14 cases of "anti-N" antibodies in hemodialysis patients in Marseille

Some medical centers re-use dialysis units sterilized with formaldehyde. In a study of 239 cases, 14 "anti-N" antibodies were found only among the 59 patients of the medical centers which re-use dialysis units. The action of formol seems to be confirmed by the presence of "anti-N" in 2 patients who had undergone prosthesis several times, but not dialysis. For these prostheses, a bone cement, sterilized with formol, was used. These "anti-N" are very often associated with cold autoagglutinins, and appear regardless of the patient's MN group. The action of formaldehyde suggests the following hypotheses:--antigenic modification;--disturbances in the immune response mechanisms;--a combination of the two. In the first hypothesis: the action of formol discovered since a long time on red cells. In the second hypothesis: the existence of auto-agglutinins only among the 14 hemo-dialysis patients with anti-N antibodies.     

Thrombophilia in mice expressing a tissue factor variant lacking its transmembrane and cytosolic domain

Mice with a targeted truncation in the gene encoding tissue factor of blood coagulation (TF) to eliminate the cytosolic domain and carrying a neo(R) cassette in intron 5 unexpectedly displayed severe spontaneous thrombosis in various vascular beds. Thrombosis was observed in heterozygous TF(+/neo) mice, causing death of over 50% of adults within 36 weeks of birth, and fulminantly exacerbating in pregnant females. Homozygous TF(neo/neo) mice were more severely affected and died within 7 weeks after birth. These TF(neo) mice primarily synthesized a mutant mRNA aberrantly spliced from exon 5 to neo(R), encoding an apparently non-vesicle-binding soluble TF lacking both the transmembrane and cytosolic domain, but still capable of blood coagulation induction. This severe thrombotic phenotype associated with the presence of a non-anchored soluble TF variant underscores the recently recognized significance of circulating TF for thrombus formation and development.     

Insulin resistance in the uremic patient: effects of hemodialysis

The carbohydrate metabolism abnormalities present in uremia have been attributed to a combination of peripheral resistance to insulin and inhibition of insulin release secondary to beta cells insensitivity. Previous studies evaluated the chronic effects of hemodialysis on glucose metabolism, while acute effects were not examined. In 12 uremic subjects undergoing hemodialysis (3 times a week) the fasting serum levels of glucose, insulin and C-peptide were measured, and the glucose/insulin ratio was calculated as an index of peripheral sensitivity to insulin before and after dialysis. While glucose did not change, insulin and C-Peptide rose significantly after dialysis. The rise in insulin and C-Peptide was directly correlated with the fall in body weight due to the fluid loss. This might indicate that the increase in insulin and C-peptide was due to a concentration phenomenon. However, it could reflect a reaction to hypoglycemia. The glucose/insulin ratio exhibited trend towards a fall after hemodialysis. Although not significant, this might indicate an acute worsening of the peripheral sensitivity to insulin, induced by the procedure.     

Sustained tumour eradication after induced caspase-3 activation and synchronous tumour apoptosis requires an intact host immune response

Effective anticancer treatments often result in the induction of large amounts of tumour cell death. In vivo, such dying tumour cells are a potential source of antigens for T-cell stimulation. Although apoptosis is generally considered nonimmunogenic, recent evidence suggests that some anticancer therapies that induce apoptosis can elicit antitumour immune responses. Here, a doxycycline-inducible, constitutively active caspase-3 (‘death switch'') was constructed in a murine tumour model to explore the impact of the host immune response to rapid, synchronous and substantial tumour cell apoptosis. In vitro, up to 80% of tumour cells underwent apoptotic cell death within 24 h and death was accompanied by the release of potential ‘danger signal'' molecules HMGB1 and HSP90. In vivo, death switch induction provoked rapid, pronounced tumour regression in immune-competent and immune-deficient mice, but sustained tumour eradication was observed only in immune-competent mice. Moreover, the majority of mice that were tumour free after death switch induction were protected from further tumour rechallenge. In addition, long-term remission after induction of the death switch was completely abrogated following depletion of CD8 T cells. These data suggest that sustained tumour eradication after substantial tumour apoptosis requires an antitumour host immune response that prevents tumour relapse. In many patients, cancer therapies produce encouraging initial responses that are only short lived. These results provide new insights that may have important implications for further development of strategies that result in long-term tumour clearance after initially effective anticancer treatment.     

The role of hybridization in the origin and spread of asexuality in Daphnia

The molecular mechanisms leading to asexuality remain little understood despite their substantial bearing on why sexual reproduction is dominant in nature. Here, we examine the role of hybridization in the origin and spread of obligate asexuality in Daphnia pulex, arguably the best‐documented case of contagious asexuality. Obligately parthenogenetic (OP) clones of D. pulex have traditionally been separated into ‘hybrid’ (Ldh SF) and ‘nonhybrid’ (Ldh SS) forms because the lactase dehydrogenase (Ldh) locus distinguishes the cyclically parthenogenetic (CP) lake dwelling Daphnia pulicaria (Ldh FF) from its ephemeral pond dwelling sister species D. pulex (Ldh SS). The results of our population genetic analyses based on microsatellite loci suggest that both Ldh SS and SF OP individuals can originate from the crossing of CP female F₁ (D. pulex × D. pulicaria) and backcross with males from OP lineages carrying genes that suppress meiosis specifically in female offspring. In previous studies, a suite of diagnostic markers was found to be associated with OP in Ldh SS D. pulex lineages. Our association mapping supports a similar genetic mechanism for the spread of obligate parthenogenesis in Ldh SF OP individuals. Interestingly, our study shows that CP D. pulicaria carry many of the diagnostic microsatellite alleles associated with obligate parthenogenesis. We argue that the assemblage of mutations that suppress meiosis and underlie obligate parthenogenesis in D. pulex originated due to a unique historical hybridization and introgression event between D. pulex and D. pulicaria.     

Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity

The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic fibrosis transmembrane conductance regulator protein (CFTR), a Cl⁻ channel not only involved in chloride secretion but as well in glutathione (GSH) transport. Thus, we tested whether the inhibition of CFTR could protect against cisplatin-induced nephrotoxicity. Using a renal proximal cell line, we show that the specific inhibitor of CFTR, CFTR_inh-172, prevents cisplatin-induced cell death and apoptosis by modulating the intracellular reactive oxygen species balance and the intracellular GSH concentration. This CFTR_inh-172-mediated protective effect occurs without affecting cellular cisplatin uptake or the formation of platinum-DNA adducts. The protective effect of CFTR_inh-172 in cisplatin-induced nephrotoxicity was also investigated in a rat model. Five days after receiving a single cisplatin injection (5 mg/kg), rats exhibited renal failure, as evidenced by the alteration of biochemical and functional parameters. Pretreatment of rats with CFTR_inh-172 (1 mg/kg) prior to cisplatin injection significantly prevented these deleterious cisplatin-induced nephrotoxic effects. Finally, we demonstrate that CFTR_inh-172 does not impair cisplatin-induced cell death in the cisplatin-sensitive A549 cancer cell line. In conclusion, the use of a specific inhibitor of CFTR may represent a novel therapeutic approach in the prevention of nephrotoxic side effects during cisplatin treatment without affecting its antitumor efficacy.