WESTERN EQUINE AND ST. LOUIS ENCEPHALITIS IN MAN,CALIFORNIA, 1945-1950

A large group of etiologic agents, some known and some unknown, produce in man a clinical syndrome now labeled “infectious encephalitis.”The separation, from this larger group, of single disease entities which cause similar clinical symptoms is possible, but calls for diagnostic acumen plus supporting laboratory evidence. Two etiologically specific entities, western equine encephalitis and St. Louis encephalitis, are frequently encountered in rather well-defined areas of California, the Central Valley and Imperial Valley; and there is a definite seasonal pattern of occurrence—June through October. There are certain guides that are helpful in differential diagnosis. Establishing a diagnosis on the basis of clinical evidence is difficult. Laboratory studies are of great importance not only for diagnosis in the individual case but for advancement of etiology. Specimens are worthless unless taken at proper intervals and submitted by methods described.It is probable that encephalitides caused by still unknown agents exist in California. The isolation and identification of new encephalitogenic viral agents will depend in large measure upon the submission by physicians of suitable specimens from patients with central nervous system disease in which the cause is obscure.     

Solid‐phase synthesis and screening of a library of C‐terminal arginine peptide aldehydes against Murray Valley encephalitis virus protease

Murray Valley encephalitis virus is a member of the flavivirus group, a large family of single‐stranded RNA viruses, which cause serious disease in all regions of the world. Unfortunately, no suitable antivirals are available, and there are commercial vaccines for only three flaviviruses. The solid‐phase synthesis of a library of 400 C‐terminal arginine peptide aldehydes and their screening against Murray Valley encephalitis virus protease are demonstrated. The library was utilised to elucidate several tripeptide sequences that can be used as inhibitors in further SAR studies. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Arboviruses associated with human disease in Australia

Mosquito-borne arboviruses are an important public health issue in Australia. The alphaviruses Ross River and Barmah Forest virus are widespread and active annually, and cause debilitating polyarthritis. The flaviviruses Murray Valley encephalitis, Kunjin and Japanese encephalitis virus are restricted in distribution and activity but may cause life-threatening illness, and dengue viruses are active in some areas.     

Biochemical characterisation of Murray Valley encephalitis virus proteinase

Murray Valley encephalitis virus (MVEV) is a member of the flavivirus group, a large family of single stranded RNA viruses, which cause serious disease in all regions of the world. Its genome encodes a large polyprotein which is processed by both host proteinases and a virally encoded serine proteinase, non-structural protein 3 (NS3). NS3, an essential viral enzyme, requires another virally encoded protein cofactor, NS2B, for proteolytic activity. The cloning, expression and biochemical characterisation of a stable MVEV NS2B-NS3 fusion protein is described.     

Genetic diversity of collaborative cross mice enables identification of novel rift valley fever virus encephalitis model

Rift Valley fever (RVF) is an arboviral disease of humans and livestock responsible for severe economic and human health impacts. In humans, RVF spans a variety of clinical manifestations, ranging from an acute flu-like illness to severe forms of disease, including late-onset encephalitis. The large variations in human RVF disease are inadequately represented by current murine models, which overwhelmingly die of early-onset hepatitis. Existing mouse models of RVF encephalitis are either immunosuppressed, display an inconsistent phenotype, or develop encephalitis only when challenged via intranasal or aerosol exposure. In this study, the genetically defined recombinant inbred mouse resource known as the Collaborative Cross (CC) was used to identify mice with additional RVF disease phenotypes when challenged via a peripheral foot-pad route to mimic mosquito-bite exposure. Wild-type Rift Valley fever virus (RVFV) challenge of 20 CC strains revealed three distinct disease phenotypes: early-onset hepatitis, mixed phenotype, and late-onset encephalitis. Strain CC057/Unc, with the most divergent phenotype, which died of late-onset encephalitis at a median of 11 days post-infection, is the first mouse strain to develop consistent encephalitis following peripheral challenge. CC057/Unc mice were directly compared to C57BL/6 mice, which uniformly succumb to hepatitis within 2–4 days of infection. Encephalitic disease in CC057/Unc mice was characterized by high viral RNA loads in brain tissue, accompanied by clearance of viral RNA from the periphery, low ALT levels, lymphopenia, and neutrophilia. In contrast, C57BL/6 mice succumbed from hepatitis at 3 days post-infection with high viral RNA loads in the liver, viremia, high ALT levels, lymphopenia, and thrombocytopenia. The identification of a strain of CC mice as an RVFV encephalitis model will allow for future investigation into the pathogenesis and treatment of RVF encephalitic disease and indicates that genetic background makes a major contribution to RVF disease variation.     

Vectorial role of some dermanyssoid mites (Acari, Mesostigmata, Dermanyssoidea)

Among transmissible diseases, vectorial diseases represent a major problem for public health. In the group of acarina, while ticks are the most commonly implicated vectors, other arthropods and notably Dermanyssoidea are also involved in the transmission of pathogenic agents. Since the role of this superfamily is at present largely unknown, we have reviewed the vectorial role of these mites in the appearance, survival and propagation of pathogens. Various authors have shown that Dermanyssoidea are implicated in the transmission of both bacteria (Salmonella, Spirocheta, Rickettsia or Pasteurella) and viruses (equine encephalitis viruses, West Nile virus, Fowl pox virus, the virus causing Newcastle disease and tick borne encephalitis viruses or hantaviruses). Finally, some authors have also shown their role in the transmission of some protozoa and filaria. As the vectorial character of such mites has been more clearly demonstrated (Dermanyssus gallinae, Omithonyssus bacoti and Allodermanyssus sanguineus), it would be interesting to continue studies to better understand the role of this superfamily in the epidemiology of certain zoonoses.     

A Multiplex PCR/LDR Assay for the Simultaneous Identification of Category A Infectious Pathogens: Agents of Viral Hemorrhagic Fever and Variola Virus

CDC designated category A infectious agents pose a major risk to national security and require special action for public health preparedness. They include viruses that cause viral hemorrhagic fever (VHF) syndrome as well as variola virus, the agent of smallpox. VHF is characterized by hemorrhage and fever with multi-organ failure leading to high morbidity and mortality. Smallpox, a prior scourge, has been eradicated for decades, making it a particularly serious threat if released nefariously in the essentially non-immune world population. Early detection of the causative agents, and the ability to distinguish them from other pathogens, is essential to contain outbreaks, implement proper control measures, and prevent morbidity and mortality. We have developed a multiplex detection assay that uses several species-specific PCR primers to generate amplicons from multiple pathogens; these are then targeted in a ligase detection reaction (LDR). The resultant fluorescently-labeled ligation products are detected on a universal array enabling simultaneous identification of the pathogens. The assay was evaluated on 32 different isolates associated with VHF (ebolavirus, marburgvirus, Crimean Congo hemorrhagic fever virus, Lassa fever virus, Rift Valley fever virus, Dengue virus, and Yellow fever virus) as well as variola virus and vaccinia virus (the agent of smallpox and its vaccine strain, respectively). The assay was able to detect all viruses tested, including 8 sequences representative of different variola virus strains from the CDC repository. It does not cross react with other emerging zoonoses such as monkeypox virus or cowpox virus, or six flaviviruses tested (St. Louis encephalitis virus, Murray Valley encephalitis virus, Powassan virus, Tick-borne encephalitis virus, West Nile virus and Japanese encephalitis virus).     

Serologic survey for selected arboviruses and other potential pathogens in wildlife from Mexico.

During 1988 and 1989, a serologic survey of wildlife was conducted in northeastern Mexico to determine the presence, prevalence, and distribution of arboviruses and other selected disease agents. Eighty mammal specimens were tested. Antibodies to vesicular stomatitis-Indiana, Venezuelan equine encephalitis-Mena II, Rio Grande virus, and vesicular stomatitis-New Jersey were detected predominantly in small mammals. Deer and mouflon (Ovis musimon) had antibodies to bluetongue and epizootic hemorrhagic disease. Two species had serologic evidence of recent exposure to Francisella tularensis. A white-tailed deer (Odocoileus virginianus) had antibodies to Anaplasma marginale. All specimens tested for antibodies against Yersinia pestis and Brucella abortus were negative. Sera from 315 birds were tested for antibody against five equine encephalitis viruses and six avian pathogens. During 1988, antibodies to Venezuelan equine encephalitis-Mena II, Venezuelan equine encephalitis-TC83, St. Louis encephalitis, eastern equine encephalitis, and western equine encephalitis were detected in birds of several species. Antibodies to Pasteurella multocida and Newcastle disease virus were also detected. Birds from five species presented antibodies to Mycoplasma meleagridis. Specimens tested for M. gallisepticum, M. synoviae, and Chlamydia psittaci were negative. To the best of our knowledge, this survey represents the first serologic evidence of bluetongue, Cache Valley virus, epizootic hemorrhagic disease, Jamestown Canyon virus, vesicular stomatitis-Indiana, vesicular stomatitis-New Jersey, Rio Grande virus, and tularemia reported among wildlife in Mexico.     

