KCNV2-associated retinopathy: genotype-phenotype correlations - KCNV2 study group report 3.

BACKGROUND/AIMS: To investigate genotype-phenotype associations in patients with KCNV2 retinopathy. METHODS: Review of clinical notes, best-corrected visual acuity (BCVA), molecular variants, electroretinography (ERG) and retinal imaging. Subjects were grouped according to the combination of KCNV2 variants-two loss-of-function (TLOF), two missense (TM) or one of each (MLOF)-and parameters were compared. RESULTS: Ninety-two patients were included. The mean age of onset (mean±SD) in TLOF (n=55), TM (n=23) and MLOF (n=14) groups was 3.51±0.58, 4.07±2.76 and 5.54±3.38 years, respectively. The mean LogMAR BCVA (±SD) at baseline in TLOF, TM and MLOF groups was 0.89±0.25, 0.67±0.38 and 0.81±0.35 for right, and 0.88±0.26, 0.69±0.33 and 0.78±0.33 for left eyes, respectively. The difference in BCVA between groups at baseline was significant in right (p=0.03) and left eyes (p=0.035). Mean outer nuclear layer thickness (±SD) at baseline in TLOF, MLOF and TM groups was 37.07±15.20 µm, 40.67±12.53 and 40.38±18.67, respectively, which was not significantly different (p=0.85). The mean ellipsoid zone width (EZW) loss (±SD) was 2051 µm (±1318) for patients in the TLOF, and 1314 µm (±965) for MLOF. Only one patient in the TM group had EZW loss at presentation. There was considerable overlap in ERG findings, although the largest DA 10 ERG b-waves were associated with TLOF and the smallest with TM variants. CONCLUSIONS: Patients with missense alterations had better BCVA and greater structural integrity. This is important for patient prognostication and counselling, as well as stratification for future gene therapy trials.

Differential Expression of FXR and Genes Involved in Inflammation and lipid Metabolism Indicate Adipose Tissue Dysfunction in Gestational Diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is the most frequent metabolic alteration in pregnancy. Several abnormalities in visceral adipose tissue (VAT) have been described as part of its pathophysiology including hypertrophy, inflammation and altered lipid metabolism. Farnesoid X receptor (FXR) is involved in adipocyte physiology and inflammation, so its expression may correlate with the expression of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), lipoprotein lipase (LPL), and two fatty acid transporters (SLC27A2, and SLC27A4). AIM: To compare the FXR, LPL, SLC27A2, SLC27A4, TNF-α, and IL-10 mRNA expression in VAT between women with GDM and healthy pregnant (HP) women. Secondarily, to evaluate the potential correlation between these expression levels. MATERIALS AND METHODS: Cross-sectional study of 50 GDM and 50 HP women. Conventional biochemical tests were performed and relative mRNA expression in VAT was measured by RT-qPCR. RESULTS: Gene expression levels of FXR and IL-10 were lower, whereas those of LPL, as well as the TNF-α/IL-10 ratio, were higher in women with GDM compared to HP. Pre-pregnancy BMI was the main significant independent variable for FXR levels in VAT from women with GDM. In all women, LPL expression levels correlated positively with those of SLC27A2. Only in women with GDM, IL-10 expression levels correlated negatively with those of SLC27A2, and SLC27A4. CONCLUSIONS: GDM is associated with decreased expression of FXR and IL-10 and increased expression of LPL, as well as a higher TNF/IL-10 ratio in VAT. These results suggest increased lipid storage and pro-inflammatory state indicating VAT dysfunction in this metabolic disorder.

