Human Cord Blood Derived Unrestricted Somatic Stem Cells Restore Aquaporin Channel Expression, Reduce Inflammation and Inhibit the Development of Hydrocephalus After Experimentally Induced Perinatal Intraventricular Hemorrhage.

Intraventricular hemorrhage (IVH) is a severe complication of preterm birth associated with cerebral palsy, intellectual disability, and commonly, accumulation of cerebrospinal fluid (CSF). Histologically, IVH leads to subependymal gliosis, fibrosis, and disruption of the ependymal wall. Importantly, expression of aquaporin channels 1 and 4 (AQP1 and AQP4) regulating respectively, secretion and absorption of cerebrospinal fluids is altered with IVH and are associated with development of post hemorrhagic hydrocephalus. Human cord blood derived unrestricted somatic stem cells (USSCs), which we previously demonstrated to reduce the magnitude of hydrocephalus, as having anti-inflammatory, and beneficial behavioral effects, were injected into the cerebral ventricles of rabbit pups 18 h after glycerol-induced IVH. USSC treated IVH pups showed a reduction in ventricular size when compared to control pups at 7 and 14 days (both, P < 0.05). Histologically, USSC treatment reduced cellular infiltration and ependymal wall disruption. In the region of the choroid plexus, immuno-reactivity for AQP1 and ependymal wall AQP4 expression were suppressed after IVH but were restored following USSC administration. Effects were confirmed by analysis of mRNA from dissected choroid plexus and ependymal tissue. Transforming growth factor beta (TGF-ß) isoforms, connective tissue growth factor (CTGF) and matrix metalloprotease-9 (MMP-9) mRNA, as well as protein levels, were significantly increased following IVH and restored towards normal with USSC treatment (P < 0.05). The anti-inflammatory cytokine Interleukin-10 (IL-10) mRNA was reduced in IVH, but significantly recovered after USSC injection (P < 0.05). In conclusion, USSCs exerted anti-inflammatory effects by suppressing both TGF-ß specific isoforms, CTGF and MMP-9, recovered IL-10, restored aquaporins expression towards baseline, and reduced hydrocephalus. These results support the possibility of the use of USSCs to reduce IVH consequences in prematurity.

Estrogen Treatment Reverses Prematurity-Induced Disruption in Cortical Interneuron Population.

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV+), somatostatin-positive (SST+), calretinin-positive (CalR+), and neuropeptide Y-positive (NPY+) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV+ and CalR+ neurons were abundant, whereas SST+ and NPY+ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV+ or GAD67+ neurons and increased SST+ interneurons in the upper cortical layers. Importantly, 17 ß-estradiol treatment in preterm rabbits increased the number of PV+ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV+ and excess of SST+ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.SIGNIFICANCE STATEMENT Premature birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth in humans is associated with reduced population of parvalbumin-positive (PV+) neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17 ß-estradiol treatment increased the number of PV+ neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence the present study highlights prematurity-induced reduction in PV+ neurons in human infants and reversal in their population by estrogen replacement in preterm rabbits. Because preterm birth drops plasma estrogen level 100-fold, estrogen replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.

Hemangiopericytoma: collision with meningioma and recurrence.

Intracranial hemangiopericytomas are a rare type of primary brain tumor, representing only about 0.5% of all primary brain tumors. Even more rare is the co-existence of two juxtaposed primary brain tumors, termed a "collision" tumor. This report provides the first documentation in the literature of a hemangiopericytoma colliding with a meningioma, and recurring after treatment with gross total resection. Surgical samples were fully evaluated with hematoxylin and eosin and reticulin staining, as well as immunohistochemical analysis. Results were classically representative of a hemangiopericytoma (World Health Organization grade II) and of a meningioma (World Health Organization grade I). This report of a unique collision tumor not only augments the repertoire of collision tumor combinations described in literature but also provides follow-up on the clinical outcome of the patient, thereby raising clinically relevant issues ranging from presentation to treatment paradigms.

Intravascular lymphomatosis of the brain in a patient with myelodysplastic syndrome.

