Synaptotagmin-11 facilitates assembly of a presynaptic signaling complex in post-Golgi cargo vesicles.

GABAB receptors (GBRs), the G protein-coupled receptors for GABA, regulate synaptic transmission throughout the brain. A main synaptic function of GBRs is the gating of Cav2.2-type Ca2+ channels. However, the cellular compartment where stable GBR/Cav2.2 signaling complexes form remains unknown. In this study, we demonstrate that the vesicular protein synaptotagmin-11 (Syt11) binds to both the auxiliary GBR subunit KCTD16 and Cav2.2 channels. Through these dual interactions, Syt11 recruits GBRs and Cav2.2 channels to post-Golgi vesicles, thus facilitating assembly of GBR/Cav2.2 signaling complexes. In addition, Syt11 stabilizes GBRs and Cav2.2 channels at the neuronal plasma membrane by inhibiting constitutive internalization. Neurons of Syt11 knockout mice exhibit deficits in presynaptic GBRs and Cav2.2 channels, reduced neurotransmitter release, and decreased GBR-mediated presynaptic inhibition, highlighting the critical role of Syt11 in the assembly and stable expression of GBR/Cav2.2 complexes. These findings support that Syt11 acts as a vesicular scaffold protein, aiding in the assembly of signaling complexes from low-abundance components within transport vesicles. This mechanism enables insertion of pre-assembled functional signaling units into the synaptic membrane.

Preassembly of specific Gßγ subunits at GABAB receptors through auxiliary KCTD proteins accelerates channel gating.

GABAB receptors (GBRs) are G protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GBRs regulate fast synaptic transmission by gating Ca2+ and K+ channels via the Gßγ subunits of the activated G protein. It has been demonstrated that auxiliary GBR subunits, the KCTD proteins, shorten onset and rise time and increase desensitization of receptor-induced K+ currents. KCTD proteins increase desensitization of K+ currents by scavenging Gßγ from the channel, yet the mechanism responsible for the rapid activation of K+ currents has remained elusive. In this study, we demonstrate that KCTD proteins preassemble Gßγ at GBRs. The preassembly obviates the need for diffusion-limited G protein recruitment to the receptor, thereby accelerating G protein activation and, as a result, K+ channel activation. Preassembly of Gßγ at the receptor relies on the interaction of KCTD proteins with a loop protruding from the seven-bladed propeller of Gß subunits. The binding site is shared between Gß1 and Gß2, limiting the interaction of KCTD proteins to these particular Gß isoforms. Substituting residues in the KCTD binding site of Gß1 with those from Gß3 hinders the preassembly of Gßγ with GBRs, delays onset and prolongs rise time of receptor-activated K+ currents. The KCTD-Gß interface, therefore, represents a target for pharmacological modulation of channel gating by GBRs.

Radially Displaced Perilunate Injuries: A Report of Two Cases.

We present two unusual cases of radially displaced perilunate dislocations, one of which involved acute ulnar nerve compression requiring Guyon's canal release. The first case underwent closed reduction and cast immobilization but developed scapholunate instability, necessitating secondary ligament reconstruction. The second case, treated with open reduction and fixation, resulted in persistent volar intercalated segment instability of the proximal row and ulnar nerve paresthesia 1 year after surgery.

The interaction of the ribotoxin α-sarcin with complex model lipid vesicles.

Fungal ribotoxins are extracellular RNases that inactivate ribosomes by cleaving a single phosphodiester bond at the universally conserved sarcin-ricin loop of the large rRNA. However, to reach the ribosomes, they need to cross the plasma membrane. It is there where these toxins show their cellular specificity, being especially active against tumoral or virus-infected cells. Previous studies have shown that fungal ribotoxins interact with negatively charged membranes, typically containing phosphatidylserine or phosphatidylglycerol. This ability is rooted on their long, non-structured, positively charged loops, and its N-terminal ß-hairpin. However, its effect on complex lipid mixtures, including sphingophospholipids or cholesterol, remains poorly studied. Here, wild-type α-sarcin was used to evaluate its interaction with a variety of membranes not assayed before, which resemble much more closely mammalian cell membranes. The results confirm that α-sarcin is particularly sensitive to charge density on the vesicle surface. Its ability to induce vesicle aggregation is strongly influenced by both the lipid headgroup and the degree of saturation of the fatty acid chains. Acyl chain length is indeed particularly important for lipid mixing. Finally, cholesterol plays an important role in diluting the concentration of available negative charges and modulates the ability of α-sarcin to cross the membrane.