Enfermedad renal diabética: puesta al día / Update on diabetic kidney disease

Introducción: La Diabetes Mellitus (DM) es una enfermedad inflamatoria sistémica de alta prevalencia e incidencia a nivel mundial. Dentro de las complicaciones crónicas, la enfermedad renal diabética es una de las más frecuentes y que marca el pronóstico. Objetivos: El objetivo de este artículo es hacer una revisión actualizada de la enfermedad renal diabética, a la luz de los cambios en los paradigmas que se han generado en los últimos años con respecto a sus nuevas definiciones, el papel de la inflamación en su desarrollo, la gestión del riesgo cardiovascular y los nuevos tratamientos. La enfermedad renal diabética puede presentarse en aproximadamente el 30-50% de la población con diabetes mellitus tipo 1 o 2 alrededor del mundo. En la patogénesis y progresión de esta condición se distinguen tres ejes fundamentales el hemodinámico, metabólico e inflamatorio. Es importante siempre hacer gestión del riesgo cardiovascular. El diagnóstico se debe hacer con el cálculo de la tasa de filtrado glomerular y la relación albuminuria / creatinuria en muestra ocasional. Los objetivos en el tratamiento deben ser: el control metabólico, reducir o enlentecer la progresión de la enfermedad renal y disminuir los desenlaces cardiovasculares. Conclusión: El tratamiento de la ERD debe ser holístico, desde intervenciones no farmacológicas, como la modificación de los estilos de vida, hasta los nuevos medicamentos como el uso de inhibidores SGLT-2, Agonistas del receptor GLP-1 y el uso antagonistas selectivos del receptor mineralocorticoide como finerenona. El futuro es promisorio.

Introduction: Diabetes mellitus (DM) is a systemic inflammatory disease of high prevalence and incidence worldwide. Among the chronic complications, diabetic kidney disease is one of the most frequent and determines the prognosis. Objectives: The objective of this article is to make an updated review of diabetic kidney disease, in light of the changes in the paradigms that have been generated in recent years concerning to the new definitions, the role of inflammation-causing disease, cardiovascular risk management, and the new treatments. Diabetic kidney disease can present in approximately 30-50% of the population with diabetes mellitus type 1 or 2 around the world. In the pathogenesis and progression of this condition, three fundamental axes are distinguished: the hemodynamic, the metabolic, and the inflammatory. It is important to manage cardiovascular risk. The diagnosis must be made by calculating the glomerular filtration rate and the albuminuria/creatinuria ratio in a random urine sample. The objectives of the treatment should be: metabolic control, reduce or slow the progression of kidney disease and improve cardiovascular outcomes. Conclusion: The treatment of diabetic kidney disease should be holistic, from non-pharmacological interventions, such as lifestyle changes, to new medications such as the use of SGLT-2 inhibitors, GLP-1 receptor agonists, and the use of selective mineralocorticoid receptor antagonists such as finerenone. The future is promising.

Good functional results with open reduction and internal fixation for locked posterior shoulder fracture-dislocation: a case series.

BACKGROUND: There is no standardized therapeutic strategy for locked posterior shoulder fracture-dislocation (PSFD), and no consensus exists on the analysis of preoperative factors. This retrospective study aimed to evaluate functional results and complications in a series of PSFD cases managed with open surgical treatment. METHODS: Patients diagnosed with locked PSFD who underwent open surgical treatment with reduction and osteosynthesis between April 2016 and March 2020 were included. All participants were treated with open reduction and internal fixation. Functional assessment used the modified University of California, Los Angeles (UCLA) mod scale, American Shoulder and Elbow Surgeons (ASES) questionnaire, subjective shoulder value (SSV), and visual analog scale (VAS). Complications were evaluated clinically and radiologically by X-ray and computed tomography. RESULTS: Twelve shoulders were included (11 patients; mean age, 40.6 years; range, 19- 62 years). The mean follow-up duration was 23.3 months (range, 12-63 months). The UCLA mod, ASES, SSV, and VAS scores were 29.1±3.7, 81.6±13.5, 78±14.8, and 1.2±1.4 points, respectively. The overall complication rate was 16.6%, with one case of post-traumatic stiffness, 1 case of chronic pain, and no cases of avascular necrosis. CONCLUSIONS: Open surgical treatment of locked PSFD can achieve good functional results. A correct understanding of these injuries and good preoperative planning helped us to achieve a low rate of complications.

Downregulation of SLC16A11 is Present in Offspring of Mothers with Gestational Diabetes.

