Gonyautoxins 2/3 Local Periarticular Injection for Pain Management after Total Knee Arthroplasty: A Double-Blind, Randomized Study.

The purpose of this study was to compare the efficacy of periarticular infiltration of gonyautoxin 2/3 (GTX 2/3) and a mixture of levobupivacaine, ketorolac, and epinephrine for pain management after total knee arthroplasty (TKA). Forty-eight patients were randomly allocated to receive periarticular infiltration of 40 µg GTX 2/3 (n = 24) diluted in 30 mL of sodium chloride 0.9% (study group) or a combination of 300 mg of levobupivacaine, 1 mg of epinephrine, and 60 mg ketorolac (n = 24) diluted in 150 mL of sodium chloride 0.9% (control group). Intraoperative anesthetic and surgical techniques were identical for both groups. Postoperatively, all patients received patient-controlled analgesia (morphine bolus of 1 mg; lockout interval of 8 minutes), acetaminophen, and ketoprofen for 72 hours. A blinded investigator recorded morphine consumption, which was the primary outcome. Also, the range of motion (ROM) and static and dynamic pain were assessed at 6, 12, 36, and 60 hours after surgery. The incidence of adverse events, time to readiness for discharge, and length of hospital stay were also recorded. The median of total cumulative morphine consumption was 16 mg (range, 0-62 mg) in the GTX 2/3 group and 9 mg (range, 0-54 mg) in control group, which did not reach statistical difference (median test, p = 0.40). Furthermore, static and dynamic pain scores were similar at all time intervals. GTX 2/3 was inferior in range of motion at 6 and 12 hours; nevertheless, we noted no difference after 36 hours. No differences between groups were found in terms of complications, side effects, or length of hospital stay. No significant differences were found between groups in terms of breakthrough morphine requirement. However, local anesthetic use resulted in an increased ROM in the first 12 hours. This prospective randomized clinical trial shows that GTX 2/3 is a safe and efficient drug for pain control after TKA; nevertheless, more studies using GTX 2/3 with larger populations are needed to confirm the safety profile and efficiency. This is level 1 therapeutic study, randomized, double-blind clinical trial.

Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

C-type lectin receptors MR and DC-SIGN are involved in recognition of hemocyanins, shaping their immunostimulatory effects on human dendritic cells.

Hemocyanins are used as immunomodulators in clinical applications because they induce a strong Th1-biased cell-mediated immunity, which has beneficial effects. They are multiligand glycosylated molecules with abundant and complex mannose-rich structures. It remains unclear whether these structures influence hemocyanin-induced immunostimulatory processes in human APCs. We have previously shown that hemocyanin glycans from Concholepas concholepas (CCH), Fissurella latimarginata (FLH), and Megathura crenulata (KLH), participate in their immune recognition and immunogenicity in mice, interacting with murine C-type lectin receptors (CLRs). Here, we studied the interactions of these hemocyanins with two major mannose-binding CLRs on monocyte-derived human DCs: MR (mannose receptor) and DC-SIGN (DC-specific ICAM-3-grabbing nonintegrin). Diverse analyses showed that hemocyanins are internalized by a mannose-sensitive mechanism. This process was calcium dependent. Moreover, hemocyanins colocalized with MR and DC-SIGN, and were partly internalized through clathrin-mediated endocytosis. The hemocyanin-mediated proinflammatory cytokine response was impaired when using deglycosylated FLH and KLH compared to CCH. We further showed that hemocyanins bind to human MR and DC-SIGN in a carbohydrate-dependent manner with affinity constants in the physiological concentration range. Overall, we showed that these three clinically valuable hemocyanins interact with human mannose-sensitive CLRs, initiating an immune response and promoting a Th1 cell-driving potential.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections.

Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in ARID1B, providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day.

Análisis de la comunicación intra-familiar de los resultados genéticos diagnósticos en cáncer hereditario / Analysis of intra-familial communication of diagnostic genetic results in hereditary cancer

A lo largo de la consulta de Asesoramiento Genético se hace un gran énfasis en la necesidad de comunicar la información del riesgo familiar y del estudio genético a los familiares. Además, los informes clínicos especifican los familiares en situación de riesgo. Sin embargo, desconocemos el patrón de comunicación intra-familiar de los resultados genéticos diagnósticos tras el asesoramiento. Objetivo: Realizar un estudio descriptivo sobre el patrón de comunicación de resultado del estudio genético diagnóstico en predisposición hereditaria al cáncer en la Unidad de Asesoramiento Genético del ICO. Método: Se ha realizado un estudio descriptivo mediante entrevista telefónica a una muestra de casos índice atendidos en la Unidad de Asesoramiento Genético que recibieron el resultado de un diagnóstico genético, explorando a qué familiares han comunicado estos resultados (patrón de comunicación familiar). Del mismo modo, se han recogido variables demográficas, personales y del propio resultado genético, para explorar si alguna de ellas pudiera modificar el patrón de comunicación. Resultados: La mayoría de los pacientes comunican los resultados de los estudios genéticos a sus familiares. Sin embargo, esta comunicación no es completa, por lo que es posible diseñar estrategias de intervención que mejoren el patrón de comunicación de los pacientes que reciben estudios genéticos diagnósticos en el contexto de la predisposición hereditaria al cáncer

Throughout the Genetic Counselling process a great emphasis is done on the need to communicate the familial risk information and the genetic study to the relatives. In addition, the clinical reports specify the relatives at risk situation. However, the familial communication pattern of genetic results after the counselling remains unknown. Objective: To conduct a descriptive study about the communication pattern of results of the diagnostic genetic test in hereditary predisposition to cancer at the ICO Genetic Counselling Unit. Methods: A descriptive study has been performed by telephone interview on a sample of index individuals attended at the Genetic Counselling Unit. Patients were asked whether if they had communicated their genetic study results and to whom. Similarly, demographic, personal and genetic result itself variables have been collected to explore whether any of them could modify the communication pattern. Results: Most patients report the results of the genetic studies to their relatives. However, this communication is not complete, so it is possible to design intervention strategies which may improve the communication pattern of the patients who receive diagnostic genetic tests in the context of the hereditary predisposition to cancer

Recomendaciones para el uso clínico del microarray genómico en diagnóstico prenatal / Recommendations for the clinical use of genomic microarray in prenatal diagnosis

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Enfermedad aórtica familiar no sindrómica: una entidad infradiagnosticada / Nonsyndromic Familial Aortic Disease: an Underdiagnosed Entity

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Diagnóstico prenatal en el segundo trimestre de displasia torácica asfixiante / Prenatal diagnosis in the second trimester of asphyxiating thoracic dysplasia

Describimos un caso de diagnóstico prenatal de síndrome de Jeune. Debido a su baja incidencia, es excepcional realizar el diagnóstico de este síndrome a las 21 semanas de gestación en una paciente de riesgo bajo. La displasia torácica asfixiante o síndrome de Jeune es una displasia esquelética hereditaria de carácter autonómico recesivo. El diagnóstico prenatal se puede realizar por ecografía; este síndrome se caracteriza por tórax pequeño, costillas cortas, anormalidades pélvicas, braquimelia rizomélica, y anomalías renales y hepáticas, entre otras. En nuestro caso, el diagnóstico prenatal fue confirmado con la necropsia

A case of prenatal diagnosis of Jeune’s syndrome is described. Because the incidence of this syndrome is low, diagnosis in the 21st week of pregnancy is exceptional. Jeune’s syndrome, or asphyxiating thoracic dysplasia, is a skeletal dysplasia with autosomal recessive inheritance. Prenatal diagnosis can be established by ultrasonographic findings of a small thorax, short ribs, pelvic abnormalities, rhizomelic brachymelia, and renal and liver anomalies, among others. In the present case, the prenatal diagnosis was confirmed at necropsy (AU)