phase of this research, which was to determine the usefulness of EABR obtained intraoperatively with the intracochlear TE after the resection of a VS and to calculate its diagnostic accuracy to assess the functionality of the AN for CI. DESIGN: This was a prospective, multicenter study of diagnostic accuracy. It was conducted in three tertiary referral centers between January 2015 and 2018. This study was designed following the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement guidelines. The STARD statement are guidelines to improve the completeness and transparency of reports of diagnostic accuracy studies. The diagnostic accuracy of the EABR evoked with the intracochlear TE after tumor removal was studied. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Patients eligible for the study were consecutive adults undergoing surgery for VS with simultaneous CI. The test under evaluation (index test) was the EABR obtained with the intracochlear TE after resection of the tumor. The reference test (gold standard) was the presence of auditory perception with the CI, defined as the presence of sound detection on an audiogram at 500, 1000, 2000, and 4000 Hz of no greater than 50 dB. In all the cases, auditory perception was verified by the presence of a positive EABR evoked with the CI. RESULTS: Twenty-one patients were included during the study period; seven patients were excluded from the diagnostic efficacy analysis due to inconclusive EABR results or absence of the gold standard to compare (they did not finally receive the CI). Thus, the outcome of the gold standard was assessed in 14 cases: 9 cases had positive EABR, all of them obtained auditory perception with the CI, and 5 cases had negative EABR, only one case had auditory perception with the CI, which constitutes the only false negative of this study. Accuracy of the TE was 93% (95% confidence interval, 66 to 100%), sensitivity 90% (95% confidence interval, 71 to 100%), specificity 100% (95% confidence interval, 100 to 100%), positive predictive value 100% (95% confidence interval, 100 to 100%), and negative predictive value 80% (95% confidence interval, 45 to 100%). CONCLUSIONS: EABR elicited with the intracochlear TE had a diagnostic accuracy of 93% for predicting auditory perception with CIs after VS removal. These results suggest that the intracochlear TE can be used intraoperatively after tumor removal to test the integrity of the AN as a useful tool to complement the surgeon's perception for decision-making regarding implantation.

Factores de riesgo y características vocales en los cantantes de coros amateur / Mapping of vocal risk in amateur choir singers

INTRODUCCIÓN: Los cantantes son uno de los grupos de profesionales de la voz con mayor prevalencia de patología vocal y están expuestos a muchos factores de riesgo. Esto se acrecienta en el caso de los cantantes de coros amateurs que no suelen recibir nociones de técnica vocal. MÉTODO: Se estudiaron las características vocales y los factores de riesgo de 39 cantantes de coros amateur mediante el índice de incapacidad vocal abreviado (VHI-10), el índice de incapacidad vocal para el canto (S-VHI), laringoestroboscopia y análisis vocal. RESULTADOS: Los cantantes que no habían recibido clases de técnica vocal obtuvieron puntuaciones más altas tanto en el VHI-10 (10.5; p=.001) como en el S-VHI (55.9; p=.010) frente a los que sí (4 en el VHI-10 y 31.4 en el S-VHI). Respecto al sexo, encontramos que las mujeres alcanzan puntuaciones más altas (51.6) que los hombres (35) en el S-VHI (p=.019). En la muestra encontramos 9 sujetos (23.1%) con signos de fatiga vocal y 6 (15.4%) con reflujo. En el análisis acústico la frecuencia es más alta en la voz cantada (278.1HZ) que en la hablada (168.4Hz), los armónicos también son mayores en voz cantada (28dB) que en voz hablada (22dB), los valores de jitter son más altos en la voz hablada (0.24) que en la cantada (0.14) y los del shimmer también son más altos en la voz hablada (1.71) que en la cantada (1.23). CONCLUSIONES: La falta de nociones de técnica vocal en cantantes de coros amateur condiciona una mayor puntuación en los test VHI-10 y S-VHI, así como alteraciones en la laringe