BACKGROUND: Studies have identified that diseases in pregnancy affect fetal growth and development of the newborn. In Mexican population, the gene SLC16A11 has been identified as a factor that increases the risk of developing type 2 diabetes mellitus. To date, information is scarce about its expression in gestational diabetes mellitus (GDM); epigenetic modifications due to maternal hyperglycemic state could be identified early in fetal development. PURPOSE: This study aimed to determine the SLC16A11 expression and methylation status in umbilical cord blood of newborns offspring of mothers with or without GDM. METHODS: Cross-sectional, analytic study. Pregnant patients undergoing caesarean delivery with and without GDM in the Unidad Medica de Alta Especialidad Hospital de Gineco-obstetricia #4 Luis Castelazo Ayala, Instituto Mexicano del Seguro Social, were invited to participate. DNA was extracted from the mothers' blood cells, or umbilical cord blood cells of their newborns, and subjected to methylation status. Total RNA was used to evaluate the SLC16A11 expression by endpoint RT-PCR. Variables were analyzed with Student t. Values of p <0.05 were considered statistically significant. RESULTS: A SLC16A11 downregulation was observed for newborns, while methylation status was found in only 1 of 68 mother-child pairs. Somatometry of newborns showed no differences between groups. Differences were found in total cholesterol, triglycerides, ALT, glucose, and HbA1c. CONCLUSIONS: For the first time, a differential expression for SLC16A11 was observed in offspring. Downregulation in this gene expression could characterize the offspring from GDM. No difference was found in somatometry of newborns of mothers with and without GDM.

Variable expressivity of BEST1-associated autosomal dominant vitreoretinochoroidopathy (ADVIRC) in a three-generation pedigree.

OBJECTIVE: Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is associated with pathogenic variants in BEST1, which typically causes visual impairment in the late stage of disease. We present a pedigree with variable expressivity and the youngest case in the literature with visual impairment in early childhood. METHODS AND ANALYSIS: This is a retrospective, observational, case series describing multigenerational members of one family affected with ADVIRC. Patients underwent examination, ultra-widefield fundus photography and angiography, optical coherence tomography, full-field electroretinography (ffERG) and full-field perimetry. RESULTS: Three affected members of the pedigree, one from each successive generation, were found to harbour a mutation, c.715G>A:p.Val239Met, in BEST1. The proband characterised in this report is, to our knowledge, the youngest documented case of ADVIRC in early childhood. Yet, this patient has the most severe retinal dysfunction compared with the father and paternal grandmother, whom exhibit classic characteristics of ADVIRC. Longitudinal data from the paternal grandmother showed that there was a rapid decline in ffERG responses (photopic decline worse than scotopic) from the fourth to fifth decade of life, which correlated with severe concentric constriction of visual fields. CONCLUSION: This multigenerational case series provides new insights into the ADVIRC disease spectrum and rate of progression. While ADVIRC typically causes a slowly progressive disease, we show that variable phenotypic expressivity is possible among affected members of the same family with the same mutation in BEST1. Thus, ADVIRC must also be considered in the differential diagnosis of paediatric patients with severe retinal dystrophy in early childhood.

KCNV2-Associated Retinopathy: Detailed Retinal Phenotype and Structural Endpoints-KCNV2 Study Group Report 2.

PURPOSE: To describe the detailed retinal phenotype of KCNV2-associated retinopathy. STUDY DESIGN: Multicenter international retrospective case series. METHODS: Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses. RESULTS: Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes. CONCLUSIONS: KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age.

Speaking Haptically: From Phonemes to Phrases With a Mobile Haptic Communication System.

In this article, we present three studies involving WhatsHap, a mobile system designed to deliver speech as vibrations on the forearm with minimal hardware demands and practice time. After only 4.2 h of training on a 24-haptic phoneme vocabulary and on how to combine these to form words, participants were able to generalize their phoneme identification skills to the understanding of untrained English words, correctly identifying 65% of words in phrases rendered with a user-controlled interval between words, and up to 59% with a fixed interval. Ultimately, participants were able to complete 88% of simple communicative tasks that elicited spontaneous speech and semi-structured bidirectional conversation using the apparatus. We conclude by providing insights as to how such a system may ultimately be used for communication under more natural conditions.

KCNV2-Associated Retinopathy: Genetics, Electrophysiology, and Clinical Course-KCNV2 Study Group Report 1.

PURPOSE: To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. STUDY DESIGN: This was a multicenter international clinical cohort study. METHODS: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects. RESULTS: In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades. CONCLUSION: In KCNV2-associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.

The big challenge of SARS-CoV-2 latency: testes as reservoir.

In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.

En el afán por explicar la fisiopatogenia de COVID-19 se están realizando estudios en torno a la correspondencia entre la expresión de receptores celulares de SARS-CoV-2 y las secuencias virales. La expresión de los receptores ACE2, CD147 y TMPRSS2 podría indicar blancos de infección poco explorados. Para el análisis genómico de los receptores de SARS-CoV-2 se optó por utilizar la información del BioGPS, un portal que centraliza los recursos de anotación genética, en combinación con la de The Human Protein Atlas, el portal más grande de datos del transcriptoma y proteoma humanos. También se revisaron los artículos más recientemente respecto al tema. En numerosos sitios anatómicos se observó la expresión de ARN y proteínas de los receptores del virus, que coinciden parcialmente con la información reportada en la literatura. Resaltó la alta expresión en las células de los testículos, por lo que sería importante descartar si este sitio anatómico es un reservorio de SARS-CoV-2; de no ser así, determinar el daño en las células germinales, tal como sucede en infecciones por otros virus ARN.

The big challenge of SARS-CoV-2 latency: testes as reservoir / El gran desafío de la latencia de SARS-CoV-2: el testículo como reservorio

Abstract In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.

Resumen En el afán por explicar la fisiopatogenia de COVID-19 se están realizando estudios en torno a la correspondencia entre la expresión de receptores celulares de SARS-CoV-2 y las secuencias virales. La expresión de los receptores ACE2, CD147 y TMPRSS2 podría indicar blancos de infección poco explorados. Para el análisis genómico de los receptores de SARS-CoV-2 se optó por utilizar la información del BioGPS, un portal que centraliza los recursos de anotación genética, en combinación con la de The Human Protein Atlas, el portal más grande de datos del transcriptoma y proteoma humanos. También se revisaron los artículos más recientemente respecto al tema. En numerosos sitios anatómicos se observó la expresión de ARN y proteínas de los receptores del virus, que coinciden parcialmente con la información reportada en la literatura. Resaltó la alta expresión en las células de los testículos, por lo que sería importante descartar si este sitio anatómico es un reservorio de SARS-CoV-2; de no ser así, determinar el daño en las células germinales, tal como sucede en infecciones por otros virus ARN.

In Vivo Calcium Imaging During Axon Degeneration in Zebrafish.

In vivo calcium imaging in zebrafish provides the ability to investigate calcium dynamics within neurons. Utilizing genetically encoded calcium sensors it is possible to monitor calcium signals within a single axon during axon injury and degeneration with high temporal and spatial resolution. Here we will describe in vivo, time-lapse confocal imaging methods of calcium imaging. Imaging of calcium dynamics with genetically encoded calcium sensors (GECS) within living axons can serve as a method to assess axonal physiology and effects of pharmacologic and genetic manipulation, as well as characterize responses to different injury models.

[Comparative genomic analysis: from SARS to SARS-CoV-2 virus-types. Similarities and differences]. / Análisis de genómica comparativa: del virus SARS al SARS-CoV-2. Similitudes y diferencias.

BACKGROUND: We are currently witnessing a worldwide event caused by the pandemic outbreak derived from the new SARS-CoV-2 virus, which requires the generation of knowledge. Due to its novelty, many hypotheses and theories are discussed daily regarding the origin of this new virus. Several studies are focused on demonstrating how similar it is to other viruses. OBJECTIVE: To highlight the differences of SARS-CoV-2 with other SARS viruses, from a comparative genomics analysis, and determine if these can be attributed to manipulation events. MATERIAL AND METHODS: Complete genomes of two SARS viruses were downloaded, along with other six of human coronaviruses, and 16 of SARS-type coronaviruses. These were analyzed using the BLAST Ring Image Generator tool; afterwards, the evident differences were examined by MAFFT and BLAST programs. RESULTS: High identity was observed in fragments of the mammalian SARS-like genomes with the SARS-CoV-1 and SARS-CoV-2 genomes, identifying three main nucleotide differences, in the ORF1ab nsp3 region gene, in the receptor recognition S gene, and in the ORF8 gene, with which the SARS-type strains of mammals can be separated into the SARS-CoV-1 and SARS-CoV-2 type. CONCLUSION: The complete SARS-CoV-2 genome has high identity with mammalian SARS-type strains, which is why its most probable appearance could be the result of natural evolution.

