Review. The neuropathology of kuru and variant Creutzfeldt-Jakob disease

A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt-Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes (VV, MV and MM (where M is methionine and V is valine)) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrPCJD. vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.     

Review. The changing face of kuru: a personal perspective

The epidemic of kuru is now known to have been transmitted among the Fore by ritual consumption of infected organs from deceased relatives. As cannibalism was suppressed by government patrol officers during the 1950s, most transmission had ceased by 1957, when the kuru research programme first commenced. As predicted in the 1960s, the epidemic has waned, with progressive ageing of kuru-affected cohorts over the years to 2007. The few cases seen in the twenty-first century, with the longest incubation periods, were almost certainly exposed as children prior to 1960. Although the research programme had almost no role in bringing the kuru epidemic to an end, it did provide important knowledge that was to help the wider world in controlling the later epidemics of iatrogenic and variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy.     

Autophagy is a part of ultrastructural synaptic pathology in Creutzfeldt-Jakob disease: a brain biopsy study

Ultrastructural correlates of synaptic and dendritic spines loss have never been studied in detail in human transmissible spongiform encephalopathies (TSEs)—Creutzfeldt–Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease and fatal familial insomnia (FFI). In this paper, we describe synaptic alterations as found in brain biopsies from Creutzfeldt–Jakob disease and fatal familial insomnia patients. Our material consisted of brain biopsies obtained by open surgery from one FFI case, one case of variant Creutzfeldt–Jakob disease (vCJD), seven cases of sporadic Creutzfeldt–Jakob disease (sCJD) and one case of iatrogenic (human growth hormone) Creutzfeldt–Jakob disease (iCJD). For electron microscopy, approximately 2 mm³ samples were immersion fixed in 2.5% glutaraldehyde for less than 24 h, embedded in Epon and routinely processed. Grids were examined and photographed in a transmission electron microscope. The synaptic alterations were found constantly; in practically every brain biopsy they were frequent. The accumulation of different subcellular organelles (neuroaxonal dystrophy), dark synapses and branching cisterns were the most frequent findings while concentric arrays of membranes were only rarely found. Autophagic vacuoles are formed in many synapses in all categories of human transmissible encephalopathies. We conclude that synaptic autophagy contributes to overall synaptic loss in brains affected in prion diseases.     

Loss of the N-acetylgalactosamine side chain of the GPI-anchor impairs bone formation and brain functions and accelerates the prion disease pathology

Glycosylphosphatidylinositol (GPI) is a posttranslational glycolipid modification of proteins that anchors proteins in lipid rafts on the cell surface. Although some GPI-anchored proteins (GPI-APs), including the prion protein PrP^C, have a glycan side chain composed of N-acetylgalactosamine (GalNAc)−galactose−sialic acid on the core structure of GPI glycolipid, in vivo functions of this GPI-GalNAc side chain are largely unresolved. Here, we investigated the physiological and pathological roles of the GPI-GalNAc side chain in vivo by knocking out its initiation enzyme, PGAP4, in mice. We show that Pgap4 mRNA is highly expressed in the brain, particularly in neurons, and mass spectrometry analysis confirmed the loss of the GalNAc side chain in PrP^C GPI in PGAP4-KO mouse brains. Furthermore, PGAP4-KO mice exhibited various phenotypes, including an elevated blood alkaline phosphatase level, impaired bone formation, decreased locomotor activity, and impaired memory, despite normal expression levels and lipid raft association of various GPI-APs. Thus, we conclude that the GPI-GalNAc side chain is required for in vivo functions of GPI-APs in mammals, especially in bone and the brain. Moreover, PGAP4-KO mice were more vulnerable to prion diseases and died earlier after intracerebral inoculation of the pathogenic prion strains than wildtype mice, highlighting the protective roles of the GalNAc side chain against prion diseases.     

Redescription of Polydactylus sexfilis (Valenciennes in Cuvier and Valenciennes, 1831), a senior synonym of P. kuru (Bleeker, 1853) with designation of a lectotype (Perciformes: Polynemidae)

Polydactylus kuru (Bleeker, 1853), originally described from Jakarta, Java, Indonesia, has been regarded as a valid species. However, examination of two syntypes of Polynemus kuru revealed their close similarity to three syntypes of Polynemus sexfilis Valenciennes in Cuvier and Valenciennes, 1831, in the synonym of which the former is herein included. Polydactylus sexfilis, which is widely distributed in the Indo-Pacific region, is redescribed on the basis of a newly-designated lectotype and two paralectotypes, and a wide range of non-type material. The species is characterized by six pectoral filaments, 15 or 16 pectoral fin rays, 61–67 pored lateral line scales, 8–10 scales above the lateral line, 12–14 below, 11–14 and 15–18 upper and lower series gill rakers, respectively (27–31 total), teeth present on vomer and a long second dorsal fin ray (mean 26% [range 21–30%] of standard length). Received: July 7, 2000 / Revised: August 29, 2000 / Accepted: September 30, 2000     

Amyloid- and FDG-PET in sporadic Creutzfeldt-Jakob disease: Correlation with pathological prion protein in neuropathology

Introduction. The role of positron emission tomography (PET) in Creutzfeldt-Jakob disease is less defined than in other neurodegenerative diseases. We studied the correlation between the uptake of ¹⁸F-florbetaben and ¹⁸F-fluorodeoxyglucose with pathological prion protein deposition in histopathology in a case.Methods. A patient with 80 y old with a rapid neurological deterioration with a confirmed diagnosis of CJD was studied. PET and MRI studies were performed between 13–20 d before the death. A region of interest analysis was performed using Statistical Parametric Mapping.Results. MRI showed atrophy with no other alterations. FDG-PET showed extensive areas of hypometabolism including left frontoparietal lobes as well as bilateral thalamus. Correlation between uptake of ¹⁸F-florbetaben and pathological prion protein deposition was r = 0.786 (p < 0.05). Otherwise, correlation between uptake of ¹⁸F-FDG and pathological prion protein was r = 0.357 (p = 0.385). Immunohistochemistry with β-amyloid did not show amyloid deposition or neuritic plaques.Conclusions. Our study supports the use of FDG-PET in the assessment of CJD. FDG-PET may be especially useful in cases of suspected CJD and negative MRI. Furthermore, this case report provides more evidence about the behavioral of amyloid tracers, and the possibility of a low-affinity binding to other non-amyloid proteins, such as the pathological prion protein, is discussed.     

Prevalence of depression in tuberculosis patients in comparison with non-tuberculosis family contacts visiting the DOTS clinic in a Nigerian tertiary care hospital and its correlation with disease pattern

Background Individuals with chronic diseases such as tuberculosis often have comorbid de-pression that requires frequent hospitalisations. This poses great challenges to the care of such patients.Objective This study aimed at determining the prevalence of depression in tuberculosis patients in comparison with non-tuberculosis controls, and its correlation with disease pattern.Method Eighty-eight patients with tuberculosis and 81 family members visiting the DOTS Centre at University College Hospital Ibadan Centre were screened for depression. Severity of depression was assessed using the Hamilton Depression Scale and was compared with severity of pulmonary tuberculosis.Results The prevalence of depression was 45.5% among patients and 13.4% among family members. Depression was more prevalent among patients that were elderly (P = 0.001), with extensive disease (P = 0.01), of long duration (P = 0.03), those with category 2 tuberculosis (P = 0.003), those from a nuclear family (P = 0.01) and patients that were unmarried (P = 0.02).Conclusion The impact of chronic diseases such as tuberculosis extends beyond physical impairment. It includes behavioural consequences, in this instance depression, for both the patient and the primary care givers. Thus, the care of patients with tuberculosis should be comprehensive and include consultative–liaison psychiatric care.     

