Prion science and its unsung heroes.

My first encounter with prion diseases dates to 1986. As a clinical resident in neuropathology, I was tasked with performing autopsies of patients who died of mysterious brain diseases. In his early 60s, my patient had developed a form of dementia that progressed at a terrifyingly rapid pace and eventually led to his death. I sampled the patient's brain and processed it for histological examination. The microscope revealed an eerie landscape of destruction. All that was left in the patient's cortex were astrocytes and microglia, and the few remaining neurons showed extensive vacuolation of their bodies and processes. Such blazing destruction of the brain was indicative of just one diagnosis: Creutzfeldt-Jakob disease, a spongiform encephalopathy caused by enigmatic infectious agents called prions.

Creutzfeldt-Jakob disease: one hundred years of participation in the design of the transmissible spongiform encephalopathies / Doença de Creutzfeldt-Jakob: cem anos de participação no desenho das encefalopatias espongiformes transmissíveis

Creutzfeldt and Jakob's disease (CJD) has its initial milestone in the publication issued 100 years ago that precipitated its better clinical-pathological and etiological understanding. Now, it is established that it belongs to the group of the prion diseases or transmissible spongiform encephalopathies family. CJD is itself divided into several types, the most common being sporadic that is further subdivided according to the anatomoclinical expression, but mainly due to its aetiology regarding prionic protein or genotype.

A doença de Creutzfeldt e Jakob (CJD) tem seu marco inicial na publicação emitida há 100 anos que precipitou seu melhor entendimento clínico- patológico e etiológico. Agora, está estabelecido que pertence ao grupo da família das doenças de príons ou encefalopatias espongiformes transmissíveis. A própria CJD se divide em vários tipos, sendo o mais comum o esporádico que também se subdivide de acordo com a expressão anatomoclínica, mas principalmente devido à sua etiologia em relação à proteína priônica ou genótipo.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2019.

Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2019. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2019, 513 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as 'incomplete'; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as 'definite' and seven as 'probable' prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified.

Person and ethics of a psychiatrist during National Socialism: Friedrich Meggendorfer (1880-1953).

Evaluation of sources not previously considered makes it possible to describe Friedrich Meggendorfer's role as a National Socialist university psychiatrist. Relevant archive material and literature were both assessed. The gene-hygiene affinity promulgated by Meggendorfer was based on his own scientific interests, early academic influences, and also positive reinforcement from his career choices. His application of scientific knowledge in the legitimization of National Socialist jurisdiction reflects a dark facet in Meggendorfer's life. One can also criticize his ethics in failing to use his eugenics expertise to stop 'euthanasia'. Future studies into the history of the ethical aspects of Nazi psychiatry should benefit from the setting up of criteria for the collection of biographical data. This would render comparisons and contrasts fairer and more stable.

Insights from Therapeutic Studies for PrP Prion Disease.

Although an effective therapy for prion disease has not yet been established, many advances have been made toward understanding its pathogenesis, which has facilitated research into therapeutics for the disease. Several compounds, including flupirtine, quinacrine, pentosan polysulfate, and doxycycline, have recently been used on a trial basis for patients with prion disease. Concomitantly, several lead antiprion compounds, including compound B (compB), IND series, and anle138b, have been discovered. However, clinical trials are still far from yielding significantly beneficial results, and the findings of lead compound studies in animals have highlighted new challenges. These efforts have highlighted areas that need improvement or further exploration to achieve more effective therapies. In this work, we review recent advances in prion-related therapeutic research and discuss basic scientific issues to be resolved for meaningful medical intervention of prion disease.

Creutzfeldt-Jakob disease surveillance in Australia: update to December 2014.

Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2014, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2014, and retrospectively to 1970.

Estimation of the exposure of the UK population to the bovine spongiform encephalopathy agent through dietary intake during the period 1980 to 1996.