INTRODUCCIÓN: en este momento somos testigos de un evento de magnitud mundial provocado por el brote pandémico derivado del nuevo virus SARS-CoV-2, lo cual requiere la generación de conocimiento. Por lo novedoso que resulta, muchas hipótesis y teorías son discutidas a diario respecto al origen de este nuevo virus. Varios estudios están enfocados en demostrar la similitud que el SARS-CoV-2 tiene con otros virus. OBJETIVO: resaltar las diferencias del SARS-CoV-2 con otros virus SARS, a partir de un análisis de genómica comparativa, y determinar si se pueden atribuir a eventos de manipulación. MATERIAL Y MÉTODOS: se descargaron dos genomas completos de virus SARS, seis genomas completos de coronavirus humanos y 16 de coronavirus tipo SARS; fueron analizados en un estudio de genómica comparativa mediante la herramienta BLAST Ring Image Generator, y a continuación se examinaron las diferencias evidentes mediante el uso de los programas MAFFT y BLAST. RESULTADOS: se observó una alta identidad en fragmentos de los genomas tipo SARS de mamíferos con los genomas SARS-CoV-1 y SARS-CoV-2, y se identificaron tres diferencias nucleotídicas principales: en el gen ORF1ab región nsp3, en el gen S de reconocimiento al receptor y en el gen ORF8, con el cual se pueden separar las cepas tipo SARS de mamíferos en tipo SARS-CoV-1 y SARS-CoV-2. CONCLUSIÓN: el genoma completo de SARS-CoV-2 posee una alta identidad con cepas tipo SARS de mamíferos, por lo que su aparición más probable podría ser el resultado de la evolución natural.

Multimodal imaging of ring 14 syndrome associated maculopathy.

Background: Ring 14 syndrome is a rare chromosomal disorder characterized by a ring-shaped appearance of chromosome 14. Classically findings include distinct facial characteristics, refractory epilepsy, global development delay, muscular hypotonia and ocular abnormalities. Here we report a retinal multimodal imaging analyses of a ring chromosome 14 syndrome patient with associated macular pigmentary changes.Materials and Methods: Case report of an 11-year-old female with a history of refractory epilepsy since 3 months of age was diagnosed with ring 14 syndrome after karyotype at 8 months old. She presented with muscle weakness, mild intellectual delay, associated hyperopia and punctiform yellowish lesions. Multimodal imaging including fundus photography, red-free fundus photography, fundus auto-fluorescence and spectral-domain optical coherence tomography were used to assess this patient.Results: An 11-year-old female with ring 14 syndrome caused by the fusion of terminal breakpoints in both the short arm and long arm of chromosome 14 at p11.1 and q32.3, respectively. At eye exam, the best corrected visual acuity was 20/20 at both eyes with associated hyperopia. Macula showing scattered punctiform yellowish lesions, bright on red-free fundus photography and hyperautofluorescence dots in the same area. The SD-OCT showed normal characteristics at both eyes with the exception of localized irregularity of the RPE in an area associated with a macular yellow dots.Conclusions: Ring 14 syndrome can cause hyperopia and associated macular yellow dots visible at multimodal imaging analyses. Our data support regular eye examination for all patients with ring chromosome 14 syndrome.

Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration.

BACKGROUND: Defects in retinol dehydrogenase 12 (RDH12) account for 3.4%-10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration. METHODS: A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12. RESULTS: 57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects. CONCLUSIONS: This study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

Aptamers as Diagnostic Tools in Cancer.

Cancer is the second leading cause of death worldwide. Researchers have been working hard on investigating not only improved therapeutics but also on early detection methods, both critical to increasing treatment efficacy, and developing methods for disease prevention. The use of nucleic acids, or aptamers, has emerged as more specific and accurate cancer diagnostic and therapeutic tools. Aptamers are single-stranded DNA or RNA molecules that recognize specific targets based on unique three-dimensional conformations. Despite the fact aptamer development has been mainly restricted to laboratory settings, the unique attributes of these molecules suggest their high potential for clinical advances in cancer detection. Aptamers can be selected for a wide range of targets, and also linked with an extensive variety of diagnostic agents, via physical or chemical conjugation, to improve previously-established detection methods or to be used as novel biosensors for cancer diagnosis. Consequently, herein we review the principal considerations and recent updates in cancer detection and imaging through aptamer-based molecules.

