RESUMEN

Yaws is a chronic infection that affects mainly the skin, bone and cartilage and spreads mostly between children. The new approval of a medication as treatment in 2012 has revived eradication efforts and now only few known localized foci of infection remain. The World Health Organization strategy mandates an initial round of total community treatment (TCT) with single-dose azithromycin followed either by further TCT or by total targeted treatment (TTT), an active case-finding and treatment of cases and their contacts. We develop the compartmental ODE model of yaws transmission and treatment for these scenarios. We solve for disease-free and endemic equilibria and also perform the stability analysis. We calibrate the model and validate its predictions on the data from Lihir Island in Papua New Guinea. We demonstrate that TTT strategy is efficient in preventing outbreaks but, due to the presence of asymptomatic latent cases, TTT will not eliminate yaws within a reasonable time frame. To achieve the 2030 eradication target, TCT should be applied instead.

Asunto(s)

RESUMEN

Intronic polymorphisms in the α-ketoglutarate-dependent dioxygenase gene (FTO) that are highly associated with increased body weight have been implicated in the transcriptional control of a nearby ciliary gene, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. RPGRIP1L overexpression increases POMC cell number. These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity.