Hepatitis B reactivation characterized by HBsAg negativity and anti-HbsAg antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal.

BACKGROUND: HBV reactivation is associated with high mortality rates in hematopoietic stem cell transplantation (HSCT) and prophylactic lamivudine (LMV) treatment is suggested to prevent this phenomenon. However, the duration of LMV treatment in HSCT patients is not fully defined and the time of immune recovery is considered the best parameter for a drug to be safely interrupted. In patients undergoing allogeneic HSCT, the time of immune recovery is not easy to define and may take years after transplantation and prolonged LMV treatments, which can lead to drug-resistant viral strains. CASE PRESENTATION: An anti-HBc-positive hematological patient who was undergoing prolonged immunosuppression and who experienced HBV reactivation 3 months after the suspension of a prolonged LMV prophylaxis is described. HBV-DNA matching an atypical serological profile characterized by HbsAg negativity and anti-HBs positivity was detected in the patient. The genotypic analysis of the HBV strain identified T127P, F170FL and S204R mutations of HbsAg, which can hinder HBsAg recognition in a diagnostic assay. CONCLUSIONS: HBV reactivation in the HSCT host can be sustained by HBsAg viral variants with characteristics of altered immunogenicity that cannot be detected by usual laboratory tests. This clinical case description suggests the importance of screening for serum HBV-DNA levels in the diagnosis of HBV reactivation and monitoring HBV-DNA after prophylaxis suspension, particularly in HSCT subjects who have undergone prolonged periods of LMV treatment.

Venetoclax: Bcl-2 inhibition for the treatment of chronic lymphocytic leukemia.

Venetoclax (ABT-199) is a small-molecule selective oral inhibitor of the antiapoptotic protein Bcl-2 that promotes programmed cell death of chronic lymphocytic leukemia (CLL) cells regulating the release of proapoptotic factors, such as Smac/Diablo, apoptosis-inducing factor (AIF) and cytochrome c. In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to venetoclax for patients diagnosed with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. This review will focus on the mechanism of action, preclinical studies and clinical development of venetoclax both as a monotherapy and in combination with other drugs for CLL in the current milieu of therapy dominated by novel tyrosine kinase inhibitors such as ibrutinib and idelalisib.

Plant sex chromosomes: molecular structure and function.

Recent molecular and genomic studies carried out in a number of model dioecious plant species, including Asparagus officinalis, Carica papaya, Silene latifolia, Rumex acetosa and Marchantia polymorpha, have shed light on the molecular structure of both homomorphic and heteromorphic sex chromosomes, and also on the gene functions they have maintained since their evolution from a pair of autosomes. The molecular structure of sex chromosomes in species from different plant families represents the evolutionary pathway followed by sex chromosomes during their evolution. The degree of Y chromosome degeneration that accompanies the suppression of recombination between the Xs and Ys differs among species. The primitive Ys of A. officinalis and C. papaya have only diverged from their homomorphic Xs in a short male-specific and non-recombining region (MSY), while the heteromorphic Ys of S. latifolia, R. acetosa and M. polymorpha have diverged from their respective Xs. As in the Y chromosomes of mammals and Drosophila, the accumulation of repetitive DNA, including both transposable elements and satellite DNA, has played an important role in the divergence and size enlargement of plant Ys, and consequently in reducing gene density. Nevertheless, the degeneration process in plants does not appear to have reached the Y-linked genes. Although a low gene density has been found in the sequenced Y chromosome of M. polymorpha, most of its genes are essential and are expressed in the vegetative and reproductive organs in both male and females. Similarly, most of the Y-linked genes that have been isolated and characterized up to now in S. latifolia are housekeeping genes that have X-linked homologues, and are therefore expressed in both males and females. Only one of them seems to be degenerate with respect to its homologous region in the X. Sequence analysis of larger regions in the homomorphic X and Y chromosomes of papaya and asparagus, and also in the heteromorphic sex chromosomes of S. latifolia and R. acetosa, will reveal the degenerative changes that the Y-linked gene functions have experienced during sex chromosome evolution.

Fryns syndrome: report on 8 new cases.