Idiopathic hypertrophic cranial pachymeningitis

Idiopathic hypertrophic cranial pachymeningitis is an infrequent chronic inflammatory process of unknown etiology which causes thickening of the dura mater and progressive neurologic alterations due to the compression of adjacent structures. A case is presented of an adult woman with a clinical syndrome consisting of headache, progressive visual loss and bilateral optic neuropathy. The diagnosis was based upon visualization of the thickened dura mater in neuroimaging studies and the exclusion of known causes by histopathological examination. Diagnosis and follow-up of this condition are currently easier with the use of nuclear magnetic resonance with contrast medium. Biopsy of the dura mater continues to be the gold standard for the definitive diagnosis of this disease. Steroid therapy causes clinical improvement in most of the patients; however, relapses are frequent, making necessary the concomitant use of other immunosuppressive agents such as cyclophosphamide or azathioprine. Mortality is low but definitive neurologic sequelae are common.     

Medical entomology: changes in the spectrum of mosquito-borne disease in Australia and other vector threats and risks, 1972–2004

Abstract   Our paper presents an assessment of research and operational development in relation to medically important mosquito-borne disease, mainly the arboviruses Ross River, Barmah Forest, Murray Valley encephalitis, Japanese encephalitis, Kunjin and dengue, but also with respect to malaria. Since 1972, there have been considerable gains in research output, organisational structure, communication, surveillance including quarantine inspection and operational control. This has been due to the 1974 epidemic of Murray Valley encephalitis virus extending into temperate Australia, increasing occurrence of Ross River and the dengue viruses, the discovery of Barmah Forest virus as a disease entity in 1988, and the introduction of Japanese encephalitis in 1995. Because many of the outputs involve methodologies of global import, this has resulted in an unprecedented upsurge in publications of international standard.     

Western equine encephalitis in infants; a report on three cases with sequelae

Approximately one-third of the laboratory-confirmed cases of Western equine encephalitis occur in children under the age of 10. The present paper describes three instances of Western equine encephalomyelitis virus infection in infants under one year of age, together with the resultant sequelae. The difficulties associated with diagnosis of central nervous system disturbances in very young children are discussed, and it is pointed out that in view of the frequent occurrence of clinical infections with the arthropod-borne encephalitis viruses these agents should be given serious consideration as a cause of acute central nervous system infection in childhood and as the possible etiology for obscure, severe neurological disturbances in the pediatric age groups.     

WESTERN EQUINE ENCEPHALITIS IN INFANTS—A Report on Three Cases with Sequelae

Approximately one-third of the laboratory-confirmed cases of Western equine encephalitis occur in children under the age of 10. The present paper describes three instances of Western equine encephalomyelitis virus infection in infants under one year of age, together with the resultant sequelae. The difficulties associated with diagnosis of central nervous system disturbances in very young children are discussed, and it is pointed out that in view of the frequent occurrence of clinical infections with the arthropod-borne encephalitis viruses these agents should be given serious consideration as a cause of acute central nervous system infection in childhood and as the possible etiology for obscure, severe neurological disturbances in the pediatric age groups.     

Japanese Encephalitis��A Pathological and Clinical Perspective

Japanese encephalitis (JE) is the leading form of viral encephalitis in Asia. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. JEV is endemic to many parts of Asia, where periodic outbreaks take hundreds of lives. Despite the catastrophes it causes, JE has remained a tropical disease uncommon in the West. With rapid globalization and climatic shift, JEV has started to emerge in areas where the threat was previously unknown. Scientific evidence predicts that JEV will soon become a global pathogen and cause of worldwide pandemics. Although some research documents JEV pathogenesis and drug discovery, worldwide awareness of the need for extensive research to deal with JE is still lacking. This review focuses on the exigency of developing a worldwide effort to acknowledge the prime importance of performing an extensive study of this thus far neglected tropical viral disease. This review also outlines the pathogenesis, the scientific efforts channeled into develop a therapy, and the outlook for a possible future breakthrough addressing this killer disease.     

Radiological aspects of collagen diseases

The collagen diseases, an ill-defined group of clinical entities, have as their basis a generalized alteration of the connective tissue, especially of its extracellular components. They include periarteritis nodosa, disseminated lupus erythematosus, dermatomyositis, scleroderma, rheumatic fever and rheumatoid arthritis. The radiological findings in a series of cases of these diseases were reviewed. In 28 cases of periarteritis, 20 cases showed some abnormal findings in the thorax. These included pleural effusions, pulmonary changes, pericardial effusions and cardiac enlargement. In 32 cases of disseminated lupus erythematosus, thoracic findings were noted in 21. They resembled the changes found in periarteritis. In some 25 cases of scleroderma, diverse radiological findings were noted. These included "cystic" changes in the lungs (one case) and pulmonary "hives." In the intestinal tract esophageal and small bowel alterations were found, both ectatic and stenotic. In the soft tissues of the "pressure areas" variable degrees of calcification were observed. Dermatomyositis is the rarest of the collagen disease group; only one autopsy-proven case is available for study. Chest x-rays taken a year before death showed slight cardiac enlargement. The lungs were clear. In acute rheumatic fever, x-ray examination may disclose pericardial or pleural effusion, and so-called rheumatic pneumonitis; the latter has no specific diagnostic features. Soft tissue swellings may develop around some of the joints. In rheumatoid arthritis, joint changes are numerous and fairly characteristic, and are followed in many cases by fibrous or bony ankylosis and deformities of considerable degree. Awareness of the commoner radiological changes in this entire group of diseases should result in earlier establishment of diagnosis, especially in the more obscure examples.     

Enterovirus Infections: Etiologic,Epidemiologic and Clinical Aspects

The term enteroviruses was introduced in 1957 to bring together in one large family the polioviruses, Coxsackie A and B and echoviruses, all agents for which the human alimentary tract is the natural habitat. At present more than 60 distinct members are recognized: three polioviruses, 24 Coxsackie A, six Coxsackie B and 30 echoviruses. The list of new members, particularly in the echo-group, grows regularly. The viruses are frequently widely disseminated in the summer and fall of the year, circulating chiefly among young children, causing both apparent and inapparent infection. The enteroviruses are responsible for a wide spectrum of clinical manifestations, including non-specific febrile illness, sometimes with rash, aseptic meningitis, paralytic disease, respiratory infections, pericarditis and myocarditis. There is considerable overlap in biologic behavior, and the same syndrome can be induced by many different agents.In a few instances the clinical pattern is distinct enough to suggest the group of agents involved. Thus, herpangina is associated with the Coxsackie A viruses and epidemic myalgia (devil''s grip) with the Coxsackie B group. Paralytic disease is caused primarily by the polioviruses, but recently it has been found that other members, particularly the Coxsackie B viruses and Coxsackie A7 can also cause “paralytic poliomyelitis.”The ultimate potential of enteroviruses in terms of central nervous system disease and other manifestations is unpredictable. Great variety in terms of clinical and epidemiologic behavior of known and “new” viruses has been the pattern in the past, and is likely to continue.     

Q. & A. on C. P. S

Encephalitis is a challenging public health problem in Kern County and in the San Joaquin Valley area. During the last ten years the authors have studied the epidemiology of encephalitides due to arthropod-borne viruses and the methods used in the differential dignosis of these conditions. To incriminate a virus it is necessary to demonstrate a rise in antibody titer in the blood over a period of seven to fourteen days, the first specimen to be taken as soon as possible after onset of symptoms. A variety of tests may be necessary in some cases. Among the patients included in this presentation the greater number of those with encephalitis and also of those with poliomyelitis were under 30 years of age. The age range was five weeks to 49 years. The median annual mortality rate was 4.3 deaths per 100 cases for poliomyelitis and 3.9 for encephalitis. The greatest incidence occurred during the summer months.The clinical manifestations usually observed in encephalitis are described, but it is emphasized that wide variations and even completely atypical clinical phenomena are encountered. Four representative cases are reported and treatment is discussed. Vaccination and vector control are considered as the most promising means of combating the disease.     

Klinik und Genetik der spastischen Spinalparalysen

Even before the advent of next generation sequencing (NGS), multiple loci for hereditary spastic paraplegias (HSPs) had already been identified. In the last 2 years, dozens of new disease genes have been added, accounting for a total of 52 established HSP loci and 35 known HSP disease genes. With overlapping phenotypes for distinct genetic entities, the clinical diagnosis is often demanding and high-throughput genetic testing has to parallel a diagnostic workflow. Notwithstanding this aspect, spastin (SPAST) mutations evidently constitute the most important genetic cause in autosomal dominant paraplegia 4 (SPG4). Recently, large studies established that SPAST mutations are even causative in roughly 10?% of sporadic HSP patients. In this review, we suggest a diagnostic routine for HSP and elaborate on how detailed phenotyping and extensive genotyping will assist in the diagnosis of many more HSP subtypes. This ultimately will set a basis for selective clinical observations and therapy development.     

