Laws beyond spacetime.

Quantum gravity's suggestion that spacetime may be emergent and so only exist contingently would force a radical reconception of extant analyses of laws of nature. Humeanism presupposes a spatiotemporal mosaic of particular matters of fact on which laws supervene; primitivism and dispositionalism conceive of the action of primitive laws or of dispositions as a process of 'nomic production' unfolding over time. We show how the Humean supervenience basis of non-modal facts and primitivist or dispositionalist accounts of nomic production can be reconceived, avoiding a reliance on fundamental spacetime.

Nurses' and physicians' reported difficulties and enablers to recognising and reporting child abuse in Swiss paediatric emergency and paediatric surgery departments - an observational study.

Background: Under-detection and under-reporting of child abuse remains a considerable challenge in paediatric care, with a high number of cases missed each year in Switzerland and abroad. Published data regarding the obstacles and facilitators of detecting and reporting child maltreatment among paediatric nursing and medical staff in the paediatric emergency department (PED) are scarce. Despite the existence of international guidelines, the measures taken to counteract the incomplete detection of harm done to children in paediatric care are insufficient.

Spatiotemporal Up-Regulation of Mu Opioid Receptor 1 in Striatum of Mouse Model of Huntington's Disease Differentially Affecting Caudal and Striosomal Regions.

The striatum of humans and other mammals is divided into macroscopic compartments made up of a labyrinthine striosome compartment embedded in a much larger surrounding matrix compartment. Anatomical and snRNA-Seq studies of the Huntington's disease (HD) postmortem striatum suggest a preferential decline of some striosomal markers, and mRNAs studies of HD model mice concur. Here, by immunohistochemical methods, we examined the distribution of the canonical striosomal marker, mu-opioid receptor 1 (MOR1), in the striatum of the Q175 knock-in mouse model of HD in a postnatal time series extending from 3 to 19 months.

JC virus infection of meningeal and choroid plexus cells in patients with progressive multifocal leukoencephalopathy.

JC virus (JCV) can cause a lytic infection of oligodendrocytes and astrocytes in the central nervous system (CNS) leading to progressive multifocal leukoencephalopathy (PML). JCV can also infect meningeal and choroid plexus cells causing JCV meningitis (JCVM). Whether JCV also infects meningeal and choroid plexus cells in PML patients and other immunosuppressed individuals with no overt symptoms of meningitis remains unknown.

JC Virus Infects Neurons and Glial Cells in the Hippocampus.

The human polyomavirus JC (JCV) infects glial cells and is the etiologic agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy. JCV can infect granule cell neurons of the cerebellum, causing JCV granule cell neuronopathy and cortical pyramidal neurons in JCV encephalopathy. Whether JCV also infects neurons in other areas of the CNS is unclear.

Simian Virus 40 Infection in the Spinal Cord of Simian Immunodeficiency Virus-Immunosuppressed Rhesus Macaques.

Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the CNS that usually develops in immunocompromised individuals because of reactivation of quiescent JC virus (JCV). There are only a few reports of JCV infection in the human spinal cord. Progressive multifocal leukoencephalopathy-like demyelinating lesions have been documented in the brains of simian immunodeficiency virus-infected macaques.

Progressive neurologic dysfunction in a psoriasis patient treated with dimethyl fumarate.

Progressive multifocal leukoencephalopathy (PML) has recently been described in psoriasis or multiple sclerosis patients treated with fumaric acid esters (fumarates), who had developed severe and long-standing lymphocytopenia (<500/mm(3) ). We report a psoriasis patient who presented with progressive neurologic dysfunction and seizures after 2.5 years of fumarate therapy.

Lack of Major Histocompatibility Complex Class I Upregulation and Restrictive Infection by JC Virus Hamper Detection of Neurons by T Lymphocytes in the Central Nervous System.

The human polyomavirus JC (JCV) infects glial cells in immunosuppressed individuals, leading to progressive multifocal leukoencephalopathy. Polyomavirus JC can also infect neurons in patients with JCV granule cell neuronopathy and JCV encephalopathy. CD8-positive T cells play a crucial role in viral containment and outcome in progressive multifocal leukoencephalopathy, but whether CD8-positive T cells can also recognize JCV-infected neurons is unclear.

A fatal case of JC virus meningitis presenting with hydrocephalus in a human immunodeficiency virus-seronegative patient.

JC virus (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy. Whether JCV can also cause meningitis has not yet been demonstrated. We report a case of aseptic meningitis resulting in symptomatic hydrocephalus in a human immunodeficiency virus-seronegative patient.

Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy.

Objective: To determine the frequency of hyperintense cortical signal (HCS) on T1-weighted precontrast magnetic resonance (MR) images in progressive multifocal leukoencephalopathy (PML) patients, its association with seizure risk and immune reconstitution inflammatory syndrome (IRIS), and its pathologic correlate.

Methods: We reviewed clinical data including seizure history, presence of IRIS, and MR imaging scans from PML patients evaluated at our institution between 2003 and 2012. Cases that were diagnosed either using cerebrospinal fluid JC virus (JCV) polymerase chain reaction, brain biopsy, or autopsy, and who had MR images available were included in the analysis (n=49).

Progressive multifocal leukoencephalopathy in pediatric patients: case report and literature review.

Progressive multifocal leukoencephalopathy is a rare, demyelinating disease of the central nervous system caused by JC virus. Fewer than 30 cases have been reported in HIV- and non-infected children. We report the case of a 15-year-old girl with progressive multifocal leukoencephalopathy and AIDS who presented with nystagmus, dysarthria and ataxia.

Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study.

Natalizumab, a monoclonal antibody directed against α4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Because of the limited number of histologic studies, the possible interplay between MS and PML lesions has not been investigated. We report the clinical, radiologic, and histologic findings of an MS patient who developed PML after 32 months of natalizumab monotherapy.

Inflammatory infratentorial progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis.

An 84-year-old man with rheumatoid arthritis (RA) treated with methotrexate, developed progressive confusion and cerebellar symptoms, and died approximately 2 months later. Neuropathological examination revealed progressive multifocal leukoencephalopathy (PML) involving the cerebellum and brainstem. The affected tissues displayed intense infiltrations by CD8+ T-cells and microglia.

Progressive multifocal leukoencephalopathy: why gray and white matter.

Since it was first described in 1958, progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain caused by the polyomavirus JC (JCV), has evolved tremendously. It was once considered a noninflammatory disease that affected exclusively oligodendrocytes and astrocytes in the white matter of immunosuppressed individuals and was almost always fatal. Today, we understand that PML can present during the course of an immune reconstitution inflammatory syndrome and that it affects a broader range of individuals, including patients with minimal immunosuppression and those who are treated with novel immunomodulatory medications.

JC virus encephalopathy is associated with a novel agnoprotein-deletion JCV variant.

JC virus encephalopathy (JCVE) is a newly described gray matter disease of the brain caused by productive infection of cortical pyramidal neurons. We characterized the full length sequence of JCV isolated from the brain of a JCVE patient, analyzed its distribution in various compartments by PCR, and determined viral gene expression in the brain by immunohistochemistry(IHC). We identified a novel JCV variant, JCV(CPN1), with a unique 143 bp deletion in the Agno gene encoding a truncated 10 amino acid peptide, and harboring an archetype-like regulatory region.

Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy.

The human polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, in immunosuppressed individuals. The extent of JCV infection of neurons is unclear. We determined the prevalence and pattern of JCV infection in gray matter (GM) by immunostaining in archival brain samples of 49 PML patients and 109 control subjects.

Progressive multifocal leukoencephalopathy associated with isolated CD8+ T-lymphocyte deficiency mimicking tumefactive MS.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by lytic infection of oligodendrocytes by the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression. While some case reports have documented PML in individuals with minimal or occult immunosuppression, such cases are very rare and their pathogenesis is not well understood.

JC virus latency in the brain and extraneural organs of patients with and without progressive multifocal leukoencephalopathy.

JC virus (JCV) is latent in the kidneys and lymphoid organs of healthy individuals, and its reactivation in the context of immunosuppression may lead to progressive multifocal leukoencephalopathy (PML). Whether JCV is present in the brains or other organs of healthy people and in immunosuppressed patients without PML has been a matter of debate. We detected JCV large T DNA by quantitative PCR of archival brain samples of 9/24 (38%) HIV-positive PML patients, 5/18 (28%) HIV-positive individuals, and 5/19 (26%) HIV-negative individuals.

Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons.

The polyomavirus JC (JCV) is the causative agent of progressive multifocal leukoencephalopathy and of JCV granule cell neuronopathy. We present a human immunodeficiency virus-negative patient who experienced development of multiple cortical lesions, aphasia, and progressive cognitive decline after chemotherapy for non-small-cell lung cancer. Brain biopsy and cerebrospinal fluid polymerase chain reaction demonstrated JCV, and she had a rapidly fatal outcome.

Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation.

Background: We sought to determine the prevalence of JC virus (JCV) in bone marrow samples from human immunodeficiency virus (HIV)-positive and HIV-negative patients and to determine whether bone marrow is a site of latency and neurotropic transformation of JCV, the agent of progressive multifocal leukoencephalopathy (PML).

Methods: We collected bone marrow aspirates, archival bone marrow samples, and blood and urine samples from 75 HIV-negative and 47 HIV-positive patients without PML as well as bone marrow and urine or kidney samples from 8 HIV-negative and 15 HIV-positive patients with PML. Samples were tested for JCV DNA by quantitative polymerase chain reaction and for JCV protein expression by immunohistochemical analysis.

Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) occurs most often in immunosuppressed individuals. The lesions of PML result from astrocyte and oligodendrocyte infection by the polyomavirus JC (JCV); JCV has also been shown to infect and destroy cerebellar granule cell neurons (GCNs) in 2 human immunodeficiency virus (HIV)-positive patients. To determine the prevalence and pattern of JCV infection in GCNs, we immunostained formalin-fixed paraffin-embedded cerebellar samples from 40 HIV-positive and 3 HIV-negative PML patients for JCV, and glial and neuronal markers.

Rearrangement of the JC virus regulatory region sequence in the bone marrow of a patient with rheumatoid arthritis and progressive multifocal leukoencephalopathy.

The polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML). JCV remains quiescent in kidneys, where it displays a stable archetypal regulatory region (RR). Conversely, rearranged JCV RR, including tandem repeat patterns found in the central nervous system (CNS) of PML patients, have been associated with neurovirulence.

Productive simian virus 40 infection of neurons in immunosuppressed Rhesus monkeys.

There currently is no animal model of JC virus-associated progressive multifocal leukoencephalopathy (PML). Reactivation of simian virus 40 (SV40) in immunosuppressed rhesus monkeys, however, rarely causes a PML-like illness. We sought to isolate a neurotropic clone of SV40 and determine its pathogenic potential in monkeys.

Characterization of lymphocytic infiltrates in progressive multifocal leukoencephalopathy: co-localization of CD8(+) T cells with JCV-infected glial cells.

We characterized inflammatory infiltrates in archival brain biopsy and autopsy samples from 26 HIV(+) and 20 HIV(-) patients with progressive multifocal leukoencephalopathy (PML). The predominant inflammatory cells were CD8(+) T lymphocytes. We defined CD8(+) T cell distribution with regard to JCV-infected glial cells, PML lesions and the extent of demyelination.