Efficacy of myofascial induction compared with its simulation on joint amplitude in people with axial spondylarthritis: Protocol of a randomized controlled clinical trial.

BACKGROUND: Axial spondyloarthritis (AxSpA) produces structural changes that cause alterations in body functions. One tissue that seems to have a predictive role in the etiology and progression of the disease is the soft tissue, particularly the fascia. However, little is known about the use of myofascial induction in people with AxSpA, and clinical evidence from physiotherapy regarding potential strategies is limited. OBJECTIVE: To evaluate the efficacy of myofascial induction compared with its simulation on joint amplitude in people with AxSpA. METHODS: In this randomized controlled parallel superiority clinical trial, 84 people with an AxSpA diagnosis confirmed by a rheumatologist will be randomly assigned to groups: the experimental group or the control group. The experimental group will receive myofascial induction, and the control group will undergo a simulation of the technique. Both groups will receive an examination session and six intervention sessions twice per week for three weeks. A baseline follow-up will be performed immediately after the intervention and four weeks after treatment. CONCLUSION: The results of this study may contribute to a better understanding of the efficacy of myofascial induction for joint mobility in people with AxSpA. The implications of these results have a potential transformative effect on the understanding, analysis, evaluation, and physiotherapeutic treatment of this health condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT04424589. Registered 11 June 2020.

In Silico Pipeline to Identify Tumor-Specific Antigens for Cancer Immunotherapy Using Exome Sequencing Data.

Tumor-specific antigens or neoantigens are peptides that are expressed only in cancer cells and not in healthy cells. Some of these molecules can induce an immune response, and therefore, their use in immunotherapeutic strategies based on cancer vaccines has been extensively explored. Studies based on these approaches have been triggered by the current high-throughput DNA sequencing technologies. However, there is no universal nor straightforward bioinformatic protocol to discover neoantigens using DNA sequencing data. Thus, we propose a bioinformatic protocol to detect tumor-specific antigens associated with single nucleotide variants (SNVs) or "mutations" in tumoral tissues. For this purpose, we used publicly available data to build our model, including exome sequencing data from colorectal cancer and healthy cells obtained from a single case, as well as frequent human leukocyte antigen (HLA) class I alleles in a specific population. HLA data from Costa Rican Central Valley population was selected as an example. The strategy included three main steps: (1) pre-processing of sequencing data; (2) variant calling analysis to detect tumor-specific SNVs in comparison with healthy tissue; and (3) prediction and characterization of peptides (protein fragments, the tumor-specific antigens) derived from the variants, in the context of their affinity with frequent alleles of the selected population. In our model data, we found 28 non-silent SNVs, present in 17 genes in chromosome one. The protocol yielded 23 strong binders peptides derived from the SNVs for frequent HLA class I alleles for the Costa Rican population. Although the analyses were performed as an example to implement the pipeline, to our knowledge, this is the first study of an in silico cancer vaccine using DNA sequencing data in the context of the HLA alleles. It is concluded that the standardized protocol was not only able to identify neoantigens in a specific but also provides a complete pipeline for the eventual design of cancer vaccines using the best bioinformatic practices. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00084-9.

Curative embolization of ruptured pediatric cerebral arteriovenous malformations.

