Is histological confirmation necessary to avoid futile resections? Comparative of 4 university hospitals.

OBJECTIVES: There is no consensus in the literature on preoperative histological analysis for lung cancer. The objective of this study was to assess 4 diagnostic models used in different hospitals with differing practices regarding preoperative histological diagnosis and the consequences in terms of unnecessary surgery and futile major resection. METHODS: We carried out a retrospective observational study collected from 4 university hospitals in Spain over 3 years (January 2019 to December 2021). We included all patients with a confirmed diagnosis of primary lung cancer and any patients with suspected primary lung cancer who had undergone surgery. All patients underwent computed tomography and positron emission tomography/computed tomography scans. Each multidisciplinary committee was free to choose whether to perform flexible bronchoscopic or transthoracic lung biopsy. Decisions concerning whether to perform intraoperative sample analysis, the surgical approach and the type of resection were left to the surgical team. RESULTS: We included a total of 1642 patients. The use of flexible endoscopy and its diagnostic performance varied substantially between hospitals (range: 23.8-79.3% and 25-60.7%, respectively); and the same was observed for transthoracic biopsy and its performance (range: 16.9-82.3% and 64.6-97%, respectively). Regarding major resection surgery (lobectomy or more extensive resection), the lowest rate was observed in hospital C (1%) and the highest in hospital B (2.8%), with between-hospital differences not reaching significance (P = 0.173). CONCLUSIONS: The rate of histological sampling before lung cancer surgery still varies between hospitals. In spite of very diverse multidisciplinary management, the rate of futile lobectomy is not significantly higher in hospitals with lower rates of preoperative histological analysis.

Manejo diagnóstico y terapéutico actual de la fractura de los primeros pasos / Current diagnosis and management of toddler's fracture

INTRODUCCIÓN: La fractura de los primeros pasos o fractura de toddler es una fractura espiroidea de tibia propia de la primera infancia. El objetivo es analizar su incidencia y el manejo diagnóstico y terapéutico actual. PACIENTES Y MÉTODOS: Estudio descriptivo retrospectivo de los pacientes de 0 a 3 años diagnosticados en un hospital terciario entre los años 2013 y 2017. RESULTADOS: Registrados 53 pacientes (10,6 casos/año), con una mediana de edad de 2 años y ligero predominio masculino. La radiografía inicial resultó normal en el 24,5%. Con la aproximación inicial, el 69,8% de los pacientes se diagnosticaron de fractura, el 11,3% de sospecha de fractura y el 18,9% de contusión. El 22% precisaron prueba de control; 10 radiografía (patológica 90%) y 5 ecografía (patológica 80%, 3 de ellos con radiografía inicial normal). El 80,8% de los pacientes se inmovilizaron con férula frente al 19,2% en los que se realizó inmovilización flexible o no inmovilización. Se encontraron complicaciones en el 21,4% de los pacientes inmovilizados con férula, fundamentalmente úlceras por presión (19%), que fueron más frecuentes en este grupo que en los no inmovilizados (21,4 vs. 0%; p = 0,006), sin diferencias significativas en cuanto a tiempo hasta carga. CONCLUSIONES: La radiografía simple tiene una sensibilidad limitada para el diagnóstico de la fractura de los primeros pasos. En el grupo de pacientes con radiografía normal el uso de ecografía puede contribuir al diagnóstico y a evitar radiación adicional. Aunque el tratamiento más común de esta fractura sigue siendo la inmovilización con férula, la alternativa sin inmovilización rígida no parece obtener peores resultados, incluso parece presentar menor morbilidad asociada al tratamiento

INTRODUCTION: Toddler's fracture is an accidental spiral tibial fracture, characteristic of the early childhood. The objective of this study is to determine the incidence and current diagnosis and management of this disorder. PATIENTS AND METHODS: A retrospective study was conducted on a sample of patients aged 0-3 years diagnosed with a toddler's fracture in a tertiary hospital between years 2013 and 2017. RESULTS: A total of 53 patients were registered (10.6 cases per year). The median age was 2 years, with a slight male predominance. The initial radiograph was normal in 24.5% of patients. With the initial approach, 69.8% of patients were diagnosed with fracture, 11.3% with suspected fracture, and 18.9% with contusion. A follow-up was required in 22% required a control test, using radiographs in 10 patients (pathological 90%), and ultrasound in 5 (pathological 80%, 3 of them with normal initial radiography). The large majority (80.8%) of the patients were immobilised with a cast, while flexible immobilisation or non-immobilisation was used in 19.2%. Complications were found in a 21.4% of patients immobilised with splint, mainly skin injuries (19%). These were more frequent in this group than in those that were not immobilised (21.4% vs. 0%, P = .006); with no significant differences in time to weight-bearing. CONCLUSIONS: Radiography has a limited sensitivity for the diagnosis of toddler's fracture. In the group of patients with normal radiography, the use of ultrasound can be helpful to the diagnosis and avoid additional radiation. Even though the most common treatment continues to be immobilisation with a splint, the alternative without rigid immobilisation does not seem to give worse results, even with lower morbidity associated with the treatment

[Current diagnosis and management of toddler's fracture]. / Manejo diagnóstico y terapéutico actual de la fractura de los primeros pasos.

INTRODUCTION: Toddler's fracture is an accidental spiral tibial fracture, characteristic of the early childhood. The objective of this study is to determine the incidence and current diagnosis and management of this disorder. PATIENTS AND METHODS: A retrospective study was conducted on a sample of patients aged 0-3 years diagnosed with a toddler's fracture in a tertiary hospital between years 2013 and 2017. RESULTS: A total of 53 patients were registered (10.6 cases per year). The median age was 2 years, with a slight male predominance. The initial radiograph was normal in 24.5% of patients. With the initial approach, 69.8% of patients were diagnosed with fracture, 11.3% with suspected fracture, and 18.9% with contusion. A follow-up was required in 22% required a control test, using radiographs in 10 patients (pathological 90%), and ultrasound in 5 (pathological 80%, 3 of them with normal initial radiography). The large majority (80.8%) of the patients were immobilised with a cast, while flexible immobilisation or non-immobilisation was used in 19.2%. Complications were found in a 21.4% of patients immobilised with splint, mainly skin injuries (19%). These were more frequent in this group than in those that were not immobilised (21.4% vs. 0%, P=.006); with no significant differences in time to weight-bearing. CONCLUSIONS: Radiography has a limited sensitivity for the diagnosis of toddler's fracture. In the group of patients with normal radiography, the use of ultrasound can be helpful to the diagnosis and avoid additional radiation. Even though the most common treatment continues to be immobilisation with a splint, the alternative without rigid immobilisation does not seem to give worse results, even with lower morbidity associated with the treatment.

Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor.

Drug-target binding kinetics are suggested to be important parameters for the prediction of in vivo drug-efficacy. For G protein-coupled receptors (GPCRs), the binding kinetics of ligands are typically determined using association binding experiments in competition with radiolabelled probes, followed by analysis with the widely used competitive binding kinetics theory developed by Motulsky and Mahan. Despite this, the influence of the radioligand binding kinetics on the kinetic parameters derived for the ligands tested is often overlooked. To address this, binding rate constants for a series of histamine H1 receptor (H1R) antagonists were determined using radioligands with either slow (low koff) or fast (high koff) dissociation characteristics. A correlation was observed between the probe-specific datasets for the kinetic binding affinities, association rate constants and dissociation rate constants. However, the magnitude and accuracy of the binding rate constant-values was highly dependent on the used radioligand probe. Further analysis using recently developed fluorescent binding methods corroborates the finding that the Motulsky-Mahan methodology is limited by the employed assay conditions. The presented data suggest that kinetic parameters of GPCR ligands depend largely on the characteristics of the probe used and results should therefore be viewed within the experimental context and limitations of the applied methodology.

A live cell NanoBRET binding assay allows the study of ligand-binding kinetics to the adenosine A3 receptor.

There is a growing interest in understanding the binding kinetics of compounds that bind to G protein-coupled receptors prior to progressing a lead compound into clinical trials. The widely expressed adenosine A3 receptor (A3AR) has been implicated in a range of diseases including immune conditions, and compounds that aim to selectively target this receptor are currently under development for arthritis. Kinetic studies at the A3AR have been performed using a radiolabelled antagonist, but due to the kinetics of this probe, they have been carried out at 10 °C in membrane preparations. In this study, we have developed a live cell NanoBRET ligand binding assay using fluorescent A3AR antagonists to measure kinetic parameters of labelled and unlabelled compounds at the A3AR at physiological temperatures. The kinetic profiles of four fluorescent antagonists were determined in kinetic association assays, and it was found that XAC-ser-tyr-X-BY630 had the longest residence time (RT = 288 ± 62 min) at the A3AR. The association and dissociation rate constants of three antagonists PSB-11, compound 5, and LUF7565 were also determined using two fluorescent ligands (XAC-ser-tyr-X-BY630 or AV039, RT = 6.8 ± 0.8 min) as the labelled probe and compared to those obtained using a radiolabelled antagonist ([3H]PSB-11, RT = 44.6 ± 3.9 min). There was close agreement in the kinetic parameters measured with AV039 and [3H]PSB-11 but significant differences to those obtained using XAC-S-ser-S-tyr-X-BY630. These data indicate that selecting a probe with the appropriate kinetics is important to accurately determine the kinetics of unlabelled ligands with markedly different kinetic profiles.

Development of novel fluorescent histamine H1-receptor antagonists to study ligand-binding kinetics in living cells.

The histamine H1-receptor (H1R) is an important mediator of allergy and inflammation. H1R antagonists have particular clinical utility in allergic rhinitis and urticaria. Here we have developed six novel fluorescent probes for this receptor that are very effective for high resolution confocal imaging, alongside bioluminescence resonance energy transfer approaches to monitor H1R ligand binding kinetics in living cells. The latter technology exploits the opportunities provided by the recently described bright bioluminescent protein NanoLuc when it is fused to the N-terminus of a receptor. Two different pharmacophores (mepyramine or the fragment VUF13816) were used to generate fluorescent H1R antagonists conjugated via peptide linkers to the fluorophore BODIPY630/650. Kinetic properties of the probes showed wide variation, with the VUF13816 analogues having much longer H1R residence times relative to their mepyramine-based counterparts. The kinetics of these fluorescent ligands could also be monitored in membrane preparations providing new opportunities for future drug discovery applications.

Determinacion estructural de flavonoides en el extracto etanolico de cladodios de Opuntia ficus-indica (L.) Mill. "Tuna Verde" / Structural identification of flavonoids in ethanolic extract of Opuntia ficus-indica (L.) Mill. "Tuna Verde" cladodes

Objetivos: Determinar estructuralmente los flavonoides encontrados en el extracto etanólico de cladodios de Opuntia ficus-indica (L.) Mill. "Tuna Verde". Materiales y métodos: Se preparó el extracto etanólico de cladodios de Opuntia ficus-indica (L.) Mill. Luego se detectaron sus componentes mediante un tamizaje fitoquímico. A través de cromatografía en capa fina se aislaron los compuestos fenólicos tipo flavonoides. Finalmente, usando espectroscopia UV/Vis se propuso la posible estructura de los flavonoides encontrados. Resultados: El tamizaje fitoquímico mostró presencia de compuestos fenólicos, flavonoides y glicósidos. Se propuso cinco estructuras químicas de compuestos fenólicos, todas con un núcleo en común: flavona, mediante las lecturas en el espectrofotómetro UV/Vis y por comparación con lo publicado por TJ Mabry. Conclusión: Se determinó la posible estructura química de cinco flavonoides presentes en el extracto etanólico de cladodios de Opuntia ficus-indica (L.) Mill. "Tuna Verde".

Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ß-arrestins.

The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of ß-arrestins. More specifically, the Ser(362), Ser(363) and Thr(366) residues at the carboxyl-terminal tail were primarily responsible for ß-arrestin 1 and 2 binding, internalization and ß-arrestin-mediated proliferation and adipogenesis. The Thr(350) and Ser(349) are not necessary for ß-arrestin recruitment, but are involved in the stabilization of the GHSR1a-ß-arrestin complex in a manner that determines the ultimate cellular consequences of ß-arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the ß-arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output.

ß-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells.

Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins ß-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, ß-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for ß-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.

The results of selective use of radioactive iodine on survival and on recurrence in the management of papillary thyroid cancer, based on Memorial Sloan-Kettering Cancer Center risk group stratification.

BACKGROUND: The American Thyroid Association guidelines recommend the routine use of radioactive iodine for remnant ablation (RRA) in all T3 or greater primary tumors, and selective use in patients with intrathyroidal disease >1 cm, or evidence of nodal metastases. The guidelines recognize that there is conflicting and inadequate data to make firm recommendations for most patients. The aim of this study was to analyze our institutional experience of the use of RRA in the management of papillary thyroid cancer, with a particular focus on outcomes for those patients selected not to receive RRA. METHODS: We retrospectively reviewed 1129 consecutive patients who underwent total thyroidectomy at the Memorial Sloan-Kettering Cancer Center between 1986 and 2005. Of these, 490 were pT1-2 N0, 193 pT1-2 N1, and 444 pT3-4. Details on recurrence and disease-specific survival were recorded by the Kaplan-Meier method and compared using the log-rank test. RESULTS: The five-year disease-specific survival and recurrence-free survival in the pT1/T2 N0, pT1-2 N1, and pT3-4 were 100% and 92%, 100% and 92%, and 98% and 87% respectively. Low-risk patients who were managed without RRA (who tended to have limited primary disease, pT1-2, and low-volume metastatic disease in the neck, pT1-2 N1-fewer than five nodes, all <1 cm greatest dimension) had five-year recurrence-free survival of >97%. In the group with advanced local tumors (pT3-4), those patients who did not receive RRA (who tended to have pT3 N0 disease) had five-year recurrence-free survival of >90%. CONCLUSION: Following appropriate surgical management, the majority of patients with low-risk local disease and even some patients with more advanced-stage (pT3) tumors or regional metastases have low rates of recurrence and high rates of survival when managed without RRA.

ß-Arrestin signal complex plays a critical role in adipose differentiation.

ß-Arrestins were identified as scaffold-proteins that have the capacity to desensitize G protein-coupled receptors. However, it has been found that ß-arrestins activate signaling pathways independent of G protein activation. The diversity of these signaling pathways has also been recognized for receptor tyrosine kinase. The aim of the present study was to validate the ß-arrestin-dependent signaling mechanism(s) responsible for regulation of adipogenesis. Two signal models were selected, ghrelin and insulin, based on its ß-arrestin-associated Akt activity. Herein, we found that ß-arrestin 1 and 2 were essential molecules for adipocyte differentiation. More specifically, the role of these scaffolding proteins was demonstrated by depletion of ß-arrestin 1 and 2 during ghrelin-induced adipogenesis in 3T3-L1 cells, which decreased the adipocyte differentiation and the expression levels of master regulators of early, the CCAAT/enhancer-binding protein ß (C/EBPß) and the CCAAT/enhancer-binding protein δ (C/EBPδ), and terminal, the peroxisome proliferator-activated receptor (PPARγ) and the CCAAT/enhancer-binding protein α (C/EBPα), adipogenesis. Accordingly ghrelin-induced Akt activity and its downstream targets, the mammalian target of rapamycin complex 1 (mTORC1) and the ribosomal protein S6 kinase beta-1 (S6K1), were inhibited by ß-arrestin 1 and 2 siRNAs. By contrast, assays performed during insulin-activated adipogenesis showed an intensifying effect on the adipocyte differentiation as well as on the expression of C/EBPß, C/EBPδ, PPARγ and C/EBPα. The increase in insulin-induced adipogenesis by ß-arrestin knock-down was concomitant to a decrease in the insulin receptor susbtrate-1 (IRS-1) serine phosphorylation, proving the loss of the negative feedback loop on IRS-1/phosphoinositide 3-kinase (PI3K)/Akt. Therefore, ß-arrestins control the extent and intensity of the lipogenic and adipogenic factors associated to Akt signaling, although the mechanistic and functional principles that underlie the connection between signaling and ß-arrestins are specifically associated to each receptor type.

Time Domain Optical Coherence Tomography in Familial Vitreous Amyloidosis Associated Transthyretin Met30 Mutation.

Vitreous amyloidosis is characterized by progressive loss of vision from amyloid accumulation of deposits on the retina and in the vitreous. Time domain optical coherence tomography (TD-OCT) was used in a case of familial transthyretin vitreous amyloidosis Met30 mutation to image the anterior vitreous deposits, which showed high reflectivity of very different from vitreous found in unaffected individuals. TD-OCT may be a useful adjunctive test to diagnose vitreous amyloidosis when masquerade syndromes are suspected. There may be more easeful imaging in TD-OCT of vitreous abnormalities than with spectral domain OCT (SD-OCT). Further study should be performed comparing TD versus SD-OCT in families with vitreous amyloidosis and TD vitreous amyloidosis versus TD in other intermediate uveitis.

[Endobronchial lipoma. Therapeutic considerations]. / Lipoma endobronquial. Consideraciones terapéuticas.

Endobronchial lipoma is a very rare benign tumor. The most frequent clinical presentation is caused by airway obstruction. A computed tomography finding of a homogeneous mass with fat density not enhanced by intravenous contrast material is considered diagnostic of this kind of tumor. The definitive diagnosis is given by bronchoscopy and biopsy. The treatment of choice is endoscopic resection, although open resection is sometimes required. We present a case of endobronchial lipoma that involved the left main bronchus and extended through the bronchial carina. Endoscopic treatment was initially attempted. However, open resection through superior lobectomy with carinal resection and a bronchoplastic procedure were required to avoid left pneumonectomy.

Lipoma endobronquial. Consideraciones terapéuticas / Endobronchial lipoma. Therapeutic considerations

El lipoma endobronquial es un tumor benigno extremadamente raro. La presentación clínica más habitual se debe a la obstrucción de la vía aérea. El hallazgo en la tomografía computarizada (TC) de una masa homogénea de densidad grasa y que no capta contraste se considera diagnóstico de este tipo de tumores. El diagnóstico definitivo es aportado por la broncoscopia y la biopsia. El tratamiento de elección es la resección por vía endoscópica, aunque hay casos en los que es necesaria una resección por vía abierta. Presentamos un caso de lipoma endobronquial que afectaba al bronquio principal izquierdo y que continuaba por la carina de división bronquial. En un primer momento se intentó un tratamiento endoscópico, pero finalmente fue necesario realizar una resección por vía abierta mediante lobectomía superior izquierda, reglada con resección carinal más broncoplastia, lo cual evitó la neumonectomía izquierda (AU)

Endobronchial lipoma is a very rare benign tumor. The most frequent clinical presentation is caused by airway obstruction. A computed tomography finding of a homogeneous mass with fat density not enhanced by intravenous contrast material is considered diagnostic of this kind of tumor. The definitive diagnosis is given by bronchoscopy and biopsy. The treatment of choice is endoscopic resection, although open resection is sometimes required. We present a case of endobronchial lipoma that involved the left main bronchus and extended through the bronchial carina. Endoscopic treatment was initially attempted. However, open resection through superior lobectomy with carinal resection and a bronchoplastic procedure were required to avoid left pneumonectomy (AU)

Hypopituitarism and growth hormone deficiency in adult subjects after traumatic brain injury: who and when to test.

Traumatic brain injury (TBI) was traditionally considered an infrequent cause of hypopituitarism. However recent reports strongly suggest that TBI-mediated pituitary hormones deficiency may well be more frequent than previously thought. As the prevalence of hypopituitarism is not dependent on the severity of the trauma and considering the high number of TBI events in all industrialized countries a screening procedure for detecting hormone deficiencies in all TBI patients is not possible. In the present work a suggestion for screening a subgroup of TBI patients is discussed in order to increase the effectiveness of the whole procedure.

Diastereoselective formation of chiral iridium hydrides containing the chiral P,N-chelate ligand (4S)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-1,3-oxazoline.

The iridium complex [Ir(mu-Cl)(PN)(PPh3)]2 (1) reacts with H2 affording only the kinetic isomer OC-6-55-C of the dihydride [IrClH2(PN)(PPh3)] (2) and with methanol yielding, also exclusively, the thermodynamic isomer OC-6-53-C (2b) of the same dihydride; complex 2b has been characterised by X-ray diffractometric methods.

O problema da tuberculose multirresistente

As autoras discutem aspectos da assistência aos portadores de tuberculose multirresistente(TBMR),fazendo uma revisão bibliográfica do assunto e ressaltando a importância da equipe multidisciplinar.A TBMR não é um problema novo em nosso País e exige compromisso dos profissionais de saúde no seu controle e tratamnento.Em função disto,verifica-se a importância de destacar os diversos papéis da equipe multidisciplinar no acompanhamneto da administração da medicação,nas orientações,na busca de faltosos e avaliação de comunicantes.Ai podemos obeservar que os papeís muitas vezes se confundem,mas todos procuram trabalhar e preocupados com a solução do problema.O trabalho apresenta as ações de alguns dos profissionais envolvidos,como: médico,enfermeiro e assistente social, na assistência aos casos de TBMR