Involvement of the pontomedullary corticospinal tracts: a useful finding in the diagnosis of X-linked adrenoleukodystrophy.

PURPOSETo determine whether pontomedullary corticospinal tract involvement is a common and specific finding of adrenoleukodystrophy on MR images.METHODSMR images of 10 patients with biochemically proved adrenoleukodystrophy who were examined during the last 6 years were reviewed retrospectively to determine the frequency of corticospinal tract involvement in the medulla, pons, mesencephalon, internal capsules, and corona radiata. MR images of 10 patients with other leukodystrophies (three with Krabbe disease, two with Alexander disease, two with metachromatic leukodystrophy, two with Pelizaeus-Merzbacher disease, and one with Canavan disease) were reviewed with specific attention to the pontomedullary corticospinal tracts.RESULTSMedullary and pontine corticospinal tract involvement was present in eight of the 10 patients with adrenoleukodystrophy. Mesencephalic and internal capsular involvement was present in three patients. The coronal radiata portion of the corticospinal tracts was not involved in any of the 10 patients. No pontomedullary corticospinal tract involvement was identified in any of the 10 patients with other leukodystrophies. The difference in the frequency of pontomedullary corticospinal tract involvement between the two groups was highly significant.CONCLUSIONPontomedullary corticospinal tract involvement is a common finding in adrenoleukodystrophy and is unusual in other leukodystrophies. Awareness of this finding can facilitate the radiologic diagnosis of this disease and may expedite management of affected patients.     

Strain-related brain injury in neonatal mice subjected to hypoxia–ischemia

The development of transgenic mice has led to an increase in the use of mice as models for human disease. We hypothesized that the degree of brain damage sustained by animals in a neonatal mouse model of hypoxia–ischemia depends on the strain used. We compared three strains of mice commonly used to generate transgenic strains (C57Bl/6, 129Sv and CD1), as well as three hybrids of these strains (C57Bl/6×129Sv, CD1×C57Bl/6, and CD1×129Sv). At postnatal day 7 (P7), pups were subjected to a modified Vannucci procedure for hypoxia–ischemia as follows: permanent ligation of right common carotid artery under halothane anesthesia, 2-h recovery period, exposure to 8% oxygen at 37°C for varying durations (30, 60 or 90 min). After 5 days, animals were perfused with 4% paraformaldehyde, brains were removed, postfixed and examined histologically with cresyl violet and Perl's iron stain to assess the degree of damage. Damage was assessed blindly using a score ranging from 0 (none) to 3 (infarct) in eight regions (ant-, mid-, and post- cortex, CA1, CA2, CA3 and dentate gyrus of the hippocampus, and striatum). We found significant differences in susceptibility to brain damage and mortality depending on the strain used. While determining the maximal degree of injury with the least amount of mortality for each strain, it was found that some strains (CD1) are particularly susceptible to brain damage in this model, while others (129Sv) are resistant.     

Neutrophil protein kinase Cdelta as a mediator of stroke-reperfusion injury

Thrombolysis is widely used to intervene in acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Here we describe studies with mice lacking protein kinase Cdelta (PKCdelta) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue and with impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. Total body irradiation followed by transplantation with bone marrow from PKCdelta-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCdelta-null mice. These results indicate an important role for neutrophil PKCdelta in reperfusion injury and strongly suggest that PKCdelta inhibitors could prove useful in the treatment of stroke.     

Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis

α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the SERPINA1 gene encoding AAT and the common mutant Z allele of SERPINA1 encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency. In this study, we investigated differential expression of microRNAs (miRNAs) between PiZ and control mice and found that miR-34b/c was up-regulated and its levels correlated with intrahepatic ATZ. Furthermore, in PiZ mouse livers, we found that Forkhead Box O3 (FOXO3) driving microRNA-34b/c (miR‐34b/c) expression was activated and miR-34b/c expression was dependent upon c-Jun N-terminal kinase (JNK) phosphorylation on Ser⁵⁷⁴. Deletion of miR-34b/c in PiZ mice resulted in early development of liver fibrosis and increased signaling of platelet-derived growth factor (PDGF), a target of miR-34b/c. Activation of FOXO3 and increased miR-34c were confirmed in livers of humans with AAT deficiency. In addition, JNK-activated FOXO3 and miR-34b/c up-regulation were detected in several mouse models of liver fibrosis. This study reveals a pathway involved in liver fibrosis and potentially implicated in both genetic and acquired causes of hepatic fibrosis.

α1-Antitrypsin (AAT) deficiency is an inherited disorder that affects ∼1 in 3,000 individuals and is an important genetic cause of lung and liver disease (1). The most common defect is the Z variant of the SERPINA1 gene, which results in the production of misfolded and polymerogenic Z α1-antitrypsin (ATZ). ATZ-dependent liver disease has a wide spectrum of clinical manifestations ranging from liver insufficiency in newborns to chronic liver disease and hepatocellular carcinoma in adults (2, 3). Because of its misfolding and polymerization, ATZ is unable to efficiently traverse the secretory pathway. Accumulation of ATZ in the endoplasmic reticulum (ER) of hepatocytes has a proteotoxic effect.Expression of microRNAs (miRNAs) is affected in several liver diseases with distinct profiles across diseases with different etiologies (4). Here, we investigated differentially expressed miRNAs in the liver of PiZ mice, a transgenic animal model expressing the human ATZ (5). We then confirmed the most relevant findings in liver samples from patients. Following the identification of an important miRNA cluster involved in liver fibrosis, the upstream molecules affecting its expression, and its effector, we showed this pathway is involved in various murine models of liver fibrosis.