Cortical Laminar Necrosis associated with Osmotic Demyelination Syndrome

Cortical laminar necrosis has been rarely observed in osmotic demyelination syndrome. We report a 32-year-old female patient who became comatose after the rapid correction of hyponatremia. There were high signal intensities in the pons and bilateral deep gray nuclei on T2-weighted MRI images, and linear hyperintensities along the cerebral cortices on T1-weighted images with a diffuse gyriform enhancement. MR spectroscopic findings showed a decrease of the N-acetyl aspartate peak and an increase in those of the lipid and lactate complex. The case demonstrates that a severe form of osmotic demyelination syndrome accompanying cortical laminar necrosis can result from the rapid correction of hyponatremia

Characterization of an Acute Muscle Contraction Model Using Cultured C2C12 Myotubes

A cultured C2C12 myotube contraction system was examined for application as a model for acute contraction-induced phenotypes of skeletal muscle. C2C12 myotubes seeded into 4-well rectangular plates were placed in a contraction system equipped with a carbon electrode at each end. The myotubes were stimulated with electric pulses of 50 V at 1 Hz for 3 ms at 997-ms intervals. Approximately 80% of the myotubes were observed to contract microscopically, and the contractions lasted for at least 3 h with electrical stimulation. Calcium ion $(Ca^{2+})$ transient evoked by the electric pulses was detected fluorescently with Fluo-8. Phosphorylation of protein kinase B/Akt (Akt), 5′ AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38), and c-Jun NH2-terminal kinase (JNK)1/2, which are intracellular signaling proteins typically activated in exercised/contracted skeletal muscle, was observed in the electrically stimulated C2C12 myotubes. The contractions induced by the electric pulses increased glucose uptake and depleted glycogen in the C2C12 myotubes. C2C12 myotubes that differentiated after exogenous gene transfection by a lipofection or an electroporation method retained their normal contractile ability by electrical stimulation. These findings show that our C2C12 cell contraction system reproduces the muscle phenotypes that arise in vivo (exercise), in situ (hindlimb muscles in an anesthetized animal), and in vitro (dissected muscle tissues in incubation buffer) by acute muscle contraction, demonstrating that the system is applicable for the analysis of intracellular events evoked by acute muscle contraction

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology

Radiological Spectrum of Hepatic Mesenchymal Hamartoma in Children

OBJECTIVE: A hepatic mesenchymal hamartoma is an uncommon benign tumor in children and little is known about the spectrum of its radiological features. The purpose of this study is to describe the spectrum of radiological features of a hepatic mesenchymal hamartoma in children. MATERIALS AND METHODS: Thirteen children with a pathologically confirmed hepatic mesenchymal hamartoma (M:F = 7:6; mean age, 3 years 2 months) were included in our study. Ultrasonography (US) was performed in nine patients including color and power Doppler US (n = 7). CT scans were performed in all patients. We evaluated the imaging findings of the hepatic mesenchymal hamartomas and the corresponding pathological features. RESULTS: Each patient had a single tumor (mean diameter: 13 cm [1.8-20 cm]). On CT and/or US, four patients (31%) had a "multiseptated cystic tumor", five patients (38%) had a "mixed solid and cystic tumor", and four patients (31%) had a "solid tumor." The septa of the cystic portion were thin in the multiseptated cystic tumors and irregularly thick in the mixed solid and cystic tumors as seen on US. On a post-contrast CT scan, solid portions or thick septa of the tumors showed heterogeneous enhancement. The amount of hepatocytes was significantly different among the three tumor groups according to the imaging spectrum (p = 0.042). CONCLUSION: A hepatic mesenchymal hamartoma in children can show a wide spectrum of radiological features, from a multiseptated cystic tumor to a mixed solid and cystic tumor, and even a solid tumor

Cause and prevention of demyelination in a model multiple sclerosis lesion

OBJECTIVE: Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy. METHODS: Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated. RESULTS: Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white-gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination. INTERPRETATION: Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia. Ann Neurol 2016;79:591-604

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Genetic Cause of Cerebral Small Vessel Disease

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the Notch3 gene. The exact prevalence of this disorder was unknown currently, and the number of reported CADASIL families is steadily increasing as the clinical picture and diagnostic examinations are becoming more widely known. The main clinical manifestations are recurrent stroke, migraine, psychiatric symptoms, and progressive cognitive impairment. The clinical course of CADASIL is highly variable, even within families. The involvement of the anterior temporal lobe and the external capsule on brain magnetic resonance imaging was found to have high sensitivity and specificity in differentiating CADASIL from the much more common sporadic cerebral small-vessel disease (SVD). The pathologic hallmark of the disease is the presence of granular osmiophilic material in the walls of affected vessels. CADASIL is a prototype single-gene disorder that has evolved as a unique model for studying the mechanisms underlying cerebral SVD. At present, the incidence and prevalence of CADASIL seem to be underestimated due to limitations in clinical, neuroradiological, and genetic diagnoses of this disorder

Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor

To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872–11877) was composed of the interleukin 5 receptor α chain+ (IL-5Rα+) and IL-5Rα− fractions, and the former was the hEoP. The IL-5Rα+CD34+CD38+IL-3Rα+CD45RA− hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Rα− hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an “IL-5Rα–negative” criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35–40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m−2 (level 1) or 130 mg m−2 (level 2) on day 1, and S-1 (80–120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2–14), RR of 50% (1 CR and 13 PR: 95% CI 31–69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access

White matter changes in dementia: role of impaired drainage of interstitial fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease