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. However, it is unclear that naturalistic forms of Humeanism can maintain their commitment to there being no necessary connections among distinct entities. Furthermore, non-temporal conceptions of production render this central concept more elusive than before. In fact, the challenges run so deep that the survival of the investigated analyses into the era of quantum gravity is questionable.

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. We therefore analyzed archival formalin-fixed, paraffin-embedded brain samples from PML patients, and HIV-seropositive and seronegative control subjects by immunohistochemistry for the presence of JCV early regulatory T Ag and JCV VP1 late capsid protein. In meninges, we detected JCV T Ag in 11/48 (22.9%) and JCV VP1 protein in 8/48 (16.7%) PML patients. In choroid plexi, we detected JCV T Ag in 1/7 (14.2%) and JCV VP1 protein in 1/8 (12.5%) PML patients. Neither JCV T Ag nor VP1 protein could be detected in meninges or choroid plexus of HIV-seropositive and HIV-seronegative control subjects without PML. In addition, examination of underlying cerebellar cortex of PML patients revealed JCV-infected cells in the molecular layer, including GAD 67+ interneurons, but not in HIV-seropositive and HIV-seronegative control subjects without PML. Our findings suggest that productive JCV infection of meningeal cells and choroid plexus cells also occurs in PML patients without signs or symptoms of meningitis. The phenotypic characterization of JCV-infected neurons in the molecular layer deserves further study. This data provides new insight into JCV pathogenesis in the CNS.

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. Despite absolute lymphocyte counts remaining between 500-1000/mm(3) , his CD4(+) and CD8(+) T-cell counts were markedly low. MRI showed right hemispheric and brainstem lesions and JC virus DNA was undetectable in his cerebrospinal fluid. Brain biopsy revealed typical features of PML as well as JC virus-infected neurons. Clinicians should consider PML in the differential diagnosis of fumarate-treated patients presenting with brain lesions or seizures even in the absence of severe lymphocytopenia.

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. Brain imaging showed enlargement of ventricles but no parenchymal lesion. She had a very high JC viral load in the cerebrospinal fluid (CSF) and developed progressive cognitive dysfunction despite ventricular drainage. She was diagnosed with pancytopenia and passed away after 5.5 months. Postmortem examination revealed productive JCV infection of leptomeningeal and choroid plexus cells, and limited parenchymal involvement. Sequencing of JCV CSF strain showed an archetype-like regulatory region. Further studies of the role of JCV in aseptic meningitis and in idiopathic hydrocephalus are warranted.

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). We characterized pathologic findings in areas of the brain that displayed HCS in 2 patients and compared them with isointense cortex in the same individuals. RESULTS: Of 49 patients, 17 (34.7%) had seizures and 30 (61.2%) had HCS adjacent to subcortical PML lesions on MR images. Of the 17 PML patients with seizures, 15 (88.2%) had HCS compared with 15 of 32 (46.9%) patients without seizures (p=0.006). HCS was associated with seizure development with a relative risk of 4.75 (95% confidence interval=1.2-18.5, p=0.006). Of the 20 patients with IRIS, 16 (80.0%) had HCS compared with 14 of 29 (49.3%) patients without IRIS (p=0.04). On histological examination, HCS areas were associated with striking JCV-associated demyelination of cortical and subcortical U fibers, significant macrophage infiltration, and a pronounced reactive gliosis in the deep cortical layers. INTERPRETATION: Seizures are a frequent complication in PML. HCS is associated with seizures and IRIS, and correlates histologically with JCV focal leukocortical encephalitis.

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. JC virus was localized in oligodendroglia and cerebellar granule cells. This case illustrates unusual localization of inflammatory PML in a patient with RA treated with methotrexate.

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. AIM: We sought to examine up-to-date obstacles and enablers for detecting and reporting child abuse among nursing and medical staff in PED and paediatric surgery departments in Switzerland. METHODS: We surveyed 421 nurses and physicians working in PEDs and on paediatric surgical wards in six large Swiss paediatric hospitals using an online questionnaire between February 1, 2017, and August 31, 2017. RESULTS: The survey was returned by 261/421 (62.0%) respondents (complete n = 200, 76.6%; incomplete n = 61, 23.3%) with a preponderance of nurses (n = 150/261; 57.5%), 106/261 (40.6%) physicians, and 1/261 (0.4%) psychologists (n = 4/261; 1.5% missing profession). The stated obstacles to reporting child abuse were uncertainty about the diagnosis (n = 58/80; 72.5%), feeling unaccountable for notification (n = 28/80; 35%), uncertainty of whether reporting has any consequences (n = 5/80; 6.25%), lack of time (n = 4/80; 5%), forgetting to report (n = 2/80; 2.5%), and parental protection (n = 2/80; 2.5%) (unspecific answer, n = 4/80; 5%, multiple answers were possible, therefore items don not sum up to 100%). Even though most (n = 249/261 95.4%) respondents had previously been confronted with child abuse at/outside work, only 185/245 (75.5%) reported cases; significantly fewer nursing (n = 100/143, 69.9%) than medical staff (n = 83/99, 83.8%) (p = 0.013). Furthermore, significantly more nursing (n = 27/33; 81.8%) than medical staff (n = 6/33; 18.2%) (p = 0.005) reported a discrepancy between the number of suspected and reported cases (total 33/245 (13.5%). An overwhelming amount of participants were strongly interested in mandatory child abuse training (n= 226/242, 93.4%) and in the availability of standardised patient questionnaires and documentation forms (n = 185/243, 76.1%). CONCLUSION: In line with previous studies, insufficient knowledge about and lack of confidence in detecting the signs and symptoms of child abuse were the principal obstacles to reporting maltreatment. To finally address this unacceptable gap in child abuse detection, we recommend the implementation of mandatory child protection education in all countries where no such education has been implemented in addition to the introduction of cognitive aid tools and validated screening tools to increase child abuse detection rates and ultimately prevent further harm to children.

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. In the same samples, we detected JCV regulatory region DNA by nested PCR in 6/19 (32%) HIV-positive PML patients, 2/11 (18%) HIV-positive individuals, and 3/17 (18%) HIV-negative individuals. In addition, JCV DNA was detected in some spleen, lymph node, bone, and kidney samples from the same groups. In situ hybridization data confirmed the presence of JCV DNA in the brains of patients without PML. However, JCV proteins (VP1 or T antigen) were detected mainly in the brains of 23/24 HIV-positive PML patients, in only a few kidney samples of HIV-positive patients, with or without PML, and rarely in the bones of HIV-positive patients with PML. JCV proteins were not detected in the spleen or lymph nodes in any study group. Furthermore, analysis of the JCV regulatory region sequences showed both rearranged and archetype forms in brain and extraneural organs in all three study groups. Regulatory regions contained increased variations of rearrangements correlating with immunosuppression. These results provide evidence of JCV latency in the brain prior to severe immunosuppression and suggest new paradigms in JCV latency, compartmentalization, and reactivation.

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. Postmortem analysis showed diffuse cortical lesions and areas of necrosis at the gray-white junction. Immunostaining showed a productive JCV infection of cortical pyramidal neurons, confirmed by electron microscopy, with limited demyelination. This novel gray matter syndrome expands the scope of JCV clinical presentation and pathogenesis.

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. We demonstrate that, contrary to the loss of many markers for striosomes, there is a pronounced up-regulation of MOR1 in these Q175 knock-in mice. We show that in heterozygous Q175 knock-in model mice [~192 cytosine-adenine-guanine (CAG) repeats], this MOR1 up-regulation progressed with advancing age and disease progression, and was particularly remarkable at caudal levels of the striatum. Given the known importance of MOR1 in basal ganglia signaling, our findings, though in mice, should offer clues to the pathogenesis of psychiatric features, especially depression, reinforcement sensitivity, and involuntary movements in HD.

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. The JCV infection was detected in 30 patients (70%); 28 (93%) of them had JCV-infected cells in the GC layer; JCV-infected GCNs were demonstrated in 15 (79%) of 19 tested cases. The JCV regulatory T antigen was expressed more frequently and abundantly in GCNs than JCV VP1 capsid protein. None of 37 HIV-negative controls but 1 (3%) of 35 HIV-positive subjects without PML had distinct foci of JCV-infected GCNs. Thus, JCV infection of GCNs is frequent in PML patients and may occur in the absence of cerebellar white matter demyelinating lesions. The predominance of Tantigen over VP1 expression in GCNs suggests that they may be the site of early or latent central nervous system JCV infection. These results indicate that infection of GCNs is an important, previously overlooked, aspect of JCV pathogenesis in immunosuppressed individuals.

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. The clone SV40CNS1 was amplified by polymerase chain reaction from the brain DNA of a simian/human immunodeficiency virus-infected monkey that had developed PML and meningoencephalitis. Compared with the SV40 prototype 776, SV40CNS1 had a small number of single-amino-acid mutations and caused a productive infection in monkey fibroblasts. It was inoculated into 2 SV40-negative, simian/human immunodeficiency virus-immunosuppressed monkeys. Both animals developed meningoencephalitis with productive SV40 infection of cerebral cortical neurons and glia in the superficial layers of the cortex and at the gray-white junction. Focal SV40-infected cells were also found in the cerebellar molecular and granule cell layers and white matter. Both animals also developed disseminated SV40 infection with nephritis and pneumonitis. Thus, SV40CNS1 is infectious and pathogenic in immunosuppressed monkeys, but it induces encephalitis with fulminant productive infection in cortical neurons and systemic disease, rather than PML. These findings shed new light on SV40 neurotropism and expand the host cell range of this virus.

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. The precise site and mechanism of JCV RR transformation is unknown. We present herein a patient with rheumatoid arthritis treated with methotrexate, who developed PML and had a rapid fatal outcome. JCV DNA polymerase chain reaction (PCR) was positive in cerebrospinal fluid (CSF), bone marrow, blood, and urine. Double-immunohistochemical staining demonstrated that 9% of bone marrow CD138(+) plasma cells sustained productive infection by JCV, accounting for 94% of JCV-infected cells. JCV RR analysis revealed archetype and rearranged RR forms in bone marrow, whereas RR with tandem repeat was predominant in blood. These results suggest that the bone marrow may be a potential site of JCV pathogenic transformation. Further studies will be needed to determine the prevalence of JCV in bone marrow of immunosuppressed individuals at risk of PML and characterize the RR and phenotype of these JCV isolates.

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. We determined the prevalence and pattern of JCV infection of the hippocampus in archival samples from 28 patients with known JCV infection of the CNS and 66 control subjects. Among 28 patients, 11 (39.3%) had JCV infection of hippocampus structures demonstrated by immunohistochemistry. Those included gray matter (dentate gyrus and cornu ammonis, subiculum) in 11/11 and afferent or efferent white matter tracts (perforant path, alveus, fimbria) in 10/11. In the hippocampus, JCV infected granule cell and pyramidal neurons, astrocytes, and oligodendrocytes. Although glial cells expressed either JCV regulatory T Antigen or JCV VP1 capsid protein, infected neurons expressed JCV T Antigen only, suggesting an abortive/restrictive infection. None of the 66 control subjects had evidence of hippocampal JCV protein expression by immunohistochemistry or JCV DNA by in situ hybridization. These results greatly expand our understanding of JCV pathogenesis in the CNS.

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. We used immunohistochemistry to determine the prevalence of T cells in neuron-rich areas of archival brain samples from 77 patients with JCV CNS infections and 94 control subjects. Neurons predominantly sustained a restrictive infection with expression of JCV regulatory protein T antigen (T Ag), whereas glial cells were productively infected and expressed both T Ag and the capsid protein VP1. T cells were more prevalent near JCV-infected cells with intact nuclei expressing both T Ag and VP1 compared with those expressing either protein alone. CD8-positive T cells also colocalized more with JCV-infected glial cells than with JCV-infected neurons. Major histocompatibility complex class I expression was upregulated in JCV-infected areas but could only be detected in rare neurons interspersed with infected glial cells. These results suggest that isolated neurons harboring restrictive JCV infection do not upregulate major histocompatibility complex class I and thus may escape recognition by CD8-positive T cells.

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. To determine whether simian virus 40 (SV40) can infect and cause PML lesions in spinal cords of immunosuppressed macaques, we examined archival spinal cord samples from 15 simian immunodeficiency virus-infected rhesus monkeys with acquired immunodeficiency syndrome and SV40 infection of the brain. Among those, 6 (40%) had SV40-infected cells in the spinal cord, including 1 with PML-like lesions, 1 with PML-like lesions and meningoencephalitis, 2 with meningoencephalitis, 1 with gray matter gliosis, and 1 with no lesions. One animal with a large PML-like lesion had extensive demyelination and SV40 infection of astrocytes, oligodendrocytes, and meningeal cells. None of the 6 animals had SV40-infected spinal cord neurons. These observations indicate that, like JCV in immunosuppressed humans, SV40 can infect glial cells and cause PML-like lesions in the spinal cord of immunosuppressed rhesus macaques. Rhesus macaques could serve as an animal model to study polyomavirus infection and pathogenesis in the spinal cord.

Meningoencephalitis and demyelination are pathologic manifestations of primary polyomavirus infection in immunosuppressed rhesus monkeys.

The human polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS that occurs in immunosuppressed individuals. Because polyomavirus-induced CNS pathology usually occurs as a result of the reactivation of latent virus, little is known about the disease manifestations of a primary polyomavirus-induced disease in man. To model such a primary infection, SV40-negative rhesus monkeys were immunosuppressed by infection with the virus SHIV-89.6P and then superinfected with the polyomavirus SV40. The animals developed CNS pathology characterized by both demyelination and meningoencephalitis. This observation suggests that a primary polyomavirus infection can be associated with an inflammatory CNS process. These data shed new light on the pathogenic mechanisms of primate polyomaviruses in the immunocompromised host.

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. Following combined antiretroviral therapy, she developed immune reconstitution inflammatory syndrome, which proved fatal.

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. Furthermore, JCV-infected glial cells are frequently located at the gray matter-white matter junction or within the gray matter, causing demyelinating lesions within cortical areas. Finally, JCV variants can also infect neurons, leading to the recognition of two distinct clinical entities: JCV granule cell neuronopathy and JCV encephalopathy.