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.     

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.     

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.     

Disease-causing mutations in Parkin impair mitochondrial ubiquitination,aggregation, and HDAC6-dependent mitophagy

Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson''s disease (AR-JP). How parkin suppresses Parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these “mito-aggresome” structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP–causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of Parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson''s disease.     

NONPOLIOVIRUSES AND PARALYTIC DISEASE

A number of nonpolioviruses have been implicated as the probable etiologic agents of paralytic illness clinically resembling poliomyelitis, including certain immunotypes of Coxsackie group A, Coxsackie group B, and ECHO viruses, and the viruses of mumps, herpes simplex and arthropod-borne encephalitides. A number of well documented cases provide evidence that some of these viruses may on occasion be the causative agents of severe, even fatal, myelitis, bulbomyelitis or encephalomyelitis, but they have been associated much more frequently with cases of “poliomyelitis” in which there has been slight to moderate paresis. In the aggregate, various “nonpolioviruses” have been encountered in approximately 10 per cent of the patients with clinical poliomyelitis studied, but it is uncertain how many of these cases may represent coincidental infections not causally related to the current illness.     

Production of Artificial “Case Histories” by using a Small Computer

This paper describes a method of producing artificial “case histories” by using probability theory and clinical data from a series of 600 patients with acute abdominal pain. A series of 12 such cases were distributed to clinicians, medical students, medical secretaries and technicians, and members of the general public. For each “case” most clinicians concurred with the intended diagnosis. So did the medical secretaries and technicians; indeed this group were more confident of their chosen diagnoses than were the clinicians.It is suggested that clinicians are concerned to a large extent with the consequences of a diagnosis as well as its accuracy, and are motivated to some degree by a fear of the consequences of failure. They may be justified in adopting this policy, for when “errors” in diagnosis are harshly penalized the clinicians were infinitely more effective than any of the other groups.     

Rift valley fever virus lacking the NSs and NSm genes is highly attenuated, confers protective immunity from virulent virus challenge, and allows for differential identification of infected and vaccinated animals

Rift Valley fever (RVF) virus is a mosquito-borne human and veterinary pathogen associated with large outbreaks of severe disease throughout Africa and more recently the Arabian peninsula. Infection of livestock can result in sweeping “abortion storms” and high mortality among young animals. Human infection results in self-limiting febrile disease that in ~1 to 2% of patients progresses to more serious complications including hepatitis, encephalitis, and retinitis or a hemorrhagic syndrome with high fatality. The virus S segment-encoded NSs and the M segment-encoded NSm proteins are important virulence factors. The development of safe, effective vaccines and tools to screen and evaluate antiviral compounds is critical for future control strategies. Here, we report the successful reverse genetics generation of multiple recombinant enhanced green fluorescent protein-tagged RVF viruses containing either the full-length, complete virus genome or precise deletions of the NSs gene alone or the NSs/NSm genes in combination, thus creating attenuating deletions on multiple virus genome segments. These viruses were highly attenuated, with no detectable viremia or clinical illness observed with high challenge dosages (1.0 × 10⁴ PFU) in the rat lethal disease model. A single-dose immunization regimen induced robust anti-RVF virus immunoglobulin G antibodies (titer, ~1:6,400) by day 26 postvaccination. All vaccinated animals that were subsequently challenged with a high dose of virulent RVF virus survived infection and could be serologically differentiated from naïve, experimentally infected animals by the lack of NSs antibodies. These rationally designed marker RVF vaccine viruses will be useful tools for in vitro screening of therapeutic compounds and will provide a basis for further development of RVF virus marker vaccines for use in endemic regions or following the natural or intentional introduction of the virus into previously unaffected areas.     

CEREBRAL COMPLICATIONS INCURRED DURING PREGNANCY AND THE PUERPERIUM

In a statistical study of maternal mortality cases in Franklin County, Ohio, with a total of 170 deaths in a ten-year period (1948-1957), there were 36 fatal cases with cerebral complications of various types. Intracranial hemorrhage was the cause of death in 17 cases; subarachnoid hemorrhage in eight; intracerebral hemorrhage in eight and subdural hemorrhage in one case. There were nine cases of intracranial tumor with fatality. In a miscellaneous group of ten “cerebral deaths” infectious processes were the cause in eight cases, including tuberculous meningitis, purulent meningitis, brain abscess, acute (cerebromedullary) poliomyelitis, “viral” encephalitis, toxoplasmosis and tetanus.In a smaller clinical (nonfatal) group with cerebral complications occurring during pregnancy and the puerperium, two patients with subarachnoid hemorrhages made spontaneous recovery. A diagnosis of intracerebral hemorrhage was made in three instances, in two of which operation was done and evacuation of blood clots was accomplished. One patient recovered spontaneously from a minimal hemorrhage.Five other persons had cerebral thrombosis, three in the third month of pregnancy and two in the immediate puerperium. All recovered, with some residual deficits.Three patients with intracranial tumor were successfully treated surgically but with disappointing results ultimately (one case each of cerebellar medulloblastoma, cerebral astrocytoma and supratentorial meningioma).Only when the obstetrician, neurologist and the neurosurgeon are fully aware of the signs, symptoms, and many times the rapid course of these cerebral complications of pregnancy, can there be any material lowering of the morbidity and mortality. Emphasis should be placed on the early investigation of all neurological complaints during pregnancy and the puerperium, with immediate institution of an aggressive diagnostic and therapeutic regimen.     

The Changing Epidemiology of Coccidioidomycosis in Los Angeles (LA) County,California, 1973–2011

Coccidioidomycosis, also known as Valley Fever, is often thought of as an endemic disease of central California exclusive of Los Angeles County. The fungus that causes Valley Fever, Coccidioides spp., grows in previously undisturbed soil of semi-arid and arid environments of certain areas of the Americas. LA County has a few large areas with such environments, particularly the Antelope Valley which has been having substantial land development. Coccidioidomycosis that is both clinically- and laboratory-confirmed is a mandated reportable disease in LA County. Population surveillance data for 1973–2011 reveals an annual rate increase from 0.87 to 3.2 cases per 100,000 population (n = 61 to 306 annual cases). In 2004, case frequency started substantially increasing with notable epidemiologic changes such as a rising 2.1 to 5.7 male-to-female case ratio stabilizing to 1.4–2.2. Additionally, new building construction in Antelope Valley greatly rose in 2003 and displayed a strong correlation (R = 0.92, Pearson p<0.0001) with overall LA County incidence rates for 1996–2007. Of the 24 LA County health districts, 19 had a 100%-1500% increase in cases when comparing 2000–2003 to 2008–2011. Case residents of endemic areas had stronger odds of local exposures, but cases from areas not known to be endemic had greater mortality (14% versus 9%) with notably more deaths during 2008–2011. Compared to the 57 other California counties during 2001–2011, LA County had the third highest average annual number of cases and Antelope Valley had a higher incidence rate than all but six counties. With the large number of reported coccidioidomycosis cases, multi-agency and community partnering is recommended to develop effective education and prevention strategies to protect residents and travelers.     

Inferring species trees from gene trees in a radiation of California trapdoor spiders (Araneae, Antrodiaetidae, Aliatypus)

Background

The California Floristic Province is a biodiversity hotspot, reflecting a complex geologic history, strong selective gradients, and a heterogeneous landscape. These factors have led to high endemic diversity across many lifeforms within this region, including the richest diversity of mygalomorph spiders (tarantulas, trapdoor spiders, and kin) in North America. The trapdoor spider genus Aliatypus encompasses twelve described species, eleven of which are endemic to California. Several Aliatypus species show disjunct distributional patterns in California (some are found on both sides of the vast Central Valley), and the genus as a whole occupies an impressive variety of habitats.

Methodology/Principal Findings

We collected specimens from 89 populations representing all described species. DNA sequence data were collected from seven gene regions, including two newly developed for spider systematics. Bayesian inference (in individual gene tree and species tree approaches) recovered a general “3 clade” structure for the genus (A. gulosus, californicus group, erebus group), with three other phylogenetically isolated species differing slightly in position across different phylogenetic analyses. Because of extremely high intraspecific divergences in mitochondrial COI sequences, the relatively slowly evolving 28S rRNA gene was found to be more useful than mitochondrial data for identification of morphologically indistinguishable immatures. For multiple species spanning the Central Valley, explicit hypothesis testing suggests a lack of monophyly for regional populations (e.g., western Coast Range populations). Phylogenetic evidence clearly shows that syntopy is restricted to distant phylogenetic relatives, consistent with ecological niche conservatism.

Conclusions/Significance

This study provides fundamental insight into a radiation of trapdoor spiders found in the biodiversity hotspot of California. Species relationships are clarified and undescribed lineages are discovered, with more geographic sampling likely to lead to additional species diversity. These dispersal-limited taxa provide novel insight into the biogeography and Earth history processes of California.     

Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

Summary: Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals. Four human retroviruses are currently known, including human immunodeficiency virus type 1, which causes AIDS, and human T-lymphotropic virus type 1, which causes cancer and inflammatory disease. For many years, there have been sporadic reports of additional human retroviral infections, particularly in cancer and other chronic diseases. Unfortunately, many of these putative viruses remain unproven and controversial, and some retrovirologists have dismissed them as merely “human rumor viruses.” Work in this field was last reviewed in depth in 1984, and since then, the molecular techniques available for identifying and characterizing retroviruses have improved enormously in sensitivity. The advent of PCR in particular has dramatically enhanced our ability to detect novel viral sequences in human tissues. However, DNA amplification techniques have also increased the potential for false-positive detection due to contamination. In addition, the presence of many families of human endogenous retroviruses (HERVs) within our DNA can obstruct attempts to identify and validate novel human retroviruses. Here, we aim to bring together the data on “novel” retroviral infections in humans by critically examining the evidence for those putative viruses that have been linked with disease and the likelihood that they represent genuine human infections. We provide a background to the field and a discussion of potential confounding factors along with some technical guidelines. In addition, some of the difficulties associated with obtaining formal proof of causation for common or ubiquitous agents such as HERVs are discussed.     

California encephalitis virus,a newly described agent

In three cases of encephalitis in humans that occurred in the area where the newly described California virus was isolated from mosquitoes, serological evidence seemed to indict the California virus as the etiological agent. In the case of an infant with very severe disease, the serological evidence was convincing; the evidence was almost as strong in the case of a seven-year-old boy; the results in an adult were equivocal. Inapparent infection in man is quite common as indicated by neutralization tests on the sera of nearly 600 residents of California, but encephalitic manifestations of infection are extremely rare. In Kern County, California, where the virus was discovered, approximately 11 per cent of the population has been infected. Infection rates are higher in adults than in very young children. Absence of neutralizing antibodies from 64 specimens of blood from persons in Japan, Washington, and other states supports the specificity of the neutralization test in man and suggests that this virus is absent or is not being similarly transmitted in some areas. Serological evidence from serial bleedings of two sick horses suggested, but did not definitely establish, that this virus leads to a naturally acquired encephalomyelitis in horses. Serological tests with the viruses of western equine and St. Louis encephalitis did not lead to any other etiological diagnosis in the sick animals studied. Results of neutralization tests on the sera of eight horses and three cows in Kern County suggested extremely high infection rates, and an immunity rate of 18 per cent was noted in rabbits and ground squirrels. In the natural biological cycle rabbits and ground squirrels are suspected as the possible counterpart of birds in the St. Louis and western equine virus cycles. There is no evidence from field or laboratory to indicate that birds become infected with the California virus. Sera from 33 mammals other than man were collected from Northern California and Washington. All were free from neutralizing antibodies, again supporting the specificity of positive findings from Kern County.     

Hospital Infections Caused by a Group of Recently Recognized Strains of Staphylococcus aureus

A survey was made of the phage-types of staphylococci responsible for cross-infection in a large veterans'' hospital between 1961 and 1964. An earlier survey had shown that in 1959 most of the infections were caused by staphylocci of the “80/81/82” group. In 1961 a new group of staphylococci were first recognized and provisionally designated as “Atypical Group III” strains; these were non-typable by the usual typing phages but showed inhibition patterns with some of the Group III phages. The “Atypical Group III” staphylococci all showed one or other of four patterns of multiple antibiotic resistance. By 1963 these resistant “Atypical Group III” staphylococci had become more frequent than “80/81/82” strains as causative agents of cross-infection, although both groups have continued to cause infections in the hospital. “Atypical Group III” strains mainly infected surgical wounds and skin ulcers, whereas “80/81/82” strains commonly produced primary skin sepsis, such as boils.     

The Normal Thyroidal Uptake of Iodine

The range of values for the 24-hour thyroidal accumulation of radioactive iodine in euthyroid persons varies with geographic location. In the San Bernardino Valley region of Southern California the “normal range” is 6 percent to 33 percent in euthyroid subjects. This is lower than in studies from other areas of the United States. The urinary iodide excretion and the absolute iodine uptake of the thyroid are higher than in studies from many other areas of the United States, pointing to iodine abundance as the reason for this difference. The geographic variation and the possibility of changing dietary iodine intake of normal persons point to the necessity of current and local determinations of the “normal range” of the thyroidal uptake of radioiodine if the results of this thyroid function test are to be properly interpreted.     

Clinical Presentation of Acute Abdomen: Study of 600 Patients

This paper presents the clinical features of 600 patients suffering from abdominal pain of acute onset and admitted to either the General Infirmary or St. James''s Hospital, Leeds. The survey was initially retrospective, but later put on a prospective basis. Roughly two-thirds of these 600 patients presented a “typical” picture of the disease with which they presented, while the remaining third presented one or more atypical features. Since other prospective studies have indicated that the diagnostic accuracy of a group of clinicians in respect of the acute abdomen is roughly 65% it is tentatively suggested (a) that clinical diagnosis contains a large element of “pattern-matching,” and (b) that such a policy can be expected to be ineffective in roughly one-third of all cases of acute abdominal pain.     

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.     

Occupational Dermatoses in Ontario, 1955 to 1962

In Ontario in 1962, with a compensationeligible labour force of 1,814,000, 10 out of each 1000 workers received compensation for some occupational dermatosis, as defined here; 36 out of each 1000 workers received compensation for some cause. Contact dermatitides made up 5042 of 7448 cases of occupational disease for which compensation and/or medical aid was paid in 1955 and 1956. In eight years, 1955 to 1962 (inclusive), of a total of 534,557 “compensation only” cases, 7023 received payment for contact dermatitis. The average yearly cost of compensation of a worker with a contact dermatitis was estimated at $1113; the annual total cost, at $900,000. The average cost of an occupational dermatosis was $368; the annual total cost, $10 million. Occupational dermatoses account for almost one-third of all compensation costs. The cost of “medical aid only” is excluded from all of these estimates. In contact dermatitis, primary irritants (chemicals) are still the main causative agents. Skin sensitizers, the epoxy resins particularly, have become more prominent in recent years. There is no all-purpose barrier cream or protective clothing. Proper personal hygiene remains the most effective preventive agent in industry.     

Psychiatric assessment of patients with “20th-century disease” (“total allergy syndrome”)

“Twentieth-century disease”, or “total allergy syndrome”, is a condition attributed to hypersensitivity to the environment that may sometimes be seen as so serious that the patient is incapable of living in the modern world. Although the popular media frequently carry stories about it, there is little scientific literature. It is diagnosed by clinical ecologists, who maintain, among other theories, that susceptible individuals experience an overload in assaults by artificial materials in the environment. The patients usually have multiple ill defined symptoms for which no organic cause can be found, but they vigorously resist psychiatric referral, as they attribute their symptoms to allergy. A group of 18 patients who were purportedly suffering from 20th-century disease were referred to a university psychiatric consultation liaison service. They virtually all had a long history of visits to physicians, and their symptoms were characteristic of several well known psychiatric disorders. The case histories and management of three of them are presented. Although this group of patients may have been atypical in that they had more severe psychologic symptoms, the experience indicates that a psychiatric diagnosis ought to be considered. The symptoms of 20th-century disease have much in common with other conditions known to physicians for centuries.     

PRINCIPLES OF DIAGNOSING OCCUPATIONAL DISEASES—Special Considerations to Avoid “Creating” an Entity

The traditional diagnostic procedure adhered to in general medicine is too frequently neglected when a physician is confronted with a possible occupational disease. Also, the proper diagnosis in occupational medicine requires additional effort along lines of investigation not necessary in general medicine. Failure to conform to the basic steps as outlined in this paper will distort known entities or “create” false ones.     

Limitations of Radiology in the Differentiation of Diverticulitis and Diverticulosis of the Colon

While barium enema is the most useful investigation in the primary diagnosis of diverticular disease of the colon, this paper presents further evidence that the terms “diverticulosis” and “diverticulitis” are unsatisfactory and shows that a radiological classification on the traditional criteria is not accurate in determining whether or not inflammation is associated with colonic diverticula.