Molecular cloning and sequence analysis of prion protein gene in Xiji donkey in China

Prion diseases are a group of human and animal neurodegenerative disorders caused by the deposition of an abnormal isoform prion protein (PrP^Sc) encoded by a single copy prion protein gene (PRNP). Prion disease has been reported in many herbivores but not in Equus and the species barrier might be playing a role in resistance of these species to the disease. Therefore, analysis of genotype of prion protein (PrP) in these species may help understand the transmission of the disease. Xiji donkey is a rare species of Equus not widely reared in Ningxia, China, for service, food and medicine, but its PRNP has not been studied. Based on the reported PrP sequence in GenBank we designed primers and amplified, cloned and sequenced the PRNP of Xiji donkey. The sequence analysis showed that the Xiji donkey PRNP was consisted of an open reading frame of 768 nucleotides encoding 256 amino acids. Amino acid residues unique to donkey as compared with some Equus animals, mink, cow, sheep, human, dog, sika deer, rabbit and hamster were identified. The results showed that the amino acid sequence of Xiji donkey PrP starts with the consensus sequence MVKSH, with almost identical amino acid sequence to the PrP of other Equus species in this study. Amino acid sequence analysis showed high identity within species and close relation to the PRNP of sika deer, sheep, dog, camel, cow, mink, rabbit and hamster with 83.1–99.7% identity. The results provided the PRNP data for an additional Equus species, which should be useful to the study of the prion disease pathogenesis, resistance and cross species transmission.     

Genome wide computational analysis of Brugia malayi helicases: a comparison with human host

The availability of Brugia malayi genome sequence has paved ways for the search of homologues for a variety of genes. Helicases are ubiquitous enzymes involved in all the nucleic acid metabolic pathways and are essential for the development and growth. The genome wide analysis of B. malayi for different helicases showed the presence of a number of DEAD box helicases, 7 DEAH box helicases, RecQ helicases, repair helicases, super killer helicases, MCM2-7 complex, Rad54 and two subunits of Ku helicase. The comparison of protein sequence of each helicase with its human counterpart indicated characteristic differences in filarial helicases. There are noticeable differences in some of the filarial helicases such as DHX35, RecQL1 and Ku. Further characterization of these helicases will help in understanding physiological significance of these helicases in filarial parasites, which in future can be utilized for chemotherapy of parasitic infection.     

Mothers produce less aggressive sons with altered immunity when there is a threat of disease during pregnancy

Maternal experience before and during pregnancy is known to play a key role in offspring development. However, the influence of social cues about disease in the maternal environment has not been explored. We indirectly exposed pregnant mice to infected neighbours by housing them next to non-contagious conspecifics infected with Babesia microti. We examined the effect of this indirect immunological exposure on both the females and their adult offspring. Exposed females had higher levels of serum corticosterone and increased kidney growth compared with those with uninfected neighbours. These exposed females subsequently produced offspring that as adults showed an accelerated immune response to B. microti and less aggression in social groups. We suggest that ambient information regarding disease is used adaptively to maximize offspring survival and reproductive success in a challenging environment. Our results shed light on the impact of social information and maternal effects on life histories, and have important consequences for our understanding of epidemiology and individual disease susceptibility in humans and other animals. They also lead us to question the suitability of some laboratory housing conditions during experimental procedures, which may impact negatively upon both animal welfare and the validity of animal science.     

