Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity.

BACKGROUND: The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation. OBJECTIVES: To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. METHODS: A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. RESULTS: CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. CONCLUSIONS: Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.

[COVID-19 and arrhythmias]. / COVID-19 et troubles du rythme.

In the pandemic caused by the SARS-CoV2 virus, arrhythmias were not in the foreground. However, the virus seems to affect many organs and the cardiac tropism is now well known. Knowledge in this area is still far from exhaustive, but several series published concerning patients with COVID-19 find a significant proportion of arrhythmias, some of which can potentially lead to a fatal outcome. These rhythm disorders are mainly supraventricular, such as atrial fibrillation (AF) or flutter but also ventricular disorders like ventricular tachycardias (VT) ventricular fibrillation (VF) and more rarely torsades de pointe (TdP). The causes are multiple, due to the multiorgan damage caused by the virus and potential drug interactions. In addition, the question of monitoring rhythm disorders that may emerge in the medium and long term after an infection remains to be explored.

[Infections in interventional electrophysiology]. / Infections en rythmologie interventionnelle.

The implantation of pacemakers and defibrillators carries the highest risk of infection in interventional electrophysiology. The use of implantable cardiac devices is continually increasing with almost 2 million devices implanted worldwide each year. The recipients' profile may also be associated with an increased risk of infection. Several measures can be implemented to reduce the risk of device-related infection. Systematic antibiotic prophylaxis has proven to be beneficial provided that prescription modalities are respected, especially with respect to the selection of the appropriate molecule and timing of administration prior to the procedure. Despite all the precautions taken during surgery (asepsis, prophylactic antibiotic therapy….) the estimated rate of peri-procedural infection is around 2%. Device related infections are associated with a high rate of morbidity and mortality as well as substantial healthcare costs. Staphylococcus aureus (SA) and epidermidis (SE) are the pathogenic agents involved in most cases. Prevention is crucial given the difficulties in treating such infections because of the near-systematic need to remove the device and antibiotic resistance. Leadless pacemakers and subcutaneous defibrillators are potential alternatives to implantable endocardial devices, albeit with certain limitations. A group of experts has recently issued consensus paper on the prevention, diagnosis and treatment of infections associated with endocardial implantable cardiac devices.

[Transcatheter aortic valve implantation and conduction disturbances]. / Implantation percutanée de valve aortique et troubles conductifs.

Transcatheter aortic valve implantation (TAVI) is currently becoming the treatment of choice for patients with calcific aortic stenosis. Despite several technical improvements, the incidence of conduction disturbances has not diminished and remains TAVI's major complication. These disturbances include the occurrence of left bundle branch block and/or high-grade atrioventricular block often requiring pacemaker implantation. The proximity of the aortic valve to the conduction system (conduction pathways) accounts for the occurrence of these complications. Several factors have been identified as carrying a high risk of conduction disturbances like the presence of pre-existing right bundle branch block, the type of valve implanted, the volume of aortic and mitral calcifications, the size of the annulus and the depth of valve implantation. Left bundle branch block is the most frequent post TAVI conduction disturbance. Whereas the therapeutic strategy for persistent complete atrioventricular block is simple, it becomes complex in the presence of fluctuating changes in PR interval and left bundle branch block duration. The QRS width threshold value (150-160 ms) indicative of the need for pacemaker implantation is still being debated. Although there are currently no recommendations regarding the management of these conduction disturbances, the extension of TAVI indications to patient at low surgical risk calls for a standardization of our practice. However, a decision algorithm was recently proposed by a group of experts composed of interventional cardiologists, electrophysiologists and cardiac surgeons. There are still uncertainties about the appropriate timing of pacemaker implantation and the management of new onset left bundle branch block.

[Survey into cardiac pacing in the Ile-de-France area for the year 2001: evaluation of indications]. / Enquête sur la stimulation cardiaque en Ile-de-France pour l'année 2001: evaluation des indications.

UNLABELLED: A survey into the implantation of cardiac pacemakers during 2001 in the Ile-de-France area was carried out by the French National Insurance Medical Service in order to evaluate performance in all centres performing more than 10 primary implantations per year. METHODS AND RESULTS: In 2001, 12 centres out of a total of 49 performed less than 50 primary implantations per year, representing 5% of the total regional activity, which was estimated to be 6414 procedures. The remaining 95% of procedures were spread evenly among 8 high-throughput centres (> 200 primary implantations per year) and 29 medium-throughput centres (50 to 200 primary implantations per year). Indications for pacing were analysed retrospectively by a team of regulatory doctors on a sample of 2176 patients with reference to the ACC/AHA/NASPE guidelines. After examination of the medical records, the indication was ranked as being class I, II or Ill (absence of indication). A valid indication was lacking in 8.2% of cases. Sinus node dysfunction represented 74.6% of the non-indications, and this classification had the predictive factors of asymptomatic dysfunction, and treatment with anti-arrhythmic or bradycardic medication. The proportion of class III interventions was significantly lower in the high-throughput centres (5.8 vs 9.9%, p < 0.05). CONCLUSION: 8.2% of primary pacing procedures were not indicated and resulted principally from asymptomatic sinus node dysfunction.

Determination of zolpidem and zopiclone in serum by capillary column gas chromatography.

A gas chromatographic method using a short, high-resolution capillary column connected to a specific thermoionic detector and requiring a simple and short extraction step without evaporation was developed for the rapid and precise determination of two new hypnotics, zolpidem and zopiclone, in serum at concentrations greater than 5 ng/mL. The assay was linear between 5 and 200 ng/mL, with coefficients of intra- and interassay variation less than 5% for both. The method was validated and then used to analyze zolpidem serum concentrations in nine rabbits after oral administration of 0.5 mg/kg and zopiclone serum concentrations in six patients treated orally with a 7.5-g dose.

Quinidine disposition in relation to antipyrine elimination and debrisoquine phenotype in alcoholic patients with and without cirrhosis.

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.

[Atrial flutter with 1/1 nodo-ventricular conduction with amiodarone. From physiopathology to diagnosis]. / Flutter atrial à conduction nodo-ventriculaire 1/1 sous amiodarone. De la physiopathologie au dépistage.

Atrial flutter with 1/1 nodo-ventricular conduction is a classical complication of Vaughan-Williams's Class I antiarrhythmic drugs. The increase of the flutter cycle and weak action of the antiarrhythmic on the atrioventricular node leads to 1/1 conduction of atrial depolarisation to the ventricles. In view of their marked action on the atrioventricular node, this type of pro-arrhythmic effect is very unexpected with Class III antiarrhythmics. The authors report 7 cases of 1/1 atrial flutter with oral amiodarone observed between 1994 and 2001. The patients were 6 men and 1 woman with an average age of 58 +/- 14 years. Four of them had underlying cardiac disease; none were hyperthyroid. The initial arrhythmia was 2/1 atrial flutter (n = 4), 1/1 atrial flutter (n = 2) and atrial fibrillation (n = 1). Treatment was preventive with doses of 400 mg/day associated with carvedilol in one patient and 200 mg/day in another. The other five patients all received loading doses of 9200 +/- 2400 mg over 10 +/- 4 days. The symptoms were palpitations (n = 2) associated in one patient with hypotension, one syncope, one near syncope and one cardiogenic shock. The ventricular cycle of the 1/1 flutter was 287 +/- 33 ms. The QRS duration was 136 +/- 35 ms with ventricular tachycardia-like appearances in 3 cases. An adrenergic trigger factor was noted in 5 patients. One patient required emergency cardioversion. The authors discuss the physiopathology of 1/1 flutter and theoretical diagnostic methods are proposed. In conclusion, amiodarone does not always prevent the occurrence of 1/1 nodo-ventricular conduction in atrial flutter.

Bile and blood ratios of cyclosporin and its metabolites in patients on continuous infusion during the first three weeks after liver transplantation.

Ten patients with orthotopic liver transplants were investigated during routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun®) was administered by continuous infusion at a constant rate of 5 mg/kg/day, modified to keep the blood cyclosporin concentration within the target range (400 to 500 µg/L). The concentrations of cyclosporin and combined cyclosporin-metabolites in blood, bile and urine were assayed daily during the 3 post-transplantation weeks that the patients spent in intensive care.All patients developed cholestatis and cytolysis during the first week. The severity of these liver transplant disorders increased in 5 patients and decreased in the other 5 in the second week. The pharmacokinetics of cyclosporin differed in the 2 groups: in patients without severe hepatic disorders, the blood metabolites/cyclosporin ratio (M/C) stabilised at 1.2 ± 0.4 in week 2 and at 0.8 ± 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctuated around 13.5 (13.5 ± 9.5 in week 2 and 13.5 ± 9.0 in week 3) and the bile metabolite/blood metabolite (bile M/blood M) ratio was very high and variable (131 ± 86 in week 2 and 159 ± 116 in week 3). Metabolites significantly accumulated in the blood of patients with severe hepatic disorders (M/C = 2.8 ± 0.6 in week 2 and 3.5 ± 1.0 in week 3); bile C/blood C (2.6 ± 2.1 in week 2 and 3.4 ± 1.1 in week 3) and bile M/blood M (11.9 ± 7.8 in week 2 and 12.5 ± 7.9 in week 3) significantly decreased and showed less interindividual variability.Blood cyclosporin is usually monitored to help optimise the dosage. However, if this was extended to include the monitoring of metabolites in the blood, and cyclosporin and metabolites in the bile, it could provide an early indication of severe hepatic disorders in patients with transplanted livers.

[Posterior luxation of lens or implant: surgical treatment using a perfluorocarbon solution. Technique and results of 13 cases]. / Luxation postérieure du cristallin ou d'un implant: traitement chirurgical utilisant un perfluorocarbone liquide. Technique et résultats à propos de 13 cas.

We used perfluorocarbon liquids in the management of 6 cases of posterior dislocation of the lens and 7 cases of (sub-) luxation of a posterior chamber intraocular lens (IOL). The perfluorocarbon liquid was injected into the vitreous cavity after complete vitrectomy, to bring back the lens or IOL to the posterior chamber where it can be easily removed. The main characteristics of perfluorocarbon liquids used in this indication are their high specific gravity and their good surface tension. Because of these two qualities, when injected in a vitrectomized eye, the perfluorocarbon liquid forms a bubble, filling the vitreous cavity from the posterior pole to the ora serrata with the dislocated lens or IOL floating on its surface. We found this technique to be helpful and quite atraumatic in this difficult surgical situation. Complications included regressive corneal edema in 6 cases and retinal dialysis with localized detachment in 3 cases.

[Glucocorticoid-induced hypertrophic cardiomyopathy in premature infants: apropos of 4 cases]. / Myocardiopathie hypertrophique induite par les glucocorticoïdes chez le prématuré: à propos de quatre cas.

BACKGROUND: The steroidal treatment used to prevent bronchopulmonary dysplasia (BD) in the preterm babies may be the cause of several complications, one of them being hypertrophic cardiomyopathy. CASE REPORT: Four infants developed hypertrophic cardiomyopathy during glucocorticoid (dexamethasone and/or betamethasone) treatment for bronchopulmonary dysplasia. In one of them, septal hypertrophy led to left ventricular outflow tract obstruction and congestive heart failure. All four were premature infants born after 2 weeks of gestation and weighing 780 to 1,080 g. The first echocardiographic changes appeared between the 4th and 15th day of the glucocorticoid course when the cumulated dose was respectively 1.82-1.87-3.51 and 3.86 mg/kg. Hypertrophic cardiomyopathy resolved completely between 2 and 4 weeks after cessation of the treatment. CONCLUSION: The glucocorticoid dosage to prevent BD should be reduced to 0.3 mg/kg/j and the myocardial function should be monitored by repeated echocardiograms during the first 15 days of treatment.

[Macular edema caused by contraction of the posterior hyaloid in diabetic retinopathy. Surgical treatment of a series of 22 cases]. / Oedèmes maculaires induits par la contraction de la hyaloïde postérieure dans la rétinopathie diabétique. Traitement chirurgical sur une série de 22 cas.

We have observed some patients with diabetic macular edema who did not respond to grid laser treatment and who improved with spontaneous posterior vitreous detachment or vitrectomy. These cases have a taut and glistening vitreo-macular interface. Three such cases are presented in detail. Pars plana vitrectomy with separation of the posterior hyaloid was performed in 22 cases. All of them had proliferative diabetic retinopathy, previously treated by panretinal photocoagulation. Fourteen cases had an ineffective macular grid laser treatment. Postoperative visual acuity was improved in 19 eyes and was unchanged in three eyes. The macular edema disappeared in 12 eyes and decreased in 10. Complications included a vitreous hemorrhage in 6 eyes, a paramacular tear in 1 eye, a reghmatogenous retinal detachment in 1 eye and cataract formation in 2 eyes. Vitreous surgery can improve the visual prognosis in cases of diabetic macular edema associated with a pathological vitreo-macular interface.