GRK et arrestines : la piste thérapeutique ?

La phosphorylation d’un récepteur couplé aux protéines G (RCPG) par une kinase spécifique, nommée GRK (G protein-coupled receptor kinase), est une première étape qui participe, avec l’action des arrestines, à l’arrêt de la transmission du signal, au cours d’un processus appelé désensibilisation. Le dérèglement de ce mécanisme de protection cellulaire, mis en évidence dans différentes situations pathologiques, relève soit de mutations génétiques d’une GRK ou d’une arrestine, soit d’une variation de leur expression. Ce dérèglement a pour conséquence de modifier l’activité des RCPG qui interviennent dans de nombreuses fonctions vitales de l’organisme. Ainsi, dans la maladie d’Oguchi, la stimulation excessive de la rhodopsine par la lumière, due à la perte de fonction de la GRK1 ou de l’arrestine 1, conduit à des problèmes d’adaptation de la vision à l’obscurité. La mise au point d’un modèle de souris hypertendues, après transfection ciblée du gène de la GRK2 au niveau des vaisseaux, suggère fortement que l’augmentation de cette GRK participe, chez l’homme, au développement de l’hypertension associée à une baisse de l’effet vasodilatateur des récepteurs β-adrénergiques. L’idée de rétablir une activité RCPG normale en agissant sur ces mécanismes de désensibilisation a été couronnée de succès dans des modèles animaux de défaillance cardiaque chronique, et laisse supposer que la modulation de l’activité des GRK ou de la fonction des arrestines pourrait constituer une piste thérapeutique. Cependant, la réalisation d’essais chez l’homme devra encore attendre la découverte de molécules pharmacologiques efficaces et non toxiques.Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of β-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests

Consensus hyperaldostéronisme primaire SFE/SFHTA/AFCE, groupe 6: Chirurgie surrénale

International audienceTreatment of primary aldosteronism (PA) aims at preventing or correcting hypertension, hypokalemia and target organ damage. Patients with lateralized PA and candidates for surgery may be managed by laparoscopic adrenalectomy. Partial adrenalectomy and non-surgical ablation have no proven advantage over total adrenalectomy. Intraoperative morbidity and mortality are low in reference centers, and day-surgery is warranted in selected cases. Spironolactone administered during the weeks preceding surgery controls hypertension and hypokalemia and may prevent postoperative hypoaldosteronism. In most cases, surgery corrects hypokalemia, improves control of hypertension and reduces the burden of pharmacologic treatment; in about 40% of cases, it resolves hypertension. However, success in controlling hypertension and reversing target organ damage is comparable with mineralocorticoid receptor antagonists. Informed patient preference with regard to surgery is thus an important factor in therapeutic decision-making.Le traitement de l’hyperaldostéronisme primaire vise à prévenir ou corriger l’hypertension, l’hypokaliémie et le retentissement direct sur les organes cibles. Les patients avec une hypersécrétion latéralisée d’aldostérone et candidats à la chirurgie peuvent bénéficier d’une surrénalectomie laparoscopique. La surrénalectomie partielle et les ablations non chirurgicales n’ont pas d’avantage avéré par rapport à la surrénalectomie totale. La morbimortalité peropératoire est faible dans les centres de référence, autorisant la chirurgie ambulatoire dans des cas sélectionnés. L’administration de spironolactone dans les semaines précédant la chirurgie permet de contrôler l’HTA et l’hypokaliémie, et peut-être de prévenir l’hypoaldostéronisme postopératoire. Dans la plupart des cas, la chirurgie corrige l’hypokaliémie, améliore le contrôle de la pression artérielle et diminue la charge des traitements pharmacologiques ; dans environ 40 %, elle guérit l’hypertension. Toutefois, le contrôle de l’hypertension et la réversibilité du retentissement sur les organes cibles sont comparables avec les antagonistes du récepteur des minéralocorticoïdes. Les préférences du patient pour ou contre la chirurgie sont donc un élément important de la décision thérapeutique, après information éclairée

Pheochromocytoma diagnosed during pregnancy: lessons learned from a series of ten patients

BACKGROUND: Pheochromocytoma (PHEO) in pregnancy is a life-threatening condition. Its management is challenging with regards to the timing and type of surgery. METHODS: A retrospective review of the management of ten patients diagnosed with pheochromocytoma during pregnancy was performed. Data were collected on the initial diagnostic workup, symptoms, treatment, and follow-up. RESULTS: PHEO was diagnosed in ten patients who were between the 10th and the 29th weeks of pregnancy. Six patients had none to mild symptoms, while four had complications of paroxysmal hypertension. Imaging investigations consisted of MRI, CT scan and ultrasounds. All had urinary metanephrines, measured as part of their workup. Three patients had MEN 2A, one VHL syndrome, one suspected SDH mutation. All patients were treated either with α/β blockers or calcium channel blockers to stabilize their clinical conditions. Seven patients underwent a laparoscopic adrenalectomy before delivery. Three out of these seven patients had a bilateral PHEO and underwent a unilateral adrenalectomy of the larger tumor during pregnancy, followed by a planned cesarean section and a subsequent contralateral adrenalectomy within a few months after delivery. Three patients had emergency surgery for maternal or fetal complications, with C-section followed by concomitant or delayed adrenalectomy. All newborns from the group of planned surgery were healthy, while two out three newborns within the emergency surgery group died shortly after delivery secondary to cardiac and pulmonary complications. CONCLUSIONS: PHEO in pregnancy is a rare condition. Maternal and fetal prognosis improved over the last decades, but still lethal consequences may be present if misdiagnosed or mistreated. A thorough multidisciplinary team approach should be tailored on an individual basis to better manage the pathology. Unilateral adrenalectomy in a pregnant patient with bilateral PHEO may be an option to avoid the risk of adrenal insufficiency after bilateral adrenalectomy

Phenolic Substitution in Fidaxomicin: A Semisynthetic Approach to Antibiotic Activity Across Species

Fidaxomicin (Fdx) is a natural product antibiotic with potent activity against Clostridioides difficile and other Gram-positive bacteria such as Mycobacterium tuberculosis. Only a few Fdx derivatives have been synthesized and examined for their biological activity in the 50 years since its discovery. Fdx has a well-studied mechanism of action, namely inhibition of the bacterial RNA polymerase. Yet, the targeted organisms harbor different target protein sequences, which poses a challenge for the rational development of new semisynthetic Fdx derivatives. We introduced substituents on the two phenolic hydroxy groups of Fdx and evaluated the resulting trends in antibiotic activity against M. tuberculosis, C. difficile, and the Gram-negative model organism Caulobacter crescentus. As suggested by the target protein structures, we identified the preferable derivatisation site for each organism. The derivative ortho-methyl Fdx also exhibited activity against the Gram-negative C. crescentus wild type, a first for fidaxomicin antibiotics. These insights will guide the synthesis of next-generation fidaxomicin antibiotics

Laparoscopy versus open adrenalectomy in patients with solid tumor metastases: results of a multicenter European study

Background: The outcome of adrenalectomy carried out by laparoscopy or open surgery for solid tumor metastases was assessed. Methods: A total of 317 patients with histologically confirmed adrenal metastatic disease collected from 30 centres in Europe underwent adrenalectomy by laparoscopy (n=146) or open laparotomy (n=171). Differences between laparoscopic and open adrenalectomy were assessed by a single Cox analysis for both procedures. Results: The median overall survival was 24.0 [95% confidence interval (CI): 21.4-26.6] months for open adrenalectomy and 45.0 (95% CI: 22.6-67.4) for laparoscopic adrenalectomy (P=0.008). Survival rates were 68%, 49%, 35% and 29% at 1, 2, 3 and 5 years for open surgery vs. 88%, 62%, 52% and 46% for laparoscopy, respectively. In the subgroup of R0 resections, the difference in survival in favor of laparoscopy (median 46 vs. 27 months) was marginally significant (P=0.073). Renal cancer [hazard ratio (HR) 0.42; 95% CI: 0.23-0.76, P=0.005], surgery of the primary tumor (HR 0.33; 95% CI: 0.19-0.54), and use of chemotherapy (HR 0.62; 95% CI: 0.43-0.88) were associated with a better survival, whereas type of resection (R1/R2 vs. R0) was associated with a worse prognosis (HR 2.29; 95% CI: 1.52-3.44, P<0.001). Conclusions: Laparoscopic adrenalectomy patients showed a longer survival than open adrenalectomy individuals, as minimally invasive approach was attempted more common in less advanced disease which led to higher number of R0 resections

Influence of Experience on Performance of Individual Surgeons in Thyroid Surgery: Prospective Cross Sectional Multicentre Study

Objective: To determine the association between surgeons’ experience and postoperative complications in thyroid surgery. Design: Prospective cross sectional multicentre study. Setting: High volume referral centres in five academic hospitals in France. Participants: All patients who underwent a thyroidectomy undertaken by every surgeon in these hospitals from 1 April 2008 to 31 December 2009. Main outcome measures: Presence of two permanent major complications (recurrent laryngeal nerve palsy or hypoparathyroidism), six months after thyroid surgery. We used mixed effects logistic regression to determine the association between length of experience and postoperative complications. Results: 28 surgeons completed 3574 thyroid procedures during a one year period. Overall rates of recurrent laryngeal nerve palsy and hypoparathyroidism were 2.08% (95% confidence interval 1.53% to 2.67%) and 2.69% (2.10% to 3.31%), respectively. In a multivariate analysis, 20 years or more of practice was associated with increased probability of both recurrent laryngeal nerve palsy (odds ratio 3.06 (1.07 to 8.80), P=0.04) and hypoparathyroidism (7.56 (1.79 to 31.99), P=0.01). Surgeons’ performance had a concave association with their length of experience (P=0.036) and age (P=0.035); surgeons aged 35 to 50 years had better outcomes than their younger and older colleagues. Conclusions: Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further

Потребительский экстремизм как правовое явление

Материалы XIII Междунар. науч. конф. студентов, магистрантов, аспирантов и молодых ученых, Гомель, 21–22 мая 2020 г