Intraventricular hemorrhage (IVH) in preterm infants leads to cerebral inflammation, reduced myelination of the white matter, and neurological deficits. No therapeutic strategy exists against the IVH-induced white matter injury. AMPA-kainate receptor induced excitotoxicity contributes to oligodendrocyte precursor cell (OPC) damage and hypomyelination in both neonatal and adult models of brain injury. Here, we hypothesized that IVH damages white matter via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and restores OPC maturation, myelination, and neurologic recovery in preterm newborns with IVH. We tested these hypotheses in a rabbit model of glycerol-induced IVH and evaluated the expression of AMPA receptors in autopsy samples from human preterm infants. GluR1-GluR4 expressions were comparable between preterm humans and rabbits with and without IVH. However, GluR1 and GluR2 levels were significantly lower in the embryonic white matter and germinal matrix relative to the neocortex in both infants with and without IVH. Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA receptor inhibition by intramuscular perampanel restored myelination and neurologic recovery in rabbits with IVH. NBQX administration also reduced the population of apoptotic OPCs, levels of several cytokines (TNF␣, IL-␤, IL-6, LIF), and the density of Iba1 ϩ microglia in pups with IVH. Additionally, NBQX treatment inhibited STAT-3 phosphorylation, but not astrogliosis or transcription factors regulating gliosis. Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-induced inflammation and restores myelination and neurologic recovery in preterm rabbits with IVH. Therapeutic use of FDA-approved perampanel treatment might enhance neurologic outcome in premature infants with IVH. Key words: AMPA; myelination; NBQX; oligodendrocyte; perampanel Significance StatementIntraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH.

Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3β inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These hypotheses were tested in autopsy samples from preterm infants and in a rabbit model of IVH. Induction of IVH reduced expressions of activated β-catenin, TCF-4, and Axin2 transcription factors in preterm newborns. Both AR-A014418 (ARA) and Wnt-3A treatment activated Wnt signaling. GSK-3β inhibition by intramuscular ARA treatment accelerated maturation of OPCs, myelination, and neurological recovery in preterm rabbits with IVH compared to vehicle controls. In contrast, intracerebroventricular rh-Wnt3A treatment failed to enhance myelination and neurological function in rabbits with IVH. ARA treatment reduced microglia infiltration and IL1β expression in rabbits with IVH relative to controls, whereas Wnt3A treatment elevated TNFα, IL1β, and IL6 expression without affecting microglia density. GSK-3β inhibition downregulated, while rh-Wnt3A treatment upregulated Notch signaling; and none of the two treatments affected the Sonic-Hedgehog pathway. The administration of ARA or rh-Wnt3A did not affect gliosis. The data suggest that GSK-3β inhibition promoted myelination by suppressing inflammation and Notch signaling; and Wnt3A treatment failed to enhance myelination because of its pro-inflammatory activity and synergy with Notch signaling. GSK-3β inhibitors might improve the neurological outcome of preterm infants with IVH.

A 40-year-old male with a right-sided neck mass was diagnosed with metastatic melanoma. A repeat positron-emission tomography after treatment with combination immunotherapy demonstrated increased hypermetabolic activity in the right supraclavicular, hilar, and mediastinal regions. Immunotherapy was discontinued and a BRAF/MEK inhibitor combination was started. Repeat imaging showed a decrease in size of the neck mass; however, hilar and mediastinal lymph nodes increased in size. A fine needle aspiration of mediastinal lymph nodes was consistent with a granulomatous process. A diagnosis of a sarcoid-like reaction (SLR) was made, and he was started on steroids. A follow-up positron emission tomography showed decreased hilar and mediastinal lymph node hypermetabolic activity. We, therefore, report this rare case of immunotherapy-induced SLR to the expanding literature on immunotherapy-related adverse effects and would like to highlight that SLR can occur in conjunction with disease progression making it challenging to distinguish between the two.

SUMMARYA 26-year-old man presented with high-grade fever, chills, productive cough and episodic abdominal pain of 6 months duration. Physical examination revealed that the patient was febrile and had multiple, ill-defined, tender, indurated, erythematous nodules and plaques over the trunk and thighs. Systemic examination and investigations revealed bilateral exudative pleural effusion with an increased adenosine deaminase (ADA) level. Pulmonary tuberculosis was suspected and the patient was started on a standard four-drug antitubercular regimen. Since his fever persisted, biopsy of the plaque over the trunk was performed, which showed lobular panniculitis with atypical lymphoid cells. Immunohistochemistry showed atypical lymphoid cells, which were CD3 and CD8 positive and CD4 negative. Based on the clinical features, skin biopsy and immunohistochemistry, the diagnosis of subcutaneous panniculitis-like T-cell lymphoma was made. The patient was treated with chemotherapy followed by bone marrow transplantation, and 4-year follow-up showed complete remission of lymphoma. BACKGROUND