Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis

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The human JC polyomavirus (JCPyV): virological background and clinical implications

JC polyomavirus (JCPyV) was the first of now 12 PyVs detected in humans, when in 1964, PyV particles were revealed by electron microscopy in progressive multifocal leukoencephalopathy (PML) tissues. JCPyV infection is common in 35–70% of the general population, and the virus thereafter persists in the renourinary tract. One third of healthy adults asymptomatically shed JCPyV at approximately 50 000 copies/mL urine. PML is rare having an incidence of <0.3 per 100 000 person years in the general population. This increased to 2.4 per 1000 person years in HIV‐AIDS patients without combination antiretroviral therapy (cART). Recently, PML emerged in multiple sclerosis patients treated with natalizumab to 2.13 cases per 1000 patients. Natalizumab blocks α4‐integrin‐dependent lymphocyte homing to the brain suggesting that not the overall cellular immunodeficiency but local failure of brain immune surveillance is a pivotal factor for PML. Recovering JCPyV‐specific immune control, e.g., by starting cART or discontinuing natalizumab, significantly improves PML survival, but is challenged by the immune reconstitution inflammatory syndrome. Important steps of PML pathogenesis are undefined, and antiviral therapies are lacking. New clues might come from molecular and functional profiling of JCPyV and PML pathology and comparison with other replicative pathologies such as granule cell neuronopathy and (meningo‐)encephalitis, and non‐replicative JCPyV pathology possibly contributing to some malignancies. Given the increasing number of immunologically vulnerable patients, a critical reappraisal of JCPyV infection, replication and disease seems warranted.     

Progressive multifocal leukoencephalopathy presenting with acute sensorineural hearing loss in an intestinal transplant recipient

A 20‐year‐old male presented 3.5 years after intestinal transplantation with rapidly progressive sensorineural hearing loss. Initial brain imaging was consistent with inflammation and/or demyelination. Lumbar puncture was initially non‐diagnostic and a broad infectious workup was unrevealing. Three months after presentation, a repeat LP detected JC virus for which tests had not earlier been conducted. He continued to deteriorate despite withdrawal of prior immunosuppression and addition of mirtazapine, maraviroc, and steroids. He died of progressive neurologic decompensation 5 months after his initial presentation. This case highlights progressive multifocal leukoencephalopathy (PML) as a rare complication after solid organ transplantation and acute sensorineural hearing loss as an unusual first presenting symptom of PML. JC virus should be considered in the differential diagnosis of acute sensorineural hearing loss in any immunocompromised patient.     

Applications of the isolated-check visual evoked potential in primary open angle glaucoma with or without high myopia

AIM: To determine whether the different diameters of a specific intraocular lens (IOL) have significantly different optimised SRK/T A constants and whether these new A constants can improve refractive outcomes. METHODS: Data were collected prospectively from Jan 2011 - Dec 2012 on all patients undergoing routine cataract surgery at a district general hospital in the UK. Patients were divided into three groups according to the size of the Akreos AO MI60 IOL used. A constant for the SRK/T formula were optimised according to the size of the IOL. These optimised A constants were then used to select future refractive outcomes. RESULTS: Totally 2398 cataract operations were performed during the study period of which 1131 met the inclusion criteria. The three optimised A constants for the different sized IOLs were 118.98, 119.13 119.32. The difference between them was highly significant (P≤0.0001). Two optimised A constants for three sizes of IOL led to an improvement in refractive outcomes (from 93.4% to 94.6% of refractive outcomes within 1.00 D of predicted spherical equivalent). The optimised A constant for the largest IOL was based on a small number of cases and was not used. CONCLUSION: Optimising the A constant for the three distinct sizes of the Bausch & Lomb Akreos MI60 lens lead to three significantly different A constants. In our practice, using two different optimised A constants for three different sized IOLs give the least refractive error, however, using three optimised A constants may give better results with a larger dataset.     

Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy

We describe a patient with immunoglobulin A nephropathy who was diagnosed with progressive multifocal leukoencephalopathy (PML) and successfully treated with mefloquine, an antimalarial medication. A 67-year-old man with immunoglobulin A nephropathy presented to the hospital emergency room with fever and generalized tonic-clonic seizure. Cerebrospinal fluid (CSF) nested polymerase chain reaction (PCR) was positive for John Cunningham virus and brain MRI displayed high signal intensity in the white matter in the right parietal lobe without gadolinium enhancement. Tapering of prednisone did not arrest the disease progression and a new lesion was detected on the cerebellum. Administration of mefloquine stopped lesion progression and resulted in dramatic clinical improvement. The CSF nested PCR for the John Cunningham virus also became negative. In reviewing the literature, mefloquine has had a heterogeneous effect in PML patients, and P-glycoprotein polymorphism and proper dosage could contribute to the various effects seen. Mefloquine may be a favorable treatment option in some patients with PML, and P-glycoprotein polymorphism may play an important role in its efficacy. More large studies in other ethnic groups including polymorphism studies for the gene encoding P-glycoprotein (ABCB1/MDR1) and taking into account various underlying conditions with secondary immunosuppression should be carried out to investigate whether mefloquine is effective for treating PML.     

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.