INTRODUCTION: Singers are one of the groups of voice professionals with a higher incidence of vocal disorders which expose them to many risk factors. These risks are even higher in singers in amateur choirs, who usually lack vocal technique. METHOD: Vocal traits and risk factors of 39 amateur choir singers were studied using the VHI-10, the S-VHI, laryngeal examination and acoustic analysis. RESULTS: The singers who had not received lessons in vocal technique obtained higher marks in VHI-10 (10.5; P=.001) as well as in S-VHI (55.9; P=.010) compared to those who had (4 in VHI-10 and 31.4 in S-VHI). As regards sex, we find that women achieve higher marks (51.6) than men (35) in the S-VHI (P=.019). In the sample we find 9 subjects (23.1%) with evidence of vocal fatigue and 6 (15.4%) with reflux. In the acoustic analysis we observe that the frequency is higher in the singing voice (278.1HZ) than in the speaking voice (168.4Hz), the harmonics are also higher in the singing voice (28dB) than in the speaking voice (22dB), the jitter values are higher in the speaking voice (.24) than in the singing voice (.14), and shimmer values are also higher in the speaking voice (1.71) than in the singing voice (1.23). CONCLUSION: The lack of vocal technique in amateur choir singers determines a higher mark in the VHI-10 and S-VHI tests together with alterations to the larynx

Validation of the Hearing Handicap Inventory for Adults Scale for Spanish-Speaking Patients.

OBJECTIVE: To perform translation, cross-cultural adaptation, and validation of the hearing handicap inventory for adults scale (HHIA) to the Spanish language. STUDY DESIGN: Prospective study. SETTING: Tertiary neurotologic referral center. PATIENTS: The study included 104 hearing impaired persons. Inclusion criteria were adults with untreated hearing loss, diagnosed in the past 12 months. A control group of 30 normal hearing subjects was also recruited. INTERVENTION: HHIA was translated and translated back, and a pretest trial was performed. Feasibility, internal consistency, test-retest reliability, construct validity, and ceiling and floor effects were assessed for the present study. MAIN OUTCOME MEASURES: The mean overall score of the HHIA was 31.9 (0-100 scale, lowest to highest handicap). Cronbach's α was 0.95. Intraclass correlation coefficient was performed for each item, with an overall score of 0.95. The k coefficient scores ranged between moderate and almost perfect in all patients. The emotional score of the HHIA was correlated with the mental component of the SF-12. CONCLUSIONS: Feasibility, internal consistency, reliability, and construct validity outcomes in the current study support the validity of the Spanish version of the HHIA.

Incidental Histopathologic Finding of Sinonasal Inverted Papilloma Among Surgically Excised Polyps Increases the Risk of Tumor Recurrence.

Inverted papilloma (IP) is a benign tumor remarkable for its tendency toward recurrence. Local relapse implicates incomplete resection concerning the bone adjacent to tumor base. The high false negative rates on biopsies, mainly when nasal polyps coexist, may affect the surgical management and outcomes. Our objective was to study the impact of preoperative histologic diagnosis in IP recurrence, particularly in patients with pre-surgical diagnosis of inflammatory polyps. A retrospective analysis of 62 patients treated for IP was conducted. Demographic data and information about smoking status, alcohol intake, tumor location, histology, presence of nasal polyps, staging, malignancy, previous biopsies and surgical approach were evaluated to identify factors associated with recurrence. Prevalence of nasal polyps was higher in patients with recurrence. Smoking history, alcohol abuse, staging, histologic type, malignancy and surgical approach were not associated with recurrence. The presence of nasal polyps at endoscopy was inversely associated with the diagnosis of IP at incisional biopsy. Incidental histologic diagnosis of IP after surgery increased the risk of recurrence more than tenfold. Biopsy reporting the diagnosis of IP previous to surgery was inversely associated to recurrence. In patients with IP, coexistence of nasal polyps at initial endoscopy and lack of pathological IP diagnosis prior to surgery are strongly associated with a higher risk of recurrence. When excisional biopsy reports IP incidentally, an early revision surgery should be considered in order to avoid future aggressive surgeries because of tumor recurrence.

Multimorbidities of Pediatric Allergic Rhinitis.

PURPOSE OF REVIEW: Most children and adolescents with allergic rhinitis (AR) present extra-nasal multimorbid conditions, including conjunctivitis, asthma, atopic dermatitis, rhinosinusitis, or seromucous otitis. Additionally, they may present nasal obstructive disorders, such as septal deformity, turbinate enlargement, and adenoidal hyperplasia, which worsen nasal symptoms, especially nasal obstruction. This is a narrative review on the current state of the concomitant presence of AR and one or more multimorbidities. RECENT FINDINGS: The presence of AR and one or more accompanying multimorbidities is associated to a higher severity and duration of the disease, a negative impact on quality of life, with worse control and lack of improvement with medical treatment. Therefore, AR needs to be managed with a multidisciplinary collaborative approach. Pediatric AR needs to be considered in the context of a systemic disease, which requires a coordinated therapeutic strategy.

