Transmission of Raccoon-Passaged Chronic Wasting Disease Agent to White-Tailed Deer

The transmission characteristics of prion diseases are influenced by host prion protein sequence and, therefore, the host species. Chronic wasting disease (CWD), a prion disease of cervids, has widespread geographical distribution throughout North America and occurs in both wild and farmed populations. CWD prions contaminate the environment through scattered excrement and decomposing carcasses. Fresh carcasses with CWD prions are accessible by free-ranging mesopredators such as raccoons and may provide a route of exposure. Previous studies demonstrated the susceptibility of raccoons to CWD from white-tailed deer. In this study, we demonstrate that white-tailed deer replicate raccoon-passaged CWD prions which results in clinical disease similar to intraspecies CWD transmission. Six white-tailed deer were oronasally inoculated with brain homogenate from a raccoon with CWD. All six deer developed clinical disease, had widespread lymphoid distribution of misfolded CWD prions (PrP^Sc), and had neuropathologic lesions with PrP^Sc accumulation in the brain. The presence of PrP^Sc was confirmed by immunohistochemistry, enzyme-linked immunoassay, and western blot. The western blot migration pattern of raccoon-passaged CWD was different from white-tailed deer CWD. Transmission of raccoon CWD back to white-tailed deer resulted in an interposed molecular phenotype that was measurably different from white-tailed deer CWD.     

Transmission,Strain Diversity,and Zoonotic Potential of Chronic Wasting Disease

Chronic wasting disease (CWD) is a prion disease affecting several species of captive and free-ranging cervids. In the past few decades, CWD has been spreading uncontrollably, mostly in North America, resulting in a high increase of CWD incidence but also a substantially higher number of geographical regions affected. The massive increase in CWD poses risks at several levels, including contamination of the environment, transmission to animals cohabiting with cervids, and more importantly, a putative transmission to humans. In this review, I will describe the mechanisms and routes responsible for the efficient transmission of CWD, the strain diversity of natural CWD, its spillover and zoonotic potential and strategies to minimize the CWD threat.     

Chronic Wasting Disease Transmission Risk Assessment for Farmed Cervids in Minnesota and Wisconsin

CWD (chronic wasting disease) has emerged as one of the most important diseases of cervids and continues to adversely affect farmed and wild cervid populations, despite control and preventive measures. This study aims to use the current scientific understanding of CWD transmission and knowledge of farmed cervid operations to conduct a qualitative risk assessment for CWD transmission to cervid farms and, applying this risk assessment, systematically describe the CWD transmission risks experienced by CWD-positive farmed cervid operations in Minnesota and Wisconsin. A systematic review of literature related to CWD transmission informed our criteria to stratify CWD transmission risks to cervid operations into high-risk low uncertainty, moderate-risk high uncertainty, and negligible-risk low uncertainty categories. Case data from 34 CWD-positive farmed cervid operations in Minnesota and Wisconsin from 2002 to January 2019 were categorized by transmission risks exposure and evaluated for trends. The majority of case farms recorded high transmission risks (56%), which were likely sources of CWD, but many (44%) had only moderate or negligible transmission risks, including most of the herds (62%) detected since 2012. The presence of CWD-positive cervid farms with only moderate or low CWD transmission risks necessitates further investigation of these risks to inform effective control measures.     

Exposure Risk of Chronic Wasting Disease in Humans

The majority of human prion diseases are sporadic, but acquired disease can occur, as seen with variant Creutzfeldt–Jakob disease (vCJD) following consumption of bovine spongiform encephalopathy (BSE). With increasing rates of cervid chronic wasting disease (CWD), there is concern that a new form of human prion disease may arise. Currently, there is no evidence of transmission of CWD to humans, suggesting the presence of a strong species barrier; however, in vitro and in vivo studies on the zoonotic potential of CWD have yielded mixed results. The emergence of different CWD strains is also concerning, as different strains can have different abilities to cross species barriers. Given that venison consumption is common in areas where CWD rates are on the rise, increased rates of human exposure are inevitable. If CWD was to infect humans, it is unclear how it would present clinically; in vCJD, it was strain-typing of vCJD prions that proved the causal link to BSE. Therefore, the best way to screen for CWD in humans is to have thorough strain-typing of harvested cervids and human CJD cases so that we will be in a position to detect atypical strains or strain shifts within the human CJD population.     