Although the incidence of variant Creutzfeldt-Jakob disease (vCJD) has declined to 1 since 2012 in the UK, uncertainty remains regarding possible future cases and the size of the subclinical population that may cause secondary transmission of the disease through blood transfusion. Estimating the number of individuals who were exposed to the bovine spongiform encephalopathy (BSE) infectious agent and may be susceptible to vCJD will help to clarify related public health concerns and plan strategies. In this paper, we explore this estimate by describing the probability of potential exposure due to dietary intake throughout the BSE epidemic period from 1980 to 1996 as a stochastic Poisson process. We estimate the age- and gender-specific exposure intensities in food categories of beef and beef-containing dishes, burgers and kebabs, pies, and sausages, separating the two periods of 1980-1989 and 1990-1996 due to the specified bovine offal legislation of 1989. The estimated total number of (living) exposed individuals during each period is 5,089,027 (95% confidence interval [CI] 4,514,963-6,410,317), which was obtained by multiplying the population size of different birth cohorts by the probability of exposure via dietary intake and the probability of survival until the end of 2013. The estimated number is approximately doubled, assuming a contamination rate of [Formula: see text]. Among those individuals estimated, 31,855 (95% CI 26,849-42,541) are susceptible to infection. We also examined the threshold hypothesis by fitting an extreme-value distribution to the estimated infectious dose of the exposed individuals and obtained a threshold estimate of 13.7 bID50 (95% CI 6.6-26.2 bID50) (Weibull). The results provide useful information on potential carriers of prion disease who may pose a threat of infection via blood transfusion and thus provide insight into the likelihood of new incidents of vCJD occurring in the future.

[Development of neurology in Japan and its contribution to elucidate and resolve the sociomedical problems].

Japanese Society of Neurology (JSN) was established in 1960 with 643 members, and in 2009 it has grown up to a big society having more than 8,000 members including 3,600 neurology board specialists. JSN has greatly contributed in elucidating and resolving many socio-medical problems. I will take three topics including SMON (subacute myelo-optico-neuropathy), infectious Creutzfeldt-Jakob disease (CJD) and Minamata disease. SMON was a new epidemic disease characterized by subacute optic neuritis and myeloneuropathy associated with diarrhea and abdominal symptoms. The research committee clarified that it was a neurological complication of chinoform, a drug for gastroenteritis. CJD surveillance started in 1996 for variant CJD, and uncovered many patients who developed CJD after human dura draft. The government prohibited to use non-inactivated human dura. Minamata disease is an organic mercury poisoning of people who took fish contaminated by mercury in Minamata bay in Kumamoto or in Aganogawa river in Niigata. The factories discharged water contaminated with mercury which was accumulated in fish and shellfish. Still many victims claim for compensation to the companies and government. Neurologists in Kumamoto and Niigata greatly contributed to diagnose and treat the victims and to clarify the cause of the disease.

[History of 50 years of prion disease research].

The history of the research of the prion disease is consolidated in 50 years after the Japanese neurology association starts. It was proven that it was an infectious disease from kuru that was a local disease of New Guinea, explained how CJD, the scariest disease for a neurologist, had come to be called a prion disease, and even a newly emerging prion disease referred in the future.

Alfons Maria Jakob (1884-1931), neuropathologist par excellence. Scientific endeavors in Europe and the Americas.

The study briefly reviews the life and work of Alfons Maria Jakob (1884-1931), a notable representative of pre-war German neuropathology. Today Jakob is mainly remembered by neurologists for the spongiform encephalopathy with progressive dementia and spasticity that he, and Kiel neuropathologist Hans Gerhard Creutzfeldt (1885-1964), described independently. However, Jakob has left additional contributions to neuroanatomy, neuropathology and neuropsychiatry in the form of original articles and valuable monographs.

When cows fly: expanding cognizable injury-in-fact and interest group litigation.

This Note takes an in-depth look at standing and, specifically, the extent to which increased risk of exposure to toxins caused by a government agency's regulations constitutes a judicially cognizable injury-in-fact. Despite over a century of case law on the topic, standing doctrine remains in flux and ill defined, largely due to the constantly changing ideological makeup of the U.S. Supreme Court. The lower courts are divided on the question of whether increased risk of future harm constitutes an injury-in-fact. Using Baur v. Veneman as a case study, this Note argues for the expansion of the definition of injury-in-fact to include potential future injuries that result from a specific government policy.

Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs.

A wide variety of neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates. More recently, the genetic identification of mutations in familial counterparts to the sporadic disorders, leading to the development of in vitro and in vivo model systems, has provided insights into disease pathogenesis. The effect of many of these mutations is the abnormal processing of misfolded proteins that overwhelms the quality-control systems of the cell, resulting in the deposition of protein aggregates in the nucleus, cytosol and/or extracellular space. Further understanding of mechanisms regulating protein processing and aggregation, as well as of the toxic effects of misfolded neurodegenerative disease proteins, will facilitate development of rationally designed therapies to treat and prevent these disorders.