Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson’s disease. To date, no neuropathological reports have been ...published from patients with Parkinson’s disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed the coding region of phosphatase and tensin homolog-induced putative kinase 1 gene in a large Spanish family with six members with parkinsonism. The phenotype was characterized by an early-onset (mean: 31.6, standard deviation: 9.6 years, range: 14–45 years), slowly progressive levodopa-responsive parkinsonism, initial gait impairment and psychiatric symptoms. We identified two segregating pathogenic phosphatase and tensin homolog-induced putative kinase 1 mutations that were either in homozygous or heterozygous compound state in all affected family members. We found an exon 7 deletion (g.16089_16383del293; c.1252_1488del) and a novel + 1U1-dependent 5′ splice-site mutation in exon 7 (g.16378G > A; c.1488 + 1G > A). Leukocyte-derived messenger RNA analysis showed that both mutations caused exon 7 skipping and c.1488 + 1G > A also lead to an in-frame transcript with a 33 base-pair deletion (p.L485_R497del) resulting from activation of a 5′ cryptic exon 7 splice site. Single photon emission computed tomography quantification of striatal dopamine transporter binding (123I-Ioflupane) revealed a posterior–anterior gradient similar to that of idiopathic Parkinson’s disease, but there was no correlation between striatal reduced uptake and disease duration. Post-mortem neuropathological examination of an early-onset Parkinson’s disease carrier of two heterozygous compound phosphatase and tensin homolog-induced putative kinase 1 mutations showed neuronal loss in the substantia nigra pars compacta, Lewy bodies and aberrant neurites in the reticular nuclei of the brainstem, substantia nigra pars compacta and Meynert nucleus, but the locus ceruleus and the amygdala were spared. This is the first neuropathological report of the brain from an early-onset phosphatase and tensin homolog-induced putative kinase 1-linked parkinsonism showing that mutated phosphatase and tensin homolog-induced putative kinase 1 protein induces Lewy body pathology. Unbalanced preservation of the locus ceruleus may well play a role in the slow evolution of motor symptoms and, probably, in the psychiatric symptoms often encountered in Parkinson’s disease associated with phosphatase and tensin homolog-induced putative kinase 1 mutation.
Mass stranding events (MSEs) of beaked whales (BWs) were extremely rare prior to the 1960s but increased markedly after the development of naval mid-frequency active sonar (MFAS). The temporal and ...spatial associations between atypical BW MSEs and naval exercises were first observed in the Canary Islands, Spain, in the mid-1980s. Further research on BWs stranded in association with naval exercises demonstrated pathological findings consistent with decompression sickness (DCS). A 2004 ban on MFASs around the Canary Islands successfully prevented additional BW MSEs in the region, but atypical MSEs have continued in other places of the world, especially in the Mediterranean Sea, with examined individuals showing DCS. A workshop held in Fuerteventura, Canary Islands, in September 2017 reviewed current knowledge on BW atypical MSEs associated with MFAS. Our review suggests that the effects of MFAS on BWs vary among individuals or populations, and predisposing factors may contribute to individual outcomes. Spatial management specific to BW habitat, such as the MFAS ban in the Canary Islands, has proven to be an effective mitigation tool and mitigation measures should be established in other areas taking into consideration known population-level information.
Mutations in PINK1 and PARKIN cause recessive, early‐onset Parkinson's disease (PD). Together, these two proteins orchestrate a protective mitophagic response that ensures the safe disposal of ...damaged mitochondria. The kinase PINK1 phosphorylates ubiquitin (Ub) at the conserved residue S65, in addition to modifying the E3 ubiquitin ligase Parkin. The structural and functional consequences of Ub phosphorylation (pS65‐Ub) have already been suggested from in vitro experiments, but its (patho‐)physiological significance remains unknown. We have generated novel antibodies and assessed pS65‐Ub signals in vitro and in cells, including primary neurons, under endogenous conditions. pS65‐Ub is dependent on PINK1 kinase activity as confirmed in patient fibroblasts and postmortem brain samples harboring pathogenic mutations. We show that pS65‐Ub is reversible and barely detectable under basal conditions, but rapidly induced upon mitochondrial stress in cells and amplified in the presence of functional Parkin. pS65‐Ub accumulates in human brain during aging and disease in the form of cytoplasmic granules that partially overlap with mitochondrial, lysosomal, and total Ub markers. Additional studies are now warranted to further elucidate pS65‐Ub functions and fully explore its potential for biomarker or therapeutic development.
Synopsis
In this study, two newly generated antibodies are used to detect endogenous phospho‐ubiquitin in cells and human brain samples. pS65‐Ub is shown to be reversible, respond to mitochondrial stress and accumulate during aging and in Parkinson's disease (PD).
pS65‐Ub is amplified by the concerted action of PINK1 kinase and Parkin E3 ubiquitin ligase in response to mitochondrial stress.
pS65‐Ub specifically labels severely damaged mitochondria destined for degradation.
pS65‐Ub is a novel biomarker of mitochondrial quality control and could also serve as a potential therapeutic target for PD.
In this study, two newly generated antibodies are used to detect endogenous phospho‐ubiquitin in cells and human brain samples. pS65‐Ub is shown to be reversible, respond to mitochondrial stress and accumulate during aging and in Parkinson's disease.
Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and ...sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease.
Abbreviations: BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin
Diving air-breathing vertebrates have long been considered protected against decompression sickness (DCS) through anatomical, physiological, and behavioural adaptations. However, an acute systemic ...gas and fat embolic syndrome similar to DCS in human divers was described in beaked whales that stranded in temporal and spatial association with military exercises involving high-powered sonar. More recently, DCS has been diagnosed in bycaught sea turtles. Both cases were linked to human activities. Two Risso's dolphin (Grampus griseus) out of 493 necropsied cetaceans stranded in the Canary Islands in a 16-year period (2000-2015), had a severe acute decompression sickness supported by pathological findings and gas analysis. Deadly systemic, inflammatory, infectious, or neoplastic diseases, ship collision, military sonar, fisheries interaction or other type of lethal inducing associated trauma were ruled out. Struggling with a squid during hunting is discussed as the most likely cause of DCS.
Marine pollution, overrepresented by plastic, is a growing concern worldwide. However, there is little knowledge on occurrence and detrimental impacts of marine debris in cetaceans. To partially fill ...in this gap of knowledge, we aimed to investigate the occurrence and pathologies associated with foreign bodies (FBs) in a large cohort of cetaceans (n = 465) stranded in the Canary Islands. The Canary Islands shelter the greatest cetacean biodiversity in Europe, with up to 30 different species, of which nine are regularly present year around. We found at least one ingested FB in 36 out of 465 (7.74%) studied cetaceans, involving 15 different species, including eight out of the nine (80%) cetacean species present year-round in the Canary Islands. Risso's dolphin was the species most affected, followed by sperm whale, beaked whale and mysticetes. Plastic FB were the most common item found (80.56%). FB was directly associated with death in 13/36 (36.11%) animals. Poor body condition and deep diving behavior were found to be risk factors for FB ingestion, whereas the adult age was a protective factor. To the authors knowledge this is the first study that use statistical analysis to investigate risk and protective factors for FB ingestion. This study also provides insights of the potential impact caused by ingested FBs on the animal's health and mortality. This knowledge is critical to better understand and assess the impact of FB in cetaceans setting the scientific basis for prospective impact monitoring and future conservation policies.
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•Foreign bodies were found in 7.7% (36/465) studied cetaceans in the Canary Islands in a 16 year period.•Severe digestive disease (impactions and gastrointestinal perforations) caused the death of 13 animals (2.8%,13/465).•Plastic was the most common item found (80.6%).•Poor body condition and deep diving behavior were risk factors for foreign body ingestion.•Adult age was a protective factor for foreign body ingestion.
This manuscript contributes to increase the current understanding of the epidemiology and pathology of foreign bodies in cetaceans and provides a scientific foundation for conservation policies.
Between 1999 and 2005, 233 stranded cetaceans (comprising 19 species) were reported in the waters of the Canary Islands. Of these, 138/233 (59.2%) were subjected to a complete or partial standardized ...necropsy, including 4 Balaenopteridae, 9 Physeteridae, 8 Kogiidae, 27 Ziphiidae and 90 Delphinidae. Of these, 46/138 (33.3%) cetaceans were diagnosed with anthropogenic pathological categories (i.e. the cause of death was anthropogenic). These included fishing interaction (bycatch) (19 individuals), 'atypical' mass stranding events linked to naval exercises (13), ship collisions (8) and other anthropogenic-related pathology (6). 'Natural' (i.e. non-anthropogenic) causes of death accounted for another 82/138 (59.4%) cases, including infectious and non-infectious diseases (63), neonatal pathology (8), intra- and interspecific interactions (6) and mass strandings (5). The cause(s) of death could not be determined in 10/138 (7.3%) necropsied animals. The most common causes of death were ship collisions in 6/9 (66.6%) Physeteridae, 'atypical' mass stranding linked to naval exercises in 13/27 (48.1%) Ziphiidae, and 'natural' infectious and non-infectious diseases in 55/90 (61.1%) Delphinidae. Interaction with fishing activities was established as cause of death in 15/90 (16.7%) Delphinidae. These data show that a range of anthropogenic and natural single and mass mortality events occur in multiple cetacean species stranded in the Canary Islands.