Central and peripheral forms of C-type natriuretic peptide (CNP): evidence for differential regulation in plasma and cerebrospinal fluid

Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in human plasma, provides a new approach to studies of CNP which is rapidly degraded at source. CNP is detectable in human CSF but the presence and proportions of NTproCNP in CSF are unknown. Since CNP is widely expressed throughout the CNS, we hypothesized that the ratio of NTproCNP to CNP in CSF is greatly increased when compared to plasma and that CSF CNP peptides may contribute to their concentrations in the systemic circulation. Concurrent plasma and CSF concentrations of CNP forms were measured in 51 subjects undergoing spinal anesthesia for arranged orthopedic procedures. Elevated concentrations of NTproCNP (1045 ± 359 pmol/L), characterized by HPLC-RIA, were found in CSF and greatly exceeded those of CNP (7.9 ± 3.2 pmol/L). The ratio of NTproCNP to CNP in CSF (145 ± 55) was much higher than in plasma (31 ± 27). A significant inverse relation was found between plasma and CSF CNP concentrations (r = −0.29, p < 0.05). cGMP and neprilysin were unrelated to CNP levels in CSF. We conclude that CNP is differentially regulated across the brain in normal health. Despite markedly elevated levels of NTproCNP in CSF, it is unlikely that these contribute to systemic levels in healthy adults. Identifying NTproCNP as the dominant CNP form in CSF opens up the possibility of its use in future studies exploring CNP regulation within the CNS and possible applications in the diagnosis and monitoring of subjects with central neural disorders.     

Natural history of a bighorn sheep pneumonia epizootic: Source of infection,course of disease,and pathogen clearance

A respiratory disease epizootic at the National Bison Range (NBR) in Montana in 2016–2017 caused an 85% decline in the bighorn sheep population, documented by observations of its unmarked but individually identifiable members, the subjects of an ongoing long‐term study. The index case was likely one of a small group of young bighorn sheep on a short‐term exploratory foray in early summer of 2016. Disease subsequently spread through the population, with peak mortality in September and October and continuing signs of respiratory disease and sporadic mortality of all age classes through early July 2017. Body condition scores and clinical signs suggested that the disease affected ewe groups before rams, although by the end of the epizootic, ram mortality (90% of 71) exceeded ewe mortality (79% of 84). Microbiological sampling 10 years to 3 months prior to the epizootic had documented no evidence of infection or exposure to Mycoplasma ovipneumoniae at NBR, but during the epizootic, a single genetic strain of M. ovipneumoniae was detected in affected animals. Retrospective screening of domestic sheep flocks near the NBR identified the same genetic strain in one flock, presumptively the source of the epizootic infection. Evidence of fatal lamb pneumonia was observed during the first two lambing seasons following the epizootic but was absent during the third season following the death of the last identified M. ovipneumoniae carrier ewe. Monitoring of life‐history traits prior to the epizootic provided no evidence that environmentally and/or demographically induced nutritional or other stress contributed to the epizootic. Furthermore, the epizootic occurred despite proactive management actions undertaken to reduce risk of disease and increase resilience in this population. This closely observed bighorn sheep epizootic uniquely illustrates the natural history of the disease including the (presumptive) source of spillover, course, severity, and eventual pathogen clearance.     

Using virtual 3-D plant architecture to assess fungal pathogen splash dispersal in heterogeneous canopies: a case study with cultivar mixtures and a non-specialized disease causal agent

Background and Aims

Recent developments in plant disease management have led to a growing interest in alternative strategies, such as increasing host diversity and decreasing the use of pesticides. Use of cultivar mixtures is one option, allowing the spread of plant epidemics to be slowed down. As dispersal of fungal foliar pathogens over short distances by rain-splash droplets is a major contibutor to the spread of disease, this study focused on modelling the physical mechanisms involved in dispersal of a non-specialized pathogen within heterogeneous canopies of cultivar mixtures, with the aim of optimizing host diversification at the intra-field level.

Methods

Virtual 3-D wheat-like plants (Triticum aestivum) were used to consider interactions between plant architecture and disease progression in heterogeneous canopies. A combined mechanistic and stochastic model, taking into account splash droplet dispersal and host quantitative resistance within a 3-D heterogeneous canopy, was developed. It consists of four sub-models that describe the spatial patterns of two cultivars within a complex canopy, the pathway of rain-splash droplets within this canopy, the proportion of leaf surface area impacted by dispersal via the droplets and the progression of disease severity after each dispersal event.

