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Human Norovirus is currently the main viral cause of acute gastroenteritis (AGEs) in most countries worldwide. Nearly 50 years after the discovery of the “Norwalk virus” by Kapikian and colleagues, the scientific and medical community continue to generate new knowledge on the full biological and disease spectrum of Norovirus infection. Nevertheless, several areas remain incompletely understood due to the serious constraints to effectively replicate and propagate the virus. Here, we present a narrated historic perspective and summarize our current knowledge, including insights and reflections on current points of interest for a broad medical community, including clinical and molecular epidemiology, viral–host–microbiota interactions, antivirals, and vaccine prototypes. We also include a reflection on the present and future impacts of the COVID-19 pandemic on Norovirus infection and disease.

Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.

In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. In the safety study, which included 68,038 infants, the rates of intussusception were similar in the vaccine and placebo groups (relative risk, 0.8; 95 percent confidence interval, 0.3 to 1.8). In this randomized trial, the clinical efficacy of an oral, live pentavalent human–bovine reassortant vaccine was estimated to be 98.0 percent against severe gastroenteritis due to rotavirus. Rotavirus is the leading cause of hospitalization and death from acute gastroenteritis among infants and young children worldwide. More than 2 million hospitalizations and nearly half a million deaths are attributed to this infection annually. 1 , 2 The strategy of preventing rotavirus through vaccination derives from studies demonstrating that wild-type rotavirus infection induces immunity against subsequent rotavirus gastroenteritis. 3 – 6 Primary rotavirus infection provides substantial protection against gastroenteritis caused by the same serotype and against severe disease regardless of serotype. The four most prevalent serotypes, which account for more than 80 percent of cases of human rotavirus disease worldwide, are G1P[8], G2P[4], . . .

Antigenemia is commonly detected in rotavirus-infected children. Although rotavirus RNA has been detected in serum, definitive proof of rotavirus viremia has not been shown. We aimed to analyze a defined patient population to determine if infectious virus could be detected in sera from children with rotavirus antigenemia. Serum samples obtained upon hospitalization from children with gastroenteritis (57 stool rotavirus-positive and 41 rotavirus-negative), children with diagnosed bronchiolitis of known (n = 58) or unknown (n = 17) viral etiology, children with noninfectious, nonchronic conditions (n = 17), and healthy adults (n = 28) were tested for rotavirus antigen by enzyme immunoassay (EIA). Results of serum antigen testing were assessed for association with clinical and immunological attributes of the children. Rotavirus antigenemia was detected in 90% (51/57) of children with rotavirus-positive stools, in 89% (8/9) of children without diarrhea but with rotavirus-positive stools, in 12% (2/17) of children with bronchiolitis of unknown etiology without gastroenteritis, and in 12% (5/41) of children with gastroenteritis but with rotavirus-negative stools. Antigenemia was not detected in sera from children with noninfectious nonchronic conditions, children with bronchiolitis of known etiology and no gastroenteritis, or healthy adults. Neither age nor timing of serum collection within eight days after onset of gastroenteritis significantly affected levels of antigenemia, and there was no correlation between antigenemia and viral genotype. However, there was a negative correlation between serum rotavirus antigen and acute rotavirus-specific serum IgA (r = -0.44, p = 0.025) and IgG (r = -0.40, p = 0.01) titers. We examined 11 antigen-positive and nine antigen-negative sera for infectious virus after three blind serial passages in HT-29 cells using immunofluorescence staining for rotavirus structural and nonstructural proteins. Infectious virus was detected in 11/11 (100%) sera from serum antigen-positive children and in two out of nine (22%) sera samples from antigen-negative children (p = 0.002). Most children infected with rotavirus are viremic. The presence of viremia is directly related to the detection of antigenemia and is independent of the presence of diarrhea. Antigenemia load is inversely related to the titer of antirotavirus antibody in the serum. The finding of infectious rotavirus in the blood suggests extraintestinal involvement in rotavirus pathogenesis; however, the impact of rotavirus viremia on clinical manifestations of infection is unknown.