Gene-Edited Cell Models to Study Chronic Wasting Disease

Prion diseases are fatal infectious neurodegenerative disorders affecting both humans and animals. They are caused by the misfolded isoform of the cellular prion protein (PrP^C), PrP^Sc, and currently no options exist to prevent or cure prion diseases. Chronic wasting disease (CWD) in deer, elk and other cervids is considered the most contagious prion disease, with extensive shedding of infectivity into the environment. Cell culture models provide a versatile platform for convenient quantification of prions, for studying the molecular and cellular biology of prions, and for performing high-throughput screening of potential therapeutic compounds. Unfortunately, only a very limited number of cell lines are available that facilitate robust and persistent propagation of CWD prions. Gene-editing using programmable nucleases (e.g., CRISPR-Cas9 (CC9)) has proven to be a valuable tool for high precision site-specific gene modification, including gene deletion, insertion, and replacement. CC9-based gene editing was used recently for replacing the PrP gene in mouse and cell culture models, as efficient prion propagation usually requires matching sequence homology between infecting prions and prion protein in the recipient host. As expected, such gene-editing proved to be useful for developing CWD models. Several transgenic mouse models were available that propagate CWD prions effectively, however, mostly fail to reproduce CWD pathogenesis as found in the cervid host, including CWD prion shedding. This is different for the few currently available knock-in mouse models that seem to do so. In this review, we discuss the available in vitro and in vivo models of CWD, and the impact of gene-editing strategies.     

Secondary Hyperparathyroidism and Protein-Energy Wasting in End-Stage Renal Disease

Protein-energy wasting (PEW), a syndrome involving adverse changes in nutrition and body composition, is a serious problem associated with morbidity and mortality in patients with end-stage renal disease (ESRD). The pathogenesis of PEW is multifactorial, and the underlying mechanisms are not fully understood. However, recent translational work has provided compelling evidence for a causal role of parathyroid hormone (PTH) in the pathogenesis of adipose tissue browning and increased energy expenditure, a critical component of PEW in ESRD. These results provide a biological explanation for the clinical association between secondary hyperparathyroidism (SHPT) and PEW in hemodialysis patients and may serve as an additional rationale for treating SHPT. Large-scale clinical and epidemiological studies should determine the clinical significance of SHPT as a contributor to PEW and establish the optimal management of SHPT to ameliorate PEW.     

急性脑血管疾病中的脑耗盐综合征：附29例临床分析

目的 :观察急性脑血管病病程中并发的脑耗盐综合征。方法 :依次从我院神经科 1年中收治的各种急性脑血管病中筛选出低钠血症病例 ;根据脑耗盐综合征的诊断标准确定该综合征的病例。结果 :在 6 36例各种急性脑血管疾病中发现低钠血症 38例 ,其中脑耗盐综合征 2 9例。结论 :急性脑血管疾病的低钠血症 ,大部分是脑耗盐综合征 ,妥善处理脑耗盐综合征 ,能提高急性脑血管病的疗效     

Studies in bank voles reveal strain differences between chronic wasting disease prions from Norway and North America

Chronic wasting disease (CWD) is a relentless epidemic disorder caused by infectious prions that threatens the survival of cervid populations and raises increasing public health concerns in North America. In Europe, CWD was detected for the first time in wild Norwegian reindeer (Rangifer tarandus) and moose (Alces alces) in 2016. In this study, we aimed at comparing the strain properties of CWD prions derived from different cervid species in Norway and North America. Using a classical strain typing approach involving transmission and adaptation to bank voles (Myodes glareolus), we found that prions causing CWD in Norway induced incubation times, neuropathology, regional deposition of misfolded prion protein aggregates in the brain, and size of their protease-resistant core, different from those that characterize North American CWD. These findings show that CWD prion strains affecting Norwegian cervids are distinct from those found in North America, implying that the highly contagious North American CWD prions are not the proximate cause of the newly discovered Norwegian CWD cases. In addition, Norwegian CWD isolates showed an unexpected strain variability, with reindeer and moose being caused by different CWD strains. Our findings shed light on the origin of emergent European CWD, have significant implications for understanding the nature and the ecology of CWD in Europe, and highlight the need to assess the zoonotic potential of the new CWD strains detected in Europe.