INTRODUCTION: Embolization with the intention to cure has not been well studied in ruptured arteriovenous malformations (AVMs). Furthermore, the role of primary curative embolization of pediatric AVMs is uncertain. Hence, we aimed to characterize the safety and efficacy of curative embolization of ruptured pediatric AVMs and assess predictors of obliteration and complications. METHODS: A retrospective analysis of all pediatric (≤18 years) patients who underwent curative embolization of ruptured AVMs was conducted in two institutions between 2010 and 2022. The efficacy (complete angiographic obliteration after the last embolization session), recurrence (radiological recurrence of the lesion after confirmed obliteration in follow-up imaging), and safety (procedure-related complications and mortality) of the procedure were evaluated. RESULTS: Sixty-eight patients (38 females; mean age 12.4 ± 3.4 years) underwent a total of 109 embolization sessions. Median follow-up time was 18 months after embolization (ranged from 2 to 47 months). Complete angiographic obliteration was achieved in 42 patients (62%). In 30 patients (44%) the AVM was occluded with a single embolization session. Recurrence of a totally embolized lesion occurred in 9 patients (13%). Thirteen complications (11.9% of procedures) were observed, and no deaths were reported. A nidus size > 2 cm was the only independent predictor of complete obliteration (OR = 0.16; 95% CI 0.03 - 0.77; p = 0.030). CONCLUSION: Embolization of pediatric ruptured AVMs with curative intent can achieve acceptable obliteration rates. However, recurrence after complete obliteration and procedure-related complications of curative embolization of these lesions cannot be ignored. Ruptured AVMs ≤ 2 cm are adequate to achieve complete obliteration with curative endovascular management.

Randomized clinical trial comparing pericapsular nerve group (PENG) block and periarticular local anesthetic infiltration for total hip arthroplasty.

BACKGROUND: This randomized trial compared pericapsular nerve group block and periarticular local anesthetic infiltration in patients undergoing primary total hip arthroplasty. We hypothesized that, compared with pericapsular nerve group block, periarticular local anesthetic infiltration would decrease the postoperative incidence of quadriceps weakness at 3 hours fivefold (ie, from 45% to 9%). METHODS: Sixty patients undergoing primary total hip arthroplasty under spinal anesthesia were randomly allocated to receive a pericapsular nerve group block (n=30) using 20 mL of adrenalized bupivacaine 0.50%, or periarticular local anesthetic infiltration (n=30) using 60 mL of adrenalized bupivacaine 0.25%. Both groups also received 30 mg of ketorolac, either intravenously (pericapsular nerve group block) or periarticularly (periarticular local anesthetic infiltration), as well as 4 mg of intravenous dexamethasone.Postoperatively, a blinded evaluator carried out sensory assessment and motor assessment (knee extension and hip adduction) at 3, 6 and 24 hours. Furthermore, the blinded observer also recorded static and dynamic pain scores at 3, 6, 12, 18, 24, 36 and 48 hours; time to first opioid request; cumulative breakthrough morphine consumption at 24 hours and 48 hours; opioid-related side effects; ability to perform physiotherapy at 6, 24 and 48 hours; as well as length of stay. RESULTS: There were no differences in quadriceps weakness at 3 hours between pericapsular nerve group block and periarticular local anesthetic infiltration (20% vs 33%; p=0.469). Furthermore, no intergroup differences were found in terms of sensory block or motor block at other time intervals; time to first opioid request; cumulative breakthrough morphine consumption; opioid-related side effects; ability to perform physiotherapy; and length of stay. Compared with pericapsular nerve group block, periarticular local anesthetic infiltration resulted in lower static pain scores (at all measurement intervals) and dynamic pain scores (at 3 and 6 hours). CONCLUSION: For primary total hip arthroplasty, pericapsular nerve group block and periarticular local anesthetic infiltration result in comparable rates of quadriceps weakness. However, periarticular local anesthetic infiltration is associated with lower static pain scores (especially during the first 24 hours) and dynamic pain scores (first 6 hours). Further investigation is required to determine the optimal technique and local anesthetic admixture for periarticular local anesthetic infiltration. TRIAL REGISTRATION NUMBER: NCT05087862.

Soluble amyloid-ß precursor peptide does not regulate GABAB receptor activity.

Amyloid-ß precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release, or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.

Physical activity, sitting time, neck disability and posture in workers using visual display terminals (VDT).

BACKGROUND: Musculoskeletal pain represents a major public health problem. Workers who use visual display terminals (VDT) have suffered an increase in neck pain in recent decades. OBJECTIVE: The aim of this study was to analyze the relationship between physical activity (PA), sitting time, posture, and neck disability in a population of employed adults who use a computer at work. METHODS: In this descriptive-correlational study, 88 workers with a mean age of 48.31 years participated. All of the participants filled out the Self-Report Habit Index (SRHI), International Physical Activity Questionnaire (IPAQ), and Neck Disability Index (NDI). The postural situation was also assessed with Posture Assessment Software (PAS/SAPO). RESULTS: A significant and inverse relationship was observed between the habit of PA practice and the Body Mass Index (BMI). A total of 59.1% of the participants have a moderate PA index. There was a statistically significant relationship between the NDI and the time that workers spend sitting in a workday. A significance level of p≤0.05 was established for all the statistical analyses. CONCLUSION: The increase in sitting time produces an increase in neck disability among workers and there are no significant differences between the level of PA and the cervical angles analyzed. The promotion of leisure-time PA and the reduction of prolonged uninterrupted sitting time at work could be one of the means to reduce musculoskeletal morbidity in the working population.

Factores relacionados con absentismo laboral en una compañía minera colombiana / Factors Related to Absenteeism in a Colombian Mining Company / Fatores relacionados ao absenteísmo em uma empresa de mineração colombiana

El absentismo laboral es una condición que afecta cada día a un gran número de empresas y que repercute en los ámbitos económico, social y cultural. Objetivo: Caracterizar el absentismo laboral por causa médica durante 2021 en trabajadores del área operativa de una compañía de extracción de minerales en Antioquia (Colombia). Materiales y métodos: Estudio con enfoque cuantitativo, de tipo descriptivo, retrospectivo para caracterizar el ab-sentismo laboral de una empresa minera, teniendo en cuenta una base de datos suministrada por dicha empresa, en la cual se presentaron los registros de absentismo de los trabajadores de la mina y sus diferentes áreas durante 2021, correspondiente a un total de 1069 incapacidades. Resultados: Los factores asociados con un aumento de la frecuencia del absentismo fueron la antigüedad del trabajador en la empresa, el cargo desempeñado y el área al cual se está adscrito, teniendo así que las causas más frecuentes de absentismo fueron las enfermedades de origen común de tipo respiratorio y traumatismos. Conclusión: El absentismo laboral se encuentra relacionado con el patrón de enfermedad o accidente laboral, y su prevalencia, en cuanto a áreas y sexo, se encuentra relacionada con las características propias de la compañía.

Work absenteeism is a condition that affects a large number of companies every day, generating an economic, social and cultural impact. Objective: To characterize absenteeism due to medical reasons during the year 2021 in workers of the operative area of a mineral extraction company in Antioquia, Colombia. Material and Methods: A quantitative, descriptive, retrospective study was conducted to characterize absenteeism in the operational area of a mining extraction company in Colombia, taking into account a database provided by the company, which presents the records of absenteeism of workers in the mine and its different areas during the period of 2021, corresponding to a total of 1,069 incapacities. Results: The factors associated with an increase in the frequency of absenteeism were the worker's seniority in the company, the position held and the area to which he/she is assigned, thus having that the most frequent causes of absenteeism were common respiratory diseases and traumatisms. Conclusion: It can be concluded that absenteeism is related to the pattern of occupational illness or accident, and that the prevalence of absenteeism in terms of areas and sex is related to the company's own characteristics.

O absenteísmo é uma condição que afeta muitas empresas todos os dias e tem repercussões nas esferas econômica, social e cultural. Objetivo: Caracterizar o absenteísmo por motivos médicos durante 2021 em trabalhadores da área operacional de uma empresa de extração mineral em Antioquia (Colômbia). Materiais e métodos: Estudo quantitativo, descritivo e retrospectivo para caracterizar o absenteísmo em uma empresa de mineração, levando em conta um banco de dados fornecido pela empresa, no qual foram apresentados os registros de absenteísmo dos trabalhadores da mina e de suas diferentes áreas durante 2021, correspondendo a um total de 1069 incapacidades. Resultados: Os fatores associados a um aumento na frequência de absenteísmo foram a antiguidade do trabalhador na empresa, o cargo ocupado e a área para a qual ele foi designado, sendo que as causas mais frequentes de absenteísmo foram doenças respiratórias de origem comum e traumatismos. Conclusão: O absenteísmo está relacionado ao padrão de doença ou acidente de trabalho, e sua pre-valência, em termos de áreas e sexo, está relacionada às características próprias da empresa

