Use of ecarin clotting time in whole blood for monitoring recombinant hirudine treatment during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia

Lepirudin (Refludan is a recombinant hirudin, approved for anticoagulation treatment of heparin-induced thrombocytopenia patients with thrombosis. We report here our method for laboratory monitoring with ecarin clotting time (ECT) of hirudin therapy as anticoagulation for cardiac surgery. Ecarin is extracted from the Echis carinatus snake venom and directly converts prothrombin to its intermediate, meizothrombin. This one binds in a stoechiometric way to hirudin to be proportioned in whole blood. The activation of coagulation starts up only when the totality of the hirudin is bound to the meizothrombin. To minimize the effect of dilution related to the CEC on the prothrombin and fibrinogen levels, thus lengthening the ECT, the specimen to be tested is diluted with normal whole blood. In 1997, when we have performed our first surgery with cardiopulmonary bypass, only one team (P?tzsch et al., 1997) had described the use of the ECT in whole blood. We describe in this work our assay to dose hirudin with ECT after dilution in whole blood. This assay was used during 8 CEC among 7 patients affected with HIT (n = 6) or potentially sensitized with heparin (n = 1). Experimental conditions and interpretation of the assay are reported here. This test is fast enough to provide useful information for adjusting the dose during cardiopulmonary bypass.     

Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala. Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01257-0.     

Quantitative glycoproteomics of high-density lipoproteins

In this work, we developed a targeted glycoproteomic method to monitor the site-specific glycoprofiles and quantities of the most abundant HDL-associated proteins using Orbitrap LC-MS for (glyco)peptide target discovery and QqQ LC-MS for quantitative analysis. We conducted a pilot study using the workflow to determine whether HDL protein glycoprofiles are altered in healthy human participants in response to dietary glycan supplementation.

The optimized HDL glycoproteomics method was sensitive enough to detect the effects of dietary supplements on HDL protein glycoprofiles even in a small sample size.     

Anatomic correction of transposition of the great arteries associated with ventricular septal defect: midterm results in 50 patients

From May 1977 to August 1982 50 patients who were 1.5 to 44 months old underwent anatomic correction of transposition of the great arteries (TGA) and closure of ventricular septal defect (VSD) at our institution. Thirty-nine patients underwent preliminary pulmonary arterial banding. Hospital mortality was 32%: four patients died as a result of technical problems, seven as a result of associated lesions, three of pulmonary hypertension, and two of left ventricular failure. Three other patients died after the first postoperative month (one of mediastinitis, one at reoperation for a residual VSD, and one of pulmonary hypertension). All 31 survivors are in excellent clinical condition and are in sinus rhythm after a mean follow-up period of 31 +/- 14 months. Twenty-five patients were reinvestigated by echocardiography (M mode and two-dimensional) and/or catheterization. Parameters of left ventricular contractility were within normal limits, but systolic aortic diameter was larger than normal (p less than .01). Seven patients had stenosis of the right ventricular outflow tract and five of these required reoperation. The two persistent problems with the anatomic correction of TGA associated with VSD are a relatively high operative mortality and secondary right outflow tract stenosis. However, use of this procedure results in better left ventricular function and fewer arrhythmias than does use of atrial repair techniques and also results in the use of the anatomically left ventricle as the systemic ventricle.     

Surgical correction of tetralogy of Fallot with an iatrogenic obstruction on 1 branch of the pulmonary artery]

The au;hors report 12 cases of Fallot' tetralogy with stenosis or obstruction of one of the two branches of the pulmonary artery following palliative anterior anastomosis. The complications of correction by open heart surgery include the frequent incidence of pulmonary hypertension, which was responsible for 4 deaths. No satisfactory explanation could be found for these poor results. It is desirable to avoid the creation of asymetry in pulmonary blood supply in Fallot's tetralogy and, if such should be found, suggestions are made for its correction by open heart surgery in order to improve the prognosis.     

The pancreatic islets in diabetes

Despite the fact that heterogeneity of diabetes in man has become more and more evident in recent years, its pancreatic pathology is still represented by two distinct entities, roughly corresponding to the classic juvenile-onset and maturity-onset types of the disease.In juvenile-onset, insulin-dependent diabetes, the pancreatic islets show severe and pathognomonic changes. B cells are greatly reduced in number already at clinical onset. Contrary to classic opinion they do not always disappear in the years to follow. Insulin's, a common finding in the pancreas of recent onset juvenile diabetic subjects, is compatible with a viral infection as well as with an autoimmune reaction as the cause of B cell destruction. In the pancreas of juvenile-onset diabetic subjects the islets, which in the past have been regarded as atrophic and inactive, are actually composed of cells containing glucagon and somatostatin. There is also a profound distortion of islet organization, and many endocrine cells are scattered as single cells in the exocrine tissue. These findings may well account for the abnormal secretory behavior of the glucagon-secreting A cells in insulin-dependent juvenile-onset diabetes.In maturity-onset, noninsulin-dependent diabetes, the pancreatic pathology is extremely variable and not pathognomonic. A numeric reduction of the B cells can be demonstrated in many maturity-onset diabetic subjects, but this reduction is much more moderate than in insulin-dependent juvenile-onset diabetic subjects and does not account for the disease. The same amount of B cell reduction can be found in many elderly subjects without clinical evidence of diabetes. In many maturity-onset diabetic subjects, the cytologic characteristics of the B cells suggest a decreased responsiveness to the stimulus of hyperglycemia. Islet fibrosis and hyalinosis (amyloidosis), although common, cannot explain this secretory dysfunction. The exact site of the defect in the B cells of maturity-onset diabetic subjects remains to be defined. Further investigations are necessary to assess the role of disturbed intraislet intercellular relationships in the pathogenesis of late-onset diabetes.The dual pattern of islet pathology in diabetes in man does not preclude a more profound heterogeneity in the etiology and pathogenesis of the disease.