We describe gross, histopathological, and immunohistochemical features of Streptococcus phocae and cetacean morbillivirus coinfection in a short-beaked common dolphin Delphinus delphis. Major gross ...findings were cutaneous purulent nodules in the tail fluke, vegetative mitral valve endocarditis, and presumed postpartum pyometra. Histologic examination revealed bacterial septicemia characterized by widespread intravascular coccoid bacterial emboli. These were associated with fibrinonecrotizing to pyogranulomatous dermatitis and panniculitis, embolic pneumonia, neutrophilic and lymphoplasmacytic meningochoroiditis, random neutrophilic hepatitis, lymphoplasmacytic myocarditis and epicarditis, necrotizing adrenalitis, suppurative endometritis, and multicentric reactive lymphadenopathy. Bacteriology and molecular analysis with sequencing of the 16S rRNA gene identified S. phocae from lung, brain, and adrenal gland tissue. Immunohistochemical analysis for morbillivirus detection revealed positive immunolabeling in the epithelium of the choroid plexus of the fourth ventricle. Published reports on S. phocae infection in cetaceans are rare, and pathological details are limited. The present case indicates that S. phocae has potential pathogenic capacity in common dolphins. The pathogenesis is proposed to have involved cutaneous penetration after a skin trauma, leading to initial cutaneous disease and eventual systemic infection.
Abstract
To ensure confidence, measurements carried out by imaging radiometers mounted on satellites require robust validation using “fiducial quality” measurements of the same in situ parameter. For ...surface temperature measurements this is optimally carried out by radiometers measuring radiation emitted in the infrared region of the spectrum, collocated to that of a satellite overpass. For ocean surface temperatures the radiometers are usually on board ships to sample large areas but for land and ice they are typically deployed at defined geographical sites. It is of course critical that the validation measurements and associated instrumentation are internationally consistent and traceable to international standards. The Committee on Earth Observation Satellites (CEOS) facilitates this process and over the last two decades has organized a series of comparisons, initially to develop and share best practice, but now to assess metrological uncertainties and degree of consistency of all the participants. The fourth CEOS comparison of validation instrumentation: blackbodies and infrared radiometers, was held at the National Physical Laboratory (NPL) during June and July 2016, sponsored by the European Space Agency (ESA). The 2016 campaign was completed over a period of three weeks and included not only laboratory-based measurements but also representative measurements carried out in field conditions, over land and water. This paper is one of a series and reports the results obtained when radiometers participating in this comparison were used to measure the radiance temperature of the NPL ammonia heat-pipe blackbody during the 2016 comparison activities (i.e., an assessment of radiometer performance compared to international standards). This comparison showed that the differences between the participating radiometer readings and the corresponding temperature of the reference blackbody were within the uncertainty of the measurements, but there were a few exceptions, particularly for a reference blackbody temperature of −30°C. Reasons that give rise to the discrepancies observed at the low blackbody temperatures were identified.
Despite the profound impact that skeletal muscle disorders may pose for the daily activities of wild terrestrial and marine mammals, such conditions have been rarely described in cetaceans. In this ...study, the authors aimed to determine the nature and prevalence of skeletal muscle lesions in small and large odontocetes and mysticetes (n = 153) from 19 different species. A macroscopic evaluation of the epaxial muscle mass and a histologic examination of the longissimus dorsi muscle were performed in all cases. The only macroscopically evident change was variable degrees of atrophy of the epaxial muscles (longissimus dorsi, multifidus, spinalis) in emaciated specimens. The histopathological study revealed single or combined morphological changes in 91.5% of the cases. These changes included the following: degenerative lesions (75.2%), muscle atrophy (37.9%), chronic myopathic changes (25.5%), parasitic infestation (9.2%), and myositis (1.9%). The skeletal muscle is easily sampled during a necropsy and provides essential microscopic information that reflects both local and systemic conditions. Thus, skeletal muscle should be systematically sampled, processed, and examined in all stranded cetaceans.
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