Molnupiravir, a ribonucleoside antiviral prodrug against SARS-CoV-2, alters the voltage-gated sodium current and causes adverse events.

Molnupiravir (MOL) is a ribonucleoside prodrug for oral treatment of COVID-19. Common adverse effects of MOL are headache, diarrhea, and nausea, which may be associated with altered sodium channel function. Here, we investigated the effect of MOL on voltage-gated Na+ current (INa) in pituitary GH3 cells. We show that MOL had distinct effects on transient and late INa, in combination with decreased time constant in the slow component of INa inactivation. The 50% inhibitory concentration (IC50) values of MOL for suppressing transient and late INa were 26.1 and 6.3 µM, respectively. The overall steady-state current-voltage relationship of INa remained unchanged upon MOL exposure. MOL-induced alteration of INa may lead to changes in physiological function through sodium channels. Apart from its effect on inhibiting RNA virus replication, MOL exerts inhibitory effects on plasmalemma INa, which might constitute an additional yet crucial underlying mechanism of its pharmacological activity or adverse events.

Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes.

The extent to which the skin instructs peripheral somatosensory neuron maturation is unknown. We studied this question in Merkel cell-neurite complexes, where slowly adapting type I (SAI) neurons innervate skin-derived Merkel cells. Transgenic mice lacking Merkel cells had normal dorsal root ganglion (DRG) neuron numbers, but fewer DRG neurons expressed the SAI markers TrkB, TrkC, and Ret. Merkel cell ablation also decreased downstream TrkB signaling in DRGs, and altered the expression of genes associated with SAI development and function. Skin- and Merkel cell-specific deletion of Bdnf during embryogenesis, but not postnatal Bdnf deletion or Ntf3 deletion, reproduced these results. Furthermore, prototypical SAI electrophysiological signatures were absent from skin regions where Bdnf was deleted in embryonic Merkel cells. We conclude that BDNF produced by Merkel cells during a precise embryonic period guides SAI neuron development, providing the first direct evidence that the skin instructs sensory neuron molecular and functional maturation. SIGNIFICANCE STATEMENT: Peripheral sensory neurons show incredible phenotypic and functional diversity that is initiated early by cell-autonomous and local environmental factors found within the DRG. However, the contribution of target tissues to subsequent sensory neuron development remains unknown. We show that Merkel cells are required for the molecular and functional maturation of the SAI neurons that innervate them. We also show that this process is controlled by BDNF signaling. These findings provide new insights into the regulation of somatosensory neuron development and reveal a novel way in which Merkel cells participate in mechanosensation.

Keratinocytes can modulate and directly initiate nociceptive responses.

How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing.

Childhood invasive pneumococcal disease caused by non-7-valent pneumococcal vaccine (PCV7) serotypes under partial immunization in Taiwan.

BACKGROUND/PURPOSE: Emerging non-7-valent pneumococcal conjugate vaccine (PCV7) serotypes have replaced PCV7 serotypes in childhood invasive pneumococcal disease (IPD). This study was designed to describe the IPD caused by non-PCV7 serotypes under partial PCV7 immunization in Taiwan. METHODS: All children <18 years of age diagnosed with IPD at National Cheng Kung University Hospital from 1998 to 2010 were enrolled. Clinical and laboratory information was collected. Pneumococcal isolates were tested for antimicrobial susceptibility and interpreted using Clinical Laboratory Standard Institute guidelines (2008). Serotypes were determined using the capsular swelling method. RESULTS: One hundred and five patients with IPD were identified, including 75 PCV7 and 30 non-PCV7 isolates. Pneumonia (63.3%) was the leading clinical manifestation of non-PCV7 IPDs and 78.9% of pneumonia cases were associated with necrotizing pneumonia or empyema. Children with non-PCV7 IPDs had longer febrile days, required longer intensive care unit stays, and had a higher C-reactive protein level than those with PCV7 IPDs (p < 0.05). Serotype 3 is the most common non-PCV7 serotype (46.7%) and possesses the highest potential for pulmonary complications (p < 0.05, odds ratio: 0.114; 95% confidence interval, 0.013 - 0.973). CONCLUSION: The changing epidemiology of IPDs following the introduction of PCV7 has been noted. Expanded serotype coverage of the vaccine is warranted.

Clinical and laboratory characteristics of human immunodeficiency virus-infected adolescents: experience from a single medical center.

BACKGROUND: Recently, the proportion of adolescents diagnosed with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) has increased. The aim of this study is to evaluate the clinical and laboratory characteristics of HIV-infected adolescents in southern Taiwan. METHODS: From June 1997 to December 2010, a total of 40 HIV-infected adolescents who sought medical care in a university hospital in southern Taiwan were enrolled in the study. They were classified into three HIV at-risk groups, men who have sex with men (MSM), heterosexuals, and intravenous drug users (IDUs). Clinical and laboratory data were obtained from medical records. RESULTS: The median age of the 40 HIV-infected adolescents was 19 years. The HIV at-risk groups were MSM (22/40, 55%), heterosexuals (7/40, 17.5%), IDUs (5/40, 12.5%), and unknown (6/40, 15%). The initial median CD4 count and log plasma HIV viral load were 318 cells/mm(3) and 4.61, respectively. The seroprevalence of anti-HAV, anti-HBc, anti-HCV antibodies and HBsAg was 5.3%, 26.1%, 13% and 13%, respectively. Among 17 adolescents who had regular follow-ups more than twice, 7 (41.2%) had a concurrent sexually transmitted disease (STD). The most common STD was genital warts (41.2%) followed by syphilis (11.8%). Among 7 patients who received highly active antiretroviral agents (HAART) for more than 12 months, 5 (71.4%) had sustained virologic suppression. CONCLUSION: MSM are the largest risk group in HIV-infected adolescents in southern Taiwan and are characterized by a high prevalence of anogenital warts and low seroprevalence of anti-HAV.

Clinical perspectives of childhood tuberculosis in Taiwan.

Tuberculosis (TB) is an important public health issue in Taiwan and worldwide. Taiwan has made major progress in combating TB in the past 40 years. However, childhood TB still constitutes a significant challenge in disease control. From January to mid December 2011, 369 new cases of pediatric TB were confirmed. The relatively low case number and variable clinical presentations made it difficult for early detection. Latent TB infections in children also pose further complexity in clinical management. Knowledge of the clinical features of active and latent TB infection is crucial for efficient TB control.