BACKGROUND: A 77-year-old retired research pharmacologist with a long-standing history of anemia and a recent pathologically confirmed diagnosis of myelodysplastic syndrome was referred to a stroke unit for evaluation of slowly progressive cognitive deterioration, confusion and paroxysmal stroke-like episodes. A previous neurological work-up had revealed no noteworthy abnormalities except for chronic bilateral caudate infarctions seen on MRI and CT examinations of the brain. INVESTIGATIONS: Physical examination, laboratory testing, brain MRI scanning, EEG, transesophageal echocardiography, cerebral angiography, CT scanning, and brain biopsy. DIAGNOSIS: Intravascular lymphomatosis of the brain. MANAGEMENT: Combined chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) and rituximab.

Epithelioid ependymoma: a new variant of ependymoma: report of three cases.

OBJECTIVE: To describe the pathological features of three very similar and unusual primary central nervous system tumors that are not readily recognized as conventional ependymomas but which, by ultrastructural examination, have an ependymomatous character. METHODS: Three distinctive tumors were found in a review of our files for cases of ependymoma. In each case, hematoxylin and eosin-stained sections were reviewed, and immunostains for epithelial membrane antigen, cytokeratin, vimentin, and glial fibrillary acidic protein were performed on formalin-fixed, paraffin-embedded sections. Electron microscopy was performed in each case. RESULTS: The tumors had a diffuse myxoid background, often containing tightly clustered cells that mimicked multinucleated giant cells, but lacking perivascular pseudorosettes or central lumen rosettes. Glial fibrillary acidic protein and vimentin immunostains did not reveal perivascular processes. Epithelial membrane antigen immunostains showed a dot-like cytoplasmic immunoreactivity in some cell clusters in two of the three cases. Cytokeratin was negative in all three cases. However, ultrastructurally, the cells of each tumor had extensive surface microvilli; the giant cell-like clusters had cells with extensive close appositions, some junctions, and, in two cases, lumina with microvilli. Two of the patients were adults (both with temporal lobe tumors), and one patient was 13 years old and had a cervical spinal cord intramedullary tumor. Each tumor was sharply circumscribed from adjacent central nervous system tissue but was not encapsulated. One of the cases in an adult was mitotically highly active; this tumor recurred locally 4 years after initial gross total excision. CONCLUSION: These tumors are unusual variants of ependymoma. This pattern of ependymoma is sufficiently distinctive to be recognized in hematoxylin and eosin stains once the architecture of the epithelioid clusters is appreciated.

A murine photochemical stroke model with histologic correlates of apoptotic and nonapoptotic mechanisms.

INTRODUCTION: The neuronal cell death that occurs after ischemia-induced cerebral infarction (stroke) contains elements of apoptosis and necrosis, an intermediary form of the two, and a distinct excitotoxic process. We previously developed a photochemical model of stroke in the rat. We have now adapted this model for use in the mouse. The present manuscript describes the mouse model. METHODS: Minimal beam intensity (0.1 W/cm(2)) cold white light (8 min exposure) was used to evoke discrete infarcts in the parietal lobes of 11 mice sensitized by the administration of fresh Rose Bengal (10 mg/kg by rapid iv infusion). RESULTS: At 2 h, five out of five mice and at 6 h, six out of six mice demonstrated light microscopic histologic features like those in the rat model. These included a superior ischemic zone with shrunken and pyknotic nuclei, a middle transition zone of edematous vacuolated neuropil but normal neurons with open chromatin and retained Nissl granules, and an inferior zone with normal neurons. There was widespread nuclear terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) in the superior infarct zone in 11/11 mice. However, in the edematous vacuolated transition zone, 11/11 mice had TUNEL positive and negative nuclei randomly mixed. Light microscopic analysis of that same transition zone showed no pyknosis or chromatin bodies in the TUNEL positive or negative cells. DISCUSSION: In mice, photoactivation of Rose Bengal evoked similar infarct and transition zone patterns found previously in rats, with TUNEL evidence of apoptotic and nonapoptotic events. Thus, it will be possible to use this model for further quantitative study of apoptotic and excitotoxic events in wild and transgenic mice.