Radiologic-pathologic autopsy correlation of an internal watershed infarct, a case report

Internal watershed infarcts (IWIs) occur at the junction of the deep and superficial perforating arterial branches of the cerebrum. Despite documentation in the radiology literature, IWIs are rarely encountered at the time of autopsy. Here, we report the case of a 59-year-old incarcerated male who was brought to the emergency department after being found unresponsive on the floor of his jail cell. Initial examination and imaging demonstrated right-sided hemiplegia, aphasia, right facial droop, and severe stenosis of the left middle cerebral artery, respectively. Repeat imaging 4 days after admission and 26 days before death demonstrated advanced stenosis of the intracranial, communicating segment of the right internal carotid artery, a large acute infarct in the right posterior cerebral artery territory, and bilateral deep white matter ischemic changes with a right-sided “rosary-like” pattern of injury that is typical of IWIs. Postmortem gross examination showed that the right deep white matter lesion had progressed to a confluent, “cigar-shaped” subacute IWI involving the right corona radiata. This is the first well-documented case of an IWI with radiologic imaging and photographic gross pathology correlation. This case uniquely highlights a rarely encountered lesion at the time of autopsy and provides an excellent visual representation of internal watershed neuroanatomy

Lesiones de la articulación tarso-metatarsiana

Se presentan 16 casos de fractura-luxación tarso-metatarsiana. El objetivo de este trabajo ha sido la valoración de los resultados finales en este tipo de patología. La etiología del accidente ha sido en 6 ocasiones casual o deportiva, en 5 laboral, en 4 accidente de tráfico y 1 caída de un caballo. Las fractura-luxaciones han sido clasificadas según los criterios de Hardcastle, resultando 3 casos tipo A externo, 6 B externo, 6 B interno y 1 C total. El tratamiento realizado fue mayoritariamente reducción y osteosíntesis con agujas de Kirschner, predominando la reducción abierta. Se ha considerado parámetros radiográficos y clínicos, siguiendo los criterios del Baltimore Painful Foot Store para la valoración de resultados finales, obteniéndose 9 casos excelentes, 4 buenos, 2 reguladores y 1 malo. Se concluye que es fundamental el diagnóstico y tratamiento precoz, considerando básica la reducción anatómica estabilizada con agujas de Kirschner.We report 16 cases of tarsometatarsal fracture-dislocation. The purpose of this work was the assessment of the final outcome of these cases. The etiology was casual or sport injuries in 6 cases, industrial accidents in 5, traffic accidents in 4 and fall off a horse in 1 case. The injuries have been classified according to the Hasrdcastle modified classification, being 3 cases type A external, 6 B internqal and 1 C total. In most cases the treatment was open reduction and internal fixation with Kirschner wires. According to the guidelines of the Balitmore Painful Score for the evaluation of final outcome, there were 9 excellent results, 4 good, 2 fair and 1 poor. We conclude that the best results were obtained in those cases with early diagnose and treatment, looking for an anatomical reduction and fixation with Kirschner wires

Calmodulin regulates transglutaminase 2 cross-linking of Huntingtin

This is the publisher's version, also available electronically from "www.jneurosci.org".Striatal and cortical intranuclear inclusions and cytoplasmic aggregates of mutant huntingtin are prominent neuropathological hallmarks of Huntington's disease (HD). We demonstrated previously that transglutaminase 2 cross-links mutant huntingtin in cells in culture and demonstrated the presence of transglutaminase-catalyzed cross-links in the HD cortex that colocalize with transglutaminase 2 and huntingtin. Because calmodulin regulates transglutaminase activity in erythrocytes, platelets, and the gizzard, we hypothesized that calmodulin increases cross-linking of huntingtin in the HD brain. We found that calmodulin colocalizes at the confocal level with transglutaminase 2 and with huntingtin in HD intranuclear inclusions. Calmodulin coimmunoprecipitates with transglutaminase 2 and huntingtin in cells transfected with myc-tagged N-terminal huntingtin fragments containing 148 polyglutamine repeats (htt-N63-148Q-myc) and transglutaminase 2 but not in cells transfected with myc-tagged N-terminal huntingtin fragments containing 18 polyglutamine repeats. Our previous studies demonstrated that transfection with both htt-N63-148Q-myc and transglutaminase 2 resulted in cross-linking of mutant huntingtin protein fragments and the formation of insoluble high-molecular-weight aggregates of huntingtin protein fragments. Transfection with transglutaminase 2 and htt-N63-148Q-myc followed by treatment of cells with N-(6-aminohexyl)-1-naphthalenesulfonamide, a calmodulin inhibitor, resulted in a decrease in cross-linked huntingtin. Inhibiting the interaction of calmodulin with transglutaminase and huntingtin protein could decrease cross-linking and diminish huntingtin aggregate formation in the HD brain