Key Results

Different spatial organization, proportions and resistance levels of the cultivars of two-component mixtures were investigated. For the eight spatial patterns tested, the protective effect against disease was found to vary by almost 2-fold, with the greatest effect being obtained with the smallest genotype unit area, i.e. the ground area occupied by an independent unit of the host population that is genetically homogeneous. Increasing both the difference between resistance levels and the proportion of the most resistant cultivar often resulted in a greater protective effect; however, this was not observed for situations in which the most resistant of the two cultivars in the mixture had a relatively low level of resistance.

Conclusions

The results show agreement with previous data obtained using experimental approaches. They demonstrate that in order to maximize the potential mixture efficiency against a splash-dispersed pathogen, optimal susceptible/resistant cultivar proportions (ranging from 1/9 to 5/5) have to be established based on host resistance levels. The results also show that taking into account dispersal processes in explicit 3-D plant canopies can be a key tool for investigating disease progression in heterogeneous canopies such as cultivar mixtures.     

Integrated pest management: the push-pull approach for controlling insect pests and weeds of cereals, and its potential for other agricultural systems including animal husbandry

This paper describes the 'push-pull' or 'stimulo-deterrent diversionary' strategy in relation to current and potential examples from our own experiences. The push-pull effect is established by exploiting semiochemicals to repel insect pests from the crop ('push') and to attract them into trap crops ('pull'). The systems exemplified here have been developed for subsistence farming in Africa and delivery of the semiochemicals is entirely by companion cropping, i.e. intercropping for the push and trap cropping for the pull. The main target was a series of lepidopterous pests attacking maize and other cereals. Although the area given to the cereal crop itself is reduced under the push-pull system, higher yields are produced per unit area. An important spin-off from the project is that the companion crops are valuable forage for farm animals. Leguminous intercrops also provide advantages with regard to plant nutrition and some of the trap crops help with water retention and in reducing land erosion. A major benefit is that certain intercrop plants provide dramatic control of the African witchweed (striga). Animal husbandry forms an essential part of intensive subsistence agriculture in Africa and developments using analogous push-pull control strategies for insect pests of cattle are exemplified.     

Dissecting the copper bioinorganic chemistry of the functional and pathological roles of the prion protein: Relevance in Alzheimer's disease and cancer

The cellular prion protein (PrP^C) is a metal-binding biomolecule that can interact with different protein partners involved in pivotal physiological processes, such as neurogenesis and neuronal plasticity. Recent studies profile copper and PrP^C as important players in the pathological mechanisms of Alzheimer's disease and cancer. Although the copper-PrP^C interaction has been characterized extensively, the role of the metal ion in the physiological and pathological roles of PrP^C has been barely explored. In this article, we discuss how copper binding and proteolytic processing may impact the ability of PrP^C to recruit protein partners for its functional roles. The importance to dissect the role of copper-PrP^C interactions in health and disease is also underscored.     

Ellis-van Creveld syndrome in a fetus with rhizomelia and polydactyly. Report of a case diagnosed by genetic analysis, and correlation with pathological andradiologic findings

Ellis-van Creveld syndrome is an autosomal recessive disorder mainly characterized by a disproportionate limb dwarfism, chondroectodermal dysplasia, congenital heart disease, postaxial polydactyly, and dysplastic fingernails and teeth. Only 300 cases have been published worldwide. We report a 21-week fetus with rhizomelia and polydactyly detected. Gross photographs, radiologic studies and pathological study were performed leading to the clinico-pathological suspicion of EvC. DNA from fresh fetal tissue was extracted for sequencing the EVC and EVC2 genes. p.W215X and p.R677X mutations were identified in the EVC2 gene in the fetal sample. Parental sample analysis showed the p.W215X mutation to be inherited from the mother and the p.R677X mutation from the father. The clinical information is essential not only to arrive at a correct diagnosis in fetuses with pathologic ultrasound findings, but also to offer a proper genetic counseling to the parents and their relatives.     

Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer's disease pathology

An increasing body of evidence suggested that intracellular lipid metabolism is dramatically perturbed in various cardiovascular and neurodegenerative diseases with genetic and lifestyle components (e.g., dietary factors). Therefore, a lipidomic approach was also developed to suggest possible mechanisms underlying Alzheimer’s disease (AD). Neural membranes contain several classes of glycerophospholipids (GPs), that not only constitute their backbone but also provide the membrane with a suitable environment, fluidity, and ion permeability. In this review article, we focused our attention on GP and GP-derived lipid mediators suggested to be involved in AD pathology. Degradation of GPs by phospholipase A₂ can release two important brain polyunsaturated fatty acids (PUFAs), e.g., arachidonic acid and docosahexaenoic acid, linked together by a delicate equilibrium. Non-enzymatic and enzymatic oxidation of these PUFAs produces several lipid mediators, all closely associated with neuronal pathways involved in AD neurobiology, suggesting that an interplay among lipids occurs in brain tissue. In this complex GP meshwork, the search for a specific modulating enzyme able to shift the metabolic pathway towards a neuroprotective role as well as a better knowledge about how lipid dietary modulation may act to slow the neurodegenerative processes, represent an essential step to delay the onset of AD and its progression. Also, in this way it may be possible to suggest new preventive or therapeutic options that can beneficially modify the course of this devastating disease.     

Toward a conceptual framework for managing and conserving marine habitats: A case study of kelp forests in the Salish Sea

Kelp forests are in decline across much of their range due to place‐specific combinations of local and global stressors. Declines in kelp abundance can lead to cascading losses of biodiversity and productivity with far‐reaching ecological and socioeconomic consequences. The Salish Sea is a hotspot of kelp diversity where many species of kelp provide critical habitat and food for commercially, ecologically, and culturally important fish and invertebrate species. However, like other regions, kelp forests in much of the Salish Sea are in rapid decline. Data gaps and limited long‐term monitoring have hampered attempts to identify and manage for specific drivers of decline, despite the documented urgency to protect these important habitats. To address these knowledge gaps, we gathered a focus group of experts on kelp in the Salish Sea to identify perceived direct and indirect stressors facing kelp forests. We then conducted a comprehensive literature review of peer‐reviewed studies from the Salish Sea and temperate coastal ecosystems worldwide to assess the level of support for the pathways identified by the experts, and we identified knowledge gaps to prioritize future research. Our results revealed major research gaps within the Salish Sea and highlighted the potential to use expert knowledge for making informed decisions in the region. We found high support for the pathways in the global literature, with variable consensus on the relationship between stressors and responses across studies, confirming the influence of local ecological, oceanographic, and anthropogenic contexts and threshold effects on stressor–response relationships. Finally, we prioritized areas for future research in the Salish Sea. This study demonstrates the value expert opinion has to inform management decisions. These methods are readily adaptable to other ecosystem management contexts, and the results of this case study can be immediately applied to kelp management.     

Genetic bottlenecks and successful biological invasions: the case of a recent Lessepsian migrant

Our current understanding of the mechanisms that lead to successful biological invasions is limited. Although adaptations play a central role in biological invasions, genetic studies have so far failed to produce a unified theory. The bluespotted cornetfish, a recent Red Sea invader in the Mediterranean Sea via the Suez Canal, provides an ideal case study for research in the mechanisms of invasive genetics. In this study, we show that the invading bluespotted cornetfish underwent a severe population bottleneck that reduced the genetic diversity of this immigrant to only two mitochondrial haplotypes. Although loss of genetic diversity is considered detrimental to the need to adapt to new environments, bluespotted cornetfish experienced an unprecedented success and rapid spread across the Mediterranean.