Megaesophagus in a Line of Transgenic Rats: A Model of Achalasia

Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition.National Institutes of Health (U.S.) (Grant T32OD011141)National Institutes of Health (U.S.) (Grant P30ES002109

Patterns of Haemoproteus Beckeri Parasitism in the Gray Catbird (Dumatella Carolinensis) During the Breeding Season

We determined the prevalence and intensity of blood parasites in breeding gray catbirds (Dumatella carolinensis) at Killbuck Wildlife Area in Wayne and Holmes Counties, Ohio (USA) from June through August 2000. Of 98 catbirds sampled, 40 (40.8%) had detectable infections of Haemoproteus beckeri. Overall prevalence of H. beckeri in this population is high relative to that reported in earlier blood parasite surveys of both breeding and migrant catbirds. Mean intensity of H. beckeri infection did not vary significantly between young and old birds or among sampling periods. We found no effect of age on prevalence or intensity of H. beckeri infection. Older birds were not more likely to be infected than younger birds, despite longer exposure to arthropod vectors. Prevalence varied significantly with season and was highest in June and lowest in August. This pattern also was observed in older birds sampled repeatedly. This seasonal variation may reflect both newly acquired infections and chronic infections relapsing in response to hormonal changes associated with breeding. Evidence of transmission was observed in the single hatching year bird that lacked detectable infection in early summer, but demonstrated a very high intensity infection in late summer. These observations provide supportive evidence that hematozoa infections are acquired on the breeding grounds during the first year of life and relapse during the breeding season in subsequent years

Molecular and phylogenetic characterization of novel papillomaviruses isolated from oral and anogenital neoplasms of Japanese macaques (Macaca fuscata)

Papillomaviruses (PVs) are a diverse group of host species-specific DNA viruses, etiologically linked with various benign and malignant neoplasms of cutaneous and mucosal epithelia. Here, we describe the detection and characterization of the first two PVs naturally infecting Japanese macaques (Macaca fuscata), including the determination of their etiological association(s) with the development of original neoplasms. The molecular and phylogenetic analyses were performed on complete genome sequences of Macaca fuscata PV types 1 (MfuPV1) and 2 (MfuPV2), which were completely sequenced in samples of a malignant oral tumor and benign anogenital neoplasm of Japanese macaques, respectively. Subsequently, two type-specific quantitative real-time PCRs were developed to estimate viral loads of MfuPV1 and MfuPV2 and to evaluate their etiological roles. The in silico molecular analyses revealed that both viral genomes encode characteristic PV proteins with conserved functional domains and have a non-coding genomic region with regulatory sequences to regulate and complete the viral life cycle. However, additional experimental evidence is needed to finally confirm the presence and biological functionality of the molecular features of both novel PVs. While MfuPV1, together with PVs identified in other macaques, is classified into the Alphapapillomavirus (Alpha-PV) species 12, MfuPV2 is most likely a representative of the novel viral species within the Alpha-PV genus. Their relatively high viral loads suggest that both PVs are etiologically linked with the development of the original neoplasms

Medical imaging utilization and associated radiation exposure in children with down syndrome.

ObjectiveTo evaluate the frequency of medical imaging or estimated associated radiation exposure in children with Down syndrome.MethodsThis retrospective cohort study included 4,348,226 children enrolled in six U.S. integrated healthcare systems from 1996-2016, 3,095 of whom were diagnosed with Down syndrome. We calculated imaging rates per 100 person years and associated red bone marrow dose (mGy). Relative rates (RR) of imaging in children with versus without Down syndrome were estimated using overdispersed Poisson regression.ResultsCompared to other children, children with Down syndrome received imaging using ionizing radiation at 9.5 times (95% confidence interval[CI] = 8.2-10.9) the rate when age ConclusionsChildren with Down syndrome experienced more medical imaging and higher radiation exposure than other children, especially at young ages when they are more vulnerable to radiation. Clinicians should consider incorporating strategic management decisions when imaging this high-risk population

Correction: Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues.

[This corrects the article DOI: 10.1371/journal.ppat.1006219.]

Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues

<div><p>Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1–7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.</p></div

Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques

<div><p>Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.</p></div

Detection of anti-ZIKV antibody responses in Rhesus plasma.

<p>Rhesus macaques infected with ZIKV were analyzed for the presence of antibodies directed against ZIKV-PRABC59 by ELISA using whole virus as capture antigen with an HRP-conjugated anti-Rhesus IgM <b>(A)</b> or IgG <b>(B)</b> secondary antibody. <b>C.</b> Sera from indicated animals obtained pre-infection (d0) or at terminal bleed (d28 or 35 pi) were tested for neutralizing activity via plaque reduction neutralization titer (PRNT) assay. <b>D.</b> Fold dilution giving 50% reduction in infectious titer for each serum sample.</p

Viral loads in the tissues following necropsy of ZIKV-infected rhesus macaques.

<p>One-step qRT-PCR was used to measure ZIKV RNA loads in the tissues of animals in Cohort 2 (A), Cohort 1 (B), and Cohort 3 (C). Total RNA was generated using the Trizol method on precleared samples following bead beating. Approximately 80 different tissues were assessed for the presence of viral RNA. Shown are the tissues with positive detection in at least one of the animals per cohort. Arrows indicate samples in which virus was successfully co-cultured from tissue homogenate. Approximate limit of detection at 1e4 genomes/ml is based on a detection limit of ~100 genomes in each reaction (<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006219#ppat.1006219.s002" target="_blank">S1 Fig</a>) as indicated by the horizontal line. (D) Paraffin sections of sciatic nerve cut in cross section were hybridized with ZIKV specific chromogenic probe (red) and counterstained with hematoxylin (blue). Nerve fibers (NF) show a normal distribution within the endoneurium surrounded by perineurium (PN) and perineurial adventia (PA). Hybridization for ZIKV was robust but limited to the PA region. Original magnification was 50X.</p