International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Ganaxolone: A New Treatment for Neonatal Seizures

Neonatal seizures are amongst the most common neurologic conditions managed by a neonatal care service. Seizures can exacerbate existing brain injury, induce “de novo” injury, and are associated with neurodevelopmental disabilities in post-neonatal life. In this mini-review, we present evidence in support of the use of ganaxolone, a GABAA agonist neurosteroid, as a novel neonatal therapy. We discuss evidence that ganaxolone can provide both seizure control and neuroprotection with a high safety profile when administered early following birth-related hypoxia, and show evidence that it is likely to prevent or reduce the incidence of the enduring disabilities associated with preterm birth, cerebral palsy, and epilepsy. We suggest that ganaxolone is an ideal anti-seizure treatment because it can be safely used prospectively, with minimal or no adverse effects on the neonatal brain

Gestational age, and body weights at birth for lambs born after a normal pregnancy (Full-term control, n = 8), after experiencing 10 mins of cord occlusion <i>in utero</i> at 132 days gestation (UCO, n = 6), or after induction of preterm birth by treatmen

<p>Age at delivery shown as median (range), all other data shown as mean ± SEM.</p>*<p>indicates <i>p</i>&lt;0.05, compared to full-term controls.</p>†<p>indicates P&lt;0.05 UCO compared to preterm group. Abbreviation: UCO, umbilical cord occlusion.</p

Hematoxylin &amp; Eosin staining of full term control (A, D &amp; G), preterm control (B, E &amp; H), and UCO lambs (C, F &amp;I).

<p>Normal cytoarchitecture of the cerebral cortex was seen in both full-term (A) and preterm brains (B). In UCO brains (C) subtle alterations in the cellular composition and spatial arrangement of neurons was seen throughout the cortical gray matter. Extensive neuronal injury (arrows) in the cortical gray matter of UCO lambs as well as areas devoid of neurons (asterisks). D &amp; E show normal pathology in the cortex of full term and preterm control lambs respectively. In UCO lambs (F) some other cellular degenerative changes were observed, such as vacuolation of brain parenchyma (arrow). The insert in panel F shows a high power view of the vacuolar degeneration, histologic features consistent with hypoxic/ischemic changes. Inflammatory cell infiltration was seen in the periventricular white matter of UCO lambs (I), as marked by the box, which showed the morphological appearance of eosinophils (i), lymphocytes (ii) and neutrophils (iii) (inserts in I). These were not seen in full term (G) or preterm control lambs (H). Panels J, K &amp; L are representative images of glial fibrillary acidic protein (GFAP) staining in the periventricular white matter of full term control, preterm control and UCO lambs respectively. UCO lambs displayed reactive astrocytosis. Note the dense staining of the enlarged cell bodies and the highlighted cell processes shown in the high power insert in panel L. Scale bars: A–F = 100 µm, G–L = 50 µm.</p

Hematoxylin &amp; Eosin (A–C).

<p>Few degenerating cells were seen in the cortical gray matter of full-term (A) and preterm (B) control lambs. UCO lambs showed extensive neuronal injury displaying feature of apoptosis seen by H&amp;E staining as scattered dark, shrunken cells with pyknotic or small, densely staining nuclei and eosinophilic cytoplasm (black arrows C). The insert in panel C is a high power micrograph showing a neuron exhibiting ischemic morphology (eosinophilia, and nuclear pyknosis). Panels D–F show activated Caspase-3 immunoreativity in the cortex of a full term (D), preterm (E) and UCO (F) lambs. Note the increased immunoreactivity of activated Caspase-3 in the cortex of UCO lambs compared with both control groups. Scale bars –50 µm. Panel G: Quantitative results show cleaved caspase-3 cell counts in the corpus callosum, periventricular white matter (PVWM), external capsule, cortex and subventricular zone (SVZ) for full-term control (n = 5), preterm control (n = 5) and UCO lambs (n = 6) (G). Data are expressed as mean ± SEM. <i>p</i>&lt;0.05. White, gray and black bars represent full term, pre term and UCO lambs respectively.</p

Photomicrograph showing changes to the cerebrovasculature following UCO.

<p>Panels A–C show albumin staining in the cortical gray (CxGM) and subcortical white matter (CxWM) of a full term (A), a preterm (B) and a UCO lambs (C). Albumin extravasation (brown staining) consistent with blood brain barrier permeability disruption was observed throughout the brain in UCO lambs (C). Note the positive albumin staining around a blood vessels (circle), as well as in cells (arrows). The insert in C is a high power photomicrograph showing the albumin staining surrounding a blood vessel (BV), as well as albumin positive cells, We observed moderate levels of albumin extravasation in some pre tem control lambs (B), while no albumin staining was noted in brains of full term control lambs. Panels D, E and F show Mallory trichrome staining in the periventricular white matter of a full term (D), preterm (E) and UCO lamb (F). Microbleeds were seen in UCO brains shown by degradation products of hemorrhage staining a muddy brown. No microbleeds were detected in full term or preterm control brains. G–I show GFAP immunohistochemistry and show normal perivascular astrocytes in the periventricular white matter of a full term (G) and preterm lamb (H); while blood vessels in UCO lamb were often seen to be devoid of astrocytic contact (I). BV = blood vessel. Scale bars: A–C = 100 µm; D–I = 20 µm.</p

Luxol fast blue staining on brain sections of full term control (A), preterm control (B) and UCO lamb (C) in the corpus callosum.

<p>Myelin irregularities (disruption) seen as patchiness (asterisks in C) were detected only in UCO lambs. Panels D–F show CNPase immunohistochemistry in the corpus callosum of a full term (D), preterm (E) and UCO lamb, confirmed myelin disruption seen as patchy staining (asterisks). Myelin disruption was also seen in the periventicular white matter of UCO lambs both with luxol fast blue (I) and CNPase (L) (asterisks). Myelination in full term (G &amp; J) and preterm (H &amp; K) appeared to be intact with both stains. Scale bars = 50 µm. Quantitative results show densitometry analysis of CNPase stained myelination (M) and CNPase positive cell bodies (N) in the corpus callosum, subcortical (CxWM) and periventricular white matter (PVWM), external and internal capsule for full-term control (n = 8), preterm control (n = 4) and UCO lambs (n = 5). Data are expressed as mean ± SEM. <i>p</i>&lt;0.05. White, gray and black bars represent full term, pre term and UCO lambs respectively.</p

Fetal arterial blood gases, pH, hematocrit, blood lactate, and arterial pressure and heart rate before (−1 h), at the end of (+10 mins), and 1 to 48 h after occlusion of the umbilical cord at 132 days gestation.

<p>Data shown as mean ± SEM, n = 5 throughout, except for +24 h and +48 h (n = 4).</p>*<p><i>p</i>&lt;0.05, compared to values at −1 h. (n/a = data not available).</p

Postnatal lamb behavior was observed from the time that lambs fully cleared the birth canal (time 0).

<p>Time taken to use hind limbs (A), four legs (B), stand stable for &gt;5 sec (C), find the udder (D) and successfully suckle (E) for full-term control (n = 6), preterm control (n = 5) and UCO lambs (n = 5) were recorded. The percentage of time spent active from 4 to 23 h was also monitored (G). Data are expressed as mean ± SEM. <i>p</i>&lt;0.05.</p