Comparative Pathogenesis of Three Human and Zoonotic SARS-CoV Strains in Cynomolgus Macaques

The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. While there were significant differences in the number of host genes differentially regulated during the host responses between the three SARS-CoV strains, the top pathways and functions were similar and only apparent early during infection with the majority of genes associated with interferon signaling pathways. This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use

Host response dynamics following lethal infection of rhesus macaques with zaire ebolavirus

To gain further insight into the interdependent pathogenic processes in Ebola hemorrhagic fever (EHF), we have examined the dynamics of host responses in individual rhesus macaques infected with Zaire ebolavirus over the entire disease course. Examination of coagulation parameters revealed that decreased coagulation inhibitor activity triggered severe coagulopathy as indicated by prolonged coagulation times and decreased fibrinogen levels. This has been proposed as one of the significant mechanisms underlying disseminated intravascular coagulation in EHF patients. Furthermore, monitoring of expression levels for cytokines/chemokines suggested a mixed anti-inflammatory response syndrome (MARS), which indicates that a catastrophic uncontrolled immunological status contributes to the development of fatal hemorrhagic fever. These results highlight the pathological analogies between EHF and severe sepsis and not only contribute to our understanding of the pathogenic process, but will also help to establish novel postexposure treatment modalities

Continued Utilization of CCR5 Coreceptor by a Newly Derived T-Cell Line-Adapted Isolate of Human Immunodeficiency Virus Type 1

The differential use of CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) may be intimately involved in the transmission and progression of human immunodeficiency virus infection. Changes in coreceptor utilization have also been noted upon adaptation of primary isolates (PI) to growth in established T-cell lines. All of the T-cell line-adapted (TCLA) viruses studied to date utilize CXCR4 but not CCR5. This observation had been suggested as an explanation for the sensitivity of TCLA, but not PI, viruses to neutralization by recombinant gp120 antisera and V3-directed monoclonal antibodies, but recent studies have shown coreceptor utilization to be independent of neutralization sensitivity. Here we describe a newly isolated TCLA virus that is sensitive to neutralization but continues to utilize both CXCR4 and CCR5 for infection. This finding further divorces coreceptor specificity from neutralization sensitivity and from certain changes in cell tropism. That the TCLA virus can continue to utilize CCR5 despite the changes that occur upon adaptation and in the apparent absence of CCR5 expression in the FDA/H9 T-cell line suggests that the interaction between envelope protein and coreceptor may be mediated by multiple weak interactions along a diffuse surface

Effects of Acute and Chronic Murine Norovirus Infections on Immune Responses and Recovery from Friend Retrovirus Infection▿

Murine norovirus (MNV) is a highly infectious but generally nonpathogenic agent that is commonly found in research mouse colonies in both North America and Europe. In the present study, the effects of acute and chronic infections with MNV on immune responses and recovery from concurrent Friend virus (FV) infections were investigated. No significant differences in T-cell or NK-cell responses, FV-neutralizing antibody responses, or long-term recovery from FV infection were observed. We conclude that concurrent MNV infections had no major impacts on FV infections

Evaluation of psychological and physiological predictors of fatigue in patients with COPD

BACKGROUND: Fatigue in COPD impairs functional status; however there are few studies examining mechanistic pathways of this symptom. The aims of this study are to compare fatigue between COPD patients and healthy age-matched subjects, and to identify predictors of fatigue in COPD. METHODS: Seventy four COPD patients, mean age 69.9 (49-87) yrs, mean (SD) % predicted FEV1 46.5 (20.0) % and FEV1/FVC ratio 0.45 (0.13) and 35 healthy subjects, mean age 67.1 (50-84) yrs completed the Multidimensional Fatigue Inventory (MFI 20). Patients' assessment included Depression (HADS), lung function, BMI, muscle strength, incremental shuttle walk test (ISWT), exercise oxygen saturation (SpO2), Borg breathlessness (CR-10) and exertion (RPE). Serum level of Interleukin 6 (IL-6) was recorded. Differences in MFI 20 between groups were examined and predictors of fatigue identified using logistic regression. RESULTS: Significant differences (p < 0.01) were found between the COPD and healthy subjects for all MFI 20 dimensions. There were significant differences when classified according to GOLD and dyspnoea stages for selected dimensions only. Predictors of General Fatigue were depression, muscle strength and end SpO2 (R2 = .62); of Physical Fatigue: depression, % predicted FEV1, ISWT and age (R2 = .57); Reduced Activity: % predicted FEV1, BMI and depression (R2 = .36); Reduced Motivation: RPE, depression and end SpO2 (R2 = .37) and Mental Fatigue: depression and end SpO2 (R2 = .38). CONCLUSION: All dimensions of fatigue were higher in COPD than healthy aged subjects. Predictive factors differ according to the dimension of fatigue under investigation. COPD-RF is a multi component symptom requiring further consideration

Establishment of a Genetically Confirmed Breeding Colony of Mastomys natalensis from Wild-Caught Founders from West Africa

Mastomys natalensis are a ubiquitous and often dominant rodent across sub-Saharan Africa. Importantly, they are a natural reservoir for microbial pathogens including Lassa virus (LASV), the etiological agent of Lassa fever in humans. Lassa-infected rodents have been documented across West Africa and coincide with regions where annual outbreaks occur. Zoonotic transmission to humans most often occurs directly from infected rodents. Little is known about LASV infection kinetics and transmissibility in M.natalensis, primarily due to available animals. Here, we describe the establishment of a laboratory breeding colony of genetically confirmed M.natalensis from wild-captured rodents. This colony will provide a convenient source of animals to study LASV and other emerging pathogens that utilize M. natalensis in their enzootic lifecycles

Defining an Ultrasound- guided Regional Anesthesia Curriculum for Emergency Medicine

ObjectivesUltrasound- guided regional anesthesia (UGRA) can be a powerful tool in the treatment of painful conditions commonly encountered in emergency medicine (EM) practice. UGRA can benefit patients while avoiding the risks of procedural sedation and opioid- based systemic analgesia. Despite these advantages, many EM trainees do not receive focused education in UGRA and there is no published curriculum specifically for EM physicians. The objective of this study was to identify the components of a UGRA curriculum for EM physicians.MethodsA list of potential curriculum elements was developed through an extensive literature review. An expert panel was convened that included 13 ultrasound faculty members from 12 institutions and from a variety of practice environments and diverse geographical regions. The panel voted on curriculum elements through two rounds of a modified Delphi process.ResultsThe panelists voted on 178 total elements, 110 background knowledge elements, and 68 individual UGRA techniques. A high level of agreement was achieved for 65 background knowledge elements from the categories: benefits to providers and patients, indications, contraindications, risks, ultrasound skills, procedural skills, sterile technique, local anesthetics, and educational resources. Ten UGRA techniques achieved consensus: interscalene brachial plexus, supraclavicular brachial plexus, radial nerve, median nerve, ulnar nerve, serratus anterior plane, fascia iliaca, femoral nerve, popliteal sciatic nerve, and posterior tibial nerve blocks.ConclusionsThe defined curriculum represents ultrasound expert opinion on a curriculum for training practicing EM physicians. This curriculum can be used to guide the development and implementation of more robust UGRA education for both residents and independent providers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168368/1/aet210557.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168368/2/aet210557-sup-0001-DataSupplementS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168368/3/aet210557_am.pd