The name Fryns syndrome was given to a new variable multiple congenital anomaly syndrome, almost always lethal, described in 1978, and now known to be autosomal recessive. Since that date, 20 patients have been reported in the literature. We describe 8 new cases, 6 of which were diagnosed in a series of 112,276 consecutive births (livebirths and perinatal deaths). The prevalence of this syndrome can be estimated to be around 0.7 per 10,000 births. These new cases confirm that the most frequent anomalies are diaphragmatic defects, lung hypoplasia, cleft lip and palate (often bilateral), cardiac defects (septal defects and aortic arch anomalies), renal cysts (type II, III or IV), urinary tract malformations, and distal limb hypoplasia. Most patients also have hypoplastic external genitalia and anomalies of internal genitalia (bifid or hypoplastic uterus, immature testes). The digestive tract is also often abnormal: duodenal atresia, pyloric hyperplasia, malrotation and common mesentery are present in half of the patients. When the brain was examined, more than half were abnormal (Dandy-Walker anomaly and agenesis of corpus callosum). A few patients demonstrated cloudy cornea. We examined the eyes of three patients histologically: two of them showed retinal dysplasia with rosettes and gliosis of the retina, thickness of posterior capsula of lens and irregularities of the Bowman membrane. Four of our cases were diagnosed prenatally between 24 and 27 weeks. It is to be expected that prenatal diagnosis will be made often and earlier in the future, as the spectrum of anomalies of the Fryns syndrome can easily be evidenced by sonography.

Pharmacokinetic study of ethanol after oral administration: a new approach to enzymatic elimination.

A new approach to the enzymatic elimination of ethanol in vivo allows us by means of a one-compartment model to take into account all the phases of the ethanol concentration-time curve after oral administration. The Michaelis-Menten equation is an approximation of this model; indeed it constituted the only non-linear approach to the kinetic study of ethanol. To express the model in the form of an equation leads to a third-order system of bilinear differential equations which has no analytical solution. The identification of the model is based on the optimization of a conformity criterion between experimental values and those predicted by the model. Optimization is performed by means of an iterative algorithm minimizing non-linear functions. This method permits the estimation of initial concentrations of products involved in the enzymatic reaction (substrate, enzyme) and kinetic constants (characterizing absorption and enzymatic reaction). Kinetics in nonalcoholics, alcoholics, and former alcoholics were identified using this new model. A good fit between the experimental values and the simulated curve was obtained. The in vivo estimation of the kinetic constants of each elementary step of the enzymatic reaction represents an original approach likely to provide more knowledge of ethanol metabolism.

Non-linear kinetics of ethanol elimination in man: medico-legal applications of the terminal concentration-time data analysis.

Research regarding parameters suitable for reporting on the activity of enzymatic systems responsible for ethanol metabolism is of obvious interest in medico-legal practice. Blood ethanol concentration-time curves, following oral administration of ethanol, have been developed for ethylic and non-ethylic subjects. This study has confirmed the non-linear kinetics of ethanol elimination; however, existing non-linear models appear to be inadequate for usual medico-legal practice, because of their complexity. We observed three phases during the elimination of ethanol. The first order terminal phase is characterized by its half-life. This parameter seems adequate as a basis for determining the activity of enzyme systems responsible for the metabolism of ethanol.

Evolution of plasma acetate concentration during ethanol metabolism in man.

Following oral administration of ethanol to ethylic as well as non-ethylic volunteers, the entire time course of plasma acetate concentration has been observed. The curve shows a typical evolution in three phases: (1) a quick ascending phase (2) a steady state characterized by a mean concentration (-C) (3) a first-order decrease, characterized by its half-life (t1/2) These parameters show significant variations (increase of -C, decrease of t1/2) in the ethylic subjects, in comparison with the non-ethylic ones. The variation of the area under the acetate curve according to the dose of ethanol given, is linear. The comparison of such a development with the one, typically non-linear, of the area under ethanol curve previously analyzed for the same subjects, may guess the origin of the non-linearity of ethanol kinetics.

[Approach to ethanol metabolism in man by studying the concentration-time curves of ethanol, free enzyme and plasma acetate (author's transl)]. / Approche du métabolisme de l'éthanol chez l'homme par l'étude de l'évolution de l'alcoolémie, de la concentraion d'enzyme libre et du taux d'acétate plasmatique.

The use of a pharmacokinetic model characterized by a new theoretical approach of the enzymatic reaction allows to account for ethanol concentration-time curve (after oral administration in man) and to simulate the evolution of free enzyme concentration. The interpretation of the various phases observed during these kinetics (ethanol, free enzyme) and plasma acetate kinetics (performed in the same study) constitutes an original approach to ethanol metabolism.