Black Hole Scan

Gravitation theories selected by requiring that they have a unique anti-de Sitter vacuum with a fixed cosmological constant are studied. For a given dimension d, the Lagrangians under consideration are labeled by an integer k=1,2,...,[(d-1)/2]. Black holes for each d and k are found and are used to rank these theories. A minimum possible size for a localized electrically charged source is predicted in the whole set of theories, except General Relativity. It is found that the thermodynamic behavior falls into two classes: If d-2k=1, these solutions resemble the three dimensional black hole, otherwise, their behavior is similar to the Schwarzschild-AdS_4 geometry.Comment: Two columns, revtex, 15 pages, 5 figures, minor typos corrected, final version for Journa

APOε2 and Education in Cognitively Normal Older Subjects with High Levels of AD Pathology at Autopsy: Findings from the Nun Study

Asymptomatic Alzheimer\u27s disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p \u3c 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p \u3c 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology

Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice

BACKGROUND: Though the precise cause(s) of Alzheimer’s disease (AD) remain unknown, there is strong evidence that decreased clearance of β-amyloid (Aβ) from the brain can contribute to the disease. Therapeutic strategies to promote natural Aβ clearance mechanisms, such as the protein apolipoprotein-E (APOE), hold promise for the treatment of AD. The amount of APOE in the brain is regulated by nuclear receptors including retinoid X receptors (RXRs). Drugs that activate RXRs, including bexarotene, can increase APOE and ABCA1 production, and have been shown to decrease the Aβ burden and improve cognition in mouse models of Aβ amyloidosis. Although recent bexarotene studies failed to replicate the rapid clearance of Aβ from brains, behavioral and cognitive effects of this compound remain controversial. FINDINGS: In efforts to clarify these behavioral findings, mutant APP/PS1 mice were acutely dosed with bexarotene. While ABCA1 was upregulated in mutant APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or cognitive deficits in these mice. CONCLUSIONS: We recommend rigorous preclinical study to evaluate the mechanism and utility of such a compound for AD therapy

PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity

Mutations in the ATP13A2 gene (PARK9, OMIM 610513) cause autosomal recessive, juvenile-onset Kufor-Rakeb syndrome and early-onset parkinsonism. ATP13A2 is an uncharacterized protein belonging to the P5-type ATPase subfamily that is predicted to regulate the membrane transport of cations. The physiological function of ATP13A2 in the mammalian brain is poorly understood. Here, we demonstrate that ATP13A2 is localized to intracellular acidic vesicular compartments in cultured neurons. In the human brain, ATP13A2 is localized to pyramidal neurons within the cerebral cortex and dopaminergic neurons of the substantia nigra. ATP13A2 protein levels are increased in nigral dopaminergic and cortical pyramidal neurons of Parkinson's disease brains compared with normal control brains. ATP13A2 levels are increased in cortical neurons bearing Lewy bodies (LBs) compared with neurons without LBs. Using short hairpin RNA-mediated silencing or overexpression to explore the function of ATP13A2, we find that modulating the expression of ATP13A2 reduces the neurite outgrowth of cultured midbrain dopaminergic neurons. We also find that silencing of ATP13A2 expression in cortical neurons alters the kinetics of intracellular pH in response to cadmium exposure. Furthermore, modulation of ATP13A2 expression leads to reduced intracellular calcium levels in cortical neurons. Finally, we demonstrate that silencing of ATP13A2 expression induces mitochondrial fragmentation in neurons. Oppositely, overexpression of ATP13A2 delays cadmium-induced mitochondrial fragmentation in neurons consistent with a neuroprotective effect. Collectively, this study reveals a number of intriguing neuronal phenotypes due to the loss- or gain-of-function of ATP13A2 that support a role for this protein in regulating intracellular cation homeostasis and neuronal integrit

Spatial and temporal variation in the population density of the gold-ringed tanager (Bangsia Aureocincta : Thraupidae), endemic and vulnerable species of Colombia, in the Tatama national natural park.

Para conocer el estado de conservación de una especie es necesario determinar su abundancia y el cambio de ésta en el tiempo a través de programas rigurosos de monitoreo. Especialmente, cuando esta especie ha sido seleccionada como objeto de conservación de las áreas protegidas, su monitoreo se convierte en la herramienta de base para evaluar la efectividad del manejo. La bangsia del Tatamá (Bangsia aureocincta) se seleccionó como valor objeto de conservación –VOC– del Parque Nacional Natural Tatamá –PNN Tatamá–; este parque representa la integridad ecológica de la confluencia Andino-Pacífica en esta zona. Para conocer su estado de conservación y tendencia, se estimó la densidad poblacional usando el método de muestreo por distancia con puntos de conteo, en dos localidades separadas por 50 km lineales con una réplica temporal en 2016 y otra en 2018. Las densidades estimadas en 2016 fueron de 152 individuos/km2 (IC95% = 84 - 272; CV= 29,99) y 1036 individuos/ km2 (IC95% = 745 - 1442, CV= 16,82) y para 2018 de 341 individuos/km2 (IC95% = 213 - 547; CV= 23,96) y de 118 individuos/km2 (IC95% = 78 - 181, CV= 21,4). Estos resultados reflejan variaciones espaciales y temporales en la densidad de la especie que probablemente sean producto de migraciones longitudinales o altitudinales. No obstante, ante la falta de conocimiento de la historia natural de la especie, no es posible asociar estos movimientos a algún factor en particular.To know the conservation status of a species it is necessary to determine its abundance and the trends in a framework of rigorous monitoring program. Furthermore, when these species are the conservation target of the conservation strategies as protected areas, their monitoring is the way to assess the effectivity of the management. Bangsia del Tatama (Bangsia aureocincta) was chosen as a conservation target of the Tatama National Natural Park and it represents the ecological integrity of the Andino-Pacific confluence in this zone. To know its conservation status, we evaluate the population density using distance sampling method with point transect in two localities separated by 50 lineal kilometers with a temporal replica in 2016 and other in 2018. The population density found were in 2016 of 152 individuals/km2  (IC95% = 84 - 272; CV= 29,99) and 1036 individuals /km2 (IC95% = 745 - 1442, CV= 16.82), and to 2018 of 341 individuals /km2 (IC95% = 213 - 547; CV= 23.96) and 118 individuals/ km2 (IC95% = 78 - 181, CV= 21.4). These results show spatial and temporal variations in the density of the species, probably by longitudinal or altitudinal migrations. However, there is not enough knowledge of the natural history of the species to relate these movements to some factor

Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration

Mutations in the vacuolar protein sorting 35 homolog (VPS35) gene at the PARK17 locus, encoding a key component of the retromer complex, were recently identified as a new cause of late-onset, autosomal dominant Parkinson's disease (PD). Here we explore the pathogenic consequences of PD-associated mutations in VPS35 using a number of model systems. VPS35 exhibits a broad neuronal distribution throughout the rodent brain, including within the nigrostriatal dopaminergic pathway. In the human brain, VPS35 protein levels and distribution are similar in tissues from control and PD subjects, and VPS35 is not associated with Lewy body pathology. The common D620N missense mutation in VPS35 does not compromise its protein stability or localization to endosomal and lysosomal vesicles, or the vesicular sorting of the retromer cargo, sortilin, SorLA and cation-independent mannose 6-phosphate receptor, in rodent primary neurons or patient-derived human fibroblasts. In yeast we show that PD-linked VPS35 mutations are functional and can normally complement VPS35 null phenotypes suggesting that they do not result in a loss-of-function. In rat primary cortical cultures the overexpression of human VPS35 induces neuronal cell death and increases neuronal vulnerability to PD-relevant cellular stress. In a novel viral-mediated gene transfer rat model, the expression of D620N VPS35 induces the marked degeneration of substantia nigra dopaminergic neurons and axonal pathology, a cardinal pathological hallmark of PD. Collectively, these studies establish that dominant VPS35 mutations lead to neurodegeneration in PD consistent with a gain-of-function mechanism, and support a key role for VPS35 in the development of P

Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2

Mutations in the genes encoding LRRK2 and α-synuclein cause autosomal dominant forms of familial Parkinson's disease (PD). Fibrillar forms of α-synuclein are a major component of Lewy bodies, the intracytoplasmic proteinaceous inclusions that are a pathological hallmark of idiopathic and certain familial forms of PD. LRRK2 mutations cause late-onset familial PD with a clinical, neurochemical and, for the most part, neuropathological phenotype that is indistinguishable from idiopathic PD. Importantly, α-synuclein-positive Lewy bodies are the most common pathology identified in the brains of PD subjects harboring LRRK2 mutations. These observations may suggest that LRRK2 functions in a common pathway with α-synuclein to regulate its aggregation. To explore the potential pathophysiological interaction between LRRK2 and α-synuclein in vivo, we modulated LRRK2 expression in a well-established human A53T α-synuclein transgenic mouse model with transgene expression driven by the hindbrain-selective prion protein promoter. Deletion of LRRK2 or overexpression of human G2019S-LRRK2 has minimal impact on the lethal neurodegenerative phenotype that develops in A53T α-synuclein transgenic mice, including premature lethality, pre-symptomatic behavioral deficits and human α-synuclein or glial neuropathology. We also find that endogenous or human LRRK2 and A53T α-synuclein do not interact together to influence the number of nigrostriatal dopaminergic neurons. Taken together, our data suggest that α-synuclein-related pathology, which occurs predominantly in the hindbrain of this A53T α-synuclein mouse model, occurs largely independently from LRRK2 expression. These observations fail to provide support for a pathophysiological interaction of LRRK2 and α-synuclein in vivo, at least within neurons of the mouse hindbrai