Prion diseases, otherwise known as transmissible spongiform encephalopathies (TSEs), are invariably fatal infectious neurodegenerative disorders of animals and humans. Prions are composed largely or exclusively of self-replicating protein aggregates of PrP^Sc, which is a misfolded isoform of the cellular prion protein (PrP^C). Most human prion diseases, including Creutzfeldt–Jakob disease (CJD) and sporadic fatal insomnia, occur sporadically and are thought to result from the spontaneous misfolding of PrP^C into PrP^Sc. Mutations in the coding sequence of the gene encoding PrP (PRNP) in inherited diseases such as familial CJD, fatal familial insomnia, and Gerstmann–Sträussler–Scheinker syndrome are thought to potentiate spontaneous misfolding of PrP^C to PrP^Sc (1). The intrinsic transmissibility of prions has also resulted in epidemics of acquired prion diseases (2), with significant public health consequences. Examples include iatrogenic CJD transmission caused by prion-contaminated human growth hormone preparations and dura mater grafts, and variant CJD resulting from human exposure to bovine spongiform encephalopathy (BSE) prions.Animal prion diseases also occur as contagious forms giving rise to outbreaks such as classical scrapie in small ruminants and chronic wasting disease (CWD) in cervids (3). In addition to their impact on human health, exemplified by zoonotic BSE transmission (2), epidemic animal prion diseases, such as CWD in North America (NA) (4), have significant ecologic and economic consequences. First identified in captive deer in Northern Colorado in the 1960s, CWD is now known to affect wild and farmed cervid populations in 26 states and three Canadian provinces. Disease was introduced to the Republic of Korea following importation of subclinical elk (Cervus canadensis) from Canada (5). The irrevocable spread of CWD in NA raises serious concerns about the survival of cervid populations, as well as for the risks posed to other animals and to humans (6).Prion diseases are caused by different prion strains, which are thought to be encoded by conformational variants of PrP^Sc (7, 8). While different PrP^Sc conformers can be discriminated using biochemical approaches, assessing infectious properties of prions in susceptible hosts remains the gold standard for strain characterization. Such analyses are of the utmost importance for trace-back studies of iatrogenic (9, 10) or zoonotic prion strains (11, 12), for identifying spillover hosts (13), for estimating the zoonotic potential of classical and atypical scrapie strains (14, 15), and for understanding the epidemiology and evolution of strains in contagious prion diseases (16–20).In Europe, CWD was detected for the first time in wild Norwegian reindeer (Rangifer tarandus) and moose (Alces alces) in 2016 (21, 22). The emergence of CWD in Europe necessitates characterization of the strain properties of these CWD prions of uncertain origin to explore a possible link with NA CWD. Knowledge about Norwegian CWD strains is essential to assess their risk to animal and human health, and to develop evidence-based policies to control and limit the spread of the disease (23).In a previous study, we found that bank voles carrying isoleucine at codon 109 (Bv109I) are highly susceptible to CWD isolates from the United States. After subpassage in Bv109I, the same vole-adapted CWD strain was isolated from NA mule deer (Odocoileus hemionus), white-tailed deer (Odocoileus virginianus), and elk isolates, which was characterized by an unprecedented short disease duration and peculiar and recognizable strain features (24). Here, we extended our previous characterizations of NA CWD isolates and compared the biological properties of CWD isolates from Norway and NA by transmission to the Bv109I genetic line of bank voles.     

Virome Variation during Sea Star Wasting Disease Progression in Pisaster ochraceus (Asteroidea,Echinodermata)

Sea star wasting disease (SSWD) is a condition that has affected asteroids for over 120 years, yet mechanistic understanding of this wasting etiology remains elusive. We investigated temporal virome variation in two Pisaster ochraceus specimens that wasted in the absence of external stimuli and two specimens that did not experience SSWD for the duration of our study, and compared viromes of wasting lesion margin tissues to both artificial scar margins and grossly normal tissues over time. Global assembly of all SSWD-affected tissue libraries resulted in 24 viral genome fragments represented in >1 library. Genome fragments mostly matched densoviruses and picornaviruses with fewer matching nodaviruses, and a sobemovirus. Picornavirus-like and densovirus-like genome fragments were most similar to viral genomes recovered in metagenomic study of other marine invertebrates. Read recruitment revealed only two picornavirus-like genome fragments that recruited from only SSWD-affected specimens, but neither was unique to wasting lesions. Wasting lesion margin reads recruited to a greater number of viral genotypes (i.e., richness) than did either scar tissue and grossly normal tissue reads. Taken together, these data suggest that no single viral genome fragment was associated with SSWD. Rather, wasting lesion margins may generally support viral proliferation.     

