The Influence of Different Treatment Combinations on Skin Laxity and Dimpling.

OBJECTIVE: The aim of the study was to identify the effectiveness of the combination of tissue stabilized guided subcision, microfocused ultrasound, and minimally invasive calcium hydroxylapatite injections in various sequences for treating skin surface irregularities of the buttocks and thighs. MATERIAL AND METHODS: 61 females (body mass index: 22.6 ± 2.4 kg/m², age: 37.2 ± 6.8 years) were enrolled in this randomized interventional prospective study. Treatment arms included a variable combination and sequence of three treatment modalities: (1) Tissue-stabilized guided subcision, (2) microfocused ultrasound, and (3) calcium hydroxylapatite injections. Six months after the final intervention skin laxity and skin dimpling severity scores were assessed by the study participants, the treating physicians and by eleven blinded independent board-certified experts. RESULTS: No adverse events were observed during the study that required intervention outside the standard of care treatment protocol. The combination of three treatment modalities was shown to provide greater improvement in skin laxity 1.88 (95% CI, 0.66–5.37) and skin dimpling 1.31 (95% CI, 0.61–2.81) scores as compared to any combination of two modalities. The combination of concomitant microfocused ultrasound and calcium hydroxylapatite injections followed three months later by tissue stabilized guided subcision yielded the greatest improvement in skin laxity 2.23 (95% CI, 0.51–9.82) and skin dimpling 1.79 (95% CI, 0.67–4.78) at 9-month follow-up. CONCLUSION: This study provides evidence for the effectiveness of combination therapies for the improvement of skin surface irregularities on the buttocks and thighs. J Drugs Dermatol. 2020;19(11): 1030-1038. doi:10.36849/JDD.2020.5117.

Cellular N-myristoyltransferases play a crucial picornavirus genus-specific role in viral assembly, virion maturation, and infectivity.

In nearly all picornaviruses the precursor of the smallest capsid protein VP4 undergoes co-translational N-terminal myristoylation by host cell N-myristoyltransferases (NMTs). Curtailing this modification by mutation of the myristoylation signal in poliovirus has been shown to result in severe assembly defects and very little, if any, progeny virus production. Avoiding possible pleiotropic effects of such mutations, we here used pharmacological abrogation of myristoylation with the NMT inhibitor DDD85646, a pyrazole sulfonamide originally developed against trypanosomal NMT. Infection of HeLa cells with coxsackievirus B3 in the presence of this drug decreased VP0 acylation at least 100-fold, resulting in a defect both early and late in virus morphogenesis, which diminishes the yield of viral progeny by about 90%. Virus particles still produced consisted mainly of provirions containing RNA and uncleaved VP0 and, to a substantially lesser extent, of mature virions with cleaved VP0. This indicates an important role of myristoylation in the viral maturation cleavage. By electron microscopy, these RNA-filled particles were indistinguishable from virus produced under control conditions. Nevertheless, their specific infectivity decreased by about five hundred fold. Since host cell-attachment was not markedly impaired, their defect must lie in the inability to transfer their genomic RNA into the cytosol, likely at the level of endosomal pore formation. Strikingly, neither parechoviruses nor kobuviruses are affected by DDD85646, which appears to correlate with their native capsid containing only unprocessed VP0. Individual knockout of the genes encoding the two human NMT isozymes in haploid HAP1 cells further demonstrated the pivotal role for HsNMT1, with little contribution by HsNMT2, in the virus replication cycle. Our results also indicate that inhibition of NMT can possibly be exploited for controlling the infection by a wide spectrum of picornaviruses.