Severe ciguatera poisoning in Madagascar: A case report

In a single outbreak on the East coast of Madagascar, more than 500 people, 98 of whom died, were poisoned by the flesh of a shark, Carcharhinus amboinensis. From clinical symptoms it can be concluded that this poisoning is due to ciguatera toxins. It is the first case of a severe outbreak caused by a shark, and it is the first case with a mortality rate of 20%.     

Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents.

The efficient and non-toxic nuclear delivery of steric-block oligonucleotides (ON) is a prerequisite for therapeutic strategies involving splice correction or exon skipping. Cationic cell penetrating peptides (CPPs) have given rise to much interest for the intracellular delivery of biomolecules, but their efficiency in promoting cytoplasmic or nuclear delivery of oligonucleotides has been hampered by endocytic sequestration and subsequent degradation of most internalized material in endocytic compartments. In the present study, we compared the splice correction activity of three different CPPs conjugated to PMO(705), a steric-block ON targeted against the mutated splicing site of human beta-globin pre-mRNA in the HeLa pLuc705 splice correction model. In contrast to Tat48-60 (Tat) and oligoarginine (R(9)F(2)) PMO(705) conjugates, the 6-aminohexanoic-spaced oligoarginine (R-Ahx-R)(4)-PMO(705) conjugate was able to promote an efficient splice correction in the absence of endosomolytic agents. Our mechanistic investigations about its uptake mechanisms lead to the conclusion that these three vectors are internalized using the same endocytic route involving proteoglycans, but that the (R-Ahx-R)(4)-PMO(705) conjugate has the unique ability to escape from lysosomial fate and to access to the nuclear compartment. This vector, which has displays an extremely low cytotoxicity, the ability to function without chloroquine adjunction and in the presence of serum proteins. It thus offers a promising lead for the development of vectors able to enhance the delivery of therapeutic steric-block ON in clinically relevant models.     

Androgen sensitivity of skeletal muscle: Nondependence on the motor nerve in the frog forearm

The effects of castration and of subsequent androgen administration on fiber size were investigated in several frog skeletal muscles. Four months after castration, cross-sectional cell area decreased by 70% and 14%, respectively, in the flexor carpi radialis and flexor carpi centralis muscles of the forearm and only by 2% in the ileo fibularis muscle of the thigh. Injection of testosterone propionate induced a hypertrophic response that reversed the effects of androgen deprivation; after 6 weeks, complete recovery to the control value was observed in all muscles selected. This sensitivity to the exogenous androgen was not altered by denervation; a similar hypertrophic evolution was seen in the denervated right muscles and in the homologous intact left muscles of the forearms. Using the myosin ATPase reaction, the muscle histochemical patterns were unchanged in all conditions tested. These results suggest that (i) a gradient of sensitivity to androgens exists in different frog muscles; (ii) androgens control the myofiber size but not the nerve-muscle organization as can be seen from the myofibrillar ATPase pattern; and (iii) the androgen sensitivity is not dependent on the motor nerve.     

Historical overview of analytical methods for the measurement of transthyretin.

The history of prealbumin dates back to the early forties and may be divided into three parts, based on a chronological and functional approach. The first part--the discovery and the identification of prealbumin--was essentially based on classical protein chemistry methods. The second--the demonstration of prealbumin as a thyroid hormone-binding protein (thyroxine-binding prealbumin)--has greatly benefited from isotopic techniques. The third one--establishing prealbumin as a nutritional marker--was a result of field studies on nutrition. The discovery of the role of prealbumin in retinol binding led to a change in its name, prealbumin becoming transthyretin. Finally, structural studies and mutation analysis of transthyretin in patients with amyloid neuropathy have opened a new area of research.     

Tacrolimus Pharmacokinetics and Dose Monitoring After Lung Transplantation for Cystic Fibrosis and Other Conditions

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.