Vocal Changes Following Thyroid Surgery: Prospective Study of Objective and Subjective Parameters.

OBJECTIVE: Vocal changes are frequent following a surgical procedure to the thyroid gland. Even though they are a recognized morbidity, their bases are yet to be defined as well as their effect on vocal parameters. This study investigates the objective and subjective changes that occur after the surgery. STUDY DESIGN: This study is a prospective analysis of consecutive cases. SETTING: This study was conducted in a single-center tertiary care facility. SUBJECTS AND METHODS: Patients programmed for any thyroid procedure in Hospital Universitario Ramón y Cajal were enrolled consecutively to perform the vocal analysis before and after the surgery from April 2014 to April 2016. Patients were divided according to the vocal fold motility, and their vocal and aerodynamic parameters were obtained by means of electroglottography and phonatory aerodynamic system. Patients filled in the 10-item Voice Handicap Index (VHI-10) questionnaire. Statistical analysis was performed comparing vocal and aerodynamic parameters and quality of life before and after the surgery. RESULTS: 218 patients met inclusion criteria and completed the protocol. A total of 86.6% of the sample showed no vocal motility impairment, whereas the rest of the patients showed a paresis or a paralysis. Maximum phonatory time and VHI-10 questionnaire showed a statistically significant difference (P < 0.05) between groups. No differences were assessed regarding other vocal parameters. CONCLUSIONS: Efforts are still needed to understand the groundings and magnitude of the vocal changes after a thyroid surgery.

Translation and validation of the MD Anderson Dysphagia Inventory (MDADI) for Spanish-speaking patients.

BACKGROUND: The main objective of this study was to perform the adaptation and cultural translation and validation of the MD Anderson Dysphagia Inventory (MDADI) questionnaire for the Spanish language. METHODS: A total of 69 patients were diagnosed with head and neck cancer treated with surgery; radiotherapy and chemoradiotherapy were included. MDADI was translated and a feasibility, internal consistency, test-retest reliability, and construct validity were assessed. RESULTS: The mean overall score of the MDADI was 51.9 (18-85). Internal consistency for total score was 0.908. The overall score of intraclass correlation coefficient was 0.98 and kappa coefficient scores were almost perfect (test-retest reliability). All domains of MDADI were significantly correlated with physical and mental domains of the SF-12. Construct validity was also evaluated with food texture measures, and with TNM classification. CONCLUSION: The translation and validation of the Spanish version of the MDADI was performed and can be considered an important patient-reported outcomes tool for dysphagia-related quality of life.

Specification of Drosophila neuropeptidergic neurons by the splicing component brr2.

During embryonic development, a number of genetic cues act to generate neuronal diversity. While intrinsic transcriptional cascades are well-known to control neuronal sub-type cell fate, the target cells can also provide critical input to specific neuronal cell fates. Such signals, denoted retrograde signals, are known to provide critical survival cues for neurons, but have also been found to trigger terminal differentiation of neurons. One salient example of such target-derived instructive signals pertains to the specification of the Drosophila FMRFamide neuropeptide neurons, the Tv4 neurons of the ventral nerve cord. Tv4 neurons receive a BMP signal from their target cells, which acts as the final trigger to activate the FMRFa gene. A recent FMRFa-eGFP genetic screen identified several genes involved in Tv4 specification, two of which encode components of the U5 subunit of the spliceosome: brr2 (l(3)72Ab) and Prp8. In this study, we focus on the role of RNA processing during target-derived signaling. We found that brr2 and Prp8 play crucial roles in controlling the expression of the FMRFa neuropeptide specifically in six neurons of the VNC (Tv4 neurons). Detailed analysis of brr2 revealed that this control is executed by two independent mechanisms, both of which are required for the activation of the BMP retrograde signaling pathway in Tv4 neurons: (1) Proper axonal pathfinding to the target tissue in order to receive the BMP ligand. (2) Proper RNA splicing of two genes in the BMP pathway: the thickveins (tkv) gene, encoding a BMP receptor subunit, and the Medea gene, encoding a co-Smad. These results reveal involvement of specific RNA processing in diversifying neuronal identity within the central nervous system.

Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program.

A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in Drosophila and mouse. We find that, compared with the nerve cord, the brain displays extended progenitor proliferation, more elaborate daughter cell proliferation and more rapid cell cycle speed in both Drosophila and mouse. These features contribute to anterior CNS expansion in both species. With respect to genetic control, enhanced brain proliferation is severely reduced by ectopic Hox gene expression, by either Hox misexpression or by loss of Polycomb group (PcG) function. Strikingly, in PcG mutants, early CNS proliferation appears to be unaffected, whereas subsequent brain proliferation is severely reduced. Hence, a conserved PcG-Hox program promotes the anterior expansion of the CNS. The profound differences in proliferation and in the underlying genetic mechanisms between brain and nerve cord lend support to the emerging concept of separate evolutionary origins of these two CNS regions.

Comparison of cricothyroid approximation and glottoplasty for surgical voice feminization in male-to-female transsexuals.

OBJECTIVE: To compare voice feminization and quality of life (QoL) of Male-to-Female Transsexuals (MtF Ts) after cricothyroid approximation (CTA) or glottoplasty (GL). STUDY DESIGN: Retrospective study. METHODS: Fifty-three MtF Ts were studied between 2007 and 2016. Voice assessment was based on fundamental frequency (F0 ), perceptual rating on GBRAS Hirano scale (Grade, Breathiness, Roughness, Asthenia, Strain), QoL related to voice on the Voice Handicap Index-10 Spanish validated version (VHI-10 Sv) and self-perceived femininity of the voice (SpFv), and overall satisfaction with the surgical technique (Sst) on a visual analogue scale (VAS). Demographic data and complications related to surgery were also recorded. RESULTS: Twenty-eight MtF Ts underwent CTA and 23 GL. The mean age was 35 years. The median follow-up period was 40 months. Mean F0 improved after surgery for both groups, but this increase was 27 Hz higher after GL than after CTA (P < 0.05). After CTA, F0 decreased over time but remained stable after GL. The GBRAS score did not change after CTA; the roughness item and total score increased from 0 to 1 after GL (P < 0.05). VHI-10 Sv scores decreased similarly in both groups. SpFv increase was higher after GL. The Sst was mild and similar in both groups. One case of severe dysphonia (4%) resulting from a big and fibrous sinequia occurred after GL. CONCLUSION: Both CTA and GL increase F0 , improving QoL in MtF Ts. However, F0 increase is higher and more long-lasting after GL. More risk of postoperative roughness is described after GL. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2101-2109, 2018.

Translation, Cultural Adaptation, and Preliminary Evaluation of the Spanish Version of the Transgender Voice Questionnaire for Male-to-Female Transsexuals (TVQ MtF).

OBJECTIVE: This study aimed to perform translation, cross-cultural adaptation, and validation of the Spanish version of the Transsexual Voice Questionnaire for Male-to-Female Transsexuals (TVQ MtF). STUDY DESIGN: This is a prospective study. SETTING: The study was conducted by the Gender Identity Unit and the Voice Unit of a tertiary hospital referral center for surgical feminization of the voice. SUBJECTS AND METHODS: The study had two parts: translation and adaptation of the TVQ MtF with the following actions: translation (with authorization and consensus of the authors of the original questionnaire), back-translation, pretesting, and final version; and preliminary study of the psychometric properties (feasibility, internal consistency, test-retest reliability, construct validity, discriminant validity, and ceiling and floor effects). Thirty male-to-female transsexual women filled out the questionnaire, and 18 of the 30 filled out the questionnaire approximately 2 weeks after filling it out for the first time. RESULTS: Feasibility was 100%. Cronbach α was 0.976. The intraclass correlation coefficient was 0.885. The Spearman correlation coefficient between TVQ MtF and the physical component of SF-12 v2 was 0.102 (P value = 0.592) and between TVQ MtF and the mental component was -0.263 (P value = 0.161). A ceiling effect was not found. A floor effect was found in two questionnaires (6.7%). CONCLUSION: Feasibility, internal consistency, and reliability outcomes in our study support the validity of the authorized Spanish version of the TVQ MtF.