Modeling Abundance of Culicoides stellifer,a Candidate Orbivirus Vector,Indicates Nonrandom Hemorrhagic Disease Risk for White-Tailed Deer (Odocoileus virginianus)

(1) Background: Hemorrhagic diseases in white-tailed deer (Odocoileus virginianus) are caused by orbiviruses and have significant economic impact on the deer ranching industry in the United States. Culicoides stellifer is a suspected vector of epizootic hemorrhagic disease virus (EHDV), with recent field evidence from Florida, but its natural history is poorly understood. Studying the distribution and abundance of C. stellifer across the landscape can inform our knowledge of how virus transmission can occur locally. We may then target vector management strategies in areas where viral transmission can occur. (2) Methods: Here, we used an occupancy modeling approach to estimate abundance of adult C. stellifer females at various physiological states to determine habitat preferences. We then mapped midge abundance during the orbiviral disease transmission period (May–October) in Florida. (3) Results: We found that overall, midge abundance was positively associated with sites in closer proximity to large-animal feeders. Additionally, midges generally preferred mixed bottomland hardwood and agricultural/sand/water habitats. Female C. stellifer with different physiological states preferred different habitats. (4) Conclusions: The differences in habitat preferences between midges across states indicate that disease risk for deer is heterogeneous across this landscape. This can inform how effective vector management strategies should be implemented.     

慢性肾脏病心血管疾病的新危险因素

心血管传统危险因素已不能完全解释慢性肾脏病（CKD）患者心血管疾病的高发率。CKD本身是一种血管病变状态,一系列新危险因素的研究为CKD心血管疾病的防治提供了新的干预靶点。     

慢性阻塞性肺疾病与心血管疾病相关性研究进展

众所周知,慢性阻塞性肺疾病是一种常伴随有显著肺外表现的慢性炎症性疾病,心血管疾病风险增加即此类肺外表现之一。慢性阻塞性肺疾病与心血管疾病之间相关机制复杂,吸烟、衰老、缺氧、全身性炎症、氧化应激及用药等多种因素均可能参与其中。现就其潜在关联机制的研究现状予以综述。     

慢性肾脏病与外周动脉疾病研究进展

慢性肾脏病患者外周动脉疾病发生率远高于普通人群,且和患者的心血管事件的危险性及病死率相关。现简述近年来有关慢性肾脏病患者中外周动脉疾病的流行病学、危险因素、临床表现的特点,并提出适合其特点的诊断和治疗方法。     

慢性肾脏疾病的心血管并发症及其处理

心血管疾病是慢性肾脏疾病的重要并发症及透析患者的重要死亡原因,重视心血管疾病预防和治疗对改善慢性肾脏疾病患者的预后具有极重要的意义。现就近年来慢性肾脏疾病并发心血管疾病的流行病学情况、临床预后及相关处理等问题作一简要综述。     

Colicinogeny in Chronic Inflammatory Bowel Disease

Bure? J, Horák V, Bure?ová E, Fixa B, Komárková O, Hartmann M. Colicinogeny in chronic inflammatory bowel disease. Scand J Gastroenterol 1986, 21, 819-823

There are several indirect arguments for a possible role of colicins in chronic inflammatory bowel disease (IBD). Colicinogeny was therefore investigated in 54 patients with ulcerative colitis, 39 patients with Crohn's disease, and 160 clinically healthy controls. No significant difference was found among the examined groups. The leukocyte migration inhibition test (with colicins as antigens) was performed to estimate cellular hypersensitivity to colicins. Migration indices not exceeding the normal range in controls contrasted with abnormal values found in 36% of ulcerative colitis and 80% of Crohn's disease patients. The results are believed to be proof of cellular hypersensitivity of IBD patients to colicins of their own Escherichia coli strains. The importance of this finding must be further clarified.     