Clinical and diagnostic management of toxoplasmosis in the immunocompromised patient

With the advent of the highly active antiretroviral therapy (HAART), the natural course of HIV infection has markedly changed and opportunistic infections including toxoplasmosis have declined and modified in presentation, outcome and incidence. However, TE is a major cause of morbidity and mortality especially in resource-poor settings but also a common neurological complication in some countries despite the availability of HAART and effective prophylaxis. In most cases toxoplasmosis occurs in brain and toxoplasmic encephalitis (TE) is the most common presentation of toxoplasmosis in immunocompromised patients with or without AIDS. The need of a definitive diagnosis is substantial because other brain diseases could share similar findings. Rapid and specific diagnosis is thus crucial as early treatment may improve the clinical outcome. Classical serological diagnosis is often inconclusive as immunodeficient individuals fail to produce significant titres of specific antibodies. Polymerase chain reaction (PCR) has a high diagnostic value in the acute disease, but like many 'in-house' PCR assays, suffers from lack of standardization and variable performance according to the laboratory. Molecular diagnosis of toxoplasmosis can be improved by performing real-time PCR protocols. This article summarises the clinical manifestations, diagnostic procedures and management strategies for this condition.     

Partial nucleotide sequence of the Murray Valley encephalitis virus genome. Comparison of the encoded polypeptides with yellow fever virus structural and non-structural proteins

The sequence of 5400 bases corresponding to the 5'-terminal half of the Murray Valley encephalitis virus genome has been determined. The genome contains a 5' non-coding region of about 97 nucleotides, followed by a single continuous open reading frame that encodes the structural proteins followed by the non-structural proteins. Amino acid sequence homology between the Murray Valley encephalitis and yellow fever (Rice et al., 1985) polyproteins is 42% over the region sequenced. The start points of the various Murray Valley encephalitis virus-coded proteins have been assigned on the basis of this homology and a consistent set of potential proteolytic cleavage sites identified, the sequences of which are similar in Murray Valley encephalitis and yellow fever. The deduced Murray Valley encephalitis gene order is 5'-C-prM (M)-E-NS1-ns2a-ns2b-NS3-3'. The genome organization of Murray Valley encephalitis and yellow fever appears to be identical and the sizes of the predicted virus-coded proteins similar between the two viruses. Both viruses encode a basic capsid protein followed by three glycoproteins; the glycoproteins appear to have the conventional topology of N terminus outside with a C-terminal membrane-spanning domain. There are conserved glycosylation sites in prM, the precursor to the M protein of the virion, and in NS1, a non-structural protein of uncertain function. The glycosylation sites in E, the major envelope protein of the virion, are not conserved as to position. We predict the existence, in flavivirus-infected cells, of two small, hydrophobic peptides, ns2a and ns2b, which show only limited amino acid sequence homology. Finally, about half of the amino acid sequence of NS3 has been obtained; NS3 is a hydrophilic non-structural protein that shows 55% amino acid sequence similarity between Murray Valley encephalitis and yellow fever over the region sequenced and is probably involved in RNA replication.     

Molecular-based identification and phylogeny of genomic and proteomic sequences of mosquito-borne flavivirus

Mosquito-borne flaviviruses (MBFVs) are important cause of emerging and re-emerging human diseases nearly worldwide, transmitted by arthropod vectors (mostly aedes and culex mosquitoes), with particular reference to yellow fever virus, Japanese encephalitis virus, dengue fever virus, St. Louis encephalitis virus, Murray Valley encephalitis virus, etc. In over 100 countries, more than 2.5 billion people are at risk of infection, and approximately 20 million infections are reported annually. Through the analysis of gene sequence data of these virus populations it is possible to infer phylogenetic relationships, which in turn can yield important epidemiological information, including their demographic history. Early attempts to define the evolutionary relationships and origins of viruses in the genus flavivirus are hampered by the lack of genetic information particularly amongst the MBFVs. In this study, complete genome, translated polyprotein, structural and non-structural proteins of MBFVs have been targeted and revealed an extensive series of clades defined by their epidemiology and disease associations. The branching patterns of at the deeper nodes of the resultant trees were different from those reported in the previous study. The significance of these observations is discussed.