The outbreaks of Zika virus (ZIKV) infection in Brazil, 2015–2016, were associated with severe congenital malformations. Our translational study aimed to test the efficacy of the antiviral agent ...sofosbuvir (SOF) against vertical transmission of ZIKV and the associated congenital syndrome (CZS), using a rhesus monkey model. Eight pregnant macaques were successfully infected during the organogenesis phase with a Brazilian ZIKV strain; five of them received SOF from two to fifteen days post-infection. Both groups of dams showed ZIKV-associated clinical signals, detectable ZIKV RNA in several specimens, specific anti-ZIKV IgM and IgG antibodies, and maternal neutralizing antibodies. However, malformations occurred only among non-treated dam offspring. Compared to non-treated animals, all SOF-treated dams had a shorter ZIKV viremia and four of five neonates had undetectable ZIKV RNA in blood and tissue samples. These results support further clinical evaluations aiming for the prevention of CZS.
•The antiviral agent sofosbuvir has proven to reduce the Zika virus (ZIKV) viral load in cell culture and mouse models.•The efficacy and the safe use of sofosbuvir have not been tested in pregnancy of humans.•Pregnant rhesus monkeys, experimentally infected with ZIKV, were treated with sofosbuvir.•ZIKV-associated foetal malformations and demise were confirmed in the rhesus model.•All but one sofosbuvir-treated dams' offspring had undetectable ZIKV RNA in blood and tissue samples.
To evaluate the feasibility, safety and efficacy of exercise training in patients with immune-mediated necrotising myopathies (IMNM).
Eight consecutive sedentary patients with IMNM (5 anti-signal ...recognition particle and 3 anti-hydroxy-methyl-glutaryl coenzyme A reductase) were engaged in this study. Disease status was based on International Myositis Assessment and Clinical Studies Group (IMACS) core set measures. Physical performance was evaluated by cardiopulmonary exercise test, repetition maximum (RM) protocol, handgrip dynamometry, sit-to-stand (STS) and timed up-and-go (TUG) tests. All these parameters were measured at baseline and after a 12-week, twice-a-week, supervised exercise training comprising aerobic and strength exercises.
Patients (aged 61 years on average) were very disabled at the beginning of the disease (mean duration of 17.7 months), but after being aggressively treated with a treat-to-target approach, they presented only mild symptoms that were well-controlled with oral immunosuppression and low disease status scores by the time of the exercise intervention. No disease relapsing, worsening of the IMACS set scores or adverse events were observed throughout the training period. Patients also increased aerobic capacity (e.g. time to achieve anaerobic threshold and time to achieve exhaustion), muscle strength (e.g. 1RM bench press) and function (e.g. STS test).
Supervised exercise training did not impair disease status and seemed to be feasible, safe and effective in patients with IMNM. Moreover, exercise training increased aerobic capacity, muscle strength and function, suggesting that this could be a novel potential coadjuvant therapy in IMNM.
Reactions of methyl 4-O-allyl-2,3-di-O-benzyl-6-deoxy-6-(3-iodobenzoylamino)-α-D-galactopyranoside, its gluco epimer, methyl ...2,3-di-O-benzyl-6-deoxy-6-(3-iodobenzoylamino)-4-O-(1-pentenyl)-α-D-glucopyranoside and its ortho-regioisomer with tri-n-butyltin hydride were performed in different conditions. Depending on reaction conditions the three meta-iodo isomers gave a surprising amount of biphenyl compounds. The 2-iodo isomer led only to the undesired but expected hydrogenolysis product. No cyclized products were isolated in all the reactions. The structures of the new biphenyl products were elucidated by ¹H and 13C NMR spectroscopy, DEPT, COSY, HMQC and HMBC experiments and ESI-MS/MS. Mechanisms for the formation of these new biphenyl derivatives and hypotheses to explain the different outcomes for radical reactions of 3- or 2-iodobenzamides were presented.
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