Acondroplasia: actualización en diagnóstico, seguimiento y tratamiento / Achondroplasia: Update on diagnosis, follow-up and treatment

La acondroplasia requiere un seguimiento multidisciplinario, con el objetivo de prevenir y manejar las complicaciones, mejorar la calidad de vida y favorecer su independencia e inclusión social. Esta revisión se justifica por las múltiples publicaciones generadas en los últimos años que han llevado a cabo un cambio en su gestión. Se han desarrollado diferentes guías y recomendaciones, entre las que destacan la realizada por la Academia Americana de Pediatría en 2005 recientemente actualizada (2020), la guía japonesa (2020), el primer Consenso Europeo (2021) y el Consenso Internacional sobre el diagnóstico, abordaje, enfoque multidisciplinario y manejo de individuos con acondroplasia a lo largo de la vida (2021). Sin embargo, y a pesar de estas recomendaciones, actualmente existe una gran variabilidad a nivel mundial en el manejo de las personas con acondroplasia, con consecuencias médicas, funcionales y psicosociales en los pacientes y sus familias. Por ello, es fundamental integrar estas recomendaciones en la práctica clínica diaria, teniendo en cuenta la situación particular de cada sistema sanitario. (AU)

Achondroplasia requieres a multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021). However, and despite these recommendations, there is currently a great worldwide variability in the management of people with achondroplasia, with medical, functional and psychosocial consequences in patients and their families. Therefore, it is essential to integrate these recommendations into daily clinical practice, taking into account the particular situation of each health system. (AU)

Industrial Particulate Pollution and Historical Land Use Contribute Metals of Concern to Dust Deposited in Neighborhoods Along the Wasatch Front, UT, USA.

The Salt Lake Valley, UT, USA, is proximal to the desiccating Great Salt Lake (GSL). Prior work has found that this lakebed/playa contributes metals-laden dust to snow in the Wasatch and Uinta Mountains. Dust and industrial particulate pollution are also delivered to communities along the Wasatch Front, but their sources, compositions, and fluxes are poorly characterized. In this study, we analyzed the dust deposited in 18 passive samplers positioned near the GSL, in cities in and near the Salt Lake Valley for total dust flux, the <63 µm dust fraction, 87Sr/86Sr, and trace element geochemistry. We compared spatial patterns in metal flux and abundance with community-level socioeconomic metrics. We observed the highest dust fluxes at sites near the GSL playa. Within the urban corridor, 87Sr/86Sr and trace element relative abundances suggest that most of the dust to which people are regularly exposed may be fugitive dust from local soil materials. The trace metal content of dust deposited along the Wasatch Front exceeded Environmental Protection Agency screening levels and exhibited enrichment relative to both the upper continental crust and the dust collected adjacent to GSL. Sources of metals to dust deposited along the Wasatch Front may include industrial activities like mining, oil refining, as well as past historical pesticide and herbicide applications. Arsenic and vanadium indicated a statistically significant positive correlation with income, whereas lead, thallium, and nickel exhibited higher concentrations in the least wealthy and least white neighborhoods.

Achondroplasia: Update on diagnosis, follow-up and treatment.

Achondroplasia requieres multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life of people who suffer from it and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021). However, and despite these recommendations, there is currently a great worldwide variability in the management of people with achondroplasia, with medical, functional and psychosocial consequences in patients and their families. Therefore, it is essential to integrate these recommendations into daily clinical practice, taking into account the particular situation of each health system.

Consensus guide on prophylactic gonadectomy in different sex development.

The risk of suffering from gonadal germ cell tumors (GCT) is increased in some patients with different sexual development (DSD), mainly in those with Y chromosome material. This risk, however, varies considerably depending on a multitude of factors that make the decision for prophylactic gonadectomy extremely difficult. In order to make informed recommendations on the convenience of this procedure in cases where there is potential for malignancy, this consensus guide evaluates the latest clinical evidence, which is generally low, and updates the existing knowledge in this field.

Thyroid Function in 509 Premature Newborns Below 31 Weeks of Gestational Age: Evaluation and Follow-up

Objective: Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation. Methods: Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT4 <0.8 ng/dL and/or TSH >5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated. Results: Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight. Conclusion: This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates.