Dynein axonemal heavy chain 10 deficiency causes primary ciliary dyskinesia in humans and mice / 医学前沿

Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.

Comparison of interscalene brachial plexus block and intra-articular local anesthetic administration on postoperative pain management in arthroscopic shoulder surgery / Comparação de bloqueio do plexo braquial por via interescalênica e administração de anestésico local intra-articular no manejo da dor no pós-operatório de cirurgia artroscópica do ombro / Comparación de bloqueo del plexo braquial por vía interescalénica y administración de anestésico local intraarticular en el manejo del dolor en el postoperatorio de cirugía artroscópica del hombro

BACKGROUND AND OBJECTIVES: In this study, the aim was to compare postoperative analgesia effects of the administration of ultrasound-guided interscalene brachial plexus block and intra-articular bupivacaine carried out with bupivacaine. METHODS: In the first group of patients 20 mL 0.25% bupivacaine and ultrasound-guided interscalene brachial plexus block (ISPB) were applied, while 20 mL 0.25% bupivacaine was given via intra-articular (IA) administration to the second group patients after surgery. Patients in the third group were considered the control group and no block was performed. Patient-controlled analgesia (PCA) with morphine was used in all three groups for postoperative analgesia. RESULTS: In the ISPB group, morphine consumption in the periods between 0-4, 6-12 and 12-24 postoperative hours and total consumption within 24 h was lower than in the other two groups. Morphine consumption in the IA group was lower than in the control group in the period from 0 to 6 h and the same was true for total morphine consumption in 24 h. Postoperative VASr scores in the ISPB group were lower than both of the other groups in the first 2 h and lower than the control group in the 4th and 6th hours (p < 0.05). In the IA group, VASr and VASm scores in the 2nd, 4th and 6th hours were lower than in the control group (p < 0.05). CONCLUSION: Interscalene brachial plexus block was found to be more effective than intra-articular local anesthetic injection for postoperative analgesia. .

JUSTIFICATIVA E OBJETIVOS: Comparar os efeitos na analgesia no pós-operatório da administração de bloqueio do plexo braquial por via interescalênica guiado por ultrassom e bupivacaína intra-articular, feito com bupivacaína. MÉTODOS: No primeiro grupo de pacientes, 20 mL de bupivacaína a 0,25% e bloqueio do plexo braquial por via interescalênica guiado por ultrassom (BPBI) foram administrados, enquanto 20 mL de bupivacaína a 0,25% foram administrados por via intra-articular (IA) ao segundo grupo de pacientes após a cirurgia. Os pacientes do terceiro grupo foram considerados grupo controle e nenhum bloqueio foi feito. Analgesia controlada pelo paciente (ACP) com morfina foi usada nos três grupos para analgesia pós-operatória. RESULTADOS: No grupo BPBI, o consumo de morfina nos períodos entre 0-4, 6-12 e 12-24 horas após a cirurgia e o consumo total em 24 horas foram mais baixos do que nos outros dois grupos. O consumo de morfina no grupo IA foi menor do que no grupo controle no período de 0-6 horas, como também foi menor o consumo total de morfina em 24 horas. Os escores EVAr no pós-operatório do grupo BPBI foram menores do que os escores dos dois outros grupos nas primeiras duas horas e menores do que os do grupo controle nos períodos de 4 e 6 horas (p < 0,05). No grupo IA, os escores EVAr e EVAm nos períodos de 2, 4 e 6 horas foram menores do que no grupo controle (p < 0,05). CONCLUSÃO: O bloqueio do plexo braquial por via interescalênica mostrou ser mais eficaz do que a injeção intra-articular de anestésico local para analgesia pós-operatória. .

JUSTIFICACIÓN Y OBJETIVOS: En este estudio, nuestro objetivo fue comparar en el período postoperatorio los efectos analgésicos de la administración de la bupivacaína en el bloqueo del plexo braquial por vía interescalénica guiado por ecografía y bupivacaína intraarticular. MÉTODOS: En el primer grupo de pacientes se administraron 20 mL de bupivacaína al 0,25% y se llevó a cabo el bloqueo del plexo braquial por vía interescalénica (BPBI) guiado por ecografía, mientras que al segundo grupo de pacientes se le administraron 20 mL de bupivacaína al 0,25% por vía intraarticular (IA) tras la cirugía. Los pacientes del tercer grupo fueron considerados como grupo control y en ellos no se realizó ningún bloqueo. La analgesia controlada por el paciente con morfina se usó en los 3 grupos para la analgesia postoperatoria. RESULTADOS: En el grupo BPBI, el consumo de morfina en los períodos entre 0-4, 6-12 y 12-24 h del postoperatorio y el consumo total en 24 h fueron más bajos que en los otros 2 grupos. El consumo de morfina en el grupo IA fue menor que en el grupo control en el período de 0-6 h, como también fue menor el consumo total de morfina en 24 h. Las puntuaciones EVAr en el postoperatorio del grupo BPBI fueron menores que las de los otros 2 grupos en las primeras 2 h y menores que los del grupo control en los períodos de 4 y 6 h (p < 0,05). En el grupo IA, las puntuaciones EVAr y EVAm en los períodos de 2, 4 y 6 h fueron menores que en el grupo control (p < 0,05). CONCLUSIÓN: El BPBI mostró ser más eficaz que la inyección intraarticular de anestésico local para analgesia postoperatoria. .

Structural analysis of flagellar axonemes from inner arm dynein knockdown strains of Trypanosoma brucei

Trypanosoma brucei is a protozoan flagellate that causes African sleeping sickness. Flagellar function in this organism is critical for life cycle progression and pathogenesis, however the regulation of flagellar motility is not well understood. The flagellar axoneme produces a complex beat through the precisely coordinated firing of many proteins, including multiple dynein motors. These motors are found in the inner arm and outer arm complexes. We are studying one of the inner arm dynein motors in the T. brucei flagellum: dynein-f. RNAi knockdown of genes for two components of dynein-f: DNAH10, the a heavy chain, and IC138, an intermediate chain, cause severe motility defects including immotility. To determine if motility defects result from structural disruption of the axoneme, we used two different flagellar preparations to carefully examine axoneme structure in these strains using transmission electron microscopy (TEM). Our analysis showed that inner arm dynein size, axoneme structural integrity and fixed central pair orientation are not significantly different in either knockdown culture when compared to control cultures. These results support the idea that immotility in knockdowns affecting DNAH10 or IC138 results from loss of dynein-f function rather than from obvious structural defects in the axoneme.

Nitric oxide synthase activity and endogenous inhibitors in rats recovered from allergic encephalomyelitis

We have previously reported that in comparison with normal rats, the presence of experimental allergic encephalomyelitis (EAE) leads to decreased endogenous inhibitory activity (EIA) of Ca2+-dependent nitric oxide synthase (NOS) in both brain and serum, and increased expression of protein 3-nitrotyrosine (NT) in brain. In this work we show that animals recovered from the clinical signs of EAE are not different from controls in terms of either brain NOS activity, EIA of NOS, or NT expression. These results suggest that parallel to the reversal of the disease symptoms, a normalization of the production of nitric oxide and related species occurs.