A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene.

PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center.

BACKGROUND: Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. RESULTS: We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. CONCLUSIONS: Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.

Synthesis of C2-Symmetric Diphosphormonoamidites and Their Use as Ligands in Rh-Catalyzed Hydroformylation: Relationships between Activity and Hydrolysis Stability.

A series of diphosphoramidites has been synthetized with a piperazine, homopiperazine, and an acyclic 1,2-diamine unit in the backbone. New compounds were tested alongside related N-acyl phosphoramidites as ligands in the Rh-catalyzed hydroformylation of n-octenes to investigate their influence on the activity and regioselectivity. A subsequent study of their hydrolysis stability revealed that the most stable ligands induced the highest activity in the catalytic reaction.

Actividad antimicrobiana in vitro de Cederla adorata L. (cedro) / n vitro antimicrobial activity of Cederla adorata L. (cedar)

Introducción: la corteza del fuste de Cedrela adorata L (cedro) es utilizada por la población para el tratamiento del asma, como vermífuga, antibacteriana, febrífuga y en cocimiento para dolores cuando se sufren caídas o golpes. Objetivo: identificar los metabolitos secundarios presentes en esta parte de la planta y evaluar su posible actividad antibacteriana. Métodos: se recolectó la corteza del fuste de Cedrela adorata. El material vegetal fue lavado, desinfectado, secado y seguidamente se procedió a su pulverización. Este polvo se utilizó en la elaboración de los diferentes extractos y tintura. La tintura obtenida se concentró y se fraccionó sucesivamente con n-hexano, cloroformo, acetato de etilo y agua. A estos extractos se les realizó el tamizaje fitoquímico, ensayos microbiológicos y cromatografía de capa fina. Resultados: las pruebas in vitro efectuadas a los extractos obtenidos a partir de la tintura 20 por ciento, demostraron que estos presentan actividad antibacteriana frente a Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Shigella sp., Salmonella enterica y Enterobacter aerogene; destacándose los resultados obtenidos frente al Staphylococcus aureus, para el extracto hexánico de cedro. En estos extractos están presentes en mayor proporción alcaloides, triterpenos o esteroles, y quinonas, que son los responsables de esta actividad, lo cual se logró corroborar con la identificación de estos metabolitos secundarios mediante la cromatografía de capa fina y el tamizaje fitoquímico realizados. Conclusiones: mediante la cromatografía de capa fina y el tamizaje fitoquímico de los extractos se identificaron alcaloides, triterpenos o esteroles, y quinonas, que pueden ser los responsables de la actividad antibacteriana

Introduction: the stem bark of Cedrela adorata L (cedar) is used by the population to treat asthma, as vermifuge, antibacterial and febrifuge, and in the form of decoction to relieve the pain caused by falls or bumps. Objective: identify the secondary metabolites present in this part of the plant and evaluate their potential antibacterial activity. Methods: stem bark from Cedrela adorata was collected. The plant material was washed, disinfected, dried and pulverized. The powder obtained was used to make the various extracts and the tincture. The latter was concentrated and successively fractionated with n-hexane, chloroform, ethyl acetate and water. The extracts underwent phytochemical screening, microbiological assays and thin-layer chromatography. Results: in vitro tests of the extracts obtained from the 20 percent tincture showed antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Shigella sp., Salmonella enterica and Enterobacter aerogen. Antibacterial activity of the hexanic cedar extract against Staphylococcus aureus was noteworthy. Alkaloids, triterpenes or sterols, and quinones, which are found in a large proportion in the extracts, are responsible for the above-mentioned antibacterial activity. Identification of these secondary metabolites was confirmed through thin-layer chromatography and phytochemical screening. Conclusions: the alkaloids, triterpenes or sterols, and quinones potentially responsible for antibacterial activity were identified through thin-later chromatography and phytochemical screening

Tamizaje fitoquímico de Cassia uniflora Mill / Phytochemical screening of Cassia uniflora Mill

Introducción: Cassia uniflora Mill se emplea en el control aleloquímico de Parthenium hysterophorus; se ha reportado que presenta actividad larvicida frente a Aedes aegypti. Tradicionalmente se ha usado como antiespasmódico y para el tratamiento de erupciones cutáneas. Objetivo: realizar un tamizaje fitoquímico a los extractos etéreo, alcohólico y acuoso de la especie Cassia uniflora Mill para conocer los metabolitos secundarios que sean de interés biológico en la terapéutica. Métodos: se recolectaron partes aéreas y subterráneas de la planta, se lavaron, desinfectaron, secaron, pulverizaron y se sometieron a extracciones sucesivas con solventes de polaridad creciente. Los extractos se filtraron y se realizaron ensayos fitoquímicos de identificación. Resultados: el tamizaje fitoquímico, efectuado a los extractos etéreo, alcohólico y acuoso de las hojas, tallos, cáscaras de los frutos, semillas y raíces, demostró la existencia de varias familias de metabolitos secundarios de interés biológico y farmacológico, entre los que se destacan, por su significativa presencia, las quinonas y las coumarinas. Conclusiones: de acuerdo con la diversidad de metabolitos secundarios presentes en las partes evaluadas de C. uniflora, así como los efectos biológicos reportados para la especie, sería interesante realizar nuevos estudios que aporten evidencias sobre su eficacia y seguridad, como forma de avalar su empleo tradicional.

Introduction: Cassia uniflora Mill is used for the allelochemical control of Parthenium hysterophorus; and its larvicidal activity on Aedes aegypti has been reported. It has also been applied as antispasmodic agent and as treatment of cutaneous rash. Objective: to perform a phytochemical screening on alcoholic, ethereal and aqueous extracts from the Cassia uniflora Mill species to identify the secondary metabolites of biological interest in therapeutics. Methods: aerial and underground parts of the plant were harvested, washed, disinfected, dried, powdered and subjected to successive extractions with solvents of increasing polarity. The extracts were filtered to carry out phytochemical tests for identification. Results: the phytochemical screening of ethereal, alcoholic and aqueous extracts from leaves, stems, fruit peels, seeds and roots, confirmed the existence of several families of secondary metabolites of biological and pharmacological interest such as quinones and coumarins that stand out because of their significance presence. Conclusions: according to the diversity of secondary metabolites in the tested parts of Cassia uniflora Mill, as well as the biological effects reported for this species, it would be interesting to conduct new studies to find pieces of evidence on its effectiveness and safety, as a way of supporting traditional use of this plant.

Control de la calidad de formulaciones farmacéuticas obtenidas de cassia uniflora mill / Quality control of pharmaceutical formulations obtained from cassia uniflora mill

Introducción: Cassia uniflora Mill tiene una alta biodisponibilidad; se utiliza en el tratamiento de dolores espasmódicos, erupciones cutáneas e infecciones de origen bacteriano. Sus partes más empleadas son las hojas y las semillas. Objetivo: Determinar las especificaciones del control de la calidad para las tinturas a 20 por ciento de las hojas y las semillas de Cassia uniflora Mill. Material y Métodos: Las tinturas a 20 por ciento se prepararon a partir de los polvos de las hojas y las semillas, utilizando como menstruo una solución hidroetanólica. La determinación de las especificaciones del control de la calidad de las tinturas se realizó para cuatro parámetros: pH, índice de refracción, sólidos totales y densidad relativa. Resultados: Los datos obtenidos en el control de la calidad de las tinturas a 20 por ciento se encuentran dentro de los rangos de calidad establecidos en las normas utilizadas. Discusión: Los parámetros de calidad muestran que las tinturas a 20 por ciento de hojas y semillas de Cassia uniflora Mill no tuvieron cambios relevantes que afecten su calidad farmacéutica, por tanto, poseen un determinado grado de estabilidad. Conclusiones: Las especificaciones del control de la calidad de las tinturas indican que, bajo las condiciones aplicadas, los productos elaborados presentan inocuidad, y constituyen una garantía de calidad para su empleo terapéutico.

Introduction: Cassia uniflora Mill has a high biological availability; It is used in treatments for spasmodic pains, cutaneous eruptions and some infections of bacteriological origin. The most useful parts are its leaves and seeds. Objectives: To determine the specifications of quality control for tinctures made up from leaves and seeds of Cassia uniflora Mill at 20 percent. Material and methods: Tincture at 20 percent was made up of the powders of leaves and seeds, using as menses a hydroethanolic solution. Determination of quality control specifications of the tinctures were made taking into account four parameters: pH, refraction index, total solids and relative density. Results: Data obtained in the quality control of the tinctures at 20 percent are among the ranks of quality established by the standards. Discussion: Quality parameters show that tinctures at 20 percent from leaves and seeds of Cassia uniflora Mill had no relevant changes that could affect its pharmacological quality, therefore they have a certain degree of stability. Conclusions: The specifications of the quality control made to the tinctures indicate that under the conditions applied the elaborated products are innocuous, so they are totally guaranteed for therapeutically use.