Morphometric study of adipocytes on breast cancer by means of photonic microscopy and image analysis.

Worldwide, breast cancer (BrCa) is currently the leading cause of deaths associated to malignant lesions in adult women. Given that some studies have mentioned that peritumoral adipocytes may contribute to breast carcinogenesis, present work sought to quantitative evaluate the morphometry of these cells in a group of adult women. Three thousand six hundred sixty four breast adipocytes, that came from biopsies of a group of adult females with different types of breast carcinomas (ductal, lobular, and mixed) and one with normal tissues, were evaluated through an image analysis (IA) process regarding six morphometric descriptors: area (A), perimeter (P), Feret diameter (FD ), aspect ratio (AR), roundness factor (RF), and fractal dimension of cellular contour (FDC ). Data showed that the adipocytes of the normal tissues group were bigger (A: 3398 ± 2331 µm2 , P: 239 ± 83 µm, and FD : 79.9 ± 24.5 µm) than those from BrCa samples (A: 2860 ± 1933 µm2 , P: 214 ± 66 µm, and FD : 73.2 ± 22.5 µm), and presented a more irregular contour (FDC of 1.370 ± 0.037 for normal group and of 1.335 ± 0.049 for the oncologic one). Moreover, it could be accounted that adipocytes of mixed carcinomas were largest (FD : 75.1 ± 22.4 µm) than those of lobular lesions (FD : 61.6 ± 22.6 µm), while the adipocytes of ductal carcinomas were the most oval (AR: 1.421 ± 0.524) and roughest (FDC : 1.324 ± 0.050) cells. IA results suggest that BrCa lesions can be categorized through a quantitative morphometric evaluation of peritumoral adipocytes. These findings could let the development of an analytical tool to help the Pathologist to enhance the accuracy of the oncologic diagnose.

DNA Methylation of Cellular Retinoic Acid-Binding Proteins in Cervical Cancer.

This study determined the methylation status of cellular retinoic acid-binding protein (CRABP) gene promoters and associated them with demographic characteristics, habits, and the presence of human papilloma virus (HPV) in patients with cervical cancer (CC), low and high squamous intraepithelial lesions, and no intraepithelial lesion. Women (n = 158) were selected from the Colposcopy Clinic of Sanitary Jurisdiction II in Ciudad Juarez, Chihuahua, Mexico. Demographic characteristics and habit information were collected. Cervical biopsy and endocervical scraping were used to determine methylation in promoter regions by methylation-specific polymerase chain reaction technique. We found hemi-methylation patterns in the promoter regions of CRABP1 and CRABP2; there was 28.5% hemi-methylation in CRABP1 and 7.0% in that of CRABP2. Methylation in CRABP1 was associated with age (≥35 years, P = 0.002), family history of cancer (P = 0.032), the presence of HPV-16 (P = 0.013), and no alcohol intake (P = 0.035). These epigenetic changes could be involved in the CC process, and CRABP1 has the potential to be a predictive molecular marker of retinoid therapy response.

Deficiencia de micronutrientes en la dieta del paciente con lesiones precancerosas del cérvix de una clínica de colposcopía en Ciudad Juárez, México / Micronutrient deficiency in the diet of the patient with precancerous cervix lesions on a colposcopy clinic at Ciudad Juárez, Mexico

Introducción: las lesiones intraepiteliales escamosas (LIE) son un estado de transición hacia el cáncer cervicouterino (CaCu) y un déficit de cronutrientes puede acelerar este proceso. Por ello, determinar la existencia de este déficit y conocer qué factores se asocian permitiría una posible prevención en esta población de riesgo. Objetivo: determinar la presencia de alguna deficiencia de micronutrientes involucrados en el proceso anticancerígeno y asociar este déficit con hábitos y factores demográficos en pacientes con LIE de Ciudad Juárez, Chihuahua, México. Métodos: en un estudio transversal analítico fueron seleccionadas 102 pacientes con LIE. Se realizó una encuesta dietaría (recordatorio de 24 horas) para estimar la ingesta de micronutrientes. La deficiencia fue determinada con un consumo < 75% de la ingesta diaria recomendada o sugerida (IDR o IDS) en México. Algunos hábitos y factores demográficos fueron obtenidos mediante la entrevista con la paciente. Se realizó un modelo de regresión logística para asociar la presencia de deficiencia con factores que afectan a la ingesta o incrementan el requerimiento de micronutrientes. Resultados: el retinol, ácido fólico, zinc, vitaminas C y E, considerados como micronutrientes en el proceso anticancerígeno del CaCu, se encontraron por debajo del 75% de la IDR. Aquellas mujeres con sobrepeso, obesidad y amas de casa se asociaron significativamente con la deficiencia de micronutrientes. Conclusión: el sobrepeso, la obesidad y la ocupación han sido asociados para presentar deficiencias de micronutrientes en este estudio. Estas variables convergen en una posible inseguridad alimentaria, la cual podría asociarse al incremento de incidencia de CaCu en México (AU)

Introduction: Squamous Intraepithelial Lesions (SIL) is a state of transition to cervical cancer (CC), and micronutrient deficiencies can speed up this process. Therefore, determining the existence of this deficit and know what factors are associated would allow for possible prevention in this population at risk. Objective: To determine the presence of some micronutrient deficiencies involved in the anti-carcinogenic process, also associate this deficit with habits and demographic factors in patients with SIL in Ciudad Juarez, Chihuahua, Mexico. Methods: An analytic cross-sectional study, 102 patients were selected with SIL. A dietary survey (24-hour recall) was performed to estimate the intake of micronutrients. The deficiency was determined when the consumption was less than 75% of the Recommended Dietary Allowances (RDA) or suggested in Mexico. Some habits and demographic factors were obtained by interview with the patient. A logistic regression was performed to associate the presence of deficiencies with factors that affecting the intake or increase the requirement of micronutrients. Results: Retinol, folic acid, zinc, vitamins C and E, considered micronutrients in the anti-carcinogenic process CC, were less than 75% of the RDA. Women with overweight, obesity and housewives, were significantly associated with micronutrient deficiencies. Conclusion: Overweight, obesity and occupation have been associated to present micronutrient deficiencies in this study. These variables converge on a possible food insecurity, which could be associated with increased incidence of CC in Mexico (AU)

Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx.

Calcium is a key regulator of axon degeneration caused by trauma and disease, but its specific spatial and temporal dynamics in injured axons remain unclear. To clarify the function of calcium in axon degeneration, we observed calcium dynamics in single injured neurons in live zebrafish larvae and tested the temporal requirement for calcium in zebrafish neurons and cultured mouse DRG neurons. Using laser axotomy to induce Wallerian degeneration (WD) in zebrafish peripheral sensory axons, we monitored calcium dynamics from injury to fragmentation, revealing two stereotyped phases of axonal calcium influx. First, axotomy triggered a transient local calcium wave originating at the injury site. This initial calcium wave only disrupted mitochondria near the injury site and was not altered by expression of the protective WD slow (WldS) protein. Inducing multiple waves with additional axotomies did not change the kinetics of degeneration. In contrast, a second phase of calcium influx occurring minutes before fragmentation spread as a wave throughout the axon, entered mitochondria, and was abolished by WldS expression. In live zebrafish, chelating calcium after the first wave, but before the second wave, delayed the progress of fragmentation. In cultured DRG neurons, chelating calcium early in the process of WD did not alter degeneration, but chelating calcium late in WD delayed fragmentation. We propose that a terminal calcium wave is a key instructive component of the axon degeneration program. SIGNIFICANCE STATEMENT: Axon degeneration resulting from trauma or neurodegenerative disease can cause devastating deficits in neural function. Understanding the molecular and cellular events that execute axon degeneration is essential for developing treatments to address these conditions. Calcium is known to contribute to axon degeneration, but its temporal requirements in this process have been unclear. Live calcium imaging in severed zebrafish neurons and temporally controlled pharmacological treatments in both zebrafish and cultured mouse sensory neurons revealed that axonal calcium influx late in the degeneration process regulates axon fragmentation. These findings suggest that temporal considerations will be crucial for developing treatments for diseases associated with axon degeneration.