SARS-CoV-2 Omicron (B.1.1.529) Infection of Wild White-Tailed Deer in New York City

There is mounting evidence of SARS-CoV-2 spillover from humans into many domestic, companion, and wild animal species. Research indicates that humans have infected white-tailed deer, and that deer-to-deer transmission has occurred, indicating that deer could be a wildlife reservoir and a source of novel SARS-CoV-2 variants. We examined the hypothesis that the Omicron variant is actively and asymptomatically infecting the free-ranging deer of New York City. Between December 2021 and February 2022, 155 deer on Staten Island, New York, were anesthetized and examined for gross abnormalities and illnesses. Paired nasopharyngeal swabs and blood samples were collected and analyzed for the presence of SARS-CoV-2 RNA and antibodies. Of 135 serum samples, 19 (14.1%) indicated SARS-CoV-2 exposure, and 11 reacted most strongly to the wild-type B.1 lineage. Of the 71 swabs, 8 were positive for SARS-CoV-2 RNA (4 Omicron and 4 Delta). Two of the animals had active infections and robust neutralizing antibodies, revealing evidence of reinfection or early seroconversion in deer. Variants of concern continue to circulate among and may reinfect US deer populations, and establish enzootic transmission cycles in the wild: this warrants a coordinated One Health response, to proactively surveil, identify, and curtail variants of concern before they can spill back into humans.     

Correlation of Genotypes and Route of Transmission with Histologic Activity and Disease Stage in Chronic Hepatitis C

Our objective was to evaluate the histopathological features of chronic hepatitis C of 64 liver biopsies and to correlate this with the route of transmission of hepatitis C virus, the genotype of HCV, and the patient's age. Moderate chronic hepatitis was the most frequently observed (62.5%). Cirrhosis was observed in 14 patients (21.9%) and was more frequently found among patients over 40 years of age (34.3% vs 6.9%, P = 0.025). The mean histopathological activity index (HAI) was significantly higher in the sporadic (10 ± 3.1) than the posttransfusional (7.5 ± 3.7) and the intravenous drug use (IVDU) groups (6.3 ± 2.8) (P < 0.02). Moreover the sporadic group showed more fibrosis (P < 0.04) than the posttransfusional group. No liver cirrhosis was found in the IVDU group. The overall prevalence of HCV variants was: 54.7% type 1b, 4.6% type 1a, 37.5% type 2c, 1.6% type 2b, 1.6% type 2. The genotype distribution showed no relation to the HAI, hepatitis activity (grade), and fibrosis (stage) of the liver disease. In conclusion, the sporadic route of transmission of HCV was related to a more severe chronic hepatic disease, a finding that could influence future antiviral therapies. The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our data suggests that the ultimate consequence of HCV chronic infection depends on patient age rather than on HCV genotype.     

死胎胎盘组织中HBcAg表达的临床和病理研究

观察乙型肝炎病毒在胎盘、肝组织中的表达和引起胎盘组织的病理改变情况。采集40例乙型肝炎产妇产下的死胎，常规尸检，取胎盘、肝组织，SP法检测HBsAg，常规病理观察；回访婴母产前静脉血HBV的检测结果。HBcAg阳性颗粒在死胎胎盘的蜕膜细胞、滋养层细胞、绒毛间质细胞、绒毛毛细血管内皮细胞浆、血管中呈点、灶关分布，细胞的核不着色。HBV呈单项阳性、小三阳、大三阳的婴母分娩的死胎胎盘组织中HBcAg阳性率；死胎胎盘的蜕膜细胞、滋养层细胞、绒毛间质细胞、绒毛毛细血管内皮细胞中HBcAg阳性率，彼此比较，差异不显著（P＞0．05）。死胎胎盘绒毛发育迟缓、慢性绒毛炎、单脐动脉的发生经；HBV呈单项阳性、小三阳、大三阳的婴母分娩的死胎肝组织中HBcAg阳性率，彼此比较，差异显著（P＜0．05）。HBV绩婴传播可能还存在一种从母体面向胎儿的细胞转移方式；HBV可以导致胎盘发育不良和屏障功能障碍；死胎胎盘组织中HBcAg阳性经与孕妇HBV静脉中HBV标志无关；胎盘组织中可能存在HBC复制；死胎肝组织中HBcAg阳性表达与孕妇HBV感染状态、静脉中HBV标志有关。