Luke 22:38 often functions in a symbiotic relationship with Luke 22:51 to reinforce the picture of Jesus as a principled pacifist. If Jesus is countenancing some sort of violent action, his rebuke at his arrest makes it clear that he rejects the way of violence altogether. Some interpreters go so far as to suggest that Jesus commands the use of swords earlier precisely to rebuke their use later. Both verses, however, contain ambiguous Greek expressions, neither of which supports the contention that Jesus is rejecting violence per se. As with Luke 22:51, it is misguided to push Luke 22:38 in a pacifistic direction. The ambiguous ... (\"It is enough\") is not a rhetorical ploy to cut the conversation short, nor does it mark out violence-prone disciples as the \"lawless ones\" of Isa 53. Rather, once released from the neutralizing effects of Luke 22:51 as an interpretive control, Luke 22:38 offers an altogether different picture of Jesus's stance toward violence.

The structure of GlyRα3 in complex with a selective potentiator that decreases neuropathic pain in an animal model identifies a novel allosteric regulatory mechanism. Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported \"compound 52\" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.

Jesus's refusal to be defended by the sword at his arrest plays a significant role in popular and scholarly understandings of Jesus as a committed pacifist. Of the four NT accounts, the Gospel of Luke offers Jesus's most forceful and unequivocal rebuke: \"No more of this!\" (Luke 22:51 NRSV), translating ... Such a translation, however, is tendentious and misleading, seemingly the result of a twentieth-century translational bias that has exerted enormous influence on subsequent biblical translation and interpretation. An analysis of Luke's lexical usage, grammar, and context rather suggests that, instead of rebuking his disciples, Jesus is reminding them of the divine plan to which Jesus must not only submit, but which he must actively carry out. In Luke's narrative framework, Satan has received permission to sift the disciples in the present hour of darkness, and the disciples must not interfere with the divine permissio. This apocalyptic reading allows the words ... their more natural force: \"permit until this,\" or, more pointedly, \"allow the arrest to continue.\" The subsequent healing of the high priest's slave guarantees the continuation of the plan and expresses Jesus's control over the situation more than his presumed compassion or love. The implications for Christian ethics are considerable: Jesus may have been a \"pacifist\" but not in the way one might think.

Luke 22:38 often functions in a symbiotic relationship with Luke 22:51 to reinforce the picture of Jesus as a principled pacifist. If Jesus is countenancing some sort of violent action, his rebuke at his arrest makes it clear that he rejects the way of violence altogether. Some interpreters go so far as to suggest that Jesus commands the use of swords earlier precisely to rebuke their use later. Both verses, however, contain ambiguous Greek expressions, neither of which supports the contention that Jesus is rejecting violence per se. As with Luke 22:51, it is misguided to push Luke 22:38 in a pacifistic direction. The ambiguous ἱκανόν ἐστιν (“It is enough”) is not a rhetorical ploy to cut the conversation short, nor does it mark out violence-prone disciples as the “lawless ones” of Isa 53. Rather, once released from the neutralizing effects of Luke 22:51 as an interpretive control, Luke 22:38 offers an altogether different picture of Jesus's stance toward violence.

Infections with group A rotaviruses are common among infants and young children worldwide. 1 – 6 The outcome ranges from asymptomatic infection to severe, life-threatening diarrhea. 6 – 10 Rotavirus is the leading cause of severe diarrhea among children and causes an estimated 870,000 deaths annually in developing countries. 1 – 3 , 11 , 12 The disease burden of rotavirus is so great that development of a vaccine is a global priority for public health. 11 , 12 Epidemiologic studies of rotavirus have suggested that natural immunity is acquired after early exposure to the virus and that many children acquire immunity only after several infections. 10 , 13 – 18 However, observations . . .