Progressive multifocal leukoencephalopathy (PML) typically affects the CNS white matter of the central nervous system. We present an human immunodeficiency virus-infected patient with polyomavirus JC infection restricted to granule cell neurons of the cerebellum and with corresponding neurological symptomatology. Magnetic resonance imaging demonstrated cerebellar atrophy without white matter lesions and stereotactic biopsy showed selective infection of the cerebellar granular cell layer, with preservation of Purkinje cells and absence of classic progressive multifocal leukoencephalopathy histopathology in underlying white matter. Evolution over 8 years was marked by symptomatic improvement corresponding to highly active antiretroviral therapy (HAART), with modest increase in CD4(+) T-cell counts. We propose to call this novel syndrome JCV granule cell neuronopathy (JCV GCN).

Numerous approaches to a quantum theory of gravity posit fundamental ontologies that exclude spacetime, either partially or wholly. This situation raises deep questions about how such theories could relate to the empirical realm, since arguably only entities localized in spacetime can ever be observed. Are such entities even possible in a theory without fundamental spacetime? How might they be derived, formally speaking? Moreover, since by assumption the fundamental entities can't be smaller than the derived (since relative size is a spatiotemporal notion) and so can't 'compose' them in any ordinary sense, would a formal derivation actually show the physical reality of localized entities? We address these questions via a survey of a range of theories of quantum gravity, and generally sketch how they may be answered positively.Comment: 18 pages, 1 figure, accepted for publication in Studies in History and Philosophy of Modern Physic

JCV can productively infect granule cell neurons of the IGCL of the cerebellum. This suggests a role for JCV infection of neurons in cerebellar atrophy occurring in HIV-infected individuals.

Background We sought to determine the prevalence of JCV in bone marrow samples from HIV-positive and HIV-negative patients and whether the bone marrow is a site of latency and neurotropic transformation of JC virus, the agent of progressive multifocal leukoencephalopathy(PML). Methods We collected bone marrow aspirates, archival bone marrow, 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 PCR and JCV protein expression by immunohistochemistry. JCV regulatory regions (RR) were characterized by sequencing. Results JCV DNA was detected in bone marrow specimens of 10/75(13%) of HIV-negative, and 22/47 (47%) of HIV-positive patients without PML, but in 3/8(38%) HIV-negative and 4/15(27%) HIV-positive patients with PML. JCV DNA(2-1081 cps/μg cellular DNA) was detected in multiple leukocyte subpopulations of blood and bone marrow samples. JCV large T antigen, but not VP1 capsid protein, was expressed in bone marrow plasma cells. Bone marrow JCV RR sequences were similar to those usually found in brain of PML patients. Conclusions The bone marrow is an important reservoir and possible site of neurotropic transformation for JCV.

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.

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The polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML) and of JCV granule cell neuronopathy(JCV GCN). We present an HIV-negative patient who developed multiple cortical lesions, aphasia and progressive cognitive decline after chemotherapy for non-small-cell lung cancer. Brain biopsy and CSF PCR demonstrated JCV and she had a rapidly fatal outcome. Post-mortem analysis showed diffuse cortical lesions and areas of necrosis at the graywhite junction. Immunostaining revealed 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.

Theories of quantum gravity generically presuppose or predict that the reality underlying relativistic spacetimes they are describing is significantly non-spatiotemporal. On pain of empirical incoherence, approaches to quantum gravity must establish how relativistic spacetime emerges from their non-spatiotemporal structures. We argue that in order to secure this emergence, it is sufficient to establish that only those features of relativistic spacetimes functionally relevant in producing empirical evidence must be recovered. In order to complete this task, an account must be given of how the more fundamental structures instantiate these functional roles. We illustrate the general idea in the context of causal set theory and loop quantum gravity, two